Biotechnology

Gene Mapping by In Situ Hybridization

2009-07-19T22:19:00.000-07:00

The previous mapping methods are indirect in that they provide information on the physical location of a gene on a particular chromosome but without actually visualizing the gene's map position. A more direct approach is in situ hybridization, which involves hybridizing DNA (or RNA) probes directly to metaphase chromosomes spread on a slide and visualizing the hybridization signal (and thus the location of the gene to which the probe hybridizes) under a microscope.

The DNA in metaphase chromosomes is denatured in place (hence, in situ) on the slide, and hybridization of a labeled probe is allowed to proceed. Methods for mapping single-copy gene sequences by in situ hybridization originally were laborious and slow, requiring long exposures of the slides under photographic emulsion to detect the location of hybridized probe that had been labeled with low-level isotopes, such as tritium. Mapping with confidence required analysis of many metaphase spreads to distinguish the real hybridization signal from background radioactivity. However, more sensitive techniques have now been developed that enable rapid detection of hybridized probes labeled non radioactively with compounds that can be visualized by fluorescence microscopy (Fig). Even in a single metaphase spread, one can easily see the position of the gene being mapped.

In combination with banding methods for chromosome identification, fluorescence in situ hybridization can be used to map genes to within 1 to 2 million base pairs (1000 to 2000 kb) along a metaphase chromosome. Although this degree of resolution is a considerable improvement over other methods, it is still substantially larger than the size of most individual genes.

Figure: Gene mapping by in situ hybridization of a biotin-labeled DNA probe for the human muscle glycogen phosphorylase gene (MGP) to a spread of human metaphase chromosomes. Location of the MGP gene is indicated by the bright spots seen over each chromatid at the site of the gene in band q13 of chromosome 11. The mapping of MGP to 11q13 also assigns the locus for McArdle disease, an autosomal recessive myoglobinuria caused by deficiency of MGP. (Photograph courtesy of Peter Lichter, Yale University)

The deafness gene

2009-05-23T00:55:00.000-07:00

The mutation of MicroRNA mir-96 leads to progressive loss of hearing if present in single copy, and deafness if present in two copies

The journal Nature Genetics have posted the results of a search conducted under the projects "Sirocco" and "Eurohear", funded by the European Union. The discovery concerns the association between a new type of gene and the progressive loss of hearing, because the mir-96 gene is a small piece of RNA that affect the process of generation of other molecules in sensory hair cells of the inner ear .

The results come from the collaboration of two research groups, one Spanish and one English.

Karen Steel, one of the coordinators of the team of British Sanger Institute, said "We were able to demonstrate relatively quickly if the mice that were carriers of one copy of the variant of this gene suffer from progressive loss of hearing, and if they were carrying both genes, they were suffering from severe hearing loss. The principal questions to be answered concerning the possibility to determine which variant was involved and how influences on hearing "

Having identified the chromosome 7, the possible location of the gene altered the two groups of researchers have sequenced the gene in each "homologous genomic regions in man and mouse that are associated with hearing loss" and showed the presence of a mutation in the gene mir - 96.

Miguel Angel Moreno-Pelayo, author of the study and researcher at the Hospital Ramon y Cajal in Spain, said "We know a number of genes associated with deafness in humans and mice, but we discovered with surprise that this belongs to a new class of MicroRNA genes defined. No one had observed a mutation that can cause disease in a couple of MicroRNA sequence. This is the first MicroRNA gene associated with hearing loss and e 'is significant that the first to be associated with a hereditary condition. "

Experts recognize that the MicroRNA may bind to the active messengers in the generation of cell protein, effectively stopping the process and now have discovered that it is possible to analyze the role of mutation in mice. It seems the sensory hair cells in the mutant mice are affected by mir-96 gene, while mice carrying two copies of the gene mutant hair cells are deformed from birth and cells subjected to a degeneration in the early stages of life.

Morag Lewis of the Sanger Institute, who discovered the mutation, commented "The mutation, or variation of a single letter of genetic code from A to T in this tiny extension, is sufficient to cause a serious loss in mice" .

This mechanism also occurs in humans but, according to analysis of the two families used as a sample, the mutation does not happen ever in the same regions where the mouse, although affect neighboring regions, and always very important for the proper functioning of mir-96 .

A study on a large scale identify the genes implicated in mental retardation

2009-05-21T20:14:00.000-07:00

Bringing to fruition one of the largest genetic sequencing efforts of a complex disease, an international scientists funded in part identified nine genes on the X chromosome involved in learning difficulties. Their mute leads to mental retardation. The study was published in the journal Nature Genetics.

The mental retardation is defined as the functional deficiency that leads to significant limitations of intellectual functioning and a lack of conceptual, social or practical capacity. Symptoms appear before eighteen years. This type of deficiency is more common in males, and thus it was considered that it was long linked to chromosome X: Because males have one chromosome X, a genetic mutation, which is more likely to have an impact, since they do not have a second to compensate for the mutation.

To learn more about mental retardation linked to chromosome X (XLMR), scientists and partly supported by projects funded GEN2PHEN ( "Genotype-phenotype-to databases: a holistic solution") and EURO-MRX ( "The genetic and neurobiological basis X of-linked mental retardation "), have sequenced about 720 of the 800 genes of known chromosome X in more than 200 households of the United Kingdom, United States, Australia, Europe and South Africa, which had been diagnosed with learning difficulties associated to chromosome X.

Until now, with the help of genetic sequencing techniques, were identified about 80 genes involved nell'XLMR. The discovery of these new genes will contribute to improving clinical practice and advice to families with members suffering from learning difficulties linked to chromosome X.

Dr Lucy Raymond of Cambridge Institute for Medical Research at the University of Cambridge, UK, comments: "This new research reveals yet other genes that can be included to enhance the diagnosis in the case of families with learning difficulties and enable to develop in future a more complete genetic advice, putting the parents and extended family in terms of taking decisions more informed. "

But the study offers further study: "Beyond these important discoveries of new genes associated with learning difficulties, we have discovered a small percentage - just over 1% - gene coding for the protein of the X chromosome, if muted seem to have no effect on the characteristics of the individual, "says prof. Stratton. "It is interesting to note how a number of coding genes can be lost without obvious effects on the normal of an individual: it is a surprising result, and it will be necessary to continue research in this field".

Scientists are launching a warning to geneticists: if the silencing of some genes has no effect observed on the individual, researchers should exercise caution in assuming that the presence of a silenced gene in a patient means there is a relationship between the disease and The gene in question.

RNA recreated in the laboratory from inorganic compounds

2009-05-21T20:12:00.000-07:00

Researchers at the University of Manchester, lead by John Sutherland, illustrated in an article published in Nature, the process which created ribonucleotides (units of RNA, the molecule basis of all life processes) starting from simple elements, such as those that were presumably the primordial soup, the aqueous solution from which have formed the first organic molecules four billion years ago.

So far, in experiments of this type are started immediately by adding a phosphate sugars and nitrogen bases. In this study, scientists started by the most simple and have played the environmental conditions by heating the solution. BY the solution is obtained a residue of hybrid molecules, which were re-hydrated and heated, allowed to evaporate and irradiated with UV light in order to reproduce the cycle of the ecosystem primordial environment.

At each step the resulting molecules seemed increasingly complex and the addition of phosphate end, which has functioned as a catalyst and regulator of acidity "Surprisingly it was a ribonucleotide format!" as reported by Sutherland and continues "We suspect that there is something out there good, but it took 12 years to discover.

In twenty years of attempts had shown no concrete evidence of the formation of RNA from the reaction of simple molecules and chemicals while known for some time.

Now because of this research is another step to demonstrate the validity of the theory that places the RNA as the starting point of the life on Earth, although still not shown that this method can create molecules of RNA complete.

Sutherland, however, hopes to further develop his research to solve the doubts remained.

Engineered in situ Bioremediation

2009-05-18T22:49:00.000-07:00

Intrinsic bioremediation is satisfactory at some places, but it is slow process due to poorly adapted microorganisms, limited ability of electron acceptor and nutrients, cold temperature and high concentration of contaminants. When site conditions are not suitable, bioremediation requires construction of engineered systems to supply materials that stimulate microorganisms. Engineered in situ bioremediation accelerates the desired biodegradation reactions by encouraging growth of more microorganisms via optimizing physico-chemical conditions (Bouwer et al, 1998). Oxygen and electron acceptors (e.g. NO3 -1 and SO4 2-) and nutrients (e.g. nitrogen and phosphorus) promote microbial growth in surface.

Surface treatment using above-ground Reactor, injection of oxygen, acid nutrient and extraction walls

When contamination is deeper, amended water is injected through wells. But in some in situ bioremediation systems both extraction and injection wells are used in combination to control the flow of contaminated ground water combined with above-ground bioreactor treatment and subsequent reinjection of nutrients spiked effluent are done.

Intrinsic Bioremediation

2009-05-18T22:48:00.000-07:00

Conversion of environmental pollutants into the harmless forms through the innate capabilities of naturally occurring microbial population is called intrinsic bioremediation. However, there is increasing interest on intrinsic bioremediation for control of all or some of the contamination at waste sites. The intrinsic i.e inherent capacity of microorganism, to metabolize the contaminants should be tested at laboratory and field levels before use for intrinsic bioremediation. Through site monitoring programmes progress of intrinsic bioremediation should be recorded time to time. The conditions of site that favors intrinsic bioremediation are ground water flow throughout the year, carbonate minerals to buffer acidity produced during biodegradation supply of electron acceptors and nutrients for microbial growth and absence of toxic compounds. The other environmental factors such as pH concentration, temperature and nutrient availability determine whether or not biotransformation takes place. Bioremediation of waste mixtures containing metals such as Hg, Pb, As and cyanide at toxic concentration can create problem (Madsen, l99l).

The ability of surface bacteria to degrade a given mixture of pollutants in ground water is dependent on the type and concentration of compounds, electron acceptor and duration of bacteria exposed to contaminants. Therefore, ability of indigenous bacteria degrading contaminants can be determined in laboratory by plate count and macrocosm studies.

In situ Bioremediation

2009-05-18T22:31:00.000-07:00

In situ bioremediation is the clean up approach which directly involves the contact between microorganisms and the dissolved and sorbed contaminants for biotransformation (Bouwer and Zehnder, 1993). Biotransformation in the surface environment is a very complex Process. Potential advantages of in situ bioremediation methods include minimal site disruption, simultaneous treatment of contaminated soil and ground water, minimal exposure of public and site personnel, and low costs. But the disadvantages are

(i) time consuming method as compared to other remedial methods,

(ii) seasonal variation of microbial activity resulting from direct exposure to prevailing environmental factors, and lack of control of these factors, and

(iii) problematic application of treatment additives (nutrients, surfactants and oxygen)

(Christodoultos and Kontsospyros, 1998). The microorganisms act well only when the waste materials help them to generate energy and nutrients to build up more cells. When the native microorganisms lack biodegradation capacity, genetically engineered microorganisms (GEEMs) may be added to the surface during in situ bioremediation. But stimulation of indigenous microorganisms is preferred over addition of GEEMs.

There are two types of in situ bioremediation: intrinsic and engineered in situ bioremediation.

Stem cells without foreign DNA induced in humans

2009-05-18T00:32:00.001-07:00

Researchers have developed a method to produce human pluripotent stem cells induced, or CSPI, which contain no foreign DNA potentially harmful.

This result is important for the use of these cells in basic research in biology and is a key step in light of CSPI produce usable medical therapy without the risk that elements inserted into their genome interfere with normal cell development.

When researchers in the early stages reprogrammed adult cells and fetal to become CSPI, they used viruses to insert transformed key genes in the cell nucleus can trigger the process of reprogramming. Jungying Yu and his colleagues now describe an alternative to this approach. They added genes to circular DNA fragments called plasmids in general independent of cellular chromosomes. Then they introduced plasmids in human foreskin cells by a process called nucléofection. The proteins expressed by genes carried by plasmids were then able to reprogram cells by CSPI.

Finally, the CSPI began to lose their plasmid over cell division and then the researchers managed to isolate that do more focused. In their article, the authors state that other teams have recently reported methods with the same objective but their process is currently the only producing CSPI completely devoid of human vectors and transgenic sequences.

BIOREMEDIATION

2009-05-14T10:59:00.000-07:00

Bioremediation is the use of living microorganisms to degrade environmental pollutants or prevent pollution. It is a technology for removing pollutants from the environment, restoring contaminated sites and preventing future pollution. However, it has global, regional, and local application. The basis of bioremediation is the enormous natural capacity of microorganisms to degrade organic compounds. This capacity could be improved by applying the GMMs.

In Japan, academic, industrial and governmental research is tightly coordinated for global application of environmental biotechnology. Researchers are exploiting large scale application of bioremediation that can affect desert formation, global climate change and the life cycle of materials. Attempts are being made to develop microorganisms that can help reverse desert formation. This work is based on developing biopolymers that retain water and reverse desert formation. Alcaligens luteus is being used to produce 'super bio absorbent', a polysaccharide which is composed of glucose and glucuronic acid. These can absorb and hold more than thousand times of its own weight of water.

Using the information from fundamental research bioremediation technology has been used to remove environmentally hazardous chemicals, accumulated in their cells or detoxify them into non-toxic forms. Several members of algae, fungi and bacteria are known to solubilize, transport and deposit the metals, and detoxify dyes and complex chemicals.

The toxic waste materials remain in vapor, liquid or solid phases; therefore, bioremediation technology varies accordingly whether the waste material involved is in its natural setting or is removed and transported into a fermenter (bioreactor). On the basis of removal and transportation of wastes for treatment, basically there are two methods: in situ bioremediation and, ex situ bioremediation.

Wastes as Renewable Source of Energy

2009-05-06T08:53:00.000-07:00

Waste is the spoilage, loss or destruction of either matter or energy, which is unsuable to man. Gradually increasing civilization through industrialization and urbanization, has led to increase in generation of wastes into environment from various sources. Waste generation is, therefore, a necessary outcome of consumption, and also because of insufficient process, general ignorance, wasteful habits and social attitudes (Ray, 1979).

Ray (1979) classified the wastes into energy wastes and material wastes. The main source of energy in the developed and developing countries is petroleum oil, followed by coal. In India, about 50 per cent oil is imported each year. Coal mines are concentrated only in a few regions. Coal is used in generation of electricity, steam engines and fire. Most potential energy of coal is wasted during electric generation in thermal power plants. Thermal loss in India is about 20-30 per cent because of lack of suitable technologies. Based on the chemical nature, material wastes are of various types;

(i) Inorganic wastes (those generated by metallurgical and chemical industries, coal mines, etc.),

(ii) Organic wastes (agricultural products, dairy and milk products, slaughter houses, sewage, forestry, etc.), and

(iii) Mixed wastes (those discharged from industries dealing with textiles, dyes, cake and gas, plastic, wool, leather, petroleum, etc.). The inorganic wastes may be recovered by chemical/ mechanical treatment, whereas organic and mixed wastes require biological as well chemical treatments.

Moreover, the wastes occur in three states, the solid, liquid and gaseous ones. The solid wastes can be burnt, thermally decomposed, anaerobically digested to get methane and other combustible gases or biologically converted to a variety of products. Liquid wastes are most troublesome, because of the presence of non-retractable chemicals, and their further return to environment through surface waters. Gaseous wastes include the toxic gases such as NO2, NO2, NH3, CO2, CO2, SO2, etc. When concentration of these gases increases in the atmosphere they cause gaseous pollution, which has its bad impact on plant and animal lives. The organic wastes and residues become a source of renewable energy in multifarious ways.

Genetically modified mosquitoes to fight against malaria

2009-05-04T11:27:00.001-07:00

United States - The best ally in the fight against malaria could be the mosquito itself. Understanding the immune system would allow researchers to develop a technique effective in the long term. The anti-malaria mosquito or antibodies injected into the human body and transmitted to mosquitoes could one day be more effective than the nets themselves.

According to a new study, the mosquitoes have an immune system that destroys 80 to 90% of malaria parasites that enter the body of the insect. Some experts believe it would be more effective to tackle malaria when the virus is in the insect before being transmitted to humans.

Researchers have discovered the mechanism that activates defenses mosquitoes. In the blood of the mosquito, three proteins form a complex which "binds to the parasite responsible for malaria and pierces the membrane, thereby destroying the layer that protects the parasite, said George Christophides, coauthor of the report published in Science.

According to a first scenario, scientists could create a genetically modified mosquito and improve its ability to eliminate the causative agent of malaria. The key is to find factors that would give new genes against malaria and a selective advantage to spread rapidly through mosquito populations through breeding, "says Gregory Lanzaro, director of the Vector Genetics Lab at the University of California.

The second option would be to develop antibodies that can counter the parasitic forms when they settled early in the mosquito, and antibodies to pass through the human body. "The mosquito's immune system does not produce antibodies to itself," said Marcelo Jacobs-Lorena, a professor of immunology at the Institute of Malaria Research in Baltimore. But if people are vaccinated with these antibodies, they will be transmitted to mosquitoes when they feed on the blood of vaccinated individuals. Combined with a second protective vaccine, it could be a real solution.

The study was conducted with a strain of parasite type that primarily affects rodents and mosquitoes on laboratory somewhat genetically different wild mosquitoes. It does therefore may not be what actually happens in nature. "This is a significant discovery, but it must be validated with the parasites that affect men," confirms Dr. Jacobs-Lorena.

Mapping by Gene Dosage

2009-05-04T07:27:00.000-07:00

A conceptually related approach also takes advantage of structurally rearranged chromosomes for gene mapping but does not rely on having to first segregate the abnormal chromosomes into somatic cell hybrids. This approach depends on detection of dosage differences in either gene products or the gene sequences themselves between patients, cell lines containing different numbers of copies of a particular gene. Although this method requires very careful analysis and interpretation, it has been used to assign genes to or exclude them from a region involved in a duplication or deletion. It was originally used to assign genes to chromosome 2l by detecting levels of enzyme activity in cell lines from patients with Down syndrome (three doses of chromosome 2L) that were higher than levels in cell lines from chromosomally normal Persons (two doses). At the DNA level the dosage approach has been used increasingly to assign DNA markers to the X chromosome (by comparing DNA dosage in persons with one [ie., a normal male karyotype] to five [ie., a 49, XXXXX karyotype] X chromosomes) (Fig 1) or to small regions bf a particular chromosome (by examining collections of patients with partial trisomies [three copies] or monosomies [one copy];.

One of the most direct applications of mapping by gene dosage is the-regional assignment of X-linked disease genes by examining males with cytogenetically detectable deletions of part of the X chromosome. In one well-studied case, a boy (B. B.) with no known history of any genetic disease presented with four normally distinct -X- linked conditions: Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CGD), retinitis pigmentosa (RP), and a rare red blood cell phenotype. Careful cytogenetic analysis revealed a small but detectable deletion in band Xp21 (Fig 2). The coexistence of four single-gene disorders with the small chromosome deletion led to the conclusion that the genes for these four X- linked traits mapped to the deleted interval .Extension of this type of analysis to other individuals simultaneously affected with multiple X-linked diseases has allowed the regional assignment of a number of genes in this region of the X chromosome (Fig. 6). The case of B. B. turned out to be even more significant for medical genetics because (as described more fully later in this chapter) his deleted X chromosome was used directly to allow cloning of the genes for both DMD and CGD. This provides yet another example of how recognition of the unusual in medicine-in this case, the occurrence of multiple genetic diseases in a single individual - can provide important new information about normal genes, their organization, and their function.

Figure 1. Examples of mapping by dosage analysis. DNA probe 1 used at the left can be mapped to the X chromosome because the intensity of hybridization appears to be a function of the number of Xs present in each DNA sample. DNA probe 2 shows the same intensity hybridization in lanes 1 to 3, but is missing from lane 4. This locus maps to the Y chromosome.

Figure 2. Regional localization of X-linked genes in patients with X chromosome deletions. Correlation of the extent of the cytogenetic deletion with the particular disorders present in each case allows fine mapping of the individual disease genes to particular regions on the X Chromosome DMD = Duchenne muscular dystrophy, OTC : ornithine transcarbamylase deficiency, CGD : chronic granulmatous disease, RP: retinitis pigmentosa, GKD: glycerol kinase deficiency, AHC: congenital adrenal hypoplasia.

The parasexual system of human chromosome segregation

2009-05-04T07:15:00.000-07:00

The parasexual system of human chromosome segregation makes it possible to map any gene or DNA segment that can be distinguished between the species to a particular human chromosome. When the residual human chromosomes present in a panel of independent somatic cell hybrids are compared to the presence or absence of a particular human gene in the same series of hybrids, that human gene can be seen to correlate completely with the presence or absence of a specific chromosome. In this way for example the presence or absence of the gene for hexosaminidase A (HEXA), mutations at which cause Tay Sachs disease, could be shown to correlate with human chromosome L5.

All hybrids that retained a human chromosome 15 contained the human HEXA gene; all those that no longer had chromosome 15 did not contain human HEXA. This perfect concordance was observed only for chromosome 15 and not for any other human chromosome thus allowing assignment of the HEXA gene to chromosome 15. In this type of analysis, the presence of a human gene can be monitored either by activity measurements (if the gene is expressed in somatic cell hybrids), by using electrophoresis to distinguish human from rodent cell activity or, more commonly now, by DNA hybridization methods with the Southern blotting technique and restriction enzyme differences to distinguish the human gene from the rodent gene. By using this type of concordance analysis in a panel of inter specific somatic cell hybrids' many hundreds of genes have been assigned to individual Human chromosomes. Genes that have been mapped to the same chromosome are said to be synthetic (literally, "on the same thread"), regardless of how close together or how far apart they lie on that chromosome.

Figure 1: Metaphase chromosome spread from a mouse/human somatic cell hybrid. Human chromosomes can be identified by a detection method that specifically labels human but not mouse DNA. This hybrid contains six human chromosomes, identified as chromosomes 13, 20 (two copies), and the X (three copies). (Courtesy of V. E. powers, Stanford University.)

Figure 2: A panel of mouse/human somatic cell hybrids, each containing 2 to 73 human chromosomes, was used to test for the presence or absence of the human hexosaminidase A gene (HEXA) by means of Southern blotting of DNA prepared from the hybrids (see Fig. 8-3). There is a perfect correlation between the presence or absence of HEXA and the presence or absence of human chromosome 15. For all other human chromosomes, there are hybrids that contain HEXA but are missing the chromosome, and there are hybrids that contain the chromosome but are missing HEXA. Thus these results indicate that the HEXA gene must be on human chromosome 15.

Studies such as these using human/rodent hybrids allow assignment of a gene to a particular chromosome. Additional resolution can be gained by the segregation in hybrids of structurally abnormal human chromosomes. If a particular gene cosegregates in a panel of rodent/ human somatic cell hybrids with a deleted or translocated chromosome, then the gene can be localized to the portion of the chromosome retained in the hybrids. Alternatively, if a gene is known to map to a particular chromosome but is absent from a hybrid containing a deleted or translocated copy of that chromosome, then the gene can be assigned to the portion of the chromosome that is missing. Figure 4 depicts two structurally abnormal X chromosomes used in gene mapping to localize X-linked genes and DNA sequences to particular regions of the X chromosome. By examination of hybrids containing portions of these translocation chromosomes, the X chromosome could be divided into three intervals and different genes assigned to each. Extension of this strategy and examination of increasingly smaller regions of the chromosome of interest in hybrids has made it possible to localize genes to even smaller regions. Although this approach significantly improves the level of, evolution, of gene mapping, the chromosome regions defined are-still quite large in comparison with the size of an average gene.

Figure 3: Southern blot experiment to map the human HEXA gene to chromosome 15, in a series of mouse/human somatic cell hybrids. Only hybrids I, III, VI, VII, and VIII contain human HEXA sequences, which can be distinguished from the mouse gene sequences by different restriction sites in the gene in the two species.

Figure 4. Regional mapping of X-linked genes by analysis of X; autosome translocation chromosomes in somatic cell hybrids. The reciprocal products of two different X; autosome translocations are segregated in somatic cell hybrid clones and can be analyzed for the presence or absence of genes from the human X chromosome. The combined results allow regional localization of the three genes to different portions of the-X, as indicated at the right.

The genome of the cow fully decoded

2009-05-01T09:52:00.000-07:00

The first detailed analysis of the bovine genome sequence, led by the Sequencing Center Baylor College of Medicine in Houston, was published in the prestigious journal Science. A search to which the Institute of Agronomic Research (Inra) participated for France.

The cow becomes the third domestic animal whose genome was completely sequenced, after the chicken and dog. Sequencing the bovine genome has required 6 years of work and involvement of more than 300 scientists from 25 countries, the sequencing itself but also for the assembly, annotation and analysis of significant issue résultats.Conclusion this sequencing the bovine genome is much closer to that of humans that may be the mouse or rat. It includes at least 22 000 genes, most of which are found in the human species. The majority of cattle chromosomes are large fragments of our own chromosomes, sometimes whole chromosomes.

All of these results is completely available to scientists of all countries through public databases. Researchers will now continue to explore in depth this sequence.

New Study Describes First Large-Scale Computer Simulation Of Gene Therapy

2009-04-30T08:02:00.001-07:00

In a recent issue of The Journal of Chemical Physics, published by the American Institute of Physics (AIP), a group of researchers at the University of California, Berkeley and Los Alamos National Laboratory describe the first comprehensive, molecular-level numerical study of gene therapy. Their work should help scientists design new experimental gene therapies and possibly solve some of the problems associated with this promising technique.

"There are several barriers to gene delivery," says Nikolaos Voulgarakis of Berkeley, the lead author on the paper. "The genetic material must be protected during transit to a cell, it must pass into a cell, it must survive the cell's defense mechanisms, and it must enter into the cell's guarded nucleus."

If all of these barriers can be overcome, gene therapy would be a valuable technique with profound clinical implications. It has the potential to correct a number of human diseases that result from specific genes in a person's DNA makeup not functioning properly -- or at all. Gene therapy would provide a mechanism to replace these specific genes, swapping out the bad for the good. If doctors could safely do this, they could treat or even cure diseases like cystic fibrosis, certain types of cancer, sickle cell anemia, and a number of rare genetic disorders.

Safety is a primary concern when working with gene therapy. Some of the first attempts at gene therapy used viruses to insert DNA into cells -- something that viruses naturally do anyway. Viruses can be dangerously toxic, however, and this fact was tragically demonstrated a decade ago when an 18-year-old boy enrolled in a gene therapy study had a massive immune reaction to the viruses used. He died just a few days into the treatment from multiple organ failure, precipitating an immediate halt to the trial.

Since then, many alternatives to viruses have emerged for use in gene therapy, including synthetic molecules like "dendrimers," a word that derives from the Greek word for "tree." Similar to trees, dendrimers are branching molecules that are slightly positively charged. This allows them to be loaded with DNA (which is slightly negative charged) for insertion into a cell.

Dendrimers seem to offer many advantages over viruses. They may be much less toxic, and they may offer other advantages in terms of cost, ease of production, and the ability to transport very long genes. If they can be designed to efficiently -- and safely -- shuttle genes into human cells, then they may be a more practical solution to gene therapy than viruses.

So far, laboratory experiments with different types of dendrimers have shown that they can insert genes into cells, but only with very low efficiency. Hoping to discover the key to improving this efficiency, Voulgarakis and his colleagues simulated the detailed, atomic-level physical process of dendrimers entering cells. They varied parameters like the dendrimer size and the length of the DNA they carry. Modeling these parameters on a computer is a fast, inexpensive approach for testing different ideas and optimizing the delivery vehicle.

What they uncovered were the key factors that determine the success of dendrimers as gene delivery vehicles -- things like the charges of the dendrimers and their target cell membranes, the length of DNA, and the concentration of surrounding salt. Their work has illuminated some of the molecular-level details that should help clinicians design the most appropriate gene vectors.

"Our study indicates that, over a broad range of biological conditions, the dendrimer/nucleic acid package will be stable enough to remain on the surface of the cell until translocation," says Voulgarakis.

Dendrimers are also used clinically for delivering cancer drugs to tumors, and for helping to image the human body. In the future, Voulgarakis and his colleagues plan to study the possibility of using dendrimers as drug delivery vehicles.

Somatic Cell Hybrids and Gene Mapping

2009-04-30T02:32:00.000-07:00

One of the principal applications of somatic cell genetics to gene mapping involves the transfer of genetic material from a human cell to another type of cell in culture, a procedure called gene transfer. The amount of transferred DNA may range from a short segment of chromosomal DNA to much of an entire genome. Gene transfer is a well-known mechanism in bacterial, viral, and fungal genetics, and geneticists have long recognized that the frequency with which two genetic markers are transferred together can be used as a measure of their physical proximity in the donor genome. Thus, not long after it became clear that human and other mammalian cells could be maintained in culture, human geneticists searched for ways to transfer human genes from one cell to another in the laboratory as a Para sexual means of segregating different genes and their alleles.

The most widely used approach, developed in the 1950s, involves fusion of cells from different species to make interspecific somatic cell hybrids. Cultured somatic cells growing as monolayers or in suspension, as well as living cells obtained directly from patients, can be fused by using either inactivated Sendai virus or polyethylene glycol. These agents promote fusion of membranes, from two types of cell, thus forming homokaryons (if two cells of the same type fuse) or heterokaryorns (if two cells of different type fuse), in which two nuclei are maintained separately in the same cytoplasm (refer image). After mitosis and cell division, the two nuclear contents are mixed in a single "hybrid" nucleus. Under appropriate selective culture conditions, the two parental cell types, as well as hybrids derived from homokaryons, are incapable of survival, thus selecting for growth of intercell hybrids. Although a number of selective schemes have been developed, one of the first and most commonly used involves selection in medium containing hypoxanthine, aminopterin, and thymidine (the so-called HAT medium). Cells can grow in HAT medium only if they possess the enzyme hypoxanthine guanine phosphoribosyl transferase (HPRT), which utilizes hypoxanthine and guanine in DNA synthesis cells deficient in HPRT activity (HPRT -) require de novo synthesis of purines foi survival and cannot survive in HAT medium because aminopterin inhibits purine (as well as pyrimidine) biosynthesis.

When HPRT- rodent cell lines (usually either mouse or hamster) are fused with HPRT+ human cells, only rodent/human somatic cell hybrids are capable of prolonged growth in HAT medium: the parental mouse or hamster line dies in HAT, and the parental human cells (depending on their source) are selected against by virtue of their lack of long-term growth potential (if peripheral leukocytes are used), their generally ,low growth (if primary skin fibroblasts are used), or their fortuitous and characteristic sensitivity (in comparison with rodent cells) to the compound ouabain. Somatic cell hybrids are originally polyploid, containing the full chromosome complement of both the rodent and human parental cells. In time, however, many of the chromosomes of one of the species are lost because their continued presence is not required for hybrid survival. Only the chromosome carrying the gene for a marker being selected (for example, the X chromosome, carrying the HPRT gene) is necessarily present in all cells, although, in general, at least a few other donor chromosomes also persist. The basis for chromosome loss or retention is still unknown; the important characteristic of rodent/human somatic cell hybrids is that it is the human, not rodent, chromosomes that are preferentially lost, resulting in hybrid cells retaining different numbers and combinations of human chromosomes, as determined by a number of karyotyping techniques that distinguish between rodent and human chromosomes.

Figure: Inter specific somatic cell hybridization scheme. After cell fusion, human/rodent somatic cell hybrid clones are selected in a selection system, such as HAT medium. These cell hybrids preferentially lose human chromosomes, which makes it possible to isolate hybrid clones containing different combination of human chromosomes. These clones can then be analyzed for the presence or absence of a particular human gene, thus allowing assignment of the gene to a specific human chromosome.

Somatic Cell Genetics

2009-04-30T02:31:00.000-07:00

Somatic cell genetics, in broad terms, is the study of gene organization, expression, and regulation in cultured cells of somatic origin. As an approach to many problems in human and medical genetics, it has been remarkably successful since the 1950s. Somatic cell genetics was originally seen as a way of investigating single-gene and chromosomal disorders in long-term culture in the laboratory rather than in living patients. The approach has many obvious advantages. If a cell line from a patient with a rare disorder or an unusual karyotype can be established when the patient is available, it can be frozen more or less permanently in liquid nitrogen and studied later by different groups of investigators at any convenient time, even decades after the demise of the patient.

The field of gene mapping has taken advantage of the ability of a number of different cell types to grow, sometimes indefinitely, in cell culture (see the box on p. 168). Indeed, it is doubtful that many of the advances in gene mapping could have come about so quickly without the capability of culturing somatic cells. Physical mapping of genes encompasses a variety of different methods, designed to provide mapping information of different types and different levels of resolution, ranging from an entire chromosome to the single base pair.

Physical Mapping of Human Genes

2009-04-29T01:21:00.000-07:00

The assignment of genes to particular human chromosomes initially relied exclusively on family studies in large pedigrees to ascertain the mode of inheritance. X-linked traits could be assigned to the X chromosome because of their unique pattern of transmission. In addition, a few autosomal traits could be assigned to individual chromosomes because of the fortuitous discovery of their co transmission through many meioses with other well-known autosomal genes. This was a generally slow and painstaking business, however, until the discovery in the 1960s that mammalian chromosomes, and particularly human chromosomes, could be made lo "segregate" in somatic cells in culture, not just in germ cells in family studies, thus establishing a so-called "Parasexual" alternative for gene mapping. Because of its central importance to the field of gene mapping, we first discuss the establishment and growth of cells in culture and then describe the specific applications of this approach to physical gene mapping.. Continue reading...

The Human Gene Map: Gene Mapping and Linkage Analysis:

2009-04-29T01:14:00.001-07:00

Geneticists working in many different organisms depend on the mapping of genes to establish the identity of genes controlling different traits. Gene mapping in human and medical genetics has proven to be no exception to this pattern and has, in addition, paid a rich dividend in providing information of enormous practical value for biology and medicine. Human gene mapping is one of the most rapidly expanding areas of study in medical genetics today.

This is largely due to the realization that gene mapping can provide a direct route for identifying genes responsible for genetic diseases. As applications of gene mapping information to disease diagnosis, gene isolation, and genetic counseling have become more widely appreciated, the impetus behind achievement of a complete human gene map-an encyclopedia of all of our genes and their associated genetic disorders has gained strength. Today, medical journals are full of reports assigning genetic diseases to particular chromosomes, and medical charts are full of laboratory reports in which genetic markers have been used to assist in providing accurate genetic counseling or diagnoses.

There are two fundamentally different approaches for assembling gene maps of human chromosomes: physical mapping and genetic mapping. Physical mapping uses a variety of methods to assign genes to particular locations along a chromosome. With these methods, map positions are described in units that are a reflection of some physical measurement performed with somatic cells in the laboratory. Genetic mapping on the other hand, is the measurement of the tendency of two genes to segregate together through meiosis in family studies and thus is a description of a gene's meiotic behavior rather than its physical location. We discuss both types of mapping and examine several of their applications for identifying and isolating particular human genes and for providing diagnostic information in medical genetics.

The Growth of Human Cells in Culture

2009-04-29T00:56:00.000-07:00

Techniques for cell culture took a long time to develop and to become widely used, partly because of the strict nutritional requirements of cultured cells and partly because successful maintenance of a culture for long periods requires exacting precautions to avoid contamination by microorganisms, yeasts, or other cultured cell lines. The nutritional requirements include the use of a semi defined medium with 5 to L5 percent fetal or newborn calf serum (containing largely unidentified growth factors), as well as glucose, amino acids, vitamins, minerals, salt, and a buffering system.

The kinds of cultures most frequently used in human and medical genetics, including gene mapping studies, include the following: Peripheral Lymphocytes in Short-Term Cultures. These cells do not meet the requirement of long-term survival, persisting in culture for only about 72 hours. Such short-term cultures are used extensively for chromosome analysis.

Fibroblasts. Fibroblasts are among the most useful cell types for somatic cell genetic studies, including physical gene mapping. They are cultured from small explants of skin or other tissue. The cells, which have a characteristic spindle shape, grow in monolayers attached to a plastic or glass substratum and must be sub-cultured at frequent intervals because overcrowding leads to contact inhibition of growth.

Fibroblast cultures usually maintain the karyotype of the original cells (normal or abnormal), although clones of cells with somatically altered karyotypes arise in culture rarely. Fibroblast cultures senesce after about 30 to 100 generations in culture; the duration of survival in culture is longer for cell lines set up from young persons than for cell lines from older persons. Fibroblasts cultured from patients with a suspected genetic disorder are a common source of metaphase chromosomes for cytogenetic analysis, of cell extracts for biochemical studies, and of DNA for molecular studies. In addition, human fibroblasts are often used in somatic cell hybridization experiments for gene mapping.

Permanent Lines of Transformed Cells. Some cell lines undergo transformation in culture and become capable of unlimited growth, either spontaneously or experimentally by viral Infection; other permanent cell lines are established directly from tumors. Such lines do not exhibit contact inhibition, do not senesce, and do not maintain a stable karyotype, but often exhibit characteristics of the type of transformed cell from which they were derived. As such, they are quite useful for analysis of the genetic basis of transformation and malignancy.

Lymphoblast Cell Lines. Although cultures of peripheral blood lymphocytes do not ordinarily persist in culture, they can be induced to do so when transformed by the Epstein-Barr virus. Lymphoblast cultures, derived from B-cell lineages, grow in suspension, rather than as an attached monolayer of cells, and do not senesce. Thus they are an essentially permanent source of material from patients with genetic disorders.

Fetal Cell Lines. Fetal cells can be obtained prenatally either by sampling amniotic fluid by amniocentesis or by chorionic villus sampling from a pregnant woman. A proportion of fetal cells so obtained retain at least some growth potential in culture, although such cultures tend not to grow as well (or for as long) as skin fibroblasts. Amniotic fluid cell or chorionic villus cultures are used for determining the fetal karyotype, for analysis of enzyme levels, and for DNA analysis to provide prenatal diagnosis.

Genes Linked to Stroke May Raise Risk by a Third, Study Finds

2009-04-16T04:59:00.000-07:00

Two gene variants newly linked to stroke may increase by about 30 percent a person’s risk for the third-leading cause of death in the U.S., according to a study of about 20,000 patients.

A genetic region containing the variants was implicated in more than one in 10 stroke cases, according to a study published yesterday in the New England Journal of Medicine. The variants are located near the so-called NINJ2 and WNK1 genes. NINJ2 is known to be active after a nerve injury, producing a protein that helps determine how well the brain tolerates decreased blood flow, the researchers said. WNK1 is linked with changes in the severity of high blood pressure, they said.

Stroke was the top reason for serious long-term disability in the U.S. in 2008, costing about $65.5 billion in lost wages and medical treatment, according to the American Heart Association. While the risk is three times greater if a parent has had a stroke, previous studies have yielded inconsistent findings about the role of specific genes, researchers said.

“The genes that determine stroke aren’t well known,” said Donna Arnett, a professor of epidemiology at the University of Alabama at Birmingham who wasn’t involved in the study, in a telephone interview. “It definitely tells us something about the physiology of stroke we wouldn’t have picked out alone.”

Researchers scanned patients’ whole genomes to find what was associated with stroke using the Human Genome Project and several large population studies, said Sudha Seshadri, one of the study authors and an associate professor of neurology at Boston University.

2 Million Variations

The scientists reviewed more than 2 million variations in DNA, called single nucleotide polymorphisms, or SNPs, she said.

Arnett said the test results need to be replicated in other studies. To date, there are no commercial tests to determine if a patient has the genetic variations linked to stroke.

“You can’t go to your doctor tomorrow and ask for this test,” she said.

The involvement of NINJ2 points scientists in a new direction for research, Arnett said. The gene is expressed in many places, including the brain, and may inspire scientists to try to understand its relationship. In time, that may lead to treatments or new ways of screening people for stroke, she said.

The original research drew its data from 19,603 white people in four large studies in the U.S. and the Netherlands. After identifying genetic region linked with increased risk, the researchers replicated the findings in a group of 2,430 black North Americans and 652 white people in the Netherlands.

Almost 780,000 strokes occur in the U.S. every year, according to the U.S. Centers for Disease Control and Prevention in Atlanta.

Previously Unsuspected

NINJ2 wasn’t previously suspected to be involved in any cardiovascular incidents, said Walter Koroshetz, the deputy director at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, in a telephone interview.

“Without this study, of all the proteins you have in your body, this wouldn’t be at the top of the list for stroke,” said Koroshetz, who wasn’t involved in the study. “Now, this jumps to the top of the list to study for stroke.”

Warning signs of a stroke include numbness or weakness on one side of the body, sudden confusion, trouble seeing in one or both eyes, and loss of balance or coordination, according to the Mayo Clinic Web site.

Besides a family history, risk factors include age of 55 or older, high blood pressure, diabetes and smoking. Women are more likely to die of strokes than men, although they have strokes at the same rate, according to the Mayo Clinic.

“Although we know so much about the risk factors for stroke, we still can’t predict who gets one and who doesn’t,” Boston University’s Seshadri said.

Genetic Aspects of Development

2009-04-09T04:54:00.000-07:00

A central question of biology is the nature of the regulation of gene expression that allows a fertilized ovum to develop into a mature organism. Genes differ in their expression both in time and in space. The early stages of development are concerned with the establishment and differentiation of the morphological structures of the body. Despite its clinical relevance and the extensive descriptive information available about the morphology of the human embryo (Moore, 1988), knowledge of the genes that control the process is still sparse. For many practical and ethical reasons, research on human embryos is limited, and almost all our information about these processes has come from studies in other organisms, most often the fruit fly Drosophila. Many of the genetic manipulations used with Drosophila have now become possible with the mouse, raising the prospect of rapid progress and new insights in the genetic analysis of mammalian development.

Not infrequently, the process of human development goes wrong. The most abnormal embryos and fetuses, of course, are not born alive but are aborted spontaneously at some stage between fertilization and viability. Still, a significant proportion of pregnancies end with the birth of a child with some congenital anomaly or are selectively terminated because an anomaly has been identified in the fetus. The identification and delineation of syndromes of congenital abnormalities constitutes the field of dysmorphology, one of the most rapidly advancing specialties within clinical genetics.

Factors affecting Hardy-Weinberg Equilibrium

2009-04-09T04:03:00.000-07:00

The Hardy-Weinberg law makes several fundamental assumptions that are not always true of actual human populations:

1. The population is characterized by random mating, with little if any stratification, assortative mating, or inbreeding.

2. The locus under consideration exhibits a constant mutation rate, and mutant alleles lost by death are replaced by new mutations.

3. There is no selection for or against a particular phenotype; all genotypes at a locus are equally viable.

4. The population is sufficiently large that there has been no random fluctuation of frequencies resulting from transmission of any one genotype simply by chance.

5. There has been no charge in the population structure by migration, which can gradually change gene frequencies by increasing or decreasing the number of increasing or decreasing the number of individuals with a particular genotype.

If in a given population one or more of these assumptions does not hold true, the genotypes in that population may not be in Hardy-Weinberg equilibrium.

The concept of Genetic Polymorphism

2009-04-08T02:08:00.000-07:00

Many loci are characterized by a number of relatively common alleles that allow members of a naturally occurring population to be categorized into sharply distinct phenotypes. Genetic polymorphism is defined as the occurrence of multiple alleles at a locus, where at least two alleles appear with frequencies greater than 1 percent. By convention, then, polymorphic loci are those at which at least 2 percent of the population is heterozygous. However, because many polymorphic loci are characterized by a large number of different alleles, the proportion of heterozygote at some loci is much greater. Again by convention, alleles with frequencies of less than 1 percent are called rare variants. As discussed further, most (but not all) deleterious mutations that lead to genetic disease are of this latter, rare class.

Over the years, a large number of different human enzymes and other proteins have been screened for electrophoretic variants in different populations. Of all loci tested, about one third have been found to exhibit detectable polymorphism in at least one major ethnic or racial group and often in all major population groups (Haris, 1980; Cavalli-Sforza and Bodmer, 1971).

The widespread occurrence of genetic polymorphism implies that any individual is likely to be heterozygous at many different gene loci. What is the proportion of loci in a given individual at whom there will be two different alleles, each specifying a structurally distinct form of the gene product? It has been estimated from surveys of many enzymes that any individual is likely to be heterozygous at approximately 6 percent of enzyme-encoding loci. Correcting for the lack of detection of electrophoretically silent mutations, one can estimate that any individual is likely to be heterozygous for alleles determining structurally different polypeptides at approximately 12 to 18 percent of all loci. This figure is sometimes called the average heterozygosity, and it underscores the striking degree of biochemical individuality that exists within the human species.

Embryology of the reproductive system

2009-04-06T23:50:00.000-07:00

The embryology of the male and the female reproductive systems:

By the sixth week of development in both sexes, the primordial germ cell have migrated from their earlier extra embryonic location to the gonadal ridges, where they are surrounded by the sex cords to form a pair of primitive gonads. Up to this time, the developing gonad, whether chromosomally XX or XY, is bipotential.

The current concept is that development into an ovary or a testis is determined by the coordinated action of a sequence of genes that lead to ovarian development when no Y chromosome is present or to testicular development if a Y is present. The ovarian pathway is followed unless a gene on the short arm of the Y, designated TDF (testis-determined factor), acts as a switch, diverting development into the male pathway. The search for the major testis-determined gene is one of the leading current problems in medical genetics.

In the presence of Y Chromosome, the medullary tissue forms typical testes with seminiferous tubules and Leydig cells, which, under the stimululation of human chorionic gonadotropin from the placenta, become capable of androgen secretion. The spermatogonia, derived from the primordial germ cells by 200 or more successive mitosis, form the walls of the semiferous tubules together with supporting Sertoli cells.

If no Y chromosome is present, the gonad, by default, forms an ovary; the cortex develops, the medulla regresses, and oogonia begin to develop within follicles. The oogonia are derived from the primitive germ cells by a series of about 30 mitoses, for fewer than the number required for spermatogenesis. Beginning at about the end of the third month, the oogonia enter meiosis I, but this this process is arrested at a stage called dictyotene, in which the cell remains until ovulation occurs many years later. Many of the oogonia degenerate before birth, and only about 400 mature into ova during the 30 years or so of sexual maturity of the female.

While the primordial germ cells are migrating to the genital ridges, thickenings in the ridges indicate the developing genital ducts, the mesonephric (formerly called Wolffian) and paramesonephric (formely called Mullerian) ducts. In the male, the Leydig cells of the fetal testes produce androgen, which stimulates the mesonephric ducts to form the male genital ducts, and the Sertoli cells produce a hormone that suppresses formation of the paramesonephric ducts. In the female (or in an embryo with no gonads), the mesonephric ducts regress, and the paramesonephric ducts develop into the female duct system. In the early embryo, the external genitalia consist of a genital tubercle, paired labioscrotal swellings, and paired urethral folds. From this undifferentiated state, male external genitalia develop under the influence of androgens, or, in the absence of a testis, female external genitalia are formed regardless of whether an ovary is present.

Complementary DNA Libraries - cDNA

2009-04-05T19:50:00.000-07:00

Another common type of libraries used to isolate genes is the cDNA library, which represents complementary DNA (hence cDNA) copies of the mRNA population present within a particular tissue. Such cDNA libraries are often preferable to genomic libraries as a source of cloned genes

1. because the obtained clone is a different representation of the coding sequences, without introns or other noncoding sequences found in genomic DNA, and

2. because the the use of a particular mRNA source often enriches substantially for the sequences derived from a given gene known to be expressed selectively in that tissue. For example, the beta-globin gene is represented at only one part per million in a human genomic library, but it is a major mRNA transcript in red blood cells. Thus a cDNA library prepared from red blood cells represents an excellent cloning source to isolate globin gene cDNAs. Similarly, a liver or muscle cDNA library is a good source of clones for genes known to be expressed preferentially or exclusively in those tissues.

A number of methods have been developed to clone cDNAs, all of which rely on the enzyme reverse transcriptase, a RNA-dependent DNA polymerase that can synthesize a cDNA strand from an RNA template. Reverse transcriptase requires a primer to initiate DNA synthesis. Usually, a sequence of polythymine residues (oligo-dT) is used; this short homopolymer binds to the polyA tail at the 3' end of mRNA molecules and thus primers synthesis of a complementary copy. This single-stranded cDNA is then converted to a double-stranded molecule by one of the several available methods, and the double-stranded cDNA can then be ligated into a suitable vector, usually a plasmid or a bacteriophage, to create a cDNA library representing all of the original mRNA transcripts found in the starting cell type or tissue. Some cleverly engineered vectors contain transcription and translation signals adjacent to the cloning cDNA in E.coli or in yeast. Such so-called expression vectors can then be screened with antibodies raised against, for example the protein whose gene one is trying to isolate.

Representive cDNA libraries from different tissues or different times of development are valuable resources for gene cloning. Many such libraries are now widely available.

Genes in Population

2009-04-05T19:49:00.000-07:00

Genetics is unique among the various disciplines in medicine because of its focus on a familiar rather than on an individual patient. Medical genetics is concerned not only with making the correct diagnosis in a particular case but with determining the genotypes of other family members and estimating recurrence risks both for the parents of an affected person and for his or her sibs, as well as for more distant relatives. Furthermore, because such risks are usually affected not only by the genotypes of persons from the general population who have married into the family, genetic counselling must take into account like livelihood of specific genotypes in different populations. Thus in order both to make a genetically correct clinical diagnosis and to determine recurrence risks as part of effective genetic counselling, it often matters , for example, whether a family has its origins in the British Isles or in the Mediterranean or in Finland, whether the family is Caucasian, Black, or Asian. In genetics more than in any other medical speciality, the patient is a reflection of the population to which he or she belongs.

Population Genetics is the study of the distribution of genes in population and of how the frequencies of genes and genotypes are maintained or changed. Population genetics has much in common with epidemiology, the study of the interrelationships of the various genetic and evnironmental factors that determine the frequency and distribution of diseases in human communities. The two areas fuse in the field of genetic epidemiology, which is chiefly concerned with diseases that have complex patterns of inheritance or are caused by a combination of heritable and environmental factors. This approach has already improved our understanding of the genetics of many diseasesm especially the common disorders of adult life.

Molecular Biomimetics: Nanotechnology And Bionanotechnology . Utilizing Genetically Engineered Peptides

2009-04-02T10:38:00.000-07:00

Nature provides inspiration for designing materials and systems which derive their functions from highly organized structures. Biological hard tissues are hybrid materials having both inorganics within a complex organic matrix, the molecular scaffold controlling inorganic structures. Biocomposites incorporate both biomacromolecules such as proteins, lipids and polysaccharides, and inorganic materials, such as hydroxyapatite, silica, magnetite, and calcite.

The ordered organization of hierarchical structures in organisms begins via the molecular recognition of inorganics by proteins which control interactions and followed by the highly efficient self assembly across scales. Following the molecular biological principle, proteins could also be utilized in controlling materials formation in practical engineering via self-assembled, hybrid, functional materials structures. In molecular biomimetics, material-specific peptides could be the key in the molecular engineering of biology-inspired materials.

With the recent developments of nanoscale engineering in physical sciences and the advances in molecular biology, we now combine genetic tools with synthetic nanoscale constructs to create a novel methodology. We first genetically select and/or design peptides with specific binding to functional solids, tailor their binding and assembly characteristics, develop bifunctional peptide/protein genetic constructs with both material binding and biological activity, and utilize these as molecular-synthesizers, erectors, and assemblers. Here, we give an overview of solid-binding peptides as novel molecular agents coupling bio- and nanotechnology.

Mimicking Biopolymers On A Molecular Scale: Nano(bio)technology Based On Engineered Proteins

2009-04-02T10:37:00.000-07:00

Proteins are ubiquitous biopolymers which adopt distinct three-dimensional structures and fulfil a multitude of elementary functions in organisms.

Recent systematic studies in molecular biology and biotechnology have improved the understanding of basic functional and architectural principles of proteins, making them attractive candidates as concept generators for technological development in material science, in particular in biomedicine and nano(bio)technology.

This paper highlights the potential of molecular biomimetics in mimicking high performance proteins and provides concepts for applications in four case studies, i.e. the biopolymers involved in spider silk, anti-freeze proteins, blue mussel adhesive proteins, and viral ion channels.

Electromagnetic Communication Between Cells - Signals Pass Through Glass

2009-04-02T10:34:00.000-07:00

A new study by researchers at the Swiss Tropical Institute (Basel) and CNRS (Paris, France) has found that populations of the single-celled ciliate Paramecium caudatum can influence each other using signals that pass through glass, affecting fundamental aspects of cellular life such as growth and energy uptake.

The study, which is published by the online, open-access, peer-reviewed journal PLoS ONE, is significant because chemical signals cannot transmit through a glass barrier, but electromagnetic signals can. Hence, the single-celled organisms studied here can use a communication system that is based on radiation. Even though the idea of organisms signaling via radiation was discussed between the two world wars, research into molecule based-communication has advanced much further. Accumulating studies, however, support the idea that both these communication systems co-exist and interact.

The study on Paramecium shows (indirectly) that cells use at least two frequencies when influencing each other: one in the UV and one in the visible (or longer waves) range. The cells increase or decrease growth and energy uptake in response to changing cell numbers within a population, despite being separated by an impervious material (normal or quartz glass, which allow the passage of different wavelengths of radiation) from a neighboring population. The results of the random or random-blind experiments (preformed in light-proof black boxes) present a different view from previous studies reporting on direction or growth enhancement only.

Although reactions to radiation and ultra-weak light emission (biophotons) of organisms are known, endogenous electromagnetic communication is still scarcely described. Technically, we are not yet able to observe the sending and receiving structures of the cell because of their ultra-small dimensions. However, we can define the cell as the sending and receiving unit. New experiments will ask more about the function of the communication and in particular will look for electromagnetic regulation of population growth.

Blood Test For Brain Injuries Gains Momentum

2009-04-02T10:32:00.000-07:00

A blood test that can help predict the seriousness of a head injury and detect the status of the blood-brain barrier is a step closer to reality, according to two recently published studies involving University of Rochester Medical Center researchers.

News stories about tragic head injuries - from the death of actress Natasha Richardson to brain-injured Iraq war soldiers and young athletes - certainly underscore the need for a simpler, faster, accurate screening tool, said brain injury expert Jeffrey Bazarian, M.D., M.P.H., associate professor of Emergency Medicine, Neurology and Neurosurgery at URMC, and a co-author on both studies.

The S-100B blood test recently cleared a significant hurdle when a panel of national experts, including Bazarian, agreed for the first time that it could be a useful tool for patients with a mild injury, allowing them to safely avoid a CT scan.

Previous studies have shown the S-100B serum protein biomarker to increase rapidly after an injury. If measured within four hours of the injury, the S-100B test accurately predicts which head injury patients will have a traumatic abnormality such as hemorrhage or skull fracture on a head CT scan. It takes about 20 minutes to get results and could spare many patients unnecessary radiation exposure.

Physicians at six Emergency Departments in upstate New York, including the ED at Strong Memorial Hospital in Rochester, this year will continue to study the accuracy of the test among 1,500 patients. Scientists plan to use the data to apply for U.S. Food and Drug Administration approval.

"The S-100B blood test is an important part of the tool set we need to improve our treatment of patients with brain injuries," Bazarian said. "It's not the ultimate diagnostic test, but it may make things easier for patients, and it will help doctors sort through difficult clinical decisions."

The test is used routinely in 16 European countries as a screening device. If a person falls and gets a head injury in Munich, Germany, during Oktoberfest, for example, a neurosurgeon is on duty within 500 meters of the beer tent, ready to administer the blood test, Bazarian said.

But in the United States, the current, accepted standard screening tool for head injuries is still the CT scan, which shows bleeding in the brain but does not detect more subtle injury to the brain's neurons, which can result in lasting neurological defects. In fact, 95 percent of CT scans look normal for patients with a relatively mild but potentially life-altering injury, Bazarian said.

There are more than 1 million emergency visits annually for traumatic brain injury (TBI) in the U.S. The majority of these visits are for mild injuries, primarily the result of falls and motor vehicle crashes. The challenge for doctors is to identify which of these patients has an acute, traumatic intracranial injury, something that is not always evident, and which patients can be observed and sent home.

Widespread use of the blood test could result in a 30 percent reduction of CT scans, according to the report by the national panel of brain experts, which published updated clinical guidelines in the December 2008 Annals of Emergency Medicine, and the April 2009 Journal of Emergency Nursing.

Bazarian and colleague Brian J. Blyth, M.D., assistant professor of Emergency Medicine at URMC, additionally found that the S-100B test can relay critical information about how the blood-brain barrier (BBB) is functioning after a head injury. Blyth was the first author on this study, reported electronically March 3, 2009, in the Journal of Neurotrauma.

In the context of head injuries, the BBB acts like a gate between the brain tissue and peripheral circulation. The gate often opens after injury, but not always. Knowing the status of the BBB helps doctors to decide if medications given to repair damage will actually reach the brain. The time between injury and irreversible brain swelling is short - and many drug studies have failed to find a therapy that leverages this time frame and works as designed.

Before the S-100B blood test, the best way to know if the BBB was open was to perform an invasive procedure called a ventriculostomy. (Doctors insert a catheter through the skull and into the brain, withdrawal fluid, and compare the concentration of albumin protein in the cerebrospinal fluid to the concentration in the blood.)

In a pilot study of 20 patients, however, Blyth found that serum S-100B concentrations could accurately predict the function of the blood-brain barrier 12 hours after injury, eliminating the need for the invasive procedure.

The study compared levels of S-100B proteins to the CSF-serum albumin quotient (Qa), the gold standard measurement signaling a brain injury. Researchers compared nine people with a known severe head injury, to 11 people who suffered from non-traumatic headaches.

Blyth and Bazarian believe the research may impact future drug studies. "The disability and death rates from brain injuries have not improved much in the past 20 years," Blyth said. "Many clinical trials for new medications have failed, probably because it was difficult to know if the blood-brain barrier was open and the drugs were reaching its target. Our study shows that any diagnostic test for brain injury should incorporate a way to measure the status of the blood-brain barrier into its design."

How Does Microglia Examine Damaged Synapses?

2009-04-02T10:28:00.000-07:00

Microglia, immune cells in the brain, is suggested to be involved in the repair of damaged brain, like a medical doctor. However, it is completely unknown how microglia diagnoses damaged circuits in an in vivo brain. Japanese group led by Professor Junichi Nabekura and Dr Hiroaki Wake of National Institute for Physiological Sciences, NIPS, Japan, successfully took a live image how microglia surveys the synapses in the intact and ischemic brains of mice by using two-photon microscopic technology. They report their finding in Journal of Neuroscience on April 1, 2009.

They took an intense tune-up of their two-photon microscopy and achieved to visualize the fine structures of neurons and glias of mice in the range of 0 to 1 mm from the brain surface (world-leading deep imaging technology).

Surprisingly even in the normal (intact brain), microglias actively reached out their processes selectively for neuronal synapses at an interval of one hour with a contact duration of 5 minutes. More frequently microglias contacted on more active synapses. Once the brain received the damage such as ischemic infarction, microglial surveillance of synapses was much prolonged in duration, up to 2 hours. Frequently after the prolonged survey by microglia, damaged synapses were eliminated. This is the first report to show how microglia actively surveys the synapses in vivo and determines the fate of synapses, remained or eliminated

"Dynamic change of microglial surveillance of neuronal circuits in damaged brain, observed here, could contribute to establish the therapeutic approach targeted to damaged circuits", said Professor Nabekura.

Amniotic Fluid May Provide New Source Of Stem Cells For Future Therapies

2009-04-01T09:17:00.000-07:00

For the first time, scientists have shown that amniotic fluid (the protective liquid surrounding an embryo) may be a potential new source of stem cells for therapeutic applications. The study was prepublished online on February 12, 2009, in Blood, the official journal of the American Society of Hematology.

"Building on observations made by other scientists, our research team wondered whether stem cells could be detected in amniotic fluid. We looked at the capacity of these cells to form new blood cells both inside and outside the body, and also compared their characteristics to other well-known sources of stem cells," said senior study author Marina Cavazzana-Calvo, MD, Ph.D., of INSERM, the national French institute for health and biomedical research. Isabelle Andre-Schmutz, Ph.D., of INSERM, also a senior author of the study, added, "The answer was a resounding 'yes' - the cells we isolated from the amniotic fluid are a new source of stem cells that may potentially be used to treat a variety of human diseases."

To conduct the study, amniotic fluid was collected from pregnant mice between 9.5 and 19.5 days post-coitus. Human amniotic fluid was collected during routine diagnostic procedures (amniocentesis) from volunteer donors between seven and 35 weeks of pregnancy.

Amniotic fluid (AF) cells that had markers similar to bone marrow stem cells (termed AFKL cells) were then isolated for use in experiments, as these cell markers were indicative of progenitor cells (cells that have the capacity to differentiate into other types of cells).

In vitro, AFKL cells from both mice and humans were able to generate all blood cell lineages, including red (erythroid) blood cells and white (myeloid and lymphoid) blood cells in experiments performed outside the animals. But the scientists also wanted to explore the AFKL cells' hematopoietic (blood-forming) potential in vivo. Therefore, adult mice were irradiated to destroy their capacity to produce blood cells and injected with either AFKL cells or fetal liver cells. Fetal liver was used for comparison as it is the primary source for hematopoietic cells in developing embryos.

The peripheral blood of the transplanted mice was examined every four weeks, and after 16-18 weeks the blood-forming organs (bone marrow, spleen, thymus, and lymph nodes) of the mice were dissected. Transplants using mouse AFKL cells were found to be successful; newly formed white blood cells of all lineages derived from AFKL cells appeared in most of the irradiated mice four weeks after the procedure. As expected, all of these blood cell types were detected in all of the control group mice who received fetal liver cell transplants. Scientists continued to find AFKL-derived cells in the irradiated mice four months later, demonstrating the long-term ability of the transplanted cells to produce new blood cells.

Bone marrow samples from the transplanted mice were also taken and injected in a second set of mice and the peripheral blood of this new group of irradiated mice was analyzed and their hematopoietic organs examined after 10-13 weeks. The secondary transplants with mouse AFKL cells were partially successful with some of the mice engrafting the donor cells. This finding shows that AFKL cells have the ability to self-renew, a key characteristic of stem cells.

Though the human AFKL cells failed to reconstitute the hematopoietic system in irradiated, immunodeficient mice, experiments are currently underway to overcome obstacles that may have led to this failure, such as using a low number of cells for the injection and conducting the transplant in adult mice (engraftment is easier to obtain in newborn mice).

As additional confirmation of the probability that AFKL cells are indeed stem cells, the researchers examined them for the expression of specific genes known to be involved in hematopoietic development. The overall gene expression profile of the AFKL cells was found to resemble blood cell progenitors from known hematopoiesis sites such as the aorta-gonad-mesonephros region, placenta, and the umbilical/vitelline arteries.

The American Society of Hematology (http://www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology. In September, ASH launched Blood: The Vital Connection (http://www.bloodthevitalconnection.org), a credible online resource addressing bleeding and clotting disorders, anemia, and cancer. It provides hematologist-approved information about these common blood conditions including risk factors, preventive measures, and treatment options.

Better Diabetes Self Care Might Not Mean Lower Blood Sugar

2009-03-31T07:19:00.000-07:00

People with diabetes who feel they have better control over life events are more likely to take good care of themselves and to believe they have the condition under control, but these factors do not translate to improved blood sugar levels, according to a new study of 1,034 adults.

Participants' responses to survey items on their risk tolerance, concern about their future and beliefs about their longevity had no correlation to clinical measures of their hemoglobin A1c levels, which reflect average blood glucose (or blood sugar) during the previous two to three months.

The study, which appears online in the journal Health Services Research, also found no differences by race or Hispanic ethnicity in how people took charge of their self-care.

People are not always adherent in managing their diabetes care, which affects overall health and the risk of diabetic complications, said lead study author Frank Sloan, Ph.D.

"What we are able to do here is bring some new measures to bear," said Sloan, a professor of health policy and management at the Center for Health Policy at Duke University.

Some people believe that whatever they do, they have no control over their diabetes; others are very tolerant of the risks of diabetes; and, some have a philosophy that they will live for today and not care about the future, Sloan said. "One result that comes through is that people who have self-control over life in general are more likely to adhere," he said.

"This area of study is valuable as we attempt to better understand the relationship between how people from all ethnic and cultural backgrounds perceive their destinies with diabetes," said Sue McLaughlin, a registered dietitian and president of health care and education with the American Diabetes Association.

"This study illustrates the insidious nature of hyperglycemia: it is a silent and deadly killer," added Miller, who had no affiliation with the study. Many people with diabetes assume they are in good health because they do not feel bad, she said.

Health Services Research is the official journal of the AcademyHealth and is published by John Wiley & Sons, Inc. on behalf of the Health Research and Educational Trust.

Sloan FA, Padrón NA, Platt AC. Preferences, beliefs and self-management of diabetes. Health Services Research online, 2009.

Genzyme/ACMGF Fellowship In Biochemical Genetics Awarded To Margarita Saenz, M.D.

2009-03-31T05:38:00.000-07:00

Margarita Sifuentes Saenz, MD, a Medical Genetics Fellow at The Children's Hospital in Denver, CO was honored as the 2009-2010 recipient of the Genzyme/American College of Medical Genetics Foundation (ACMGF) Clinical Genetics Fellowship in Biochemical Genetics at the ACMG 2009 Annual Clinical Genetics Meeting in Tampa, FL.

The objective of the Genzyme/ACMGF Award is to support a national fellowship program to encourage the recruitment and training of clinicians in the field of clinical biochemical genetics and especially in the diagnosis, management and treatment of individuals with metabolic diseases. This award grants $75,000 per year to a recipient selected by the ACMG Foundation through a competitive process and will provide for the sponsorship of a trainee's first year of fellowship following residency in a genetics fellowship on biochemical genetic diseases.

"The Genzyme/ACMGF Clinical Genetics Fellowship in Biochemical Genetics is especially important today as we work together to increase the genetics workforce and to advance education, research and standards of practice in medical genetics in the United States in order to improve health and save lives," said R. Rodney Howell, MD, FACMG, president of the ACMGF.

Notes:

Genzyme Corporation is a generous supporter of the American College of Medical Genetics Foundation and a member in good standing of its Partners in Science program. For more information about the Partners in Science program, go to: http://www.acmgfoundation.org

Lifetime Award In Genetics Received By Roberta A. Pagon From March Of Dimes

2009-03-28T20:24:00.002-07:00

The founder of a public database that helps doctors analyze the usefulness of genetic tests in making medical decisions is the 2009 recipient of the March of Dimes/Colonel Harland Sanders Award for lifetime achievement in the field of genetic sciences.

Roberta "Bonnie" Pagon, MD, professor of Pediatrics at the University of Washington School of Medicine in Seattle, developed the Web site genetests.org in 1992 and today is the principal investigator of this National Institutes of Health-funded program. Dr. Pagon has been a medical geneticist for more than 25 years and also is adjunct professor in the University's departments of ophthalmology and medicine. Her clinical work focuses on genetic eye diseases and syndrome delineation - reviewing the symptoms of patients who do not have a diagnosis to see if there might be a new disorder.

"Dr. Pagon is responsible for sharing critical information about the diagnosis and management of genetic diseases with physicians worldwide," said Michael Katz, MD, March of Dimes senior vice president of Research and Global Programs, who presented the award to Dr. Pagon at the Annual Clinical Genetics Meeting of the American College of Medical Genetics held here. "She is a pioneer in the field of medical genetics, and the March of Dimes is pleased to honor her."

In its 15-year history, genetests.org has grown to become an important international resource for genetic testing information. The site promotes the appropriate use of genetic testing in patient treatment and personal decision-making. For her work on GeneTests, Dr. Pagon previously received the American Society of Human Genetics 2006 Education Award.

Dr. Pagon also is a consultant to the Regional Genetics Program of Washington State and an attending physician in the Children's Hospital and Regional Medical Center Genetics Clinic. She is a member of the board of directors of the American Board of Medical Genetics (ABMG) and a member of the Clinical Practice Committee of the American College of Medical Genetics (ACMG).

She is the review board coordinator for the Collaboration, Education, and Test Translation (CETT) Program, which promotes the collaborative development of new tests for rare genetic diseases for use by doctors and patients, and supports the collection and storage of genetic test results so they can be used to guide new research.

In Response To Stress DNA Repair Mechanisms Relocate

2009-03-28T20:24:00.001-07:00

Like doctors making house calls, some DNA repair enzymes can relocate to the part of the cell that needs their help, a collaborative team of scientists at Emory University School of Medicine has found.

The signal that prompts relocation is oxidative stress, an imbalance of cellular metabolism connected with several human diseases.

The study integrated the expertise of three Emory groups and resulted in a new level of understanding of the cell's response to genetic damage. The finding could lead to new targets for anti-cancer drugs that interfere with DNA repair, says Paul Doetsch, PhD, professor of biochemistry, radiation oncology, and hematology and oncology at Emory University School of Medicine.

The results were published in the February 1 issue of Molecular and Cellular Biology. The journal's editors chose an image of yeast cells with fluorescent DNA repair enzymes for the cover.

"DNA damage and oxidative stress are very closely related," Doetsch says. "For example, the way radiation inflicts most of its damage on DNA is through oxidative stress. The more we know about how cells respond to oxidative stress, the more chances there could be to influence those responses for diagnostic or therapeutic purposes."

The DNA inside cells is continually under assault by heat, radiation and oxygen. Cells have an extensive set of repair enzymes that comb through DNA, continually excising and re-copying damaged segments. To complicate matters, mitochondria (cells' miniature power plants) have their own DNA.

Working with Doetsch, Emory graduate students Lyra Griffiths and Dan Swartzlander, and biochemists Anita Corbett and Keith Wilkinson, genetically modified strains of yeast so that two different DNA repair enzymes would be fluorescent. They were able to follow the enzymes around the cell when yeast was exposed to hydrogen peroxide, causing oxidative stress, or to other chemicals causing DNA damage.

One DNA repair enzyme they studied, Ntg1, moves to the nucleus or the mitochondria depending on where DNA damage is concentrated, the authors found. In contrast, a related enzyme, Ntg2, stays in the nucleus under all conditions.

Cells appear to direct Ntg1's relocation by briefly attaching a small protein called SUMO to what needs to be moved around, the authors found. SUMO is found in fungi, plants and animals and is already being investigated by several research groups as a possible target for anti-cancer drugs.

Revealing The Evolutionary Origin Of Bacterial Chromosomes

2009-03-28T20:19:00.000-07:00

Researchers have unveiled the evolutionary origin of the different chromosomal architectures found in three species of Agrobacterium. A comprehensive comparison of the Agrobacterium sequence information with the genome sequences of other bacteria suggests a general model for how second chromosomes are formed in bacteria.*

Agrobacteria are members of the Rhizobiaceae family, which also includes the benign, nitrogen-fixing organisms Rhizobium and Sinorhizobium. Agrobacterium tumefaciens C58 is the workhorse of the plant biotechnology science and industry, thanks to its ability to insert its own DNA into host plants.

Members of the Rhizobiaceae have genetic architectures that span single chromosomes, multiple chromosomes and circular DNA molecules (plasmids) of various sizes. The scientists used the sequence information of the genomes of three types of Agrobacterium (biovars), two of which were recently completed, and compared the sequences with those of different bacteria to shed light on the origin of the different chromosomal arrangements.

Most bacteria have only one chromosome. The Rhizobiaceae is an unusual bacterial family in that all of its members have either two chromosomes or one chromosome and very large plasmids. Until this study, it was not clear how such multichromosomal architectures had evolved.

João Setubal, associate professor at the Virginia Bioinformatics Institute and the Department of Computer Science at Virginia Tech, commented: "Thanks to the efforts of the Agrobacterium Genome Sequence Consortium and the wider research community, we have sufficient sequence data available from different bacterial species to allow the inference of a general model for bacterial genome evolution. It appears that the transfer of genes from chromosomes to large plasmids mediates second chromosome formation."

"Examination of different genome sequences within the Rhizobiales family has revealed that gene migration is rife among the different replication units," said Steve Slater, professor at the University of Wisconsin. "Genes are not only migrating between organisms but they are also moving within the cell between chromosomes and plasmids. The genetic organization of even essential genes in bacteria is much more complex and fluid than has been imagined."

"The three Agrobacterium biovars for which we now have sequences - A. tumefaciens C58, A. radiobacter K84, and A. vitis S4 - provide an exciting snapshot of chromosome evolution in progress," said Brad Goodner, associate professor at Hiram College. "In Biovars I and III, Agrobacteria gene movements have produced second chromosomes derived from plasmids, while in the biovar II strain K84 the plasmid-based replicon has yet to reach second chromosome status."

Derek Wood, associate professor at Seattle Pacific University, remarked: "The findings in this work provide substantial new evidence that second chromosomes in all bacteria studied to date have plasmid origins. While other mechanisms leading to second chromosome formation seem possible, it is intriguing that this approach has been most productive."

"Because of the biotechnological importance of Agrobacterium, the sequence information provided by these strains should be an invaluable resource for Agrobacterium researchers and the wider life sciences research community," said Barry Goldman, Biotechnology Prospecting Lead at Monsanto.

Human Papillomavirus Genotype Distribution In New Mexico Cervical Cancers

2009-03-26T10:10:00.000-07:00

DNA from human papilloma virus type 16 (HPV16) and HPV type 18 (HPV18) were found in the majority of invasive cervical cancers in New Mexico in the 1980s and 1990s, according to a population-based study published in the March 24 online issue of the Journal of the National Cancer Institute.

The mean age of women diagnosed with HPV16- or HPV18-positive cancer was 5 years younger than that of women diagnosed with cancers associated with other HPV types, which may have implications for cancer screening in the future.

Large population-based studies that examine HPV genotype distribution in the United States have been lacking. Such studies are necessary to assess the impact of HPV vaccines that aim to reduce the incidence of cervical cancer due to HPV16 and HPV18.

In the current study, Cosette M. Wheeler, Ph.D., of the University of New Mexico Health Sciences Center in Albuquerque, and colleagues used the Surveillance, Epidemiology, and End Results registry to identify 1,213 cases of in situ cervical cancer diagnosed between 1985 and 1999 and 808 cases of invasive cervical cancer diagnosed between 1980 and 1999 in New Mexico. The investigators used DNA-based testing to identify the HPV genotype that was present in tumor samples. In addition, they tested 4,007 cervical Pap test specimens from women who did not have cancer for the presence of HPV DNA.

HPV16 DNA was found in 53.2 percent of invasive cervical cancers, while HPV18 DNA was found in 13.1 percent, and HPV45 DNA in 6.1 percent. In the in situ cervical cancer samples, HPV16 DNA was detected in 56.3 percent of cases, HPV31 DNA in 12.6 percent, and HPV33 DNA in 8.0 percent. The median age at diagnosis of invasive cancer positive for HPV16 and HPV18 was 48.1 and 45.9 years, respectively. By contrast, the median age at diagnosis of invasive cancer positive for other HPV genotypes was 52.3 years.

"To our knowledge, this is the largest study of this kind conducted in a U.S. population," the authors write. "This study of HPV genotypes in New Mexico provides important baseline data for evaluating the effectiveness of newly implemented HPV-based technologies, HPV vaccines, and HPV screening in the prevention of cervical cancer. Moreover, these data can guide the future application of these technologies to maximize the cost-effective, public health benefits of these interventions."

The newly approved HPV vaccine protects against infections due to HPV16 and HPV18, which are associated with an earlier cancer diagnosis than other HPV genotypes. The authors suggest, therefore, that cervical cancer screening might safely be delayed, once the vaccine is more widely used, until women reach the age of 25. This possibility is further supported by the fact that very few women under age of 25 are diagnosed with cervical cancer.

In an accompanying editorial, Lauri E. Markowitz, M.D., of the Centers for Disease Control and Prevention in Atlanta, and colleagues describe some of the challenges the scientific and public health communities face in evaluating the impact of HPV vaccines. They also discuss issues related to cervical cancer screening and changing screening guidelines for vaccinated populations.

The work by Wheeler and colleagues provides important baseline data and raises numerous issues that must be considered, according to the editorialists. They conclude that "continued work is needed to determine the best methods for monitoring vaccine impact and optimal strategies for both primary and secondary prevention of cervical cancer."

Before Starting Dialysis, Patients Need Nephrologist Care

2009-03-26T09:52:00.000-07:00

For patients with end-stage renal disease (ESRD), receiving care from a nephrologist in the months before starting dialysis reduces the risk of death during the first year on dialysis, reports a study in the May 2009 issue of the Journal of the American Society of Nephrology (JASN). The study also shows geographic "clusters" where pre-dialysis care for patients with advanced chronic kidney disease (CKD) is not optimal. "Assistance to improve pre-dialysis care might be profitably targeted to specific treatment centers and the health care systems they serve," comments William McClellan, MD (Emory University School of Medicine, Atlanta, GA).

Dr. McClellan and colleagues analyzed data on more than 30,000 patients starting dialysis in five of the 18 US ESRD Network regions. The researchers evaluated the quality of the patients' medical care in the months before their CKD progressed to ESRD, and how that affected the patients' outcomes on dialysis.

Just over half of the patients received at least six months of pre-dialysis care from a nephrologist, as recommended by current guidelines. For these patients, the chances of surviving the first year on dialysis were about 50 percent higher than for patients who did not receive at least six months of nephrologist care. Survival rates were higher at dialysis centers where more patients received recommended care.

The researchers also unexpectedly discovered that dialysis centers with the lowest rates of recommended pre-dialysis care tended to be "clustered geographically." For example, there was a "significant circular cluster" of low pre-dialysis care centers located in Alabama and Mississippi.

Although the reasons for the geographic variations in care are unclear, the results identify specific regions that might benefit from efforts to improve care for advanced CKD patients. "The Centers for Medicare & Medicaid Services are currently conducting a pilot quality improvement initiative in ten states to determine the feasibility of such efforts," says Dr. McClellan.

Dr. McClellan reported no financial disclosures.

The study, entitled "Treatment Center and Geographic Variability in Pre-ESRD Care Associate with Increased Mortality," will appear online at http://jasn.asnjournals.org on Wednesday, March 25, 2009, doi 10.1681/ASN.2008060624.

Founded in 1966, the American Society of Nephrology (ASN) is the world's largest professional society devoted to the study of kidney disease. Comprised of 11,000 physicians and scientists, ASN continues to promote expert patient care, to advance medical research, and to educate the renal community. ASN also informs policymakers about issues of importance to kidney doctors and their patients. ASN funds research, and through its world-renowned meetings and first-class publications, disseminates information and educational tools that empower physicians.

Mutated Gene In Zebrafish Sheds Light On Blindness In Humans

2009-03-25T10:51:00.000-07:00

Among zebrafish, the eyes have it. Inside them is a mosaic of light-sensitive cells whose structure and functions are nearly identical to those of humans. There, biologists at The Florida State University discovered a gene mutation that determines if the cells develop as rods (the photoreceptors responsible for dim-light vision) or as cones (the photoreceptors needed for color vision).

Described in a paper published in the Proceedings of the National Academy of Sciences (PNAS), the landmark study of retinal development in zebrafish larvae and the genetic switch it has identified should shed new light on the molecular mechanisms underlying that development and, consequently, provide needed insight on inherited retinal diseases in humans.

From FSU's Department of Biological Science and Program in Neuroscience, doctoral candidate Karen Alvarez-Delfin (first author of the PNAS paper), postdoctoral fellow Ann Morris (second author), and Associate Professor James M. Fadool are the first scientists to identify the crucial function of a previously known gene called "tbx2b." The researchers have named the newfound allele (a different form of a gene) "lor" -- for "lots-of-rods" -- because the mutation results in too many rods and fewer ultraviolet cones than in the normal eye.

"Our goal is to generate animal models of inherited diseases of the eye and retina to understand the progression of disease and find more effective treatments for blindness," said Fadool, faculty advisor to Alvarez-Delfin and principal investigator for Morris's ongoing research. "We are excited about the mutation that Karen has identified because it is one of the few mutations in this clinically critical pathway that is responsible for cells developing into one photoreceptor subtype rather than another."

"What is striking in this case is that the photoreceptor cell changes we observed in the retinas of zebrafish are opposite to the changes identified in Enhanced S-cone syndrome (ESCS), an inherited human retinal dystrophy in which the rods express genes usually only found in cones, eventually leading to blindness," Alvarez-Delfin said. "Equally surprising is that this study and others from our lab show that while alterations in photoreceptor development in the human and mouse eyes lead to retinal degeneration and blindness, they don't in zebrafish. Therefore, the work from our Florida State lab and with our collaborators at the University of Pennsylvania, Vanderbilt University and the University of Louisville should provide a model for better understanding the differences in outcomes between mammals and fish, and why the human mutation leads to degenerative disease."

Morris calls the zebrafish an ideal genetic model for studies of development and disease. The common aquarium species are vertebrates, like humans. Their retinal organization and cell types are similar to those in humans. Zebrafish mature rapidly, and lay many eggs. The embryos are transparent, and they develop externally, unlike mammals, which develop in utero.

"This lets us study developmental processes such as the formation of tissues and organs in living animals," she said.

"From a developmental biology perspective, our research will help us unravel the competing signals necessary for generating the different photoreceptor cell types in their appropriate numbers and arrangement," Morris said. "The highly specialized nature of rods and cones may make them particularly vulnerable to inherited diseases and environmental damage in humans. Understanding the genetic processes of photoreceptor development could lead to clinical treatments for the millions of people affected by photoreceptor cell dystrophies such as retinitis pigmentosa and macular degeneration."

The mosaic arrangement of photoreceptors in fish was first described more than 100 years ago, but the J. Fadool laboratory at Florida State was the first to successfully take advantage of the pattern to identify mutations affecting photoreceptor development and degeneration.

"Imagine a tile mosaic," Fadool said. "That is the kind of geometric pattern formed by the rod and cone photoreceptors in the zebrafish retina. This mosaic is similar to the pattern of a checkerboard but with four colors rather than two alternating in a square pattern. The red-, green-, blue-, and ultraviolet-sensitive cones are always arranged in a precise repeating pattern. Human retinas have a photoreceptor mosaic, too, but here the term is used loosely, because while the arrangement of the different photoreceptors is nonrandom, they don't form the geometric pattern observed in zebrafish.

"So how do we ask a fish if it has photoreceptor defects?" he asked.

Fadool explained that because the mosaic pattern of zebrafish photoreceptors is so precise, mutations causing subtle alterations are easier to uncover than in retinas with a "messier" arrangement.

"Just as we can easily recognize a checkerboard mistakenly manufactured with some of the squares changed from black to red or with all-black squares, by using fluorescent labeling and fluorescence microscopes we can see similar changes in the pattern of the zebrafish photoreceptor mosaic," he said. "Karen showed that within the mosaic of the lots-of-rod fish, the position on the checkerboard normally occupied by a UV cone is replaced with a rod. The identity of the mutated gene is then discovered using a combination of classical genetics and genomic resources."

Three-Drug Chemotherapy Combination Increases Organ Preservation In Patients With Larynx Cancer

2009-03-25T10:50:00.000-07:00

Patients with larynx cancer who received a three-drug combination of docetaxel, cisplatin and 5-fluorouracil (TPF) during induction chemotherapy were more likely to retain larynx function than were patients treated with cisplatin and 5-fluoruracil (PF) alone, according to data from a randomized controlled trial in the March 24 online issue of the Journal of the National Cancer Institute.

Patients with locally advanced larynx and hypopharynx cancer are treated frequently with PF chemotherapy followed by radiation as an alternative to surgical removal of the larynx. Recent trials have suggested that adding docetaxel to PF might further improve patient outcomes.

To test this possibility, Gilles Calais, M.D., of the Centre Hospitalier Régional et Universitaire de Tours in France, and colleagues enrolled 213 patients with advanced larynx and hypopharynx cancer in a randomized controlled trial. Patients received induction chemotherapy with either TPF or PF. Those who responded to chemotherapy underwent subsequent radiation therapy, while those who did not respond were treated with surgery.

With a median follow-up time of 3 years, the estimated larynx preservation rate was 70.3 percent in the TPF-treated patients and 57.5 percent in the PF-treated patients. Overall, 80.0 percent of patients in the TPF group responded to therapy, compared with 59.2 percent in the PF group. Patients treated with TPF had more severe infections than those treated with PF.

The authors conclude that the treatment regimen with docetaxel was superior for patients with locally advanced cancers of the larynx and hypopharynx and that more of these patients could avoid total laryngectomy. However, they caution that "Because we proposed treatment to a select popula¬tion of patients with only larynx and hypopharynx cancer and this trial was especially designed for organ preservation, we cannot gen¬eralize the findings to all locally advanced head and neck cancers."

Panama HPV Vaccination Program Stirs Debate Over Public Health Education

2009-03-25T07:10:00.000-07:00

PRI's "The World" on Friday examined how Panama's campaign to vaccinate all girls against human papillomavirus at age 10 is raising new concerns among some public health experts over how much information the government should disclose about such programs. The vaccine, which requires a three-dose regimen, protects against certain sexually transmitted forms of HPV that cause many cervical cancers, according to "The World." Panama is the first country to make the vaccine mandatory and offer it at no cost, spending $5 million annually on the program. "The World" reports that parents have broadly welcomed the vaccination program, unlike in the U.S., where there has been some objection to vaccinating young girls on the grounds that it could encourage sexual activity.

Jose Cedeno of Planned Parenthood Panama said that the reason there has been no objection among parents of young girls is that government officials have not told parents that the vaccine protects against a sexually transmitted virus. According to "The World," the message that the inoculation is "just a 'cancer vaccine' is central to how the government promotes the program on TV and radio." Cedeno said that because there is no national sex education program in Panama, the government is missing out on an opportunity to educate the public. He noted that the vaccine does not protect against all cancer-causing strains of HPV, adding that girls need to learn how to protect themselves. However, some members of the public health community support Panama's approach. Newton Osbourne, a prominent gynecologist in Panama, said, "I think it's a good thing because if they tie it to sexual activity, it's going to bring up all kinds of controversy that I don't think is going to be all that relevant to the main issue -- we want to prevent women from getting cancer."

Rosario Turner, Panama's minister of health, said that cervical cancer is the second leading cause of death among women in the country and that women's health is a top priority for the government. According to "The World," many women in Panama do not routinely get Pap smears, making the vaccine the most effective way to protect women against HPV. Turner said that in the first few months of the program, 19,000 girls were vaccinated, including many girls from small villages. Turner acknowledged that the health department has downplayed the relationship between HPV and sexual activity. She said, "I saw the outcry over the HPV vaccine abroad and tried to avoid it by focusing only on cancer." Parents in Panama "can be sensitive about discussing sexuality," "The World" reports. For example, when the government attempted to introduce comprehensive sex education in schools last fall, "a huge debate ultimately crushed the effort," according to "The World" (Weise, "The World," PRI, 3/20).

Redefining DNA: Darwin From The Atom Up

2009-03-24T10:56:00.001-07:00

In a dramatic rewrite of the recipe for life, scientists from Florida described the design of a new type of DNA with 12 chemical letters instead of the usual four. Presented here at the 237th National Meeting of the American Chemical Society (ACS), this artificial genetic system already is helping to usher in the era of personalized medicine for millions of patients with HIV, hepatitis and other diseases.

The research may also shed light on how life arose on Earth, by producing a self-sustaining molecule capable of Darwinian evolution and reproduction, much like one that many scientists suggest arose at the dawn of life on Earth nearly four billion years ago.

Led by Steven Benner, Ph.D., this team is rewriting the rulebook that Nobel laureates James Watson and Francis Crick started when they described DNA's structure in 1953. One of the crowning discoveries of 20th century science, Watson and Crick's discovery established how the four chemical "letters" of DNA - A, T, C and G - pair up.

"This is a man on the moon goal," says Steven Benner, Ph.D. "It has dragged us kicking and screaming into uncharted territory. But we've learned all sorts of reasons about how the Watson and Crick rules don't enable technology to do useful things like highly parallel amplification of DNA or highly parallel diagnosis of human diseases. These things are worth a lot of money."

These pairing rules, for instance, make it very difficult for researchers to develop multiplexed diagnostic tests for viral diseases - tests that require identification and tagging of viral DNA. Old methods used regular DNA to bind and tag foreign genetic material. But natural DNA would often bind with non-disease DNA and generate confusing false positive and false negative results.

Benner's artificial genetic system does not operate under Watson-Crick rules, so the tagging gives accurate results. Benner's artificial alphabet already has been applied commercially. It is the basis of a viral load detector, which helps personalize the health care of those 400,000 patients annually infected with hepatitis B, hepatitis C, and HIV, the cause of AIDS,

"This is a hundred million dollar product right now," Benner noted. "It's used to manage cystic fibrosis, as well. We can also use this technology to go into biological samples and extract known genes with cancer-causing mutations. We can do all of this because we have an artificial DNA system.

For patients with HIV and hepatitis, the viral load detector can mean the difference between life and death.

Modern drug cocktails for these diseases are highly effective, reducing the viral load in the bloodstream to nearly zero. But at some point, the virus mutates, enabling it to evade the drugs and repopulate. As the viral tide rises, there are no outward symptoms in the patient, so the mutated strain is often discovered long after the virus has spread again.

The viral load detector, which relies on Benner's 12 letter system to tag DNA, may change that.

"What we want to do with personalized care is to give you a cocktail, and then monitor you and discover when the virus becomes resistant to it," explains Benner. "Now we don't want to do that too soon - that would waste a lifetime of good viral inhibitors - but not too late, of course. The patient would go in once a month to get their viral load measured. At some point the virus mutates and its viral load goes up. Then you know you better change the cocktail."

Benner says that the artificial DNA system is poised to become an essential tool in genomics research. The 12 letter alphabet already underlies new work at the National Human Genome Research Institute to connect large quantities of genomic data with human medicine.

The 12 letter system might also shed light on one of most mysterious times in Earth's history - the dawn of life nearly four billion years ago. Many scientists believe that this might have occurred when DNA's ancient cousin, RNA, began to act like a living organism.

"The idea has been that life originated on earth as RNA molecules assembled randomly and spontaneously in the prebiotic soup," says Benner. "Then, one of them found the ability to make copies of itself. In doing so, it made those copies with imperfections, so that some of its 'kids' were a bit better. Most were worse, so the better ones took over more resources. That started Darwinian processes. The rest is history."

Benner's ultimate goal is to synthesize a similar life form in his lab at the Foundation for Applied Molecular Evolution. His 12 letter genetic system is capable of nearly all of the actions that define a living thing - reproduction, growth and response to its environment - all without the benefit of genes refined over billions of years of evolution.

"But it still isn't self-sustaining," Benner explains. "You need a graduate or post-doc to come in the morning and feed it. It doesn't look for its own food. No one has gotten that first step to work. If you start making estimates of how many molecules you have to look for in order to find one that does this, you're talking about 10,000,000,000,000,000,000,000,000,000,000,000 molecules."

While Benner continues to pursue a chemical system fully capable of Darwinian evolution, he emphasized the lessons already learned from the development of the 12 letter system.

"We haven't just taken things from nature, but we've actually understood something about how chemical structure is related to genetic behavior. With that, we've been able to make new versions of it," says Benner.

Genomic Variations In African American And White Populations

2009-03-24T10:44:00.000-07:00

Deletions, duplications or rearrangements of genomic regions in the human genomes produce differences in gene copy numbers, referred to as copy number variations (CNV). Those variations account for a substantial portion of human genetic diversity, and in a few cases, have been associated with behavioural traits or increased susceptibility to disease. A study published in the open access journal BMC Genetics, describes a CNV map of the African American genome, and compares frequencies of CNVs between African American and white American/European populations.

Joseph P McElroy and colleagues from the Department of Neurology, University of California at San Francisco, recruited African Americans from 28 States and used their genomes to draw CNV comparisons with the White dataset. "To the best of our knowledge, this is the first detailed map of copy number variations in African Americans. Understanding the distributions of CNVs in a population is a first step to addressing their role in disease".

The authors employed an array of over 500,000 sequences whose position in the human genome is already known due to single nucleotide polymorphisms. They first analysed the interaction of 50 blood samples of healthy African American females with this gene chip platform, and then used the results as a reference to assess copy number variation in samples from a further 385 African Americans, and an additional set of samples from 435 White individuals. In total, 1362 CNVs were detected in African Americans and 1972 in the White cohort. Across most of the genome, the frequency of CNVs did not differ greatly between the two populations. However, there were two duplications, one on chromosome 15, and one on chromosome 17, whose frequency varied markedly between the two groups.

The research team discovered that the duplication in chromosome 17 (region 17q21) is present in 45% of White but only in 8% of African American individuals. Another independent study has implicated the same region in mental retardation caused by a deletion due to duplication. Among the deleted genes, two of them, CRHR1 (corticitropin releasing hormone receptor 1) and MAPT (microtubule-associated protein tau), were previously associated with some neurological disorders. These two genes are not contained within the 17q21 region of CNV duplication, but map very close to it.

According to McElroy, "It would be good to know if the CNV duplication of the region might have an effect on the expression of these genes, which in turn could result in neurological disease. It is also interesting to find out whether the type of mental retardation associated with this locus is more common in Whites than in Africans or African Americans. If this is true, then it might be one of the first reported diseases with differing ethnic frequencies due to CNVs."

Ambry Genetics Introduces Sequence Capture For High Throughput Sequencing Applications On Multiple Next Gen Sequencing Platforms

2009-03-23T10:31:00.001-07:00

Ambry Genetics announced capabilities of performing sequence capture for the Illumina® or Roche® Next Gen Sequencing platforms. Customers will have the option of choosing either custom 385K or pre-designed 2.1M high density arrays available through Roche NimbleGen. Sequencing can be done in-house at Ambry on the Illumina® GA II, or returned to the customer for sequencing on their platform.

"We are pleased to be offering these services to our customers", Anja Kammesheidt, Ambry's CSO states."Sequence capture in conjunction with Next Gen Sequencing provides a powerful tool kit that allows us to look at megabases of sequence in a few steps without having to go through cumbersome gene specific or long range PCR. The microarrays are used similar to a magnet to capture regions of interest. Subsequently, via sequencing-by-synthesis one is able to generate simultaneous sequence reads from millions of surface amplified DNA fragments."

In this process, a sample is prepared for sequencing by shearing of genomic DNA, hybridization of the fragments against custom or predesigned oligo tiling arrays containing candidate regions, followed by washing steps which remove non- specific targets and a final elution of the target DNA. The eluted amplified fragments are called a library, which is used to create clusters, surface-bound colonies of DNA, for example on the surface of the Illumina® GAII flow cell. These clusters are then sequenced on the genome analyzer using polymerase and differently labeled fluorescent nucleotides. Currently, sequences generated are typically 36-54 bp long, for a total of up to ~1.0 GB per lane of each flow cell with paired-end sequencing, even though longer read lengths can be achieved. Data is aligned back to reference sequences and scored for coverage, SNPs, and mutations.

About Ambry Genetics

Ambry Genetics is a CAP-accredited, CLIA-certified commercial clinical laboratory headquartered in Aliso Viejo, California. Since the company's inception in 2000, it has become a leader in providing genetic services focused on clinical diagnostics, pharmacogenomics and research support. Ambry has built a solid reputation for unparalleled service, and has been at the forefront of applying new technologies. To learn more about testing and services available through Ambry,

Pea Protein Fights Blood Pressure And Kidney Disease

2009-03-23T06:19:00.000-07:00

New research from Canada found that proteins in the common garden pea may provide a natural remedy against high blood pressure and chronic kidney disease (CKD). The pea protein could be used as a natural food product such as an additive or dietary supplement to help the millions of people worldwide that suffer from these conditions, suggested the researchers.

Dr Rotimi Aluko, a food chemist at the University of Manitoba in Winnipeg, Canada will be presenting the findings at the American Chemical Society's 237th National Meeting which is taking place this week (22 - 26 March) in Salt Lake City, Utah, USA.

Hypertension or high blood pressure is a major risk factor for people with chronic kidney disease (CKD). Estimates suggests that the number of people with CKD is on the rise in the US and other countries. 13 per cent of adults in the US, about 26 million people, have CKD. This compares with 10 per cent, or 20 million in the 1990s.

CKD is difficult to treat, and many patients progress to end-stage kidney disease and have to have dialysis or a kidney transplant. Scientists are continually looking for new ways to treat CKD and stop kidneys from deteriorating.

Peas have long held prime position as "nutrition superstars" said an American Chemical Society press statement. They contain a healthy amount of protein, fiber, and vitamins and come in a "low-fat, cholesterol-free package".

The yellow garden pea is a variety used in many parts of the world and also popular with vegetarians. For instance it makes a great basis for a soup and eastern dishes like dal, where the peas are cooked to a thick puree and flavoured with spices.

Aluko told the press that:

"In people with high blood pressure, our protein could potentially delay or prevent the onset of kidney damage."

It could also help people with kidney disease live longer by helping them maintain their blood pressure, he added.

For the study, Aluko worked with University of Manitoba colleague Dr Harold Aukema. They extracted pea protein hydrolysate from the yellow garden pea and fed a small dose each day to laboratory rats bred to have a severe type of kidney disease called polycystic kidney disease.

After 8 weeks the rats on the pea protein diet showed a 20 per cent drop in blood pressure compared to diseased rats that had only been fed on a normal diet.

Aluko said this was significant because:

"A majority of CKD patients actually die from cardiovascular complications that arise from the high blood pressure associated with kidney malfunction."

In both rats and humans, polycystic kidney disease severely reduces the output of urine, preventing the kidneys from being able to rid the body of toxins. In this study the rats fed on pea extract showed a 30 per cent increase in urine production, restoring it to within normal levels.

Aluko called this a "huge improvement", and said the rats showed no adverse side effects from eating the pea protein.

The researchers now hope to test the pea protein on humans with mild hypertension.

Speculating on how the pea protein achieves the effects they found, the researchers suggested it stimulates the production of COX-1 (cyclooxygenase -1), a protein that boosts kidney function, but they don't know for sure.

Aluko said eating yellow peas in their natural state won't give you the same health benefits as the pea protein they extracted in the lab, which can only be activated with special enzymes. If the human trials are successful, the researchers envisage their special protein being commercially available within the next two to three years.

The extract could be made into pill form or a into powder for adding to food and drinks, they said.

The research was funded through the Canadian government's Advanced Foods and Materials Network of Centre of Excellence (AFMnet). Nutri-Pea Ltd, a private Canadian company that specializes in making food products from yellow peas, also took part in the project.

The Notch Gene Accelerates Colon Carcinogenesis

2009-03-22T10:47:00.000-07:00

Professor Daniel Louvard (1) (CNRS Research Director and Director of the Curie Institute Research Centre) and his group, working in close partnership with Spyros Artavanis-Tsakonas (2), recently discovered how the Notch gene is involved in the pathogenic process leading to colon cancer. The Notch and Wnt signalling pathways play an important role in normal gut development and homeostasis. In mice, abnormal activation of these two signalling pathways increases the number of benign tumours-adenomas-in the intestine by a factor of over twenty compared with activation of the Wnt pathway alone. Moreover, these tumours grow extremely fast in the colon, mimicking the pathogenic process observed in humans. Cooperative action between these two pathways creates a favourable environment for malignant transformation. These findings (published online in PNAS) show that Notch acts as an "accelerator" in the development of colon cancer in humans, constituting an essential component of the pathogenic process. The question now is to find a "brake" that can counter this.

The gut, which represents a surface area equivalent to that of a tennis court, is in constant turnover completely renewing itself every five days. This turnover depends on the presence of stem cells and progenitor cells found in the crypts between intestinal villi. The stem cells give rise to progenitor cells which can in turn differentiate, over successive division cycles, to give the various different cell types that populate and form the gut. The key factor is to maintain a balance between differentiation and proliferation in the intestinal epithelium.

The Notch and Wnt signalling pathways are important in maintaining this balance, thereby ensuring normal development and organisation in the gut. These two systems control the proliferation and differentiation of stem cells in the intestinal crypts. The Wnt signalling pathway is tightly controlled by the APC (adenomatosis polyposis coli) gene which is associated with early-stage colon carcinogenesis: mutations in one of the two copies of this tumour suppressor gene underlie familial adenomatous polyposis, a condition characterised by the growth of hundreds or even thousands of polyps in the large intestine from adolescence on. This disease accounts for 1% of cases of colon cancer. The vast majority of sporadic cases of colon cancer are also associated with mutations in the APC gene.

The central Notch pathway

The Notch gene product acts as an "On/Off" switch. When it is On, the Notch protein triggers a cascade of intracellular signals essential to the development of all tissues in all multicellular organisms.

Notch is usually qualified as an oncogene and could represent a promising therapeutic target.

Professor Daniel Louvard, working together with Spyros Artavanis-Tsakonas, recently showed that the Notch and Wnt pathways act in concert to control the proliferation of progenitor cells in the gut. In animal models in which Wnt is aberrantly activated, the activation of Notch dramatically accelerates the rate of tumour formation in the gut, especially in the colon. In most mouse models, tumours are rarely found in the colon, unlike in human patients; the development of multiple adenomas in the mouse colon therefore mimics the human pathogenic process.

Such synergy between the Notch and Wnt genes has been observed in different animal models, suggesting that the mechanism is highly conserved throughout evolution. Professor Louvard states that "the Notch gene seems to act as an accelerator of colon carcinogenesis: its activation leads to increased cell division and therefore, an increased likelihood of mutation". However, malignant transformation requires a whole series of genetic events. Aberrant activation of the Notch and Wnt pathways creates a favourable environment for the accumulation of mutations that ultimately lead to colon cancer. Synergy of Notch and Wnt signals contributes to the earliest stages of tumourigenesis-when the tumours are referred to as polyps-the stage at which screening is so important.

Understanding the mechanisms involved in the formation, growth and transformation of these tumours will help in the search for novel therapeutic targets.

In 2005 in France, colon cancer struck more than 37,000 victims and caused 17,000 deaths. The chances of surviving this form of cancer (the third most common malignancy in the country) are closely linked to the stage at which the disease is diagnosed.

A mass colon cancer screening programme was set up at the end of 2008: every two years, everyone betwee n 50 and 74 will be sent a letter inviting them to ask their general practitioner about screening for colon cancer and consider, on a case by case basis, having a test to detect blood in their faeces.

(1) The Morphogenesis & Cell Signalling Group of the Curie Institute Cellular Compartmentalisation & Dynamics Unit; CNRS UMR144

(2) Professeur at the Collège de France and at Harvard Medical School (United States), and Director of the Curie Institute Genetics & Biology of Development Group; CNRS UMR3215/ Inserm U934

Structure-function Relationships In The Emerging Enzymes CTX-M

2009-03-22T10:45:00.001-07:00

Richard Bonnet (from the Bacteriology Laboratory of the Medical School,Clermont-Ferrand), presented at March 11, in the auditory of the National Institute of Health Dr. Ricardo Jorge, the lecture "Structure-function relationships in the emerging enzymes CTX-M", in the contexte of the three conferences os March dedicated to antibiotics resistance.

The speaker underlined the actual emergence os beta-lactamases from CTX-M family and the importance of it's conformational structure in the inactivation of beta-lactamic antibiotics.

The emergence of resistance to the most commonly used antibioticsin the treatment of infections constitutes a threat not to be minimized in public health, therefore this issue is the core activity of the National Reference Laboratory of Antibiotic Resistance(LNR-RA), from the Departament of Infectious Diseases.

Besides the patient implications, bacterial resistance to antibiotics generates considerable costs in Health Systems of most of industrialized countries.

The Discovery Of A New Signaling Pathway May Provide A Target For Structure-Based Drug Design

2009-03-22T09:54:00.000-07:00

Over the past decade various pieces of the puzzle of how signal transmission controls immunity have been coming together. Now, in Cell an international team reports a paradigm shift in the regulation of immune response. Their results show that interaction with a linear ubiquitin chain is crucial for nuclear factor kappa B activation. Their findings may also contribute towards structure-based drug design to target the defective NF-κB pathway in diseases such as cancer, inflammation and immunodeficiency.

The body's first line of defence against bacteria and viruses is the innate immune system where phagocytes identify the foreign organism and initiate an alarm reaction, often accompanied by inflammation. As a consequence, molecular cues are produced in the blood, such as Tumor Receptor Factors (TNF) or interleukin-1, and these stimulate further reactions in the immune system. But what exactly happens after the molecular cues have docked onto the cell receptors that specialize in immune response? What is the basis of signal transmission from the cellular receptors into the cellular interior? Over the past decade, the overall picture of this large puzzle has been gradually pieced together to show that modifications in the cell protein - including the addition of phosphate groups (phosphorylation) or the conjugation of small modifier ubiquitin (ubiquitination) - play a central role in controlling the immune system.

Scientists at Frankfurt's Goethe University led by Prof. Ivan Dikic have established an international collaboration to investigate the role of ubiquitin modification in these pathways. The international team includes the laboratories of Soichi Wakatsuki (Photon factory, Tsukuba, Japan), Fumiyo Ikeda (MedILS, Split, Croatia), Felix Randow (LMB, Cambridge, UK) and David Komander (LMB, Cambridge, UK). They have been investigating how a transcription factor known as the nuclear factor kappa-B (NF-κB) coordinates the gene expression necessary for the cell's immune response. NF-κB is activated by an enzyme (IkappaB-Kinase, IKK) with a regulatory subunit that brings to mind the mysterious captain in Jules Verne's science fiction novels: NEMO.

The question that had to be answered was how does NEMO activate NF-κB? This is where the work of the Frankfurt biochemists came in. They identified a subdomain of NEMO, called UBAN that binds selectively to a specific type of ubiquitin. This protein is ubiquitous in the cell and has various functions, acting as a multifaceted molecular signal. It can function as a single molecule (monoubiquitin) or in the form of chains (polyubiquitin).

In the scientific journal Cell, Ivan Dikic and his colleagues report that NEMO specifically binds to linear ubiquitin chains and that this is an essential step for NF-κB activation. This came as a big surprise to the team, since it was previously thought that other types of ubiquitin signals were critical for NEMO-dependent NF-κB activation. "This results in a paradigm change", says Ivan Dikic, "it means, that current knowledge on NF-κB activation and the role of linear ubiquitin chains needs to be updated".

In cooperation with the group of Soichi Wakatsuki, NEMO's structure could be solved. The work demonstrates that the UBAN domain binds to a linear ubiquitin chain according to the key-and-lock-principle. "These new findings not only explain the atomic details of ubiquitin chain selectivity, but can also provide useful insights into developing therapy for targeting the NF-κB pathway", reports Soichi Wakatsuki. Increased activation of the NF-κB pathway is known to be linked to development of different diseases such as cancer and inflammation.

The discovery also has direct medical relevance. "We are happy that this basic scientific discovery may explain the detrimental effect of NEMO mutations in patients suffering from X-linked ectodermal dysplasia and immunodeficiency", Ivan Dikic points out. Ectodermal dysplasia is a hereditary disease, which affects 1 to 5 children in 10,000 newborn. It causes the skin to be very thin and the perspiratory glands to malfunction. In some cases it is combined with immune deficiency. The molecular defect is a mutation in the NEMO gene, which blocks the activation of the NF-κB pathway in epidermal and immune cells.

Scientists Create Living Model Of Basic Units Of The Human Brain

2009-03-18T10:23:00.000-07:00

Researchers in the School of Life & Health Sciences at Aston University in Birmingham, UK are developing a novel new way to model how the human brain works by creating a living representation of the brain.

They are using cells originally from a tumour which have been 'reprogrammed' to stop multiplying. Using the same natural molecule the body does to stimulate cellular development, the cells are turned into a co-culture of nerve cells and astrocytes - the most basic units of the human brain.

These co-cultures can be developed into tiny, connected balls of cells called neurospheres, which can process information, which, at a very simple level, is the basis of thought. The research process does not require animal testing and since 2007 has been generously supported by the Humane Research Trust.

In the future, the tiny three-dimensional cell clusters, which are essentially very small models of the human nervous system, could be used to develop new treatments for diseases including Alzheimer's, Motor Neurone and Parkinson's Disease. These progressive and debilitating neurodegenerative conditions are becoming more common as the population of the UK ages.

Professor Michael Coleman, who is leading the research team, said: 'We are aiming to be able to study the human brain at the most basic level, using an actual living human cellular system. Cells have to be alive and operating efficiently to enable us to really understand how the brain works. In the longer term we hope that our procedure can be used to help us understand how conditions such as Alzheimer's and other neurodegenerative diseases develop. At the moment, most people are only too aware that current treatments for these conditions do not halt their progress and often have side-effects. We hope that our technique will provide scientists with a new and highly relevant human experimental model to help us understand the brain better and develop new drugs and treatments to tackle neurodegenerative disease '

Programmable Cells

2009-03-18T08:04:00.000-07:00

The roots of synthetic biology stretch back only eight years, and the discipline is so new that it does not yet have an established definition. On the one hand, it can be considered from a microscopic and fundamental perspective to a certain extent more closely related to chemistry as the synthesis of new, biologically important molecules (for example, nucleotides). Alternatively, it can be considered at the organism level, understood as the creation of new life forms (such as viruses).

The area between these two areas of research is occupied by a sub-discipline that is "more promising, in that it can help us to understand living systems, focusing on the creation of new genetic circuits formats for genes and proteins that are connected by complex interactions that can be integrated into cells to alter their function from that which they would perform in their original context, and the standardization of these circuits so that they can then be combined", explains Jordi García Ojalvo, a researcher for the Department of Physics and Nuclear Engineering working at the UPC's campus in Terrassa.

One of the current aims of biology researchers is to determine the operation of the genetic circuits that regulate cell activity, a problem that can be solved by adopting an approach derived from engineering. As García Ojalvo explains, "If you want to understand how something works, that is, how a cell carries out a specific task, construct a circuit that does the same thing". In his view, 'hard science', which primarily involves the study of inert matter, can also play an important role in the study of living matter.

A researcher with a background in hard science, who understands how these mechanisms function in other types of systems, has the skills required to select a circuit, create a mathematical model using computer simulation and analyze its function. This would make it possible to determine the conditions a circuit requires to perform a specific task. Moreover, a number of techniques and devices used in synthetic biology require the expertise of physicists and engineers, for example, ensuring that cells are handled in a carefully regulated environment (microfluidic control), and providing a high degree of optical precision. The knowledge and data that traditional biologists can provide is also important. As such, synthetic biology is widely considered to be inherently cross-disciplinary.

Although it is a new branch of scientific study, scientists working in synthetic biology did not have to start from scratch, and have been able to draw on decades of work carried out in fields such as genetic engineering, molecular biology and, more recently, systems biology. Specific milestones that have contributed to the development of synthetic biology include the discovery of the green fluorescent protein and its use as a marker in the analysis of various processes in all areas of biology, which is now a standard technique that enables scientists to observe the responses of individual cells to different actions and monitor their status in real time.

An enhanced version of nature

One of the most novel aspects of this discipline is its inherent capacity for a key concept: standardization. To draw a comparison with electronics, in the same way that a hard disk can be connected to any computer, so genetic circuits can be integrated into any cell to prompt a specific task.

Given the difficulties of analyzing the complex genetic circuits found in nature, synthetic biology offers an alternative approach to the problem: construct the simplest circuits possible, determine how they function, and increase the level of complexity step by step. Since research of this type focuses on simple circuits, involving only two or three genes, it is possible to develop mathematical models that are not only capable of predicting cell behavior in terms of the degree of protein production but can also induce specific dynamics.

This was first achieved in 2000 by a research group directed by Michael Elowitz, at the California Institute of Technology (Caltech), which constructed the first oscillator, or synthetic genetic clock. This breakthrough, which effectively marked the inception of synthetic biology as a discipline, demonstrated that cells have a built-in 'clock' which enables them to calculate time and synchronize to perform predetermined actions simultaneously.

Since then, research in this field in Spain has been carried out jointly with groups such as the UPC's Research Group on Nonlinear Dynamics, Nonlinear Optics and Lasers (DONLL), based at the Terrassa campus, coordinated by Ramon Vilaseca and formed by researchers including García Ojalvo. The group has spent six years working in the fields of synthetic biology and systems biology, first concentrating on theory and then moving into experimental work in the last two years. Research conducted in collaboration with the Elowitz group at Caltech and a group coordinated by Gurol Suel of the University of Texas Southwestern Medical Center at Dallas focuses on understanding differentiation processes (such as state changes) in bacteria, which are model organisms that can be used to study functions performed in more complex organisms.

The DONLL team is also working with a research group coordinated by Alfonso Martínez Arias, of the University of Cambridge, to understand the process by which embryonic stem cells maintain multipotentiality, which is the mechanism through which they conserve the capacity to differentiate into any type of cell. In this specific area, researchers do not use synthetic biology per se they do not construct circuits, for example but try to analyze the way in which natural circuits function. Although the work of the DONLL group is not yet targeted at a specific application, the general objective is to develop the capability to control cell behaviour externally.

Understanding living systems

One of the most notable aspects of synthetic biology, in the view of many researchers, is that it can help us to better understand living organisms. It could therefore become a fundamental tool for understanding cell machinery, as it illustrates the range of tasks that can be carried out by the components responsible for biological functions. Scientists working in this discipline are able to take a more quantitative approach to biology in general, by using models to make predictions that can then be tested in laboratory conditions.

The challenge facing researchers in synthetic biology is considerable, particularly if we consider that the human genome contains thirty thousand genes and a cell contains around one million proteins. However, a cell is more than just the sum of its parts, and its functions should be interpreted taking into account the complex combination of components involved, since the genes and proteins that make up the genome are interlinked by millions of individual connections.

For now, the aim of this discipline is simply to satisfy our curiosity, to gradually increase scientific understanding of the potential of interactions between genes and proteins, and to define and characterize the flow of information that triggers a biological process.

Bioremediation

When asked about their expectations regarding the development of synthetic biology (one of its principal applications is likely to be biomedicine), experts suggest that it will not produce many short-term applications. Nevertheless, there are already notable examples in the field of drug synthesis: a team from the Lawrence Berkeley National Laboratory in California has reconstructed in the bacteria E. coli the genetic circuit responsible for synthesizing the precursor to the anti-malarial drug artemisinin, which should lead to cheaper and more efficient production.

The environment may be the next field to benefit from advances in synthetic biology. For example, work is currently underway to design more efficient microorganisms for decontaminating ecosystems (bioremediation). Researchers are also developing biosensor devices, which will be able to recognize target substances and microorganisms and interact with them.

UV Lights Decrease Infectious TB In Hospital Room Air

2009-03-17T09:56:00.001-07:00

The simple intervention of using ultraviolet (UV) lights near the ceiling together with fans may reduce the spread of tuberculosis (TB) in hospitals, and air treatment with negative ionizers may also be effective, according to research published in PLoS Medicine.

TB transmission in overcrowded health care facilities is an important public health problem, especially in low resource settings, populations affected by HIV, and locations where drug-resistant TB occurs frequently.

Rod Escombe of Imperial College London and colleagues used guinea pigs housed on the roof of a hospital in Lima, Peru to test whether simple approaches to disinfecting air could reduce transmission of TB. With results from more than 900 guinea pigs, the researchers found that 35% of those exposed to untreated air from patient rooms developed TB infection, compared to 14% in the negative air-ionizer group, and only 9.5% of those breathing air vented from rooms during treatment with upper-room UV lights and mixing fans.

Guinea pigs are susceptible to airborne infection with M. tuberculosis, the bacterium that causes TB, and they can therefore be used as a sensitive detection system for infectious particles. By venting air from the rooms of patients with active TB through the guinea pig enclosures, the researchers were able to compare guinea pigs exposed on days when UV lights and air mixing fans were turned on in the patient rooms to other guinea pigs exposed when UV lights were off. The enclosure of a third group of guinea pigs contained the negative air ionizers.

DNA 'Patch' For Canine Form Of Muscular Dystrophy Lays The Foundation For Human Testing

2009-03-17T09:44:00.000-07:00

Using a novel genetic technology that covers up genetic errors, researchers funded in part by the National Institutes of Health have developed a successful treatment for dogs with the canine version of Duchenne muscular dystrophy, a paralyzing, and ultimately fatal, muscle disease.

The technology, known as "exon skipping" uses tailor-made snippets of DNA-like molecules as molecular "patches." These patches cover up mutant DNA sequences that code for making an important muscle protein. The mutant sequences occur in portions of the gene known as exons, which contain the information needed to make the muscle protein. By covering up the mutant regions, the DNA patches allowed the dogs to make an imperfect - but functional - version of the protein, and significantly improve their muscle functioning.

Earlier studies showed that it was possible to inject the patches into the bloodstream of mice and deliver them throughout the animals' bodies. The current finding shows that the DNA patches could be delivered by injection throughout the entire body in a much larger animal than a mouse, raising the possibility that they might be successfully delivered throughout the body to human muscles as well. Moreover, the current study represents an advance over the earlier efforts in that it was able to use several different kinds of DNA patches. A combination of different patches, known as a cocktail, would be needed to treat most of the human cases of the disease, which can involve many different exons.

The canine version of Duchenne muscular dystrophy occurs naturally in dogs, and affects the same gene that is affected in the human form of the disease.

"This is a promising finding," said Duane Alexander, M.D., director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), one of the NIH institutes that provided partial funding for the study. "It's an important step toward realizing the goal of developing a treatment that could alleviate the symptoms of this disorder."

Funding was provided through the NIH Muscular Dystrophy Consortium, which conducts research on muscular dystrophy. In addition to the NICHD, other institutes supporting the consortium are the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute of Neurological Disorders and Stroke. The NICHD provided additional funding for the study through its National Center for Medical Rehabilitation Research. Other funding was provided by the Foundation to Eradicate Duchenne, Inc., the Department of Defense CDMRP program, the Jain Foundation, Inc., the Crystal Ball Event of Hampton Roads and the Muscular Dystrophy Association, and the Ministry of Health, Labour, and Welfare of Japan.

Muscular dystrophies are a group of disorders causing muscle deterioration and weakness. Duchenne muscular dystrophy occurs almost exclusively in males, affecting 1 in every 3,500. Symptoms begin at about 3 years of age, with muscle weakness resulting in difficulty walking and talking. Most boys with the condition lose the ability to walk by age 12, and death usually occurs by the early 20s, from heart and respiratory failure.

The study was published on line in the Annals of Neurology and conducted by Toshifumi Yokota, Ph.D., and Eric Hoffman, Ph.D., of Children's National Medical Center, Washington, D.C., and Shin'ichi Takeda, M.D., Ph.D., of the National Center of Neurology and Psychiatry, Ogawa-Higashi, Kodaira, Tokyo, Japan, as well as other researchers at Children's, Carolinas Medical Center, Charlotte, N.C. and the National Center in Japan

Duchenne muscular dystrophy results from errors in the gene for dystrophin, a key component of muscles. Dr. Hoffman explained that individuals with Duchenne muscular dystrophy vary in the locations and kinds of the mutations occurring in the gene. Also, many boys with Duchenne muscular dystrophy have mutations that affect multiple exons, and so would require more than one kind of patch. The dogs in the study carried a mutation affecting multiple exons. The researchers used a cocktail containing multiple DNA patches to bypass the affected exons.

The patches, DNA-like molecules called morpholinos, are manufactured in a laboratory. Injections of the morpholino cocktail directly into the dogs' bloodstream curbed deterioration of the animals' skeletal muscles and improved muscle functioning. The injections resulted in widespread production of dystrophin-like protein, at about 26 percent of normal levels. However, the treatment was unable to prevent deterioration of the animals' hearts. The researchers theorized that the muscles of the heart are less porous than the skeletal muscles, and did not absorb sufficient quantities of the morpholinos to curb the deterioration.

The researchers said that other means of delivering the morpholinos to the heart would need to be explored.

They added, however, that the study results showed that it would be possible to use a cocktail of morpholinos to patch the multiple mutations that occur in the human form of the disorder.

New Human Genetic Link To High Levels Of 'Good' Cholesterol

2009-03-17T08:50:00.000-07:00

HDL cholesterol (HDL-C), or "good" cholesterol, carries excess cholesterol - that might otherwise block arteries - from blood vessels back to the liver for processing and elimination. As such, individuals with high plasma HDL-C levels have a decreased risk of developing coronary artery disease. Genetics contribute to determining a person's plasma HDL-C level, and in a new JCI study Daniel Rader and colleagues from the University of Pennsylvania show that mutations in the LIPG gene, which codes for an enzyme known as endothelial lipase, result in high plasma HDL-C levels.

The authors examined the LIPG gene in 585 subjects of European ancestry and identified 10 people with previously unreported rare mutated forms of this gene that were unique to subjects with very high HDL-C levels. Further studies revealed that mutations in the LIPG gene that cause loss of endothelial lipase activity were the cause of increased plasma HDL-C levels. These data provide important human genetic evidence that inhibition of endothelial lipase is likely to raise HDL-C levels in humans. Whether or not the resulting increase in HDL-C level due to this inhibition would impact cardiovascular health requires further study

Effect Of Selenium And Vitamin E On Risk Of Prostate Cancer And Other Cancers

2009-03-16T10:51:00.001-07:00

UroToday.com - In the January 7, 2009 issue of the Journal of the American Medical Association, Dr. Scott Lippman and associates presented the results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). This is a phase 3 randomized, prospective, placebo controlled trial evaluating 4 arms; placebo, selenium (200g/day), vitamin E (400IU/day), or both for prostate cancer (CaP) prevention. The trial rationale was based on the observation that these compounds tested for chemoprevention in other trials suggested benefit. Surprisingly, SELECT was stopped early as no benefit was demonstrated on interim analysis.

The plan was for a minimum of 7 years of treatment and it included men age 50 years or older for African Americans and age 55 years or older for all other races. Men were without a diagnosis of CaP, had a PSA <4ng/ml and a digital rectal examination not suspicious for CaP. SELECT was activated in 2001 and participants had office visits every 6 months. The primary end point was CaP incidence as determined by routine clinical management. Guidelines for PSA screening were not enforced, as PSA screening was controversial at the time of study design. The trial design was intent-to-treat.

A total of 35,533 men were accrued and randomly assigned at 427 centers in the US. Important risk factors were well-balanced among the groups and median overall follow-up was 5.46 years. Adherence to both study agents averaged 65% at 5 years. In September, 2008 the independent data and safety monitoring committee met and reviewed data for interim analysis. They recommended study discontinuation as there was no evidence of benefit from either study agent and no possibility of a benefit to the planned degree with additional follow-up. The 5-year incidence of CaP in the 4 groups was; placebo 4.43%, selenium 4.56%, vitamin E 4.93%, and both agents 4.56%. There was a concern over the statistically non-significant increase in CaP in the vitamin E alone group and a non-significant increase in diabetes mellitus associated with selenium. The study agents had no significant effects on the overall incidence of cardiovascular events.

Genetic Variants And Family History Predict Prostate Cancer Similar To Prostate-Specific Antigen

2009-03-16T10:50:00.001-07:00

UroToday.com - In the February 1, 2009 issue of Clinical Cancer Research, Dr. S. Lilly Zheng and colleagues tested the hypothesis that a combination of genetic variants associated with prostate cancer (CaP) risk has predictive performance similar to PSA testing.

The work is based upon identification of genetic variants in the form of single nucleotide polymorphisms (SNPs) that were identified by genome-wide association studies and correlate with a man's risk of developing CaP. Specifically, five SNPs identified from 19 SNPs implicated in other studies and tested in a population of Swedish men were modeled using unconditional logistic regression with adjustment for age and geographic region. The sensitivity, specificity and overall predictive performance of predictive models for CaP were evaluated by construction of receiver operating characteristic curves and calculation of the AUC statistics.

Among the 5 major SNPs tested, 3 were located at 8q24, 1 at 7q12, and 1 at 17q24.3. These variants were combined with a family history of CaP in the models. In the final model, a total of 22 risk alleles from the SNPs and a positive family history provided a sensitivity of 0.25 and specificity of 0.86 that were similar to that of the PSA level cutoff of 4.1ng/ml. About 14% of the controls have 11 or more of these 23 risk factors. However, the researchers could find no differences in the results when sensitivity and specificity of the genetic risk factors were used to predict for the aggressiveness of CaP, early age-diagnosed CaP or late-age diagnosed CaP. A model using age, family history, and the 11 risk SNPs had an AUC of 0.65, better than the 0.50 level that represents chance alone and similar to the 0.68 for PSA.

Metabolomic Profiles Delineate Potential Role For Sarcosine In Prostate Cancer Progression

2009-03-16T10:49:00.001-07:00

UroToday.com - In the February 12, 2009 issue of Nature, the group of Dr. Arul Chinnaiyan identified sarcosine, an N-methyl derivative of the amino acid glycine as a metabolite that is highly increased during prostate cancer (CaP) progression.

The scientists used liquid and gas chromatography coupled with mass spectrometry to interrogate the relative levels of 1,126 metabolites from 262 prostate-related biospecimens (42 tissue samples and 110 matched plasma and post-digital rectal examination urine samples). Metabolomic profiles from urine or plasma did not identify differences between biopsy-positive and biopsy-negative individuals. For tissue, benign adjacent prostate (16 samples), clinically localized CaP (12 samples) and metastatic CaP (14 samples) were studied. A total of 69 metabolites were found in CaP and/or metastatic samples but not in benign prostate samples. After further analysis, 6 metabolites were found to be significantly increased on disease progression from benign to CaP to metastatic disease.

They focused on sarcosine, as it is involved in the amino acid metabolism and methylation processes that are enriched during CaP progression. Sarcosine was markedly elevated in 79% of metastatic samples, 42% of localized samples but no benign prostate samples. They developed an assay to measure as little as 10 fetomoles of sarcosine, and in an independent tissue sample set it was significantly elevated in metastatic CaP compared to organ-confined CaP compared to benign tissue. Regarding the predictive value for the assay among patients with a PSA between 2 and 10ngml, sarcosine performed better than PSA.

Evaluation of CaP cell lines revealed increased sarcosine levels compared to benign prostate cell lines. Overexpression of the histone methyltransferase EZH2 (which can mediate cell invasion and neoplastic progression) in benign prostate epithelial cells increased sarcosine levels, whereas its knockdown diminished sarcosine levels. Addition of sarcosine to non-invasive prostate cells resulted in an invasive phenotype and increased motility. Using siRNA to block the enzyme GNMT that converts glycine to sarcosine resulted in significant reduction in cell invasion and 3-fold decrease in sarcosine levels.

Furthermore, the ETS family of fusion genes known to be involved in CaP progression was found to be directly linked to the sarcosine pathway. Induced ETS related gene expression resulted in a 3-fold increase in sarcosine expression in benign prostate cells and knockdown in aggressive cells resulted in a 3-fold reduction in sarcosine. This links the sarcosine pathway to androgen signaling and ETS gene fusion regulation. Thus, sarcosine may have both a diagnostic and therapeutic role in prostate cancer.

Medical device pioneer Stentys announced that it has extended its 'self-expanding' and 'disconnectable' technology platform to include a second major

2009-03-16T10:48:00.001-07:00

Imbalance of iron homeostasis is a common feature of prion disease-affected human, mouse, and hamster brains, according to a new study by Dr. Neena Singh and colleagues at Case Western Reserve University School of Medicine, alongside collaborators from Creighton University. These findings, published March 13 in the open-access journal PLoS Pathogens, provide new insight into the mechanism of neurotoxicity in prion disorders, and novel avenues for the development of therapeutic strategies.

Unlike other neurodegenerative conditions, prion disorders are sporadic, inherited, and infectious, and affect both humans and animals; common examples are mad cow disease in cattle, scrapie in sheep, and Creutzfeldt-Jakob disease in humans. The causative agent is a misfolded protein referred to as PrP-scrapie that replicates itself by changing the conformation of neighboring copies of the same protein, namely the prion protein. Aggregates of PrP-scrapie are toxic to brain cells and cause a spongy-like appearance in diseased brains.

Research from the Singh laboratory suggests that accumulation of PrP-scrapie alters the metabolism of iron in diseased brains. The imbalance of brain iron homeostasis worsens with disease progression, and is not an outcome of end- stage disease. Since iron is highly toxic when mismanaged, this condition is likely to contribute significantly to prion-disease-associated neurotoxicity. The likely cause of this condition is loss of normal function of the prion protein in cellular iron metabolism demonstrated recently by Singh and colleagues, combined with gain of toxic function by the redox-active PrP-scrapie complex as shown in this report.

Singh and her team were surprised to find that prion disease-affected brains are iron deficient despite a significant increase in their overall iron content. The group concludes that ferritin, a major iron storage protein, co- aggregates with PrP-scrapie in diseased brains and sequesters bound iron in the complex, creating a state of apparent iron deficiency. The brain cells respond to this condition by increasing their level of iron uptake, thus creating a vicious cycle of increased iron uptake in the presence of increased iron.

These observations contribute to our understanding of how the prion agent causes neurotoxicity, and may enable the development of novel therapeutic strategies targeted at restoring brain iron homeostasis in prion disorders.

The World Egg Bank Lands Funding To Launch Largest Frozen Egg Bank

2009-03-16T09:59:00.000-07:00

The World Egg Bank announced the completion of a comprehensive $1.5 million funding package that will enable it to grow its frozen egg registry and accelerate its marketing and operations. The World Egg Bank plans to invest over $1 million to build a registry of hundreds of ready-to-ship frozen donor eggs. The company, headquartered in Phoenix, Arizona, was formed from a recent merger of X and Y Consulting, the leading egg donor matchmaking agency, and Cryo Eggs International, the world's first commercial egg bank.

"We're focused on expanding our frozen egg donor registry to give prospective moms a wider range of options when it comes to donor selection," said Diana Thomas, President of The World Egg Bank (http://www.theworldeggbank.com). "Recipients no longer have to synchronize cycles with the donor and the donor can be anywhere in the world."

The advent of egg freezing science and frozen egg donor banks should replace the complicated procedure of using fresh donor eggs. Frozen egg donors can be selected from an online registry, and the frozen eggs can be ordered and shipped the same day to any global location. A patient's doctor thaws the egg, fertilizes it, and transfers it in the patient's uterus in an office procedure.

Because eggs are frozen, they can be quarantined over six months and retested for STDs prior to being offered on The World Egg Bank's online registry. Since the eggs have already been retrieved, the patient does not need to worry about the donor changing her mind, experiencing a medical complication, or missing a crucial medical appointment. The very existence of a frozen egg on the registry means the donor has passed all screening exams and has had successful egg retrieval - leading to stress reduction, cost savings, and additional safety for the fertility patient.

Diana Thomas first encountered the fertility industry 14 years ago, when she wanted to become a mom and realized her own eggs would not work. She went through years of personal heartache, and finally decided to seek a donor on her own. Ms. Thomas had three children with donor eggs. Based on that experience, she founded an international egg donor recruiting agency, X and Y Consulting, to help other couples find donors. The agency merged with Cryo Eggs International to form The World Egg Bank in February 2009.

About The World Egg Bank

The World Egg Bank provides fertility services to women in need of donated eggs to achieve pregnancy. Over the last 12 years the company has operated the leading match-making service in the US and internationally, bringing donors and recipients together to exchange fresh eggs. In 2004, it provided the first commercial frozen human eggs in the world. Then in 2005, the first child conceived of a frozen egg in the US was born under the care of the founders. The World Egg Bank scientific team includes the three doctors that perfected the technology for freezing and thawing human eggs. The World Egg Bank is the result of the merger of X and Y Consulting Inc. (XYC) and Cryo Eggs International L.P., (CEI) in February 2009.

Testosterone Deficiency Syndrome Risk In 50% Men With Type 2 Diabetes

2009-03-15T11:12:00.001-07:00

Data presented today at the Diabetes UK Annual Conference reveal that Testosterone Deficiency Syndrome (TDS) is found in over 50% of men with Type 2 diabetes, more than double the rate in the non-diabetic population1. TDS is associated with a 42% additional risk of developing Type 2 diabetes, and up to 60% additional risk of all-cause and coronary heart disease (CHD) mortality1.

TDS, also known as hypogonadism, describes symptomatic patients with low serum testosterone levels (generally below 12 nmol/L)2. TDS is estimated to affect one in ten men over the age of 50 years3. The data, presented by Dr Geoff Hackett and Professor Hugh Jones reveal that TDS is associated with insulin resistance, raised HbA1c, visceral adiposity, raised BMI and ED, all of which are significant CHD risk factors1.

Dr Geoff Hackett, Consultant in Sexual Medicine, Good Hope Hospital, Sutton Coldfield said; "Testosterone Deficiency Syndrome is more common than GPs realise, particularly amongst men with Type 2 diabetes. Erectile dysfunction has been shown to be a robust predictor of CHD risk in men with Type 2 diabetes and yet neither testing for low testosterone nor ED assessment are part of the QOF. Assessment of testosterone is regarded as mandatory by all published authoritative guidelines on ED management."

TDS can be treated with testosterone therapy. Data presented reveal that testosterone therapy in hypogonadal diabetic men, reduces insulin resistance and has beneficial effects on glycaemic control, waist circumference, leptin and cholesterol4.

Recently published recommendations on the identification, monitoring and treatment of hypogonadism have been formulated by major international scientific organisations, including the European Association of Urology, the European Society of Endocrinology and the European Academy of Andrology2. These state that all patients presenting with Type 2 diabetes or with ED, should have their serum testosterone levels measured on a blood sample taken in the morning between 07.00 and 11.002.

Professor Hugh Jones, Hon. Professor of Andrology and Consultant Physician and Endocrinologist, Barnsley Hospital NHS Foundation Trust, explains; "There is now substantial evidence that there is an increased prevalence of hypogonadism in men with Type 2 diabetes. Doctors should check early morning testosterone levels in men with Type 2 diabetes and symptoms of hypogonadism, which includes erectile dysfunction (ED). Testosterone therapy has in some men with diabetes been shown to improve ED and convert some who fail to respond to PDE 5 inhibitors to responders. If testosterone levels in symptomatic patients are found to be low or near the lower end of the normal range (generally below 12 nmol/l) on at least two occasions, then referral to a specialist for further investigation and treatment should be considered."

Applied Biosystems Launches New TaqMan(R) Genotyping Assays To Identify A Leading Form Of Structural Variation In The Human Genome

2009-03-15T09:48:00.000-07:00

Applied Biosystems, a division of Life Technologies Corporation (NASDAQ:LIFE), today announced the introduction of a new line of genotyping assays that enable researchers to more closely study the significant role that DNA copy number structural variation plays in human health and disease. The TaqMan® Copy Number Assays are designed to detect and quantify copy number variations (CNVs), which are one of the most frequently occurring forms of structural change within a genome. These assays will enable pharmaceutical, clinical and academic researchers to accurately detect CNVs, which are changes in the number of copies of a gene, a part of a gene, or a large stretch of DNA that occur throughout a genome.

CNVs alter DNA in a way that impacts a host of biological processes. These include the development of cancer, immune system and neurological disorders, as well as how individuals respond to treatments for disease. The TaqMan Copy Number Assays will help researchers to better understand these processes by allowing them to determine CNVs from DNA samples, through a real-time PCR reaction.

An example of this type of research is occurring at Harvard Medical School, Brigham and Women's Hospital. Researchers there are studying the locations of CNVs in the human genome, and how they can be used as biological markers for susceptibility to human diseases. They are using TaqMan Copy Number Assays to validate the discovery of CNVs identified through the use of array-based platforms.

"Patterns of specific copy number variants have already been associated with increased susceptibility to several human diseases and traits," said Charles Lee, Ph.D., an Associate Professor in the Department of Pathology at Harvard Medical School, Brigham and Women's Hospital. "The TaqMan Copy Number Assays represent an excellent complementary technology for confirming the results of our CNV discovery projects, giving us great confidence in the accuracy of our datasets."

The TaqMan Copy Number Assay solution consists of more than 1.6 million pre-designed TaqMan Copy Number Assays, and Custom TaqMan Copy Number Assays, which allow researchers to detect CNVs in a specific gene, or genome region, if that assay is not available in the pre-designed set. These solutions, in addition to data analysis software, are available on the Applied Biosystems web site.

"Scientists need a powerful genotyping tool that easily validates the discovery of genomic copy number differences in DNA samples," said Peter Dansky, President of Life Technologies' Molecular Biology Systems Division. "This technology for advanced genomics research will enable them to perform large-scale screens of biological samples, which will potentially lead to the development of biological markers that will increase their understanding of genetic variation and its role in human disease."

Applied Biosystems is a global leader in providing innovative instrument systems to accelerate academic and clinical research, drug discovery and development, pathogen detection and forensic DNA analysis. It is a market leader in providing fast, simple and effective genotyping tools. Applied Biosystems, together, with Invitrogen - a leading provider of platform independent, essential life science technologies for disease and drug research, bioproduction and diagnostics - is part of Life Technologies Corporation, which markets the life science industry's most comprehensive portfolio of solutions for molecular and cell biology. Applied Biosystems and Invitrogen products are used in nearly every major laboratory in the world.

How Brain Records Memories Highlighted In 'Mind-Reading' Experiment

2009-03-14T10:19:00.000-07:00

It may be possible to "read" a person's memories just by looking at brain activity, according to research carried out by Wellcome Trust scientists. In a study published in the journal Current Biology, they show that our memories are recorded in regular patterns, a finding which challenges current scientific thinking.

Demis Hassabis and Professor Eleanor Maguire at the Wellcome Trust Centre for Neuroimaging at UCL (University College London) have previously studied the role of a small area of the brain known as the hippocampus which is crucial for navigation, memory recall and imagining future events. Now, the researchers have shown how the hippocampus records memory.

When we move around, nerve cells (neurons) known as "place cells", which are located in the hippocampus, activate to tell us where we are. Hassabis, Maguire and colleagues used an fMRI scanner, which measures changes in blood flow within the brain, to examine the activity of these places cells as a volunteer navigated around a virtual reality environment. The data were then analysed by a computer algorithm developed by Demis Hassabis.

"We asked whether we could see any interesting patterns in the neural activity that could tell us what the participants were thinking, or in this case where they were," explains Professor Maguire, a Wellcome Trust Senior Research Fellow. "Surprisingly, just by looking at the brain data we could predict exactly where they were in the virtual reality environment. In other words, we could 'read' their spatial memories."

Earlier studies in rats have shown that spatial memories - how we remember where we are - are recorded in the hippocampus. However, these animal studies, which measured activity at the level of individual or dozens of neurons at most, implied that there was no structure to the way that these memories are recorded. Hassabis and Maguire's work appears to overturn this school of thought.

"fMRI scanners enable us to see the bigger picture of what is happening in people's brains," she says. " By looking at activity over tens of thousands of neurons, we can see that there must be a functional structure - a pattern - to how these memories are encoded. Otherwise, our experiment simply would not have been possible to do."

Professor Maguire believes that this research opens up a range of possibilities of seeing how actual memories are encoded across the neurons, looking beyond spatial memories to more enriched memories of the past or visualisations of the future.

"Understanding how we as humans record our memories is critical to helping us learn how information is processed in the hippocampus and how our memories are eroded by diseases such as Alzheimer's," added Demis Hassabis.

"It's also a small step towards the idea of mind reading, because just by looking at neural activity, we are able to say what someone is thinking."

Professor Maguire led a study a number of years ago which examined the brains of London taxi drivers, who spend years learning "The Knowledge" (the maze of London streets). She showed that in these cabbies, an area to the rear of the hippocampus was enlarged, suggesting that this was the area involved in learning location and direction. In the new study, Hassabis, Maguire and colleagues found that the patterns relating to spatial memory were located in this same area, suggesting that the rear of the hippocampus plays a key role in representing the layout of spatial environments.

Traditional Chinese Medicine Effectively Treats Eczema

2009-03-14T10:01:00.000-07:00

New research where traditional Chinese medicine was found to safely and effectively treat patients with persistent atopic dermatitis - or eczema, as it's commonly known - could lead more physicians to prescribe complementary and alternative medicine (CAM) to treat the allergic condition.

In the study presented at the 2009 Annual Meeting of the American Academy of Allergy, Asthma & Immunology (AAAAI), researchers at Mount Sinai Hospital in New York analyzed 14 patients with persistent atopic dermatitis who received traditional Chinese medicine at Ming Qi Natural Health Center in Manhattan between August 2006 and May 2008. The treatments consisted of Erka Shizheng Herbal Tea, a bath additive, creams and acupuncture.

The study authors utilized two measures: the SCORAD index to gauge atopic dermatitis severity and the Dermatology Life Quality Index (DLQI) to calculate impairment to life quality.

Baseline median scores for SCORAD and DLQI were 89 and 17, respectively. After a median of eight months treatment, the median scores fell to 11 for SCORAD and 1 for DLQI.

In all but one patient, SCORAD measures decreased between 60 to 90% after 3.3 months of treatment. More than 50% improvement in DLQI scores was documented in all but one patient after 2.4 months of treatment.

Patients also reported a reduction in the use of steroids, antibiotics and antihistamines within 3 months of being treated with traditional Chinese medicine. There were no abnormalities of liver and kidney function observed.

While the researchers concluded that the use of traditional Chinese medicine is safe and effective for patients with persistent atopic dermatitis, especially those with a severe case and significant life quality impairment, it is still recommended to speak with a physician before taking any complementary or alternative medicines.

The AAAAI represents allergists, asthma specialists, clinical immunologists, allied health professionals and others with a special interest in the research and treatment of allergic disease. Established in 1943, the AAAAI has more than 6,500 members in the United States, Canada and 60 other countries.

Breakthrough Discovery Reveals How Circadian Rhythm-Cell Energy Link Can Lead To New Treatments

2009-03-14T09:43:00.000-07:00

UC Irvine researchers have discovered that circadian rhythms - our own body clock - regulate energy levels in cells. The findings have far-reaching implications, from providing greater insights into the bond between the body's day-night patterns and metabolism to creating new ways to treat cancer, diabetes, obesity and a host of related diseases.

In addition, Paolo Sassone-Corsi, Distinguished Professor and Chair of Pharmacology, and his colleagues found that the proteins involved with circadian rhythms and metabolism are intrinsically linked and dependent upon each other. Their study appears online in Science Express.

"Our circadian rhythms and metabolism are closely partnered to ensure that cells function properly and remain healthy," Sassone-Corsi said. "This discovery opens a new window for us to understand how these two fundamental processes work together, and it can have a great impact on new treatments for diseases caused by cell energy deficiencies."

Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms. The circadian clocks are the essential time-tracking systems in our bodies that anticipate environmental changes and adapt to the appropriate time of day. Disruption of these rhythms can profoundly influence human health and has been linked to obesity, diabetes, insomnia, depression, coronary heart diseases and cancer.

Sassone-Corsi already had identified that the enzyme protein CLOCK is an essential molecular gear of the circadian machinery and interacts with a protein, SIRT1, which senses cell energy levels and modulates aging and metabolism.

In this study, he and his colleagues show that CLOCK works in balance with SIRT1 to direct activity in a cell pathway by which metabolic proteins send signals called the NAD+ salvage pathway. In turn, a key protein in that pathway, NAMPT, helps control CLOCK levels, creating a tightly regulated codependency between our circadian clock and metabolism.

"When the balance between these two vital processes is upset, normal cellular function can be disrupted," Sassone-Corsi said. "And this can lead to illness and disease."

The findings suggest that proper sleep and diet may help maintain or rebuild this balance, he said, and also help explain why lack of rest or disruption of normal sleep patterns can increase hunger, leading to obesity-related illnesses and accelerated aging.

The specific interaction between CLOCK and SIRT1 and the NAD+ salvage pathway also presents a starting point for drug development aimed at curbing cell dysfunction and death, thereby helping to solve major medical problems such cancer and diabetes.

The Genetic Dynamics Of Inbreeding Depression

2009-03-13T11:53:00.000-07:00

Researchers have taken a first look at the broad genetic changes that accompany reproductive declines in inbred populations.

Although scientists have known for more than a century that small populations of closely related plants or animals are likely to suffer from low reproductive success, the exact mechanism by which this "inbreeding depression" occurs is still the subject of debate.

The new study, in Conservation Biology, is the first to look at inbreeding depression as it relates to the expression of all of an organism's genes - to see which are more or less active in inbred populations and what they do.

By mating male and female fruit flies that were genetically identical to one another, researchers at the University of Illinois were able to determine how much the flies' genetic likeness reduced their reproductive success. They repeated the experiment in six lines of fruit flies that were identical to one another except for the composition of one of their chromosomes; only the genes of chromosome three differed between the lines.

The researchers also crossed the three highest inbred lines to one another, creating outbred lines that could be compared with the inbred ones.

Using oligonucleotide microarrays, which can measure the activity of all of an organism's genes at once, the researchers were able to see which genes were more or less active (up-regulated or down-regulated) in the inbred versus the outbred lines.

The six inbred lines of fruit flies showed a lot of variation in the degree of inbreeding depression, from 24 to 79 percent when compared with non-inbred flies. The researchers also found that 567 genes in the high inbreeding depression lines were expressed at higher or lower levels than the same genes in the other inbred lines. Only 62 percent of these genes were located on chromosome three (the only chromosome that differed between the lines) indicating that variation in chromosome three had altered gene expression on the other chromosomes.

"These results suggest that a significant amount of inbreeding depression is due to a few key genes that affect the expression of other genes," said animal biology professor and department head Ken Paige, who led the study.

Of particular note were identical changes in the expression of 46 genes in all three of the high inbreeding depression lines, Paige said, making them of interest for further study.

Genes associated with inbreeding depression could be grouped into three broad categories of function: those involved in metabolism, stress, and defense. This is a surprising finding, Paige said, "because we think of inbreeding as a random process."

Many metabolic genes were up-regulated in the inbred flies, as were genes that fight pathogens such as bacteria or viruses. A third group of genes was down-regulated. They code for proteins that protect the body from reactive atoms and molecules that can damage cells.

These changes in gene expression are shunting energy away from reproduction and undermining some basic cellular functions, Paige said.

Inbreeding depression is thought to result from a deleterious pattern of inherited genes. In general, an organism with two parents has two versions of every gene - one maternal and one paternal. These different flavors of a gene are called alleles. If the maternal and paternal alleles differ, one of them usually dominates, conferring all of its qualities to the offspring. The other, silenced allele is called "recessive."

Some alleles are detrimental to health. Most of these are recessive, meaning that they do not cause problems unless the organism inherits two copies of them - one from each parent. When the alleles differ, one (the dominant allele) often masks the deleterious effects of the other.

But the interaction of parental alleles in their offspring can be quite complex. Sometimes an allele causes a disease or disorder even if it is paired with a different allele. Sometimes several genes influence a single trait. And sometimes two different alleles can lead to a higher level of gene activity than occurs in either parent (this last phenomenon is called overdominance).

When closely related individuals mate, their offspring are likely to end up with identical alleles for many traits. Many potentially harmful recessive alleles are no longer masked by dominant alleles, so more genetic disorders arise. Similarly, offspring that inherit two identical alleles for some traits will also lose any advantages once conferred by overdominance.

Biologists have long wondered which of these mechanisms causes the reproductive failures seen in inbred populations. "It's still being debated," Paige said.

The new study found that about 75 percent of the reproductive declines seen in the inbred flies could be attributed to the loss of dominant alleles and the subsequent "unmasking" of deleterious alleles. More surprisingly, the data also indicated that 25 percent of the declines were due to the loss of overdominance.

"That means we have two mechanisms ongoing," Paige said. "One does predominate, but the other may be important, too."

The fact that a relatively large number of genes are affected by inbreeding is bad news for conservationists hoping to save small populations of plants or animals from extinction, Paige said.

It means that there is no easy fix to the problem of inbred populations. The best approach is to try to preserve and maintain genetic diversity in natural populations well before they begin their slide into an "extinction vortex," he said.

New Way To Explore DNA Devised By Researchers

2009-03-13T11:47:00.000-07:00

A team that includes researchers from the National Institutes of Health (NIH) has found a new way of detecting functional regions in the human genome. The novel approach involves looking at the three-dimensional shape of the genome's DNA and not just reading the sequence of the four-letter alphabet of its DNA bases.

In a paper published in the early online edition of Science, a team led by Elliott Margulies, Ph.D., of the National Human Genome Research Institute (NHGRI), and Thomas Tullius, Ph.D., of Boston University, describes an innovative approach for detecting functional genomic regions. By combining chemical and computer analyses, the researchers survey the landscape, or topography, of DNA structure for areas likely to play a key role in biological function.

The method involves identifying all of the grooves, bumps and turns of the DNA that makes up the human genome and then comparing those structural features to those seen in the genomes of other animal species. Structural features that have been preserved across many species are likely to play important roles in how the human body functions, while those that have changed over the course of evolution may play a less central role or no role at all.

"This new approach is an exciting advance that will speed our efforts to identify functional elements in the genome, which is one of the major challenges facing genomic researchers today," said NHGRI Scientific Director Eric Green, M.D., Ph.D. "Coupled with continued innovations in DNA sequencing, this topography-informed approach will expand our ongoing efforts to use genomic information to improve human health."

The sequence of the 3 billion DNA base pairs that make up the human genome holds the answers to many questions pertaining to human development, health and disease. Consequently, much research aimed at understanding the genome has focused on establishing the information encoded by the linear order of DNA bases. In the new study, however, researchers focused on how those bases chemically interact with each other to coil and fold the DNA molecule into a variety of shapes.

"We often think of DNA as a string of letters on a computer screen and forget that this string of letters is a three-dimensional molecule. But shape really matters," said Dr. Margulies, who is an investigator in NHGRI's Genomic Technology Branch. "Proteins that influence biological function by binding to DNA recognize more than just the sequence of bases. These binding proteins also see the surface of the DNA molecule and are looking for a shape that allows a lock-and-key fit."

In 2003, an international team of researchers finished a reference sequence of the human genome, an achievement that greatly sped efforts to find genes, which reflect the approximately 2 percent of the genome that codes for proteins. At one time, the remaining 98 percent of the genome was referred to as junk DNA. Researchers now know that this non-coding DNA contains elements that carry out important biological functions, such as turning genes off or on. However, little information exists about where these non-coding functional elements are located and how they work.

The new approach to identifying functional elements in non-coding DNA builds upon the individual efforts of Dr. Tullius, a chemistry professor who has spent more than 20 years developing methods to examine the 3-D structure of DNA, and of Dr. Margulies, a molecular biologist who uses computer methods to compare the genomes of different species.

"We brought together two diverse fields to think about this problem in a new way," said Dr. Margulies. "It took the combined expertise of a DNA chemist and computational biologist to figure out that this chemical technique could advance our understanding of comparative genomics."

"By considering the three-dimensional structure of DNA, you can better explain the biology of the genome," said Dr. Tullius. "For this achievement, Stephen Parker, a Boston University graduate student, deserves much of the credit for his development of the algorithm that incorporated DNA structure into evolutionary analysis."

In their Science paper, the researchers compared the topography of the human genome with that of 36 other mammalian species, including mouse, rabbit, elephant and chimpanzee. Using this topographic approach, they found that about 12 percent of the non-coding DNA in the human genome appears to be functionally important - twice the amount detected using methods that simply compared DNA sequences.

What accounts for the difference? Researchers say DNA sequence is not always a good indicator of function. They found that very similar DNA sequences may assume very different topographical shapes, which can have a major impact on their function or lack of function. On the other hand, different DNA sequences may assume very similar topographical shapes and perform very similar functions. So, in many instances, DNA structure may be a better predictor of function than DNA sequence.

The researchers went on to mine data organized by the PhenCode Project to see whether one-base variations in DNA sequence, called single-nucleotide polymorphisms (SNPs), in non-coding regions can cause structural changes that might lead to disease. Specifically, they conducted a topographic survey of 734 non-coding SNPs known to be associated with signs and symptoms of disease. The non-coding SNPs associated with disease tended to produce larger changes in the shape of DNA than a set of SNPs not linked to disease.

The entire study made extensive use of data sets generated by the NHGRI-funded ENCyclopedia of DNA Elements (ENCODE) project, which is a multi-institution effort to compile a parts list of the biologically functional elements in the human genome. In addition, some of Dr. Tullius's work in developing the new technology was funded through the ENCODE project.

PolyMedix Completes First-in-Man Phase I Clinical Study With Novel Heparin Antagonist PMX-60056

2009-03-13T10:32:00.000-07:00

PolyMedix, Inc. (OTC BB: PYMX), an emerging biotechnology company developing acute care products for infectious diseases and acute cardiovascular disorders, has successfully completed its first-in-man clinical study with the novel heparin antagonist drug PMX-60056. This ascending single-dose intravenous pharmacokinetic and safety study met the necessary Phase I goals of defining both a limiting single dose for ten-minute infusions and also the plasma distribution/elimination kinetics for the drug in the absence of heparin. Pending regulatory clearance, PolyMedix now expects to be able to proceed with a Phase IB proof-of-concept clinical study.

PMX-60056 is a novel small-molecule drug candidate designed to block the anticoagulant action of heparin and low molecular weight heparins (LMWH), clot prevention drugs which are commonly used in a number of applications. The data from this study demonstrate that single intravenous doses can be given at levels that will support the planned follow-on therapeutic proof-of-concept Phase IB clinical trial. Further clinical development is expected to continue for this drug as an agent for the rapid reversal of heparin after surgery, and for emergencies where heparin anticoagulation presents a clinical problem.

"We believe the completion of this first clinical study for PMX-60056 marks another important milestone for PolyMedix," said Nicholas Landekic, CEO of PolyMedix. "This novel reversing agent represents a potential fundamental breakthrough in safely reversing the anticoagulation produced by heparin and LMWH. PMX-60056 is the first and only small molecule in clinical development for this purpose. We are very proud to be developing another completely new type of drug to address a major clinical need and market opportunity, adding to our accomplishments with our novel antimicrobial drug candidate PMX-30063. We look forward to continuing further clinical development of both drug candidates."

Background

Heparin and LMWH are widely used anticoagulants, drugs to prevent blood clotting. However, they have the risk of potentially serious bleeding side effects. Protamine is currently the only approved drug used to reverse the action of heparin, and there is no approved reversing agent for LMWH. However, there are serious potential side effects associated with protamine. Based on preclinical studies conducted by PolyMedix and its collaborators, potential advantages of PMX-60056 over protamine may include reduced bleeding complications, reduced risk of immune-mediated side effects, and the ability to neutralize LMWH.

PMX-60056 was designed to bind to the pentasaccharide region found on heparin. PMX-60056 is believed to form a stable electrostatic bond to heparin, blocking its action. This molecular combination is believed to persist until removed from circulation by normal processes. In previous studies conducted by PolyMedix and other groups, PMX-60056 has been demonstrated to reverse the action of heparin in isolated human plasma, isolated human whole blood, and in animal studies in rats and dogs.

PMX-60056 is not intended for use when heparin or a LMWH are not present in the patient. However, as a new chemical entity under development for U.S. Food and Drug Administration approval, applicable regulations require that it first be investigated when administered alone without the presence of heparin or LMWH before further testing. With these Phase IA results, PolyMedix believes it has now completed this aspect of development. The results have indicated which plasma drug levels are free of side effects and which levels can be associated with side effects that would limit the amount of drug that can be administered.

Study Details

A total of fifteen healthy subjects received a single intravenous dose of up to 0.5 mg/kg infused over a ten-minute period. The subjects were grouped into different cohorts with different dosage levels which allowed for the study of the effects of increased dosages. Five different dose levels were administered, two of them unblinded. Once drug-related effects were identified, dosing became double-blind, with neither investigators nor subjects aware whether active drug or placebo was being administered.

It is known that positively charged molecules given intravenously will typically cause a rapid but transient lowering of blood pressure. Such hypotension is observed with protamine, and this study showed a similar effect to be dose-limiting for PMX-60056 at 0.4 mg/kg or more in some (but not all) subjects. This blood pressure lowering typically began soon after the start of the infusion and often began to resolve even before its end, with complete resolution usually within ten to twenty minutes. Based on the study results, PolyMedix has concluded that a ten-minute intravenous infusion of PMX-60056 should not exceed 0.35 mg/kg if there is no heparin present in the plasma at the time.

There were no clinically important adverse effects at doses under 0.4 mg/kg, and no clinically significant trends in laboratory parameters at any dose. Itching or warmth during the infusion was reported by most subjects. However, none of the subjects experienced a rash or other signs, and in each case the observed effects resolved immediately after the end of the infusion.

Analysis of the plasma-level assays indicates that a single-compartment model provides an excellent fit to the observed data, and the plasma elimination half-time is 1.5 to 2.5 minutes in the dosage range administered.

This first study has demonstrated that PMX-60056 can be given safely in the absence of heparin if ten-minute infusions include less than 0.4 mg/kg. The data suggest that the limiting side effect of hypotension is related to peak plasma drug level, which means that slower infusions could allow delivery of more drug. To investigate this possibility, PolyMedix plans to study slower infusions, of twenty and potentially thirty minutes, in an extension of this study. These longer infusions are expected to allow higher doses to be given, and will add support for potential clinical studies for the reversal of LMWH, which may require greater total amounts of drug to be administered.

The next planned clinical study is a proof-of-concept Phase IB trial, reversing the action of heparin in healthy volunteers. Because the combination with heparin is believed to occur very rapidly, little or no free PMX-60056 is expected to occur in the plasma. Dosing will begin at levels below those associated with pharmacological effects for the free drug, and increase gradually as tolerated. It is anticipated that the presence of heparin may prevent significant levels of free PMX-60056, and therefore that hypotension may not be a problem at doses required to reverse the anticoagulation. In clinical use, it is expected that the only free PMX-60056 would be the excess over the amount needed to neutralize the heparin remaining in the plasma.

For more news and information on PolyMedix, Inc. please visit www.IRGnews.com/coi/PYMX where you can find the CEO's video, a fact sheet on the company, investor presentations, and more.

Fishing For Microdeletions That Predispose An Embryo To Develop Cancer Syndromes In Later Life

2009-03-12T06:27:00.000-07:00

Researchers have used a common laboratory technique for the first time to detect genetic changes in embryos that could predispose the resulting children to develop certain cancer syndromes. Current preimplantation genetic diagnosis techniques can detect mutations in very small bits of genes or DNA, but, until now, it wasn't easy to detect deletions involving whole genes or long sections of DNA in embryos.

The study, published online 11 March in Europe's leading reproductive medicine journal Human Reproduction [1], uses a technique called fluorescent in situ hybridization (FISH) to detect losses of small parts of whole chromosomes (microdeletions) in a single cell from an embryo. The work opens the way to test for microdeletions in patients with other genetic conditions as well as the two cancer predisposition syndromes treated in this study. [2]

Professor Joris Vermeesch, coordinator of the Genomics Core and head of Constitutional Cytogenetics, and Evelyne Vanneste, a PhD student, both at the Center for Human Genetics, University Hospital Leuven (Belgium), and their colleagues used FISH to carry out PGD in embryos from three couples where the women carried microdeletions for either neurofibromatosis type 1 (NF1) or Von Hippel-Lindau disease (VHL). As a result, the woman with the VHL mutation gave birth to healthy twins from embryos selected using FISH PGD.

Neurofibromatosis type 1 (also known as Von Recklinghausen disease) is a common inherited condition with an incidence at birth of one in 3,000-3,500. NF1 patients develop tumours of the nervous system, pigmented patches of skin and can have lower IQs. In 95% of people with NF1, a mutation is found in the NF1 gene, which is a tumour suppressor gene; but five per cent of NF1 patients have microdeletions of the gene, and large microdeletions can result in more severe symptoms.

Von Hippel-Lindau (VHL) disease is a rarer cancer syndrome, occurring in about one in 36,000 births. Symptoms of the disease include benign tumours of the central nervous system and benign and malignant tumours of organs such as the kidneys, adrenal glands and pancreas. It is an inherited condition caused by a mutation in the VHL tumour suppressor gene.

The strands of DNA that twist together to form the double helix structure are made up of lots of small sections called nucleotides. The nucleotides are made up of the four DNA bases - adenine, thymine, guanine and cytosine (or A,T,C,G). Mutations that can be detected by the conventional PCR (polymerase chain reaction) technique used in PGD are usually mutations of a single nucleotide or base. A deletion or microdeletion normally involves the loss of larger numbers of nucleotides.

Prof Vermeesch explained: "Current techniques using PCR to detect abnormalities in embryos can detect one base, nucleotide or letter change in the DNA, but they cannot be used when a person has a loss of the whole gene or a lot of letters - a microdeletion. Patients with these cancer predisposition syndromes, and some other conditions, usually carry only a single microdeletion. Now, for the first time, we have used FISH to detect these microdeletions in the embryo and thus can help carriers to create offspring without those anomalies.

"Importantly, microdeletions are not so rare in neurofibromatosis type 1. It is also becoming clear that genomic disorders caused by microdeletions, duplications and copy number variations are much more frequent than previously thought. The techniques we have used in this study will help a wide range of microdeletion carriers."

For each of the three women, the researchers created probes that could be used to identify NF1 or VHL deletions in the embryos. The embryos were obtained from the women using normal assisted reproduction techniques. They took two cells from each embryo and performed FISH to probe them for the microdeletions. Only embryos that FISH had identified as being healthy, without any microdeletions, were transferred to the women's wombs.

Ms Vanneste explained that although they had to make FISH probes specific to each woman, the NF1 microdeletions found tended to recur. "Therefore, most NF1 patients with a deletion carry the same deletion and our FISH PGD conditions can be rapidly replicated and re-used in other deletion carriers. It seems likely that the number of families that can benefit from FISH PGD will increase in years to come and we are continuing to help more families using this approach. However, for each condition a new probe has to be made. This is time-consuming, but we are currently developing tools to identify all similar genetic imbalances with a single technology."

Notes:

[1] Preimplantation genetic diagnosis using fluorescent in situ hybridization for cancer predisposition syndromes caused by microdeletions. Human Reproduction. doi:10.1093/humrep/dep034

[2] PGD can be carried out already to detect a genetic susceptibility for some cancers, but only if the specific mutation is known (e.g. to detect the BRCA1/2 mutations that can lead to breast cancer developing). The majority of these cases involve a change in a single nucleotide, not a microdeletion.

Human Genome Sciences Announces Positive Results In Second Of Two Phase 3 Trials Of Albuferon(R) In Chronic Hepatitis C

2009-03-10T11:21:00.000-07:00

Human Genome Sciences, Inc. (Nasdaq: HGSI) announced that Albuferon(R) (albinterferon alfa-2b) met its primary endpoint of non-inferiority to peginterferon alfa-2a (Pegasys) in ACHIEVE 1, a Phase 3 clinical trial of Albuferon in combination with ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C (p=0.0008). Albinterferon alfa-2b is being developed by HGS and Novartis under an exclusive worldwide co-development and commercialization agreement entered into in June 2006.

"These Phase 3 data show that, with half the injections, the efficacy of Albuferon was comparable to Pegasys," said H. Thomas Watkins, President and Chief Executive Officer, HGS. "We are pleased that Albuferon met its primary endpoint in the ACHIEVE 1 trial as it also did in ACHIEVE 2/3. We look forward to the filing of global marketing applications in fall 2009, following discussions with regulatory authorities. Assuming licensure, we believe Albuferon could become a market-leading treatment for chronic hepatitis C."

Stefan Zeuzem, M.D., Professor of Medicine and Chief, Department of Medicine, J.W. Goethe University Hospital, Frankfurt, Germany, said, "These Phase 3 results in patients infected with the genotype 1 virus, evaluated together with the previously reported Phase 3 results in patients infected with the genotypes 2 and 3 viruses, suggest that albinterferon alfa-2b has the potential to become an important new treatment option for chronic hepatitis C."

"We are encouraged that albinterferon alfa-2b met the primary efficacy endpoint of non-inferiority to peginterferon alfa-2a in both of our pivotal Phase 3 studies," said David C. Stump, M.D., Executive Vice President, Research and Development, HGS. "As we found with the earlier results from ACHIEVE 2/3, the ACHIEVE 1 data show that the rate of sustained virologic response was comparable for the treatment group receiving the 900-mcg dose of albinterferon alfa-2b every two weeks, versus the treatment group receiving the standard dose of peginterferon alfa-2a once weekly. Importantly, the rate of serious and/or severe adverse events was also comparable for these treatment groups. We were pleased to see that serious pulmonary adverse events in the 900-mcg group were infrequent and all resolved with cessation of treatment."

Key Topline Findings from ACHIEVE 1

Treatment Group Receiving Albinterferon Alfa-2b 900-mcg Every Two Weeks, vs. Treatment Group Receiving Peginterferon Alfa-2a 180-mcg Every Week

-- Based on an ITT analysis of the treatment group assigned to receive 900-mcg albinterferon alfa-2b every two weeks, the topline results demonstrate that albinterferon alfa-2b met its primary efficacy endpoint of non-inferiority to peginterferon alfa-2a, with 48.2% (213/442) of patients achieving SVR in the 900-mcg albinterferon alfa-2b treatment group, vs. 51.0% (225/441) in the peginterferon alfa-2a treatment group. The primary analysis, which is adjusted for baseline stratification factors, showed a difference in SVR rates of -1.8% (95% CI -8.1%, 4.5%, p=0.0008 for non-inferiority).

-- Patients receiving 900-mcg albinterferon alfa-2b had comparable rates of serious and/or severe adverse events, vs. peginterferon alfa-2a, with 24.0% (106/442) in the albinterferon alfa-2b 900-mcg treatment group, vs. 23.1% (102/441) in the peginterferon alfa-2a treatment group.

-- Serious and/or severe pulmonary adverse events were infrequent and included the following: The rate of serious and/or severe pulmonary infections was comparable between the two groups, with 1.8% (8/442) for 900-mcg albinterferon alfa-2b, vs. 1.1% (5/441) for peginterferon alfa-2a; the rate of serious and/or severe respiratory, thoracic or mediastinal disorders was 2.5% (11/442) for 900-mcg albinterferon alfa-2b, vs. 0.5% (2/441) for peginterferon alfa-2a. Of the 11 disorders reported for 900-mcg albinterferon alfa-2b, three were classified as serious, and all three resolved off treatment.

-- Overall, adverse events observed were those typically associated with interferon therapy. The rate of discontinuations due to adverse events was 10.4% (46/442) for 900-mcg albinterferon alfa-2b, vs. 4.1% (18/441) for peginterferon alfa-2a.

Treatment Group Originally Randomized to Receive Albinterferon Alfa-2b 1200-mcg Every Two Weeks and Reduced to 900-mcg Following January 2008 Dose Modification, vs. Treatment Group Receiving Peginterferon Alfa-2a 180-mcg Every Week

Due to the dose modification announced in January 2008, patients in the treatment group originally randomized to receive albinterferon alfa-2b 1200-mcg every two weeks had their dose modified to 900-mcg albinterferon alfa-2b every two weeks. Data from all three treatment groups in the ACHIEVE 1 study were analyzed according to the original dose assignment. The following results for the treatment group originally randomized to receive 1200-mcg albinterferon alfa-2b every two weeks did not impact the primary analysis comparing the 900-mcg albinterferon alfa-2b treatment group to the peginterferon alfa-2a treatment group.

-- Based on an ITT analysis of results for the treatment group originally randomized to receive 1200-mcg albinterferon alfa-2b every two weeks, 47.3% (208/440) of patients in this treatment group achieved SVR, vs. 51.0% (225/441) in the peginterferon alfa-2a treatment group, which statistically demonstrated non-inferiority (95% CI -9.4%, 3.2%, p=0.0029, adjusted for baseline stratification factors).

-- The incidence of serious and/or severe adverse events was 28.3% (124/440) in the treatment group originally randomized to receive 1200-mcg albinterferon alfa-2b every two weeks, vs. 23.1% (102/441) in the peginterferon alfa-2a treatment group.

-- The incidence of serious and/or severe pulmonary adverse events included the following: serious and/or severe pulmonary infections were 3.2% (14/440) for 1200-mcg albinterferon alfa-2b, vs. 1.1% (5/441) for peginterferon alfa-2a; and serious and/or severe respiratory, thoracic or mediastinal disorders were 3.0% (13/440) for 1200-mcg albinterferon alfa-2b, vs. 0.5% (2/441) for peginterferon alfa-2a.

-- Overall, adverse events observed were those typically expected with interferon therapy. The incidence of discontinuations due to adverse events was 10.0% (44/440) in the treatment group originally randomized to receive 1200-mcg albinterferon alfa-2b every two weeks, vs. 4.1% (18/441) in the peginterferon alfa-2a treatment group.

Additional Safety Data of Interest from the Phase 3 Clinical Trials of Albinterferon Alfa-2b Versus Peginterferon Alfa-2a

HGS has conducted two randomized active-controlled Phase 3 clinical trials of albinterferon alfa-2b versus peginterferon alfa-2a - ACHIEVE 1 in genotype 1 chronic hepatitis C, and ACHIEVE 2/3 in genotypes 2 and 3 chronic hepatitis C. Overall, the two studies enrolled and randomized a total of 2264 treatment-naive patients.

The dose modification in January 2008 was recommended by the independent Data Monitoring Committee (DMC) based upon an interim analysis that serious pulmonary adverse events appeared to be higher in the 1200-mcg albinterferon alfa-2b treatment group.

-- Across the two Phase 3 trials, which have now been completed, rates of serious respiratory, thoracic or mediastinal disorders were: 0.7% (5/755) for 900-mcg albinterferon alfa-2b; 1.5% (11/750) for the group originally randomized to receive 1200-mcg albinterferon alfa-2b, and 0.0% (0/750) for peginterferon alfa-2a.

-- Central blinded review of chest X-rays recommended by the DMC for patients participating in the two Phase 3 trials demonstrated that the overall rates of significant interstitial findings were comparable in all three treatment groups: 4.3% (20/469) in patients randomized to receive 900-mcg albinterferon alfa-2b; 4.8% (22/454) in patients originally randomized to receive 1200-mcg albinterferon alfa-2b; and 4.5% (22/484) in patients randomized to receive 180-mcg peginterferon alfa-2a.

The incidence of fatality in the albinterferon alfa-2b Phase 3 trials was rare. All-cause mortality rates were: 0.13% (1/756) in patients randomized to receive 900-mcg albinterferon alfa-2b every two weeks; 0.53% (4/751) in patients originally randomized to receive 1200-mcg albinterferon alfa-2b every two weeks; and 0.27% (2/751) in patients randomized to receive 180-mcg peginterferon alfa-2a once-weekly.

Across the two Phase 3 trials, the overall percentage of patients who had a serious and/or severe adverse event or discontinued due to an adverse event was comparable in all dose groups: 23.2% (175/755) in patients randomized to receive 900-mcg albinterferon alfa-2b; 26.0% (195/750) in patients randomized to receive 1200-mcg albinterferon alfa-2b; and 21.6% (162/750) in patients randomized to receive 180-mcg peginterferon alfa-2a.

About the Design of the ACHIEVE 1 Trial

In the randomized, multi-center, active-controlled non-inferiority ACHIEVE 1 Phase 3 trial, 1331 treatment-naive patients with genotype 1 chronic hepatitis C were initially assigned to one of three treatment groups, including two groups that received subcutaneously administered albinterferon alfa-2b once every two weeks at doses of 900 mcg or 1200 mcg, and an active control group that received peginterferon alfa-2a once weekly at a dose of 180 mcg - with all patients receiving daily oral ribavirin concomitantly. In January 2008, a dose modification was made for patients originally assigned to receive the 1200-mcg dose of albinterferon alfa-2b. These patients had their dose modified to 900-mcg albinterferon alfa-2b every two weeks. Following the dose modification, the study continued to follow all patients randomized into the trial on an intention-to-treat (ITT) basis according to their original dose assignment. The primary data analysis compares the 900-mcg albinterferon alfa-2b treatment group to the peginterferon alfa-2a treatment group. The trial included 48 weeks of treatment, and the primary efficacy endpoint was sustained virologic response (SVR), defined as undetectable viral load (HCV RNA<10 IU/mL) at Week 72 (24 weeks following completion of treatment). A total of 2,264 patients with chronic hepatitis C have participated in the two Phase 3 trials of albinterferon alfa-2b.

About Albinterferon Alfa-2b (Albuferon)

Albinterferon alfa-2b is a genetic fusion of human albumin and interferon alfa created using the proprietary HGS albumin-fusion technology. Human albumin is the most prevalent naturally occurring blood protein in the human circulatory system, persisting in circulation in the body for approximately 19 days. Research has shown that genetic fusion of therapeutic proteins to human albumin decreases clearance and prolongs the half-life of the therapeutic proteins.

Albuferon is being developed by HGS and Novartis for the treatment of chronic hepatitis C under an exclusive worldwide co-development and commercialization agreement entered into in June 2006. HGS and Novartis will co-commercialize Albuferon in the United States and will share clinical development costs, U.S. commercialization costs and U.S. profits equally. Novartis will be responsible for commercialization in the rest of the world and will pay HGS a royalty on those sales. Clinical development, commercial milestone and other payments to HGS could total as much as $507.5 million, including $132.5 million received to date.

About Hepatitis C

Hepatitis C is an inflammation of the liver caused by the hepatitis C virus. It is estimated that as many as 170 million people worldwide are infected with hepatitis C virus. This includes nearly four million people in the United States. When detectable levels of HCV persist in the blood for at least six months, a person is diagnosed with chronic hepatitis C. Hepatitis C virus can cause serious liver disease, leading to cirrhosis, primary liver cancer and even death. Patients infected with the genotype 1 hepatitis C virus account for approximately 75% of the chronic hepatitis C patients in the U.S.

Developing Fruit Fly Embryo Is Capable Of Genetic Corrections

2009-03-10T11:03:00.000-07:00

Animals have an astonishing ability to develop reliably, in spite of variable conditions during embryogenesis. New research, published in parallel this week in PLoS Biology and PLoS Computational Biology, addresses how living things can develop into precise, adult forms when there is so much variation present during their development stages. A team led by John Reinitz at Stony Brook University, and funded by the National Institutes of Health, shows how fruit fly embryos can "forget" initial incorrect versions of their body plan and develop into recognizable adult flies.

"Our results show that groups of genes can act on one another to reduce variation and highlights the importance of genetic networks in generating robust development," said Dr. John Reinitz.

Canalization, a principle of developmental biology described more than 60 years ago by C.H. Waddington, is the property of embryonic development whereby genetic interactions can adjust biochemical reactions to bring about reliable developmental outcomes, despite variable conditions.

A great deal of progress has been made in understanding the buffering of genotypic and environmental variation, and individual mutations that reveal variation have been identified. However, the mechanisms by which genetic interactions produce canalization are not yet well understood, because this requires molecular data on multiple developmental determinants and models that correctly predict complex interactions.

"We make use of gene expression data at both high spatial and temporal resolution for the gap genes involved in the segmentation of the fruit fly Drosophila embryo," said Dr. Reinitz. "We also apply a mathematical model to show that cross regulation among the gap genes is responsible for canalization in this system." The model predicted specific interactions that cause canalization, and the prediction was validated in experiments.

"With canalization, if there is too much of one protein in the embryo, a network of genes could theoretically change the amount of that protein present, so that the outcome for the embryo was normal," said Dr. Reinitz. "Since this principle was suggested, a great deal of progress has been made in understanding the buffering of variation, but the specific mechanisms by which genetic interactions contribute to canalization have remained unclear - until now."

The authors started by measuring the concentrations of certain proteins in normal and mutant Drosophila embryos, at an early stage of development when the embryo looks like a hollow rugby ball. Each protein is synthesized from a gene, and each of the proteins measured has a regulatory role; they can turn their own gene - and others - on and off. The authors created a series of equations that could describe the diffusion of proteins and their action on their own gene and on other genes in the network. These equations show that a wide range of initial conditions (in terms of protein concentrations) lead to several possible final conditions. These final conditions, called fixed points, govern or describe the final state of the segmentation process for the fruit fly embryo. They do not allow for variability in the embryo, and they 'forget' the initial information. This mathematical property combined with their accuracy in describing the biological processes can be used towards the theoretical explanation for Waddington's canalization model.

"This study is an example of how biology is becoming a precise and quantitative field, like physics," says Reinitz.

This work is the result of an international collaboration of authors, including Manu of Stony Brook University; David H. Sharp of the Los Alamos National Laboratory, and Svetlana Surkova and Maria Samsonova of the St. Petersburg State Polytechnical University.

Molecular '2-Step' Leading To Protein Clumps Of Huntington's Disease Described By Pitt Researchers

2009-03-09T10:41:00.000-07:00

In a paper published in the early online version of Nature Structural and Molecular Biology, researchers at the University of Pittsburgh School of Medicine deconstruct the first steps in an intricate molecular dance that might lead to the formation of pathogenic protein clumps in Huntington's disease, and possibly other movement-related neurological disorders.

Huntington's is one of 10 diseases in which a certain protein, different for each disease, contains polyglutamine, a stretch of repeating blocks of the amino acid glutamine, explained Ronald Wetzel, Ph.D., professor in the Department of Structural Biology and member of the Pittsburgh Institute for Neurodegenerative Diseases at the University of Pittsburgh School of Medicine. The affected protein in Huntington's disease is called huntingtin.

Most people have a huntingtin protein whose polyglutamine segment contains 20 or so glutamines, and even a polyglutamine with as many as 35 repeats may not cause Huntington's symptoms. But the risk of developing Huntington's disease rises sharply in individuals whose polyglutamine sequences are only slightly larger. A block of 40 repeats, for example, is associated with a very high likelihood of having the disease.

"To a protein chemist, this is a fascinating situation," Dr. Wetzel said. "Polyglutamine doesn't seem to play a sophisticated role in these proteins, and it doesn't have a defined structure. Yet by changing its length to only a very slight extent, it takes on some new physical properties that somehow initiate diseases."

One consequence of the lengthening is protein aggregation, or clumping, a feature that consistently appears in brain cells of patients who have one of these neurodegenerative diseases. Many research groups, including Dr. Wetzel's, study how polyglutamine expansion alters the huntingtin protein's behavior.

In its most recent studies, the Pitt team worked out the details of how the aggregation behavior of huntingtin depends, in a surprisingly intricate way, on the neighboring segments of amino acid sequence flanking the polyglutamine.

They found that longer polyglutamine sequences have the ability to disrupt the structure of a neighboring region, 17 amino acids long, at the beginning of the protein known as the N-terminus. That sets the stage for new physical interactions with the rest of the huntingtin protein that drive it to aggregate.

"If the N-terminus is not there, huntingtin makes clumps very slowly, even if the polyglutamine stretch is rather long," Dr. Wetzel noted. "When the N-terminus is disrupted by its polyglutamine neighbor, it takes a lead role in the aggregation process, with the polyglutamine then following to consolidate and stabilize the clumps -a kind of 'aggregation two-step'."

The choreography might be similar in other polyglutamine diseases, meaning physical disruption of neighboring regions may influence the tendency for the protein to clump, he added. More research is needed to establish whether the aggregates cause disease or are merely a marker for it, and to try to develop treatments that can redirect the protein dance or perhaps halt it entirely. "For those of us interested in developing therapeutics," Dr. Wetzel notes, "the strong role played by the N-terminus in initiating aggregation gives us another possible molecular target."

Huntington's disease is an inherited disease in which progressive degeneration of certain brain neurons causes uncontrolled writhing, twisting and jerking movements, and cognitive and psychiatric problems. It was once called Huntington's "chorea", from a Greek word for dance.

Notes:

The research was funded by grants from the National Institutes of Health, the Huntington's Disease Society of America, the National Science Foundation, Petroleum Research Fund/American Chemical Society and the Commonwealth of Pennsylvania.

The University of Pittsburgh School of Medicine is one of the nation's leading medical schools, renowned for its curriculum that emphasizes both the science and humanity of medicine and its remarkable growth in National Institutes of Health (NIH) grant support, which has more than doubled since 1998. For fiscal year 2007, the University ranked sixth out of more than 3,000 entities receiving NIH support with respect to the research grants awarded to its faculty. As one of the university's six Schools of the Health Sciences, the School of Medicine is the academic partner to the University of Pittsburgh Medical Center (UPMC). Their combined mission is to train tomorrow's health care specialists and biomedical scientists, engage in groundbreaking research that will advance understanding of the causes and treatments of disease and participate in the delivery of outstanding patient care.

Stem Cell Scaffolding Makes New Brain Tissue After Stroke Damage

2009-03-09T10:35:00.000-07:00

Researchers in the UK inserted tiny scaffolds with stem cells attached into the stroke damaged brains of rats and found that they grew into new tissue to fill the holes made by the stroke damage.

The research was led by Dr Mike Modo of the Institute of Psychiatry, King's College London and took place at the Institute of Psychiatry and University of Nottingham. It is to be published in the journal Biomaterials and was funded by the Biotechnology and Biological Sciences Research Council.

The researchers found it only took 7 days for the scaffolded stem cells to fill the stroke damage holes.

Other studies have tried to fill holes left by stroke damage with stem cells but found they just migrated to surrounding tissue. However, Modo and colleagues found this problem ceases when the stem cells have a structure to cling onto.

"We would expect to see a much better improvement in the outcome after a stroke if we can fully replace the lost brain tissue, and that is what we have been able to do with our technique," said Modo in a press statement.

For the scaffolding Modo and colleagues used individual particles of a biodegradable polymer called PLGA. They "loaded" the PLGA particles with neural stem cells and injected them into the stroke cavities.

"This works really well because the stem cell-loaded PLGA particles can be injected through a very fine needle and then adopt the precise shape of the cavity," Modo explained.

"In this process the cells fill the cavity and can make connections with other cells, which helps to establish the tissue," he added.

Over the next few days they could see the cells migrating along the scaffolding made by the PLGA particles and forming into primitive brain tissue that interacts with the host brain.

"Gradually the particles biodegrade leaving more gaps and conduits for tissue, fibres and blood vessels to move into," said Modo.

Modo and colleagues used an MRI scanner to find the exact spot in the brain to inject the PLGA loaded with stem cells and also to observe the growth of new tissue.

They now want to try adding VEGF (vascular endothelial growth factor) to the PLGA and stem cell scaffold to see if it encourages new blood vessels to form in the new tissue.

"Stroke is a leading cause of disability in industrialised countries," said Professor Douglas Kell, Chief Executive of the BBSRC.

"It is reassuring to know that the technology for treating stroke by repairing brain damage is getting ever closer to translation into the clinic," he added, explaining that the work being done by Modo and colleagues provides a solid foundation for further research and better treatments.

Joe Korner, Director of Communications at The Stroke Association agrees and calls the study exciting because Modo and colleagues were able to overcome many of the challenges of converting the promising idea of stem cells into reality.

Korner said every five minutes someone in the UK has a stroke.

"This research is another step towards using stem cell therapy in treating and reversing the brain damage caused by stroke," he added, but cautioned that while this work appears to show it is possible to reverse the damage caused by stroke, therapies for stroke survivors are still a long way off since considerably more research is needed before the technique can be tried on humans.

Discovery Of Gene Mutations That Cause Childhood Brain Cancer

2009-03-09T10:30:00.000-07:00

Researchers funded by the Canadian Cancer Society have discovered eight similar genes that, when mutated, appear to be responsible for medulloblastoma - the most common of childhood brain cancers. The findings are published in the online edition of the journal Nature Genetics.

"This discovery is very promising and may help researchers develop better, more targeted treatments so that more of these children will survive and fewer will suffer debilitating side effects," says Dr. Christine Williams, Director of Research Programs, Canadian Cancer Society Research Institute.

Dr. Michael Taylor, who has a $600,000 research grant from the Canadian Cancer Society, led the study: "When these eight genes are functioning normally, we believe their role is to make a protein which tells the developing brain when it's time to stop growing. But when the genes are mutated, the brain may continue to grow out of control, leading to cancer.

"Drugs are already being developed that target these types of proteins," he says. "Our hope is that some of these drugs may be adapted and used effectively to treat medulloblastomas." Dr. Taylor is a pediatric brain surgeon at Toronto's Hospital for Sick Children:

In the study, the largest of its kind, researchers looked at more than 200 tumour samples. The samples came from children in countries all over the world including Canada, the US, England, Poland and Saudi Arabia. Paul Northcott, a PhD student in Dr Taylor's lab, analyzed and interpreted all the data over a period of 3 ½ years. "We've learned more from this study about the genetic basis of this disease than from any other previous study," Northcott says. The gene mutations they found had not been suspected as culprits in cancer formation.

About 250 Canadian children are diagnosed with various types of brain cancer every year. About 70 per cent of these survive. Brain tumours are the leading cause of childhood cancer deaths. The most common childhood brain cancer is medulloblastoma - a tumour that occurs at the back of the brain in the cerebellum. It is primarily a disease of very young children and is particularly deadly among babies under 18 months of age. In Canada, about 40 children are diagnosed with medulloblastoma every year and half of these will survive.

Many survivors experience serious physical and neurological problems from the disease itself and from the effects of very aggressive treatments on the developing brain. Treatments include surgery, radiation and chemotherapy.

Notes:

The Canadian Cancer Society is a national community-based organization of volunteers whose mission is the eradication of cancer and the enhancement of the quality of life of people living with cancer. It is the largest national charitable funder of cancer research in Canada. Last year, the Society funded close to $49.5 million in leading-edge research projects across the country. To know more about cancer, visit the website at http://www.cancer.ca/.

40 Percent Of People With Lupus Have Kidney Involvement

2009-03-09T09:26:00.000-07:00

Lupus is an unpredictable and potentially fatal autoimmune disease that affects an estimated 1.5 million Americans. The kidneys will be affected in approximately 40 percent of adults and as many as two-thirds of the children with lupus. March is National Kidney Month and the Lupus Foundation of America (LFA) is calling attention to this serious and often devastating complication of lupus.

The LFA will conduct a live chat on "Kidney Involvement and Lupus" through its website, http://www.lupus.org, on Wednesday, March 11, at 3:00 p.m. Eastern time. The guest expert will be Dr. Brad Rovin, Director of Nephrology at the Ohio State University College of Medicine.

Lupus nephritis is the term used when lupus causes inflammation in the kidneys, making them unable to properly remove waste from the blood or control the amount of fluids in the body. Abnormal levels of waste can build up in the blood, and swelling (edema) can develop. If left untreated, nephritis can cause scarring and permanent damage to the kidneys and possibly end-stage renal disease (ESRD).

Weight gain and puffiness in the feet, ankles, legs, hands, and/or eyelids are early symptoms of lupus kidney disease. The swelling often becomes worse throughout the day. The urine may also be foamy or frothy, or have a red color. Individuals experiencing these symptoms should immediately seek medical attention.

The LFA website has information about lupus kidney disease. Individuals may submit questions in advance or during the course of the chat. A transcript of the chat will be posted the following day.

Guidance on non-surgical cosmetic procedures, General Dental Council, UK

2009-03-08T10:10:00.000-07:00

The General Dental Council has confirmed its guidance on non-surgical cosmetic procedures.

This is the result of the GDC's public consultation on the scope of practice of the dental team in 2008. It sought views on what different groups of professionals could do as part of their work and what would be valid additions to conventional dentistry.

Our guidance now states:

"Registrants choosing to offer Botox or other non-surgical cosmetic procedures should note that the GDC expects the same high standards of them, whatever the type of treatment they are carrying out. In particular, they are advised to work within their knowledge and professional competence and be prepared to back up the decisions they make. Careful thought also needs to be given to maintaining professional standards in relation to advertising these services, and to the need to be indemnified."

Duncan Rudkin, Chief Executive and Registrar of the General Dental Council, said:

"This is a complex issue which the GDC has considered carefully. Our primary concern is, as always, patient protection. We urge dental professionals to think very carefully about carrying out non-surgical cosmetic procedures such as Botox. You must be certain you are trained and competent, and that you can achieve the same high standards we expect of you in other more traditional areas. Check you are indemnified for this type of work and think about how you are advertising these services. We expect our registrants to make responsible choices, putting patients first."

TomTec Announces SonoLiver(R), A Dedicated Analysis Tool Of Dynamic Vascular Enhancement Of Focal Liver Lesions Using CEUS

2009-03-08T10:04:00.000-07:00

TomTec announces the release of SonoLiver® as part of TomTec's Image-Arena™ multimodality workstation solution at the European congress of radiology in March 2009.

SonoLiver® combines in a novel way perfusion quantification tools with perfusion imaging of focal liver lesions. The unique display of dynamic vascular patterns of all phases simplifies the decision for the right diagnosis. SonoLiver® increases the diagnostic confidence and simplifies the workflow of characterizing focal liver lesions.

SonoLiver® is performing a linearization of the Contrast enhanced ultrasound data for comparable results, uses an optimized motion artefact suppression to reduce in-plane motion artefacts and enhances the dynamic vascular patterns by parametric display.

"The cooperation with Bracco enables us to offer SonoLiver as a dedicated CEUS quantification tool for focal liver lesion. SonoLiver runs within TomTec's Image-Arena™ environment which provides a full range of connectivity, data management and reporting features for an optimized clinical workflow!" said Frank Schlau, TomTec's Chief Marketing Officer.

About TomTec

TomTec Imaging Systems GmbH, with headquarter located in Munich Germany holds an inventive leadership position in the field of diagnostic medical imaging applications and Cardio PACS solutions. The company maintains close working relationships with many leading universities and device manufacturers around the world. TomTec's product portfolio encompasses a wide range of 2D and 3D/4D technologies for visualization, analysis, reporting and archiving of multimodality imaging data. TomTec solutions are applicable in the fields of Adult- and Pediatric Cardiology as well as Obstetrics, Gynaecology, Radiology, and Vascular Imaging. Visit TomTec's web site at http://www.tomtec.de

SonoLiver is a registered trademark

Shanghai Team Analyzes Mechanism That Enables Adult Cells To Behave Like Embryonic Stem Cells

2009-03-08T10:01:00.000-07:00

Agilent Technologies Inc. (NYSE:A) today announced its collaboration with a team from the Shanghai Institutes for Biological Sciences and Tongi University that has achieved new insight into how adult cells can be induced to act like embryonic stem cells (ESC), with the ability to form any type of tissue known as "pluripotency."

"The value of finding alternatives to embryonic stem cells would obviously be tremendous, and the ability to induce pluripotency in adult cells, discovered in 2006, is considered a breakthrough," said Jian Li of Agilent Technologies Shanghai, one of the article's coauthors. "Now we're gaining new understanding into how this pluripotency was actually induced."

Their findings were published in the journal"Cell Research," in an article titled "Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells" (Cell Research, 2008 18:1177-1189). The researchers observed a developmental signaling network of 16 signaling pathways, including nine that had not previously been assigned roles in maintaining or inducing pluripotency.

The study used Agilent chromatin immunoprecipitation-on-chip (ChIP-on-chip) and gene expression microarrays to study molecules known as "Yamanaka factors" and their roles in inducing pluripotency in mouse cells.

Agilent provided the microarray kits for this research under an Agilent grant issued in 2008. Microarrays are glass wafers containing large numbers of DNA probes used to analyze genomic activity. ChIP-on-chip microarrays are used to observe activity at "promoter regions" on the genome, where chemical events activate and deactivate various genes to control cellular functioning.

About Agilent Technologies

Agilent Technologies Inc. (NYSE:A) is the world's premier measurement company and a technology leader in communications, electronics, life sciences and chemical analysis. The company's 19,000 employees serve customers in more than 110 countries. Agilent had net revenues of $5.8 billion in fiscal 2008. Information about Agilent is available on the Web at http://www.agilent.com.

TECcare™ Ultra Passes AOAC Viral Testing

2009-03-08T09:48:00.000-07:00

Talley Environmental Care Ltd are pleased to announce that as part of the ongoing development and assessment programme for TECcare™ antimicrobial technology products, TECcare™ Ultra has passed the stringent AOAC testing for Norovirus and Human Influenza A, and has been shown to be highly effective at destroying these potentially life threatening pathogens.

Noroviruses are highly contagious pathogens, with as few as 100 virus particles thought to be sufficient to cause infection. Noroviruses are transmitted primarily through direct person-to-person contact or spread via contaminated food or water. These viruses are relatively stable in the environment and can survive freezing and heating to 60°C (140°F). Currently, th ere is no antiviral medication that works against Norovirus and there is no vaccine to prevent infection. Norovirus infections cannot be treated with antibiotics because antibiotics work to fight bacteria and not viruses. It is estimated that the Norovirus affects between 600 thousand - 1 million people in the UK alone every year.

Influenza can cause mild to severe illness, and is generally passed from person to person by airborne transmission (i.e., sneezing or coughing), but, the virus can also live for a short time on surfaces, therefore, it may also be spread by touching something that has been handled by someone infected with the virus and then touching your own mouth, nose, or eyes. For some people flu can lead to more serious illnesses such as bronchitis and pneumonia which may require hospital treatment.

TECcare™ antimicrobial technology now offer effective solutions to eradicate not only these viruses but a range of pathogens including MRSA, C-difficile, Salmonella and Ecoli from all areas within sensitive environments through the use of TECcare™ Ultra, and TECcare™ Control. Kevin Mearns Operations Director commented; "These new exciting test results confirm that TECcare™ Ultra will play an important role in tackling these highly disruptive and potentially deadly viruses. Innovative TECcare™ antimicrobial technologies are continually developed to meet the ever changing demands of industry and society as a whole, whilst ensuring the safety of the operatives, general public and the environment. All of the products are extensively tested and clinically proven to kill / deactivate an extensive range of pathogens including bacteria, bacterial spores, viruses, moulds and fungi."

TECcare™ technology does not contain damaging chemicals and skin irritants such as alcohols, phenols, chlorine and aldehydes and is well suited for repeated use on surfaces. It is safe and effective in use as well as being fully biodegradable and environmentally friendly.

The TECcare™ technology can be used in a variety of areas including Healthcare, Pharmaceuticals, Advanced Wound Care, Dentistry, Food and Beverage, Hospitality and Leisure, Water Treatment, Industrial Applications, Schools and Nurseries and for General Domestic Hygiene.

Magnetic Nanoparticles Navigate Therapeutic Genes Through The Body

2009-03-07T09:47:00.001-08:00

Health professionals send genes and healthy cells on their way through the bloodstream so that they can, for example, repair tissue damage to arteries. But do they reach their destination in sufficient quantities? Scientists of the PTB have developed a highly sensitive measuring method with which the efficiency of this therapy can be investigated: Small magnetic particles which are situated on the planted gene or on the planted cell can with the aid of an external magnetic field be specifically directed to the location of the damage. There the researchers determine, accurate to the picogram per cell, the quantity of the magnetic material - and thus also the quantity of the therapeutically effective genes or cells. In a joint study with the University of Bonn it became clear: By means of the magnetic method it is possible to dramatically increase the efficiency of the gene transfer in comparison to the non-magnetic method.

Magnetic nanoparticles can support or even enable gene transfer under clinically relevant experimental conditions. For the transduction of human cells, gene carriers were coupled to magnetic nanoparticles and dragged into the cells by magnetic field gradients. The efficiency of magnetic transduction turned out to be much higher than the nonmagnetic procedure. An additional welcome side effect is the "magnetization" of the cells after the incorporation of nanoparticles. This may enable the targeted transport of the cells to regions of interest.

A closer look at the underlying mechanism of magnetic gene transfer was taken by the quantification of the magnetic material that was delivered to the cells. The required highly sensitive measurements in the range of a few picogramm per cell were made by PTB using magnetorelaxometry. The good correlation between measurement data and gene transfer encourages to use magnetorelaxometry for monitoring the efficiency of gene and cell transfer, possibly even in vivo.

Saving Heart Attack Patients In The Middle Of The Night

2009-03-07T09:41:00.000-08:00

When Joyce Moss recently arrived at Loyola University Hospital with a life-threatening heart attack, it took just 42 minutes to perform an emergency balloon angioplasty.

The procedure opened up an artery that was 100 percent blocked. "There was no damage to the heart because of how quick they were," said Moss, 56, of Berwyn. "I feel good."

To further improve its emergency angioplasty times, Loyola will become the first hospital in Illinois to staff a Heart Attack Rapid Response Team (HARRT) at the hospital 24 hours a day, seven days a week. The HARRT program includes board-certified and highly-experienced interventional cardiologists, nurses and technicians.

Most hospitals do not have such personnel on site during nights and weekends. Thus, precious time is lost when the team has to be called in from home. This is especially true when staffers are delayed by snow storms or other bad weather.

"The HARRT program will provide the next leap of care for patients," said Loyola interventional cardiologist Dr. Fred Leya. Leya is among a team of interventional cardiologists who will rotate night and weekend shifts at the hospital. Leya is medical director of Loyola's cardiac catheterization lab.

Reducing angioplasty times is a coordinated effort that begins with paramedics who take patients to the hospital. There are 51 west suburban fire departments and ambulance companies in the Loyola Emergency Medical Services System. A growing number of ambulances are being equipped so that paramedics can administer 12-ead EKG exams while en route to the hospital. An EKG can confirm a heart attack, and results are radioed ahead to the hospital, said Dr. Mark Cichon, Loyola's director of emergency medical services.

Once a heart attack is confirmed, it takes less than five minutes to prep the patient. The interventional cardiologist then threads a catheter (thin tube) from an artery in the groin to the heart. The cardiologist inflates a balloon at the tip of the catheter to open the artery. In many cases, the cardiologist places a stent (wire mesh tube) to keep the artery open.

The doctor must be fast and accurate. "You become very focused," said interventional cardiologist Dr. Bruce Lewis. "It's like shooting a three-pointer with two seconds to go, except that you can't afford to miss." Lewis is a professor in the division of cardiology at Stritch.

Experience helps improve outcomes. Interventional cardiologists on the HARRT team each perform approximately 300 angioplasties per year. "We have seen just about every permutation," Lewis said.

A task force of the American College of Cardiology and American Heart Association recommends that a patient undergoing a heart attack receive a balloon angioplasty as soon as possible or at least within 90 minutes of arriving at the hospital -- known as the door-to-balloon time. Speed "is of central importance because the benefits of therapy diminish rapidly with delays in treatment," the task force said in a November, 2008 statement published in the heart association journal Circulation.

During a heart attack, a blockage in an artery stops blood flow. Heart muscle begins to die due to lack of blood and oxygen. An emergency angioplasty can reopen a blocked artery and restore blood flow. The procedure does the most good if done within one hour of the patient's arrival, known as the Golden Hour. After three hours, there may not be enough benefits to justify the risks of the procedure.

"Time is heart muscle," said Dr. David Wilber, director of Loyola's Cardiovascular Institute. "The sooner we can open the artery, the better."

A balloon angioplasty is the most effective way to reopen an artery, according to a review of 23 studies published in the British medical journal Lancet. In the studies, heart attack patients were randomly assigned to receive a balloon angioplasty or an intravenous clot-busting drug such as streptokinase. Among patients receiving clot-busting drugs, 14 percent died or suffered a stroke or subsequent heart attack, compared with only 8 percent in the angioplasty group.

Loyola is among a small but growing number of hospitals that are establishing around-the-clock angioplasty teams. Other hospitals include Detroit Medical Center, Vanderbilt Medical Center in Nashville, Tn. and Aurora St. Luke's Medical Center in Milwaukee. Detroit Medical Center has cut its door-to-balloon time to 47 minutes.

"There is increasing evidence that timely angioplasty not only results in better patient outcomes, but may actually reduce overall health care costs in the long run by cutting down the need for later diagnostic procedures, interventions, and hospitalizations." Wilber said. "This is achieved despite the additional effort and expense on the front end. As physicians and hospitals strive to improve the quality of care while controlling long-term costs, it is likely that more centers will adopt these programs."

In Moss' case, there was a blockage in a branch to one of her major heart arteries. After reopening the blockage, Lewis placed a stent. An echocardiogram later found there was no significant damage to her heart muscle.

Moss' heart attack occurred while she was driving to her job as a school bus driver. She said it felt like there was a 50-pound weight on her chest. Her left arm went numb and fell off the steering wheel. She was sweating and nauseous. She pulled off the road and called 911. "I knew it was a heart attack," she said.

Moss, who has six children and 11 grandchildren, said "It's good to still be here."

Loyola University Health System board member James Dowdle and his wife, Sally, have pledged $500,000 to help offset the initial costs of opening the program. The Dowdles have donated more than $2 million to LUHS and to Loyola University Chicago. James Dowdle, a retired executive vice president of the Tribune Co., is the 2001 recipient of the Sword of Loyola, the highest honor of Loyola University Chicago. Sally Dowdle has served as co-chair of the hospitality committee of the Stritch School of Medicine's annual award dinner.

Loyola is a nationally recognized center of excellence for heart and vascular care. It is the only Illinois hospital to be named to the Thomson Reuters 2008 list of the nation's top 30 teaching hospitals with cardiovascular residency programs. And U.S. News and World Report consistently ranks Loyola's heart program as one of the best in the country.

Based in the western suburbs of Chicago, Loyola University Health System is a quaternary care system with a 61-acre main medical center campus, the 36-acre Gottlieb Memorial Hospital campus and 22 primary and specialty care facilities in Cook, Will and DuPage counties. The medical center campus is conveniently located in Maywood, 13 miles west of the Chicago Loop and 8 miles east of Oak Brook, Ill. The heart of the medical center campus, Loyola University Hospital, is a 570-licensed bed facility. It houses a Level 1 Trauma Center, a Burn Center and the Ronald McDonald® Children's Hospital of Loyola University Medical Center. Also on campus are the Cardinal Bernardin Cancer Center, Loyola Outpatient Center, Center for Heart & Vascular Medicine and Loyola Oral Health Center as well as the LUC Stritch School of Medicine, the LUC Marcella Niehoff School of Nursing and the Loyola Center for Fitness. Loyola's Gottlieb campus in Melrose Park includes the 250-bed community hospital, the Gottlieb Center for Fitness and the Marjorie G. Weinberg Cancer Care Center.

'Personalized' Genome Sequencing Reveals Coding Error In Gene For Inherited Pancreatic Cancer

2009-03-07T08:56:00.000-08:00

Scientists at the Sol Goldman Pancreatic Cancer Research Center at the Johns Hopkins Kimmel Cancer Center have used "personalized genome" sequencing on an individual with a hereditary form of pancreatic cancer to locate a mutation in a gene called PALB2 that is responsible for initiating the disease. The discovery marks their first use of a genome scanning system to uncover suspect mutations in normal inherited genes.

The findings, they say, underscore the value of so-called "personalized genome" sequencing, which decodes a person's genes and compares the changes to those found in healthy people. "Gene sequencing has always had the potential to help us learn if a person is susceptible to certain diseases," says Alison Klein, Ph.D., director of the National Familial Pancreas Cancer Tumor Registry at Johns Hopkins. "By finding the genetic error responsible for this patient's pancreatic cancer, our team has provided an excellent example of the power of this approach."

The coding error in PALB2, which stands for "partner and co-localizer of BRCA2" causes a shortened version of the protein encoded by this gene, rendering it incapable of working with another cancer-related gene, BRCA2, to repair broken DNA. Mutations in BRCA2 are also known to cause hereditary forms of cancer.

Klein and her team caution that their finding has not yet resulted in a clinical test for the hereditary pancreas cancer gene, but laboratories at Johns Hopkins and possibly elsewhere will be developing one, which she says can be used to increase cancer surveillance for early signs of disease in those at risk.

Reporting their findings in the March 5 edition of Science Express, the Johns Hopkins researchers say they sequenced genes taken from a person with pancreatic cancer whose sister also had the disease, suggesting an inherited predisposition. "Generally, we need data from very large families to identify the inherited gene, and that was not available in this case," says Siân Jones, Ph.D., research associate at the Johns Hopkins Kimmel Cancer Center. Instead, the investigators used high-powered computer software to scan all known protein-coding genes in the patient -- approximately 20,000 of them - to find more than 15,000 variations.

Most of the variations were normal ones coding for such things as eye or hair color, but the search was designed to track down particular mutations that caused certain proteins to be shortened, a process that commonly occurs in cancer, says James Eshleman, M.D., Ph.D., associate professor of pathology and oncology.

The search yielded one gene variant, PALB2, resulting from a substitution of a single DNA letter coding for cytosine with a different one that codes for thymidine.

The research team then scanned for the PALB2 gene in 96 other individuals with pancreatic cancer who each had at least one relative with pancreatic cancer. Three of them had coding errors in the PALB2 gene that shortened the protein in a similar way. She estimates that three percent of people with hereditary pancreatic cancer have mutations in PALB2, making it the second most common gene mutation in these patients after BRCA2.

The investigators believe that their approach could be used to identify inherited alterations that predispose people to other types of cancer as well as other genetic-based diseases. "The more information we have about normal variants, the easier it will be to find disease-causing ones," says Michael Goggins, M.D., professor of pathology, medicine and oncology at Johns Hopkins.

In the future, scanning genomes for hereditary disease-causing genes could become "reasonably routine," according to Bert Vogelstein, M.D., an investigator at the Howard Hughes Medical Institute and co-director of the Ludwig Center at Johns Hopkins.

The investigators say that the cost to determine the sequence of all genes in an individual for this project was approximately $150,000, but that this cost will likely decrease considerably in the future.

Notes:

Funding for this project was provided by the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, the Virginia and D.K. Ludwig Fund for Cancer Research, the National Institutes of Health and the Michael Rolfe Pancreatic Cancer Foundation.

In addition to Klein, Eshleman, Goggins and Vogelstein, investigators who conducted the research include, Ralph Hruban, Mihoko Kamiyama, Michael Borges, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng-Ho Lin, Emily Palmisano, Keiran Brune, Elizabeth Jaffee, Christine Iacobuzio-Donahue, Anirban Maitra, Giovanni Parmigiani, Scott Kern, Victor Velculescu, and Kenneth Kinzler from Johns Hopkins.

Discovery Of A New Retinal Gene Involved In Childhood Blindness

2009-03-07T08:53:00.000-08:00

The team of Dr. Robert Koenekoop which includes Dr. Irma Lopez from the Research Institute of the MUHC at the Montreal Children's Hospital played a crucial role in the international collaboration that led to the discovery of a new gene that causes Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP), two devastating forms of childhood blindness.

This finding of this new gene, called SPATA7, is remarkable because it identifies a new retinal metabolic disease pathway that may be crucial for many patients. It also opens a new avenue for a potential genetic therapy. Gene therapy targeting different genes has recently proved successful for the same disease in human subjects. The study will be published on March 5th, 2009 in the American Journal of Human Genetics.

New cell mechanism at play

Researchers have now identified a total of fifteen genes involved in LCA, but SPATA7 is the first gene with a mutation that disrupts the protein transport between two important compartments of the cell: the endoplasmic reticulum and the Golgi apparatus. All proteins in every cell have to pass through this transport pathway; thus SPATA7 plays a major role and its mutation may affect many aspects of vision.

"Until now we were not aware that this cellular mechanism played a role in LCA or any other eye disease. This is a very important step that opens up a number of new research avenues, particularly in our understanding of the specific cellular processes involved in blindness. This finding also increases the number of potential therapeutic targets and therefore the chances of finding a treatment. We are extremely motivated by all of these new possibilities," explained Dr. Koenekoop.

First step towards gene therapy

"This is an incredible discovery that gives great hope to LCA patients and their families, that gene based therapies can and will be developed to restore sight," said Sharon Colle, President and CEO of The Foundation Fighting Blindness, the leading private charity for vision research. "We are proud to fund such important discoveries involving prominent Canadian researchers and institutions."

A careful assessment of patients with some specific genetic types of LCA also demonstrated that their retinal cells (specifically the rod and cone photoreceptors), although not functional for vision, were still present and in relatively good condition. This critical observation will allow researchers to continue on the path towards gene therapies. Therapies targeting different genes for the same disease have already shown success in the United Kingdom and in the US, meaning that LCA patients can now enjoy hope for the future.

A new and innovative technology

SPATA7 was identified using an innovative technology developed in the different laboratories involved in this international collaboration. "We started this protocol about two years ago, and it has already helped us to identify four new genes associated with LCA and RP before we discovered SPATA7," explained Dr Koenekoop.

The technique is based on DNA-chips and involves three steps: first the genetic material of the patient is screened to find mutations in 14 specific LCA and RP genes. The LCA and RP patients that are negative for this detailed screen are then subjected to a second DNA chip, this one to identify significant stretches of homozygosity in SNP markers. SNPs are single nucleotide repeats, which are natural variations in the human genome. These homozygous regions may contain new genes and are carefully probed based on functional information and then subjected to sequencing. "This method is indeed both very powerful and very promising for the future," said Dr. Koenekoop.

New Study Of Human Pancreases Links Virus To Cause Of Type 1 Diabetes - May Lead To A Vaccine

2009-03-07T08:52:00.000-08:00

A team of researchers from the Peninsula Medical School in the South West of England, the University of Brighton and the Department of Pathology at Glasgow Royal Infirmary, has found that a common family of viruses (enteroviruses) may play an important role in triggering the development of diabetes, particularly in children. These viruses usually cause symptoms similar to the common cold, or vomiting and diarrhoea. However, the team has now provided clear evidence that they are also found frequently in the pancreas of people who develop diabetes.

The research, which was carried out at Peninsula Medical School and funded by Juvenile Diabetes Research Foundation (JDRF), is published today, 6th March 2009, in the leading European diabetes journal, Diabetologia. It involved the detailed study of a unique collection of pancreases from 72 young people who died less than a year after the diagnosis of type 1 diabetes.

Type 1 diabetes usually starts in young people and results from the destruction of the insulin-producing beta cells in the pancreas. Patients who develop type 1 diabetes have to take multiple daily injections of insulin for the rest of their lives, and the condition affects around 300,000 people in the UK , including 20,000 children under the age of 15. There are a further estimated 440,000 cases of type 1 diabetes in children worldwide, with more than a fifth living in Europe.

It is accepted that children who develop type 1 diabetes inherit a genetic susceptibility to the disease, but studies of identical twins have shown that when one twin has the disease, the other twin will only have approximately a 40 per cent chance of developing diabetes - suggesting that factors additional to inheritance are also involved.

It has long been speculated that viruses might play a role in causing type 1 diabetes by infecting the beta cells of the pancreas. This new research, which has made use of unique source material collected in Glasgow, is the first to provide evidence supporting this theory in such a large number of pancreases from young people recently diagnosed with the disease. It has revealed that more than 60 per cent of the organs contained evidence of enteroviral infection of the beta cells. By contrast, infected beta cells were hardly ever seen in tissue samples from 50 children without the condition.

The new research suggests that enteroviral infection of the beta cells in children with a genetic disposition to type 1 diabetes may initiate a process whereby the body's immune system identifies beta cells as 'foreign' and rejects them, as it would a transplanted organ.

An extension of the study to adults with type 2 diabetes showed that a large proportion (40 per cent) of these patients also had enteroviral infection in their beta cells. This compared with only 13 percent of non-diabetic adults of the same age group. Unlike type 1 diabetes, type 2 diabetes usually starts in adults and is associated with obesity. The beta cells are not destroyed in this disease but their ability to make insulin is compromised. The way that enteroviruses might contribute to the development of type 2 diabetes has not been established but it is known from laboratory studies that an enteroviral infection of beta cells reduces their ability to release insulin. It is possible that in people who are obese (where there is a greatly increased demand for insulin secretion) a reduction of beta cell function, secondary to enteroviral infection, may be sufficient to trigger type 2 diabetes - although more research is required to confirm this.

Overall, the findings of this new study suggest that vaccination in childhood to prevent enteroviral infections of beta cells might be an attractive means to reduce the incidence of both common forms of diabetes. However, there are up to 100 different strains of enterovirus and more research will be needed to identify which particular enteroviruses are associated with the development of diabetes, and whether vaccines could be developed to prevent their spread.

Professor Noel Morgan from the Peninsula Medical School commented: "We are genuinely excited by the findings of our study. This is the first time that scientists have been able to provide such extensive evidence for the relationship between enteroviral infection of the beta cells and the development of type 1 diabetes. This is due in large part to the unique availability of such a large number of pancreases from young people who had died of type 1 diabetes soon after becoming ill. Not only did this give us access to extremely important research material, but it also underlines the importance of continued organ donation to the development of medical research in the UK. "

He added: "The next stages of research - to identify which enteroviruses are involved, how the beta-cells are changed by infection and the ultimate goal to develop an effective vaccine - will lead to findings which we hope will drastically reduce the number of people around the world who develop type 1 diabetes, and potentially type 2 diabetes as well."

Professor Adrian Bone from the University of Brighton said: "It is a real privilege to be part of this work which sheds light on how targeted beta-cell destruction may be triggered in individuals at risk of developing diabetes. Whilst experimental studies from many laboratories, including my own, have been able to document the "natural history" of the disease processes culminating in overt diabetes, the role of viral infections in initiating these events is still unproven and controversial.

"Indeed," he added, "viruses have been shown to be capable of both inducing and preventing the development of diabetes. The true importance of our present study lies in the translation of these earlier experimental findings into meaningful observations in children and young people with diabetes."

Pathologist, Dr Alan Foulis of the Royal Infirmary in Glasgow, observed: "It is 25 years since I started assembling this collection of pancreases from patients with recent onset type 1 diabetes, with the express purpose of looking for the presence of enterovirus. It is only very recently that techniques of sufficient sensitivity to detect the virus in such specimens have been developed. The success of this study is largely down to the excellent scientific collaboration we have enjoyed".

Karen Addington, Chief Executive of JDRF, said: "Type 1 diabetes is a life- threatening condition that requires a life-time of painful finger prick blood testing and insulin injections. Incidences are increasing by four per cent each year and there is currently no way to prevent it. We are proud to have funded this crucial piece of research, which helps shed light on the causes of this serious condition. JDRF passionately believes that research such as this brings us a step closer to improving treatment and eventually curing this condition."

Brain Tumor Treatment May Increase Number Of Cancer Stem-Like Cells

2009-03-07T08:51:00.000-08:00

A new study suggests that the standard treatment for a common brain tumor increases the aggressiveness of surviving cancer cells, possibly leaving patients more vulnerable to tumor recurrence. The research, published by Cell Press in the March 6th issue of the journal Cell Stem Cell, provides valuable insight into the molecular mechanisms that enable cancer stem-like cells to escape cytotoxic treatment and repopulate the tumor.

Glioblastoma multiforme is the most prevalent and aggressive form of primary brain tumor and is notoriously resistant to standard therapies. Dr. Eric Holland, from Memorial Sloan-Kettering Cancer Center in New York, examined the role of ABCG2, a protein linked with drug resistance, in glioma cancer stem-like cells. "ABC proteins are transporters that participate in tumor resistance by actively transporting drugs across the cell membrane, serving to protect cells from chemotherapeutic agents," offers Dr. Holland.

Dr. Holland and colleagues employed a method that allowed visualization of ABC-mediated efflux of fluorescent dye to identify and isolate "side population" (SP) cells from mouse and human glioblastomas. "Because the SP phenotype in glioma cancer stem-like cells is mainly mediated by ABCG2, as shown by the almost complete abolition of this phenotype when ABCG2 activity is blocked, we subsequently studied the oncogenic potential of ABCG2," explains Dr. Holland.

The researchers confirmed that SP cells are highly tumorigenic, have the ability to self-renew, and are resistant to chemotherapy. These results verified that ABCG2 activity, although not by itself oncogenic, is a marker for glioma stem-like cells. Further, the researchers identified a detailed molecular mechanism that modulates the activity of ABCG2 and enhances the ability of cancer stem-like cells to expel drugs.

Importantly, Dr. Holland's group also found that the chemotherapeutic drug temozolomide, the standard treatment for gliomas, increased the number of glioma cells with stem-like characteristics. The researchers speculated that because temozolomide is not an ABCG2 substrate, the increase in the SP fraction likely resulted from enrichment of cells with stem-like properties. "In the process of increasing the number of cells in tumors with stem-like properties, temozolomide may render surviving cells even more resistant to subsequent treatment with drugs that are substrates for ABCG2," explains Dr. Holland.

The researchers include Anne-Marie Bleau, Dolores Hambardzumyan, Tatsuya Ozawa, Elena I. Fomchenko, Jason T. Huse, Cameron W. Brennan, and Eric C. Holland, of the Memorial Sloan-Kettering Cancer Center, New York, NY.

Protein Structure Determined In Living Cells

2009-03-07T08:47:00.000-08:00

The function of a protein is determined both by its structure and by its interaction partners in the cell. Until now, proteins had to be isolated for analyzing them. An international team of researchers from Tokyo Metropolitan University, Goethe University, and the Frankfurt Institute for Advanced Studies (FIAS) has, for the first time, determined the structure of a protein in its natural environment, the living cell. Using nuclear magnetic resonance (NMR) spectroscopy, the researchers solved the structure of a protein within the bacterium Escherichia coli. "We have reached an important goal of molecular biology", says Prof. Peter Güntert from the Goethe University's Biomolecular Magnetic Resonance Center. (BMRZ) of The research results were published by the scientific journal Nature on March 5, 2009.

Conventionally, proteins are extracted from the cell, purified, and analyzed in single crystals or in solution. NMR spectroscopy detects signals from the nuclei of hydrogen atoms that are ubiquitous in organic molecules. Measurements in the living cell are challenging because it is difficult to distinguish between the protein of interest and the many other proteins in the cytoplasm. The Japanese researchers around Prof. Yutaka Ito solved this problem by introducing the gene of a putative heavy-metal-binding protein into the model system Escherichia coli, where the protein was in high concentration.

The success of the measurements relies on the method of "in-cell" NMR spectroscopy that was developed a few years ago by Prof. Volker Dötsch from BMRZ at Goethe University. Dötsch was able to attribute signals from living cells to specific proteins that he had labeled with the stable nitrogen isotope N-15. However, it was not possible to calculate a three-dimensional structure. "About two days of measurement time are required to measure a multidimensional NMR spectrum", says Peter Güntert. "Unfortunately, the cells survive for only a 5-6 hours without supply of oxygen and nutrients. Güntert and his colleagues compensated for the concomitant drastic reduction of the measurement time by computational reconstruction of the complete spectrum. Then, they calculated a detailed three-dimensional structure of the protein within E. coli cells using software that was developed in their research group.

The structure determination of proteins by in-cell NMR spectroscopy opens new avenues to investigate at atomic resolution how proteins participate in biological processes in living systems. In-cell NMR spectroscopy advances our understanding of the molecular basis of life, and can contribute to the development of new, better targeted pharmaceuticals.

Notes:

Since July 2007 Prof. Peter Güntert is leading the Lichtenberg professorship for NMR-based Computational Structural Biology at Goethe University that is supported with more than 1.4 million Euro by the VolkswagenFoundation.

Subclinical Cushing syndrome - therapy or surgery?

2009-03-06T05:18:00.000-08:00

According to the Annals of Surgery, performed by an experienced surgeon, laparoscopic adrenalectomy provides better results in the treatment of subclinical Cushing syndrome than conservative measures.

The authors of journal articles - Australian researchers, aims to allow kontroversiynost topics.

Their study included 45 people suffered from Cushing syndrome, 23 of whom were subjected to surgical treatment, while 22 received conservative (three patients from this group were transferred to the surgery due to an increase in adrenal over 3.5 cm). All operations are performed laparoscopically by the same surgeon.

Monitoring of the patients were on average over 7.7 years (the duration of the variance of observation - from 2 to 17 years) by two experienced endocrinologists. Patients who received surgical treatment, examined at 6 and 12 months after surgical intervention, and then - every year. Lechivshiesya conservatively examined once a year. Among other things, determined the severity of diabetes, hypertension, hyperlipidaemia, obesity and osteoporosis.

By the end of the study authors found that in the surgery group decreased the severity of diabetes / state is fully normalized in 62.5% of cases (5 of 8 patients), hypertension - 67% of cases (12 of 18 patients), hyperlipidaemia - in 37.5% (3 patients 8), obesity - 50% (3 of 6 patients). Changes in bone mineral density in patients with osteoporosis after the operation have been identified. At the same time, the group of patients who received conservative treatment, on average, reported a worsening of the above criteria.

The intensity of the epidemic of influenza in Russia has not decreased - the Research Institute of Virology RAMS

2009-03-06T04:49:00.000-08:00

MOSCOW, March 3. / ITAR-TASS /. Russian doctors recommend that the people at the first sign of flu to stay home and call a doctor. To date, the epidemic of influenza in the country was registered in 17 towns and 5 subjects of the Russian Federation.

As reported in today's press conference the head of the Laboratory of the Research Institute of Virology RAMS Elena Burtseva, data refer to total population groups - children and adults. Same flu epidemic among children in states in many more regions. " The specialist noted that the flu most often affects children, especially preschool and primary school age. That is why in the autumn so it was important to give children against the flu, she said. "Currently, vaccinate too late, but still able to nonspecific drugs - those that strengthen the immune system and support the body to fight infection," - said Burtseva. As a means of supporting it recommended interferons, vitamins, as well as traditional medicine, contain live vitamins.

The current situation of epidemic of influenza in the country, Elena Burtseva evaluated as "medium intensity". "While this intensity is not reduced," - she added. Talking about the specific types of influenza virus, an epidemiologist reported that it extended the types of the virus, which are projected in last year's World Health Organization / WHO /. It is against the types of the virus and the vaccination was carried out in Russia in the autumn.

The specialist noted the importance of compliance with the disease influenza bed rest, taking the drugs, control of the doctor. "Influenza - the disease that causes the greatest number of complications. This bronchitis, tracheitis, complications of heart and vessels by the nervous system, ophthalmologic violations," - said Elena Burtseva.

The specialist explained that the flu contagious during the first five days of human disease. She called the Russians "poberech themselves and their loved ones and do not contribute to the spread of infection - to stay home and wear gauze bandage to prevent infecting family members."

Contraception in the practice of family physician

2009-03-06T04:33:00.000-08:00

Family Planning Center of Edinburgh published in January 2009, recommendations for family physicians. It contains the following recommendations: hormonal contraceptives act by suppression of ovulation and changes in activity of the endometrium, they can also treat and prevent many of gynecological diseases. At this time there were strong evidence of the effectiveness of LNG-IUD, combined oral contraceptives, and injectable drugs containing progesterone for treatment of menorrhagia and dismenorei.

Combined oral contraceptives also have demonstrated their effectiveness in treating acne and girsutizma, they also reduce the severity of premenstrual syndrome. LNG-IUD can be used as a means of contraception, and protection of the endometrium in women receiving hormonal substitution therapy or tamoxifen. Thus, a family physician in the arsenal of available tools as treatment and prophylaxis of gynecological diseases.

Biomaterial Technology For Tissue Engineering Applications

2009-03-05T05:29:00.000-08:00

Tissue engineering is a newly emerging biomedical technology and methodology to assist and accelerate the regeneration and repairing of defective and damaged tissues based on the natural healing potentials of patients themselves.

For the new therapeutic strategy, it is indispensable to provide cells with a local environment which enhances and regulates their proliferation and differentiation for cell-based tissue regeneration.

In this review, several examples of tissue engineering applications with the cell scaffold and drug delivery system of growth factors and genes are introduced to emphasize significance of biomaterial technology in new therapeutic and research fields.

Journal of the Royal Society Interface

Journal of the Royal Society Interface is the Society's cross-disciplinary publication promoting research at the interface between the physical and life sciences. It offers rapidity, visibility and high-quality peer review and is ranked fifth in JCR's multidisciplinary category. The journal also incorporates Interface Focus, a peer-reviewed, themed supplement, each issue of which concentrates on a specific cross-disciplinary subject.

Depression Increases Risk For Heart Disease More Than Genetics Or Environment

2009-03-05T05:09:00.000-08:00

A history of major depression increases the risk of heart disease over and above any genetic risks common to depression and heart disease, according to researchers at Washington University School of Medicine in St. Louis and the VA. The findings are reported this week at the annual meeting of the American Psychosomatic Society this week in Chicago.

The researchers analyzed data gathered from more than 1,200 male twins who served in the U.S. military during the Vietnam War. The men were surveyed on a variety of health issues in 1992, including depression, and were assessed again in 2005.

In the study, investigators looked at the onset of heart disease in depressed study participants between 1993 and 2005. Men with depression in 1992 were twice as likely to develop heart disease in the ensuing years, compared to men with no history of depression.

"Based on our findings, we can say that after adjusting for other risk factors, depression remains a significant predictor of heart disease," says first author Jeffrey F. Scherrer, Ph.D., research assistant professor of psychiatry at Washington University School of Medicine and the St. Louis Veterans Affairs Medical Center. "In this study, we have demonstrated that exposure to depression is contributing to heart disease only in twins who have high genetic risk and who actually develop clinical depression. In twins with high genetic risk common to depression and heart disease, but who never develop depression itself, there was no increased risk for heart disease. The findings strongly suggest that depression itself independently contributes to risk for heart disease."

The investigators were looking for evidence of what they call incident heart disease, an event such as a heart attack, heart surgery, stent placement or medical treatment for angina. Those who had evidence of heart disease prior to the original survey in 1992 were excluded from this study.

Because twins were studied, the researchers could divide participants into risk groups: twins with high genetic and environmental risk for depression, those with moderate risk and those with a low risk. The risk groups then were compared for incident heart disease adjusting for other influences on heart disease such as smoking, obesity, hypertension and diabetes.

"By separating the twins into these groups based on their genetic and environmental risks, we are able differentiate the genetic risks common to depression and heart disease and the risks for heart disease from exposure to depression," says co-investigator Hong Xian, Ph.D., associate professor of mathematics in medicine at Washington University and health science specialist at the VA.

Twins automatically are matched by age. They normally grow up in the same family environment, and in the case of identical twins, they share identical DNA.

"If one twin has depression, but his twin brother does not, both twins will share genetic vulnerability for depression, but it turns out the twin who was not depressed has less risk for heart disease," says Scherrer. "In sum, depression itself remains a significant contributor to incident heart disease after controlling for genes, environment and mental and physical risk factors."

Scherrer and Xian plan to follow these twins as they age. They also plan to study the effects of successful depression treatment on heart disease risk.

Scherrer JF, Xian H, Franz CD, Lyons MJ, Jacobson KC. Eisen SA, Kremen WS. Depression is a risk factor for incident heart disease in a genetically informative twin design. Presented at the Annual Meeting of the American Psychosomatic Society, March 4-7, 2009: Chicago, Ill.

This research was supported by grants from the National Institute of Health and the Veterans Administration.

Prescient Medical Achieves Milestones In Clinical Studies Of VProtect(TM) Luminal Shield

2009-03-05T05:08:00.000-08:00

Prescient Medical, Inc. reached a crucial milestone in February by completing the enrollment of 30 patients in the first phase of its first-in-human clinical trial for the vProtect(TM) Luminal Shield, conducted at the Corbic Research Institute in Colombia. The Shield successfully crossed all target lesions and was safely implanted in all 30 patients, with a technical success rate of 100%. No procedural or in-hospital complications were reported for any of the patients. The patients enrolled in the study had non-calcified lesions in coronary arteries, lesions that would normally be treated with traditional balloon-expandable stents.

No major adverse coronary events (MACE) were reported at 30 days post-implant in the 28 patients who had reached that milestone. Nine-month angiographic follow-up was reported for 2 initial patients; there was no evidence of significant neointimal growth in these patients. "We are very pleased with the performance of the Shield in this preliminary study. We have achieved an excellent technical result, and soon we will know more about clinical outcomes with the Shield," said co-principal investigator Juan A. Delgado, MD of Corbic Research Institute.

Prescient Medical has also broken new ground with a study evaluating use of the vProtect(TM) Luminal Shield in non-obstructive "vulnerable plaque" lesions that may rupture and cause acute myocardial infarction. According to Dr. Delgado, "The self-expanding Shield is designed to deploy with less injury to the artery, which should reduce neointimal overgrowth compared with currently marketed bare metal stents. We think these properties make the Shield a promising treatment to stabilize vulnerable plaque and prevent major events like heart attacks."

About Prescient Medical, Inc.

Prescient Medical, Inc. is a privately held medical device company dedicated to reducing deaths from heart attacks, the leading cause of death in much of the world.

Spikes In Nitrite Can Have Heart Benefits

2009-03-05T05:06:00.000-08:00

A new study provides insight into how a short burst in nitrite can exert lasting beneficial effects on the heart, protecting it from stress and assaults such as heart attacks. In this study, just published in Circulation Research, researchers at Boston University School of Medicine have demonstrated for the first time that short elevations in circulating levels of this simple anion are sufficient to have a lasting impact on the heart by modulating its oxidation status and its protein machinery.

Nitrite, an oxidation product of the ubiquitous short-lived cell signaling molecule, nitric oxide (NO), was until recently thought to be biologically inert at the relatively low levels found in the body. Traces of nitrite are present in our diet and significant amounts are continuously produced from nitrate, another oxidation product of NO and a constituent of green, leafy vegetables. The suspicion that high levels of nitrite and nitrate may cause cancer, as well as concerns about their risk to compromise the ability of red blood cells to deliver oxygen to tissues, have led to strict regulations aimed at limiting our exposure to these substances through drinking water and food products.

In the past few years, however, multiple research groups have shown that low concentrations of nitrite exert numerous beneficial effects, ranging from anti-bacterial activities to increases in local blood flow, and that they can somehow protect tissues from damage when oxygen is suddenly cut off and then rapidly restored, as occurs during heart attacks and strokes.

To study the molecular underpinnings of this protective effect of nitrite, the researchers at Boston University School of Medicine used a rat model in which they administered nitrite only once, causing a short spike in circulating levels, as a way to simulate the types of naturally occurring increases in nitrite that follow exercise or consumption of a meal rich in nitrate.

The researchers used a systems-biology approach in which changes in multiple biological and biochemical systems (e.g., the composition of a large number of proteins, the concentration of several small molecule metabolites, and functional outcomes) are simultaneously monitored and then integrated to produce one final picture in order to provide a broader view of the impact of this treatment on the heart. They tested their theory that following these changes over time and at different doses of nitrite might help to explain the protective effects of nitrite on the heart.

"What we found was that a single brief nitrite treatment elicited persisting changes in the heart's oxidation status together with lasting alterations to numerous proteins involved in the heart's energy metabolism, redox regulation, and signaling," said David H. Perlman, a post-doctoral research associate in the Cardiovascular Proteomics Center at Boston University School of Medicine, and lead author of the study. "These alterations were particularly striking because they persisted at least 24 hours after the actual nitrite levels had returned back to normal, and they were correlated strongly with the improvements in heart function observed at the same time."

He noted that this type of protection, called 'cardiac preconditioning', is a recently discovered phenomenon shown to be caused by numerous pharmacological agents.

"The proteins we have implicated include some key proteins, such as mitochondrial aldehyde dehydrogenase, that have been shown by others to be critical to cardiac protection afforded by other agents and triggers," added Perlman. "This is exciting because it ties nitrite-triggered cardioprotection into the broader preconditioning field. Our study complements and extends other work, and identifies new players of potential importance for protection of the heart."

Perlman explained that nitrite levels in our bodies change under a number of circumstances, such as when we run up a flight of stairs or eat a big serving of salad.

"For years, the resulting bursts in nitrite were considered to be of little if any physiological relevance. Now we have good reason to believe that even small spikes in nitrite concentration can alter protein function in the heart in ways that afford protection," noted Perlman.

"We are intrigued by the breadth and magnitude of the proteomic changes in heart mitochondria elicited by a single, short-lasting elevation in nitrite concentration and believe that our findings will have broad implications for mitochondrial signalling and cardiac energetics," commented Martin Feelisch, senior author of the study. "It looks as though nitrite is triggering an ancient program aimed at fine-tuning mitochondrial function. Although the present study focussed on the heart, our observations may extend to other tissues and translate into relevant changes in muscle function elsewhere. If true, this may help explain, for example, the training effects of very short periods of exercise, which are known to be associated with elevations in circulating nitrite concentrations."

Interestingly, only low and high doses of nitrite, but not those in-between, were found to be protective. Although further studies will be needed to fully delineate the mechanisms of nitrite-induced cardioprotection, this study informs ongoing basic and translational studies by highlighting the importance of the dose-effect relationship for nitrite and the broad array of downstream targets possibly involved in its cardioprotective efficacy, the researchers concluded.

Notes:

The study, "Mechanistic Insights into Nitrite-Induced Cardioprotection Using an Integrated Metabonomic/Proteomic Approach," was carried out as a collaboration between researchers at the Cardiovascular Proteomics Center at Boston University School of Medicine under the direction of Prof. Catherine E. Costello and core lab director Prof. Mark E. McComb, Prof. Martin Feelisch and his lab members of the Whitaker Cardiovascular Institute at Boston University School of Medicine, and Prof. Houman Ashrafian of Oxford University's Department of Cardiovascular Medicine. It was supported by grants and a contract from the National Institutes of Health, National Heart Lung and Blood Institute and National Center for Research Resources, as well as a Medical Research Council Strategic Appointment Award. It is available in the February 19th online edition of Circulation Research.

Immune Reaction To Metal Debris Leads To Early Failure Of Joint Implants

2009-03-05T05:02:00.000-08:00

Researchers at Rush University Medical Center have identified a key immunological defense reaction to the metals in joint replacement devices, leading to loosening of the components and early failure.

The study, funded by the National Institutes of Health, won the annual William H. Harris, MD Award for scientific merit from the Orthopaedic Research Society. Currently posted online, it is expected to be published in the June issue of the Journal of Orthopaedic Research.

Over 600,000 total joint replacements are performed in the United States each year. The vast majority are successful and last well over 10 years. But in up to 10 percent of patients, the metal components loosen, requiring the patient to undergo a second surgery.

The loosening is often caused by localized inflammation, an immune reaction to tiny particles of debris from the components themselves as they rub against one another. No infection is involved.

"As soon as joint replacement devices are implanted, they begin to corrode and wear away, releasing particles and ions that ultimately signal danger to the body's immune system," said Nadim Hallab, associate professor at Rush University Medical Center and the study author.

There are two different types of inflammatory pathways: one that reacts to foreign bodies like bacteria and viruses, which cause an infection, and another that reacts to "sterile" or non-living danger signals, including ultraviolet light and oxidative stress.

This is the first time that researchers have shown that debris and ions from implants trigger this danger-signaling pathway.

According to Hallab, when specialized cells of the immune system, called macrophages, encounter this metallic debris, they "engulf it in sacs called lysosomes and try to get rid of the debris by digesting it with enzymes." But the particles damage the lysosomes, Hallab said, "and the cells start screaming 'danger.'"

These danger signals are detected by large complexes of proteins, called inflammasomes. The inflammasomes mobilize, precipitating a chain of chemical events that cause inflammation.

The researchers are hopeful that identification of this molecular pathway that triggers inflammation without infection could lead to new and specific therapeutic strategies to avoid the early failure of joint replacements.

Other researchers at Rush involved in the study were Marco Caicedo, Ronak Desai, Kyron McAllister, Dr. Anand Reddy, and Dr. Joshua Jacobs.

Rush University Medical Center is an academic medical center that encompasses the more than 600 staffed-bed hospital (including Rush Children's Hospital), the Johnston R. Bowman Health Center and Rush University. Rush University, with more than 1,730 students, is home to one of the first medical schools in the Midwest, and one of the nation's top-ranked nursing colleges. Rush University also offers graduate programs in allied health and the basic sciences. Rush is noted for bringing together clinical care and research to address major health problems, including arthritis and orthopedic disorders, cancer, heart disease, mental illness, neurological disorders and diseases associated with aging.

Structure-Building Role For 2 Non-Coding RNAs Pinpointed By CSHL Researchers

2009-03-05T04:57:00.000-08:00

MEN-epsilon and MEN-beta act as structural components for a domain in the cell nucleus called paraspeckles

Most of the DNA in the nucleus of each of our cells is converted into RNA, but only a small fraction of these RNA molecules serve as coding templates for the synthesis of proteins. Of the remaining RNAs, known as "non-coding" RNAs (ncRNA), the functions of a scant few are known: they inhibit the activity of genes or modify them by altering the way in which DNA is packaged within cells. What the rest of them do within cells is largely a mystery.

Professor David L. Spector, Ph.D., and a team led by graduate student Hongjae Sunwoo at Cold Spring Harbor Laboratory (CSHL), have expanded our knowledge of ncRNA functions by uncovering a unique structure-building role for two ncRNA molecules. In a paper published in the March 1st issue of Genome Research, they show that ncRNAs called MENε and MENβ organize and maintain the structure of paraspeckles, a compartment within the cell's nucleus.

RNAs as structural components

Unlike its counterparts in simple organisms like yeast, the nucleus in mammalian cells has an extraordinarily complicated internal structure. In addition to the DNA-protein complex known as chromatin, the nucleus is organized with compartments such as the nucleolus, PML bodies, Cajal bodies, and many others. Cell biologists have long wondered how these compartments are organized, knowing only that each has a definite and precise form despite not being bound and contained within a membrane.

"The idea that some of these structures might somehow be supported by RNA molecules first surfaced in studies in the 1970s," according to Professor Spector. His lab found further evidence for this idea in 2005 when they showed that paraspeckles - each nucleus has about 10 to 30 of these scattered around - fell apart when cells were treated with an enzyme that destroys RNA. "But," Spector says, "a specific RNA molecule that gives paraspeckles their structural integrity was never found."

Spector, who is an avid explorer of ncRNAs and their activities in cells, thought ncRNAs were a good candidate for such a role, especially since many of them stay in the nucleus instead of getting expelled into the cell's cytoplasm like their protein-coding RNA cousins.

ncRNAs localize to paraspeckles

Cells usually increase their production of ncRNAs when they ramp up their metabolic activity - for example, when they differentiate during development. For this reason, Spector's team, in collaboration with John Mattick's laboratory (Institute for Molecular Bioscience, University of Queensland, St Lucia, Australia), hunted for their ncRNA quarry in a type of stem cell that differentiates into muscle fibers. They narrowed their focus to 14 confirmed ncRNAs, each of which was produced at levels that were at least two times higher or lower in the differentiated cells.

"One way to figure out hints as to what ncRNAs do is to find out where they localize within cells, which might reveal the molecules they interact with and the pathways they participate in," explains Spector. Using a technique that uses a fluorescence signal to tag molecules within cells, Spector's team traced two of their 14 ncRNAs to paraspeckles, tiny compartments that look like dense dots anchored within the nucleus.

MENε and MENβ are structural organizers

The paraspeckles were larger in differentiated muscle cells than in their stem-cell precursors -a sign that their structure might depend on ncRNAs, whose levels are also higher in muscle cells. The team proved this point by inserting into the cells molecules that bind to these ncRNAs and trigger their destruction. When these specific ncRNAs were depleted in this way, the paraspeckles disappeared. In addition, when the scientists depleted the levels of the ncRNAs and blocked the production of new ncRNA molecules, paraspeckles failed to form suggesting that the ncRNAs were essential to both initiate and maintain these nuclear structures.

Thus, not only did MENε and MENβ appear to maintain paraspeckle structure; they were also critical for the assembly of new paraspeckles. Spector's team also found that MENε and MENβ latch on to a paraspeckle protein called Nono. But how and whether this interaction is related to paraspeckle structure remains to be worked out.

The function of ncRNA-built paraspeckles

Scientists are still unsure about what paraspeckles do within cells. When they were discovered in 2002, it was believed they were involved in controlling gene activity "post-transcriptionally," i.e., after a gene's DNA has been converted into RNA.

One such post-transcriptional control mechanism was uncovered in 2005 by Spector's group, who showed that paraspeckles were warehouses for storing a specific RNA molecule. Only when the cell needed to respond to stress signals was this molecule processed and released into the cytoplasm, where it was used to synthesize protein.

Scientists estimate that storing pre-made RNAs in the paraspeckles and releasing them during times of need speeds the cell's response to stress by about 25 minutes, in certain cases, and bypasses the cell's need to prepare the RNA from scratch.

"Paraspeckles might be part of the cell's rapid response mechanism to stress," says Spector. "It might allow cells to meet challenges such as viral infection more quickly." Experiments performed by others bear him out: levels of paraspeckle-building MEN RNAs have been observed to increase in mouse brain cells infected by the Rabies virus.

Spector's work on nuclear ncRNAs continues. "Whether other nuclear compartments also similarly serve as RNA stores and what roles ncRNAs might play in nuclear structure and function are questions that will keep us busy for a while," he says.

Notes:

"MEN ε/β nuclear-retained non-coding RNAs are up-regulated upon muscle differentiation and are essential components of paraspeckles," was published advance of print on December 22nd, 2008 and appears in the March 1st print issue of Genome Research.

Safer Methadone Use For Treatment Of Pain And Addiction

2009-03-04T10:35:00.000-08:00

New findings may significantly improve the safety of methadone, a drug widely used to treat cancer pain and addiction to heroin and other opioid drugs, according to researchers at Washington University School of Medicine in St. Louis and the University of Washington in Seattle.

The researchers discovered that the body processes methadone differently than previously believed. Those incorrect assumptions about methadone have been making it difficult for physicians to understand how and when the drug is cleared from the body and may be responsible for unintentional under- or overdosing, inadequate pain relief, side effects and even death.

For many years, methadone has been a mainstay in the treatment of opioid addiction. Taken orally, it suppresses withdrawal and reduces cravings. In recent years, doctors have prescribed methadone more frequently as an effective treatment for acute, chronic and cancer pain. Use of the drug for pain treatment rose 1,300 percent between 1997 and 2006. As more methadone was prescribed, however, adverse events increased by approximately 1,800 percent, and fatalities were up more than 400 percent (from 786 to 3,849) between the years 1999 and 2004.

"Unfortunately, increased methadone use for pain has coincided with a significant increase in adverse events and fatalities related to methadone," says principal investigator Evan D. Kharasch, M.D., Ph.D., an anesthesiologist and clinical pharmacologist at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis. "The important message is that guidelines used by clinicians to direct methadone therapy may be incorrect."

Kharasch, the Russell D. and Mary B. Shelden Professor and director of the Division of Clinical and Translational Research in Anesthesiology at the School of Medicine, and his colleagues report the findings in the March issue of the journal Anesthesiology and online in the journal Drug and Alcohol Dependence.

The investigators wanted to understand how protease inhibitors, drugs that keep the immune system functioning in patients with HIV, interact with methadone. For years, the enzyme P4503A was believed to be responsible for clearing methadone from the body. But when healthy volunteers were given a low dose of methadone together with protease inhibitors that caused profound decreases in the activity of P4503A, there was no reduction in the clearance of methadone.

There were two reasons to study what happened to methadone when taken together with those drugs: First, HIV-AIDS patients may receive methadone for pain and, in some cases, for accompanying substance abuse problems, along with one or more protease inhibitors. In addition, many protease inhibitors interact with the P4503A enzyme that traditionally was thought to be important to methadone clearance. In these studies, Kharasch and his team looked at interactions among methadone, the P4503A enzyme in the intestine and liver and the protease inhibitors nelfinavir, indinavir and ritonavir.

They gave study volunteers a combination of the protease inhibitors ritonavir and indinavir. Both drugs profoundly inhibited the actions of the enzyme. If that enzyme were responsible for methadone clearance, then inhibiting it should have caused methadone to build up in the body. But the researchers found that it had no effect on methadone levels.

Volunteers in the second study received the protease inhibitor nelfinavir. Again, the drug inhibited the action of the P4503A enzyme. That should have meant methadone concentrations would rise, but they actually decreased by half.

"For more than a decade, practitioners have been warned about drug interactions involving the enzyme P4503A that might alter methadone metabolism," Kharasch says. "The package insert says inhibiting the enzyme may cause decreased clearance of methadone, but our research demonstrates that P4503A has no effect on clearing methadone from the body. So the package insert appears to be incorrect, or certainly needs to be reevaluated, as do guidelines that explain methadone dosing and potential drug interactions."

That can be dangerous, Kharasch explains, because a clinician may prescribe too much or too little methadone for patients taking drugs that interact with P4503A, having been informed that they also would influence methadone clearance. Too little methadone will not relieve pain. Too much can contribute to the unintentional build-up of methadone in the system, which can cause slow or shallow breathing and dangerous changes in heartbeat. Physicians could be unintentionally prescribing methadone incorrectly.

"The highest risk period for inadequate pain therapy or adverse side effects is during the first two weeks a patient takes methadone," Kharasch says. "If we can provide clinicians with better dosing guidelines, then I believe we will be able to better treat pain and limit deaths and other adverse events."

About a dozen related liver enzymes are part of the P450 family, and Kharasch believes another enzyme from that family may be the one actually involved in methadone metabolism and clearance. His laboratory is determined to identify the correct enzyme to limit over-and under-dosing of patients taking methadone to improve addiction and pain treatment as well as patient safety. Currently, he's testing the related enzyme P4502B. Laboratory studies and preliminary clinical results indicate that P4502B may be involved, but he says more clinical research is needed.

"The research also is important for the treatment of HIV-AIDS," Kharasch says. "Protease inhibitors can interfere with the activity of P4503A but increase the activity of P4502B. This paradox is highly unusual, and because these two enzymes metabolize so many prescription drugs, there are many potential drug interactions that we'll be able to understand better if we can get a better handle on how these pathways absorb drugs into the system and clear them from the body."

Musicians' Brains 'Fine-Tuned' To Identify Emotion

2009-03-04T09:41:00.000-08:00

Looking for a mate who in everyday conversation can pick up even your most subtle emotional cues? Find a musician, Northwestern University researchers suggest.

In a study in the latest issue of European Journal of Neuroscience, an interdisciplinary Northwestern research team for the first time provides biological evidence that musical training enhances an individual's ability to recognize emotion in sound.

"Quickly and accurately identifying emotion in sound is a skill that translates across all arenas, whether in the predator-infested jungle or in the classroom, boardroom or bedroom," says Dana Strait, primary author of the study.

A doctoral student in the Henry and Leigh Bienen School of Music, Strait does research in the Auditory Neuroscience Laboratory directed by neuroscientist Nina Kraus. The laboratory has done pioneering work on the neurobiology underlying speech and music perception and learning-associated brain plasticity.

Kraus, Northwestern's Hugh Knowles Professor of Communication Sciences and Neurobiology; Richard Ashley, associate professor of music cognition; and Auditory Neuroscience Laboratory manager Erika Skoe co-authored the study titled "Musical Experience and Neural Efficiency: Effects of Training on Subcortical Processing of Vocal Expressions in Emotion."

The study, funded by the National Science Foundation, found that the more years of musical experience musicians possessed and the earlier the age they began their music studies also increased their nervous systems' abilities to process emotion in sound.

"Scientists already know that emotion is carried less by the linguistic meaning of a word than by the way in which the sound is communicated," says Strait. A child's cry of "Mommy!" -- or even his or her wordless utterance -- can mean very different things depending on the acoustic properties of the sound.

The Northwestern researchers measured brainstem processing of three acoustic correlates (pitch, timing and timbre) in musicians and non-musicians to a scientifically validated emotion sound. The musicians, who learn to use all their senses to practice and perform a musical piece, were found to have "finely tuned" auditory systems.

This fine-tuning appears to lend broad perceptual advantages to musicians. "Previous research has indicated that musicians demonstrate greater sensitivity to the nuances of emotion in speech," says Ashley, who explores the link between emotion perception and musical experience. One of his recent studies indicated that musicians might even be able to sense emotion in sounds after hearing them for only 50 milliseconds.

The 30 right-handed men and women with and without music training in the European Journal of Neuroscience study were between the ages of 19 and 35. Subjects with music training were grouped using two criteria -- years of musical experience and onset age of training (before or after age 7).

Study participants were asked to watch a subtitled nature film to keep them entertained while they were hearing, through earphones, a 250-millisecond fragment of a distressed baby's cry. Sensitivity to the sound, and in particular to the more complicated part of the sound that contributes most to its emotional content, was measured through scalp electrodes.

The results were not exactly what the researchers expected. They found that musicians' brainstems lock onto the complex part of the sound known to carry more emotional elements but de-emphasize the simpler (less emotion conveying) part of the sound. This was not the case in non-musicians.

In essence, musicians more economically and more quickly focus their neural resources on the important -- in this case emotional -- aspect of sound. "That their brains respond more quickly and accurately than the brains of non-musicians is something we'd expect to translate into the perception of emotion in other settings," Strait says.

The authors of the study also note that the acoustic elements that musicians process more efficiently are the very same ones that children with language disorders, such as dyslexia and autism, have problems encoding. "It would not be a leap to suggest that children with language processing disorders may benefit from musical experience," says Kraus.

Strait, a pianist and oboe player who formerly worked as a therapist with autistic children, goes a step further. Noting that impaired emotional perception is a hallmark of autism and Asberger's syndromes, she suggests that musical training might promote emotion processing in these populations.

Human Kin Recognition Is Self- Rather Than Family-Referential

2009-03-04T09:40:00.000-08:00

We feel more altruistic toward people who resemble us; this tendency probably evolved because it stimulated our ancestors to help their kin.

There were no mirrors then, so people could learn what kin looked like only by inspecting the faces of household members; these, however, may or may not be family. Hence, evolution might have favored a rewritable kin-image, where information about household members is replaced by any newly available information about the self.

Supporting this hypothesis, we found that even identical twins preferred helping strangers whose faces had been covertly manipulated to resemble their own rather than their co-twin's.

Protein Complex Shown To Play Pivotal Role In Stem Cell Development In Two Stanford Studies

2009-03-04T08:59:00.000-08:00

Scientists at the Stanford University School of Medicine have identified a protein complex important in controlling whether embryonic stem cells retain their ability to become any cell in the body-a quality called pluripotency-or instead embark on a pathway of maturation and specialization. The finding is an important advance in the quest by scientists to harness the unique abilities of embryonic stem cells to treat disease and generate replacement tissue for the body.

Like a musician tuning an instrument, the complex associates with and adjusts the expression levels of other proteins important in pluripotency, perhaps by affecting how the DNA is packaged within the cells in strands called chromatin. They found that this complex associates closely with other major regulators of pluripotency, including four genes known to be able to coax adult cells to display many qualities of embryonic stem cells.

"We've identified a specific mechanism to maintain pluripotency that involves large-scale, genome-wide chromatin remodeling," said Gerald Crabtree, MD. "The results are rather spectacular. They show clearly that the complex binds to and works in near-perfect concert with these four famous pluripotent factors. They are part of the same developmental program."

Crabtree is a professor of pathology and of developmental biology at the medical school, as well as a Howard Hughes Medical Investigator and a member of Stanford's Cancer Center. He is the senior author of two articles describing the work, which will be published online March 2 in the Proceedings of the National Academy of Sciences. The first author of both papers, Lena Ho, is a graduate student in Crabtree's lab.

Ho began her investigation into the function of the complex, called BAF, after other researchers had found that it was important in regulating how a cell's genetic material is wrapped around DNA packaging proteins called histones. One way of controlling how and when a gene is made into a protein involves increasing or restricting its accessibility to other proteins called transcription factors, and BAF is one of many so-called chromatin remodeling complexes that regulate this process in mammals. However, Ho found that the protein components of BAF vary according to the cell type in which they are found.

"We realized, 'Gee, there's something different between how this complex works in skin cells like fibroblasts and embryonic stem cells,'" said Crabtree. They began to look more closely at how BAF functions in embryonic stem cells.

The work also builds upon previous findings of Shinya Yamanaka, MD, PhD, of the University of California-San Francisco. The world of stem cell research was galvanized in 2007 with the discovery by Yamanaka of the four genes that can affect adult cells in such a way that they display many qualities of embryonic stem cells. That opened the door to the possibility of realizing the promise of embryonic stem cells without requiring the destruction of embryos. The technique of using these genes to create what are known as induced pluripotent stem, or iPS, cells is an active area of stem cell research.

It's not yet known exactly how embryonic-stem-cell BAF, or esBAF, works, though the researchers suspect it may have something to do with its ability to remodel chromatin around other genes involved in pluripotency. However, they did discover that esBAF, can both activate and inactivate the expression of these genes. It's possible that this refining, or focusing, role is needed to keep embryonic stem cells walking the line between self-renewal and differentiation.

The researchers are now investigating whether they can manipulate the subunits of the BAF complex in such a way to make fibroblasts pluripotent. They're also curious as to whether small molecules or chemicals modulate the complex's function. If so, it may be one step toward more efficient regenerative medicine, according to Crabtree.

Additional Stanford collaborators on the research include Jehnna Ronan; Jiang Wu, PhD; Brett Staahl; Lei Chen, MD; Ann Kuo; and Julie Lessard, PhD. The work was done in collaboration with the group of Keji Zhao, PhD, at the National Institutes of Health in Washington, D,C. The work was funded by the Howard Hughes Medical Institute; the NIH; the National Heart, Lung, and Blood Institute; and the Agency of Science, Technology and Research of Singapore.

Avidoxy(TM) DK, Simplifying Therapy For Millions Suffering From Severe Acne

2009-03-03T08:39:00.000-08:00

Avidas(TM) Pharmaceuticals, a privately held, specialty pharmaceutical company which focuses on dermatology, women's health and endocrinology, today announced the launch of Avidoxy(TM) DK (defence kit), a new patient convenience kit developed to control severe acne by attacking bacteria and by cleansing, exfoliating, moisturizing and protecting skin.

Avidoxy DK includes Avidoxy(TM) (Doxycycline Tablets), a broad spectrum oral antibiotic, in an easy-to-swallow film-coated caplet indicated as adjunctive therapy for severe acne, with complimentary defence(TM) acne wash, a specially formulated oil and alcohol-free acne wash with 2% salicylic acid that provides gentle yet effective cleansing and exfoliation of skin. Avidoxy DK also contains complimentary defence(TM) solare, a lightweight, oil-free, non-comedogenic sunscreen rich in anti-oxidants and moisturizers offering SPF 30+ of broad spectrum sun protection. Avidoxy DK is available by prescription only.

According to the American Academy of Dermatology (AAD), oral antibiotics, such as the active ingredient in Avidoxy, are a mainstay of therapy for severe acne because they reduce the P. acnes bacteria population, a contributing factor in acne. Salicylic acid, which is found in professional strength concentrations with defence acne wash, helps correct the abnormal shedding of skin cells and unclogs pores to resolve and prevent acne lesions. Everyone needs, especially acne patients, protection from the sun's damage and premature aging. Because many acne treatments can increase the skin's sensitivity to sunlight and ultraviolet light, the AAD recommends the use of a broad spectrum sunscreen such as that found in defence solare SPF 30+.

"Reduction of bacteria with effective skin cleansing, exfoliation and protection are considered by many physicians to be important treatment arms for the control of severe acne," states Charles Pamplin III, MD, Chief Medical Advisor for Avidas. "With Avidoxy DK, physicians can provide their patients with a simple and convenient way to treat this serious, yet common, skin condition."

Important Safety Information

Avidoxy is indicated as adjunctive therapy for severe acne. To reduce the development of drug-resistant bacteria and maintain the effectiveness of Avidoxy and other antibacterial drugs, Avidoxy should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

The use of drugs of the Tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown).

About Acne

Acne vulgaris (commonly called acne) is a skin disease caused by changes in the pilosebaceous units (skin structures consisting of a hair follicle and its associated sebaceous gland). Severe acne is inflammatory, but acne can also manifest in non-inflammatory forms. Acne lesions are commonly referred to as pimples, spots, zits, or acne.

About Avidas

Avidas Pharmaceuticals is a privately held company focused on the therapeutic areas of dermatology, women's health and endocrinology. The company acquires, develops, and maximizes the potential of acquired products through focused selling and precision marketing. The company is headquartered in Doylestown, PA.