eClinica 26 May 2009
http://www.ecliniqua.com/2009/05/26/ferring-target-health.html

By Deb Borfitz

May 26, 2009 | Common wisdom holds that drug makers should stay out of the business of developing information technology (IT) software and instead buy one of the many proven, off-the-shelf solutions. But that’s not necessarily the best and cheapest way to collect data or manage clinical trials.

20090526-6

Just ask Per Cantor, senior VP of clinical and non-clinical R&D at Swiss-based Ferring. Here, electronic data capture (EDC) happens via a web-based system co-developed with New York-based Target Health, a clinical research organization (CRO). The system has all the bells and whistles that Ferring desires, including easy-to-build electronic case report forms with embedded guidance and intelligence, dashboard views of study progress, and automated coding of adverse events-not to mention rapid turnaround on virtually every service request, says Cantor.

Target Health president, Jules Mitchel says that the CRO, began its EDC work with Ferring ten years and four New Drug Application (NDA) approvals ago. The relationship gives Ferring the technical features it asks for-nothing more and nothing less-as well as a lot of attention, faster study builds, and a more user-friendly end product. But the companies are not financial partners and Ferring has no exclusive rights to the software, so the relationship also serves as a development platform for Target Health’s commercially available EDC system.

20090526-7

 Ferring is a mid-sized pharmaceutical company specializing in treating diseases mainly through peptide/protein pathways and initiates about 15 new phase I-III studies annually. All of the phase II-IV trials use EDC and the technology is now migrating into the phase I arena.

The latest NDA for Ferring’s prostate cancer treatment degarelix (Firmagon) was based primarily on results of a global 600-patient study, which achieved data lock ten days after last patient visit, says Cantor. Three months later, the full regulatory dossier of 24 clinical studies was submitted to U.S. and European regulatory authorities and approval came less than ten months thereafter, in December 2008. Cantor credits the EDC system, coupled with electronic submission, for the compressed timeframe and swift approval.

Small but determined Target Health was “pushed” by Ferring to “continually develop and improve the software,” says Cantor, based on major upgrades being made to commercial EDC systems.

Over the past six months, Target Heath has co-developed a clinical trial management system (CTMS) with an international CRO and recently began co-developing both an EDC and CTMS system for Hill Top Research, a full-service CRO which operates a handful of research sites.

Target Health’s advantage over a straight technology vendor is that it’s in the trenches of clinical research and therefore knows what does and doesn’t work at the site level. “We don’t partner passively with [other companies],” says Mitchel. “If we don’t think something’s a good idea, we tell them.”

Having outgrown its homemade CTMS, Ferring is now evaluating several early-stage providers-including Target Health-that can help it build a suitable replacement utilizing the popular Microsoft SharePoint platform. Says Cantor: “This is now being debated intensely by clinical functions and our own IT group, but I think we’ll end up taking the risk and not buying off the shelf.”

As the contenders are all small companies, financial stability is one chief concern. The other is that none of them has yet to develop a full-fledged CTMS for a global pharmaceutical company. They primarily serve small biotechnology firms.

So why not just use Oracle’s Siebel or Perceptive Informatics’ IMPACT? “Those systems require a lot of resources, not just to implement but also to maintain,” says Cantor. “Plus, we want something [simpler]. What’s important to us is that it be user friendly and interface with our EDC system.”

Safety management and electronic submission systems currently on the market “work pretty well,” adds Cantor, so Ferring isn’t looking to tread on those IT grounds.

To co-develop rather than acquire technology, it helps to be a small and nimble company. “The cost and impact of changing our systems is less for us than GSK or Pfizer,” says Cantor. Most large pharmaceutical companies have already invested in a leading-brand CTMS and EDC systems and trained thousands of users.

The way Cantor sees it, Ferring has shaved 20-40% off its EDC costs by working with Target Health in lieu of an out-of-the-box solution. “But it’s the flexibility that’s important. We’re treated as their primary customer.” And that fits well with Ferring’s golden rule when acquiring and implementing new technology: “Do it as intensely and in as short of time as possible.”


Editor’s note: Borfitz will discuss how big pharma is eying “clinical cloud” solutions for its trial technology needs in a future edition of eCliniqua.

20090528-11

The H1N1 Virus, Strains of Which Have Circulated for Decades, Could Come Back in a More Virulent Form 

GoogleNews.com, Wall Street Journal, May 28, 2009, by Betsy McKay  —  Over the next several months, the new H1N1 flu virus is likely to continue to spread around the world, reaching into the southern hemisphere along with winter, then possibly staging a resurgence in the northern hemisphere come fall.

Hundreds of thousands of people could fall sick, and some will die. Public health officials will scramble to minimize the damage, as governments and drug makers continue to invest millions of dollars in a potential vaccine.

Infections seem to be slowing in many parts of the U.S., according to the CDC. It hasn’t spread in most other countries as widely as it has in Mexico and the U.S. Many of those who have died had other health problems, such as asthma or heart disease. Unlike the viruses that created the most recent three flu pandemics, this one isn’t entirely new.

Introduced into the human population by the 1918 pandemic, the H1N1 virus circulated widely in various forms until 1957, when it was replaced in another pandemic by a new strain known as H2N2. The H1N1 virus re-emerged in 1977 and has circulated ever since, changing slightly every year. But it differs from the new H1N1 virus, which is made up of swine viruses, and hasn’t circulated in humans until now.

Already, there are signs that people over 60 years old with exposure to H1N1 viruses that circulated decades ago may have some immunity. And other mild H1N1 viruses haven’t mutated to become more virulent, says Peter Palese, chairman of the department of microbiology at the Mount Sinai School of Medicine in New York, calling this new form of H1N1 a “mellow virus.”

20090528-12

Bloomberg News

A worker packaged materials used to test for viruses, including H1N1. 

It “may be less likely to be a killer virus or a virus which is highly virulent,” says Dr. Palese.

But that doesn’t mean it can’t make people seriously ill or isn’t worth combating, pandemic flu scientists say. Flu viruses are notoriously unpredictable. It’s not clear whether this virus will peter out or return next fall. If it does return, officials can’t predict whether it will cause the same mild disease, or mutate into a more virulent bug that could strike with a vengeance — like the dreaded 1918 pandemic virus that resurfaced and killed 50 million people, by some estimates.

“That really terrible experience of 1918 is in our minds. But I can’t tell you whether this virus will cause a lot of disease, some disease or no disease here in the northern hemisphere next season,” Dr. Schuchat said.

Flu viruses regularly mutate or change by swapping genes with other flu viruses to outsmart the immune systems of their human hosts. Such changes, which ensure a virus’s survival, make it possible to catch the flu from one year to the next. They can also make a mild virus like the current H1N1 strain more virulent. CDC scientists are examining potential changes to the new H1N1 strain to see if any might create a virus that would cause more severe disease, says Dan Jernigan, deputy director of the agency’s influenza division.

“There are a lot of other conditions out there that have killed many more people in the last three weeks than this has,” says Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. “But this is not about what’s happening now. It’s about what could happen.”

In New York City, the health department announced Tuesday that two more people with swine flu had died, bringing the total to four. Of particular concern to health officials is that the disease is striking mostly younger people. The virus is making its way through New York schools at an energetic pace after more than a month, with five more closing Wednesday.

Age matters. About 64% of U.S. H1N1 infections have been in people ages 5 to 24, while just 1% are over age 65, the age group that normally gets hit hardest by the flu. Some are developing severe disease: about 37% of those hospitalized with H1N1 have been between ages 19 and 49, according to a CDC analysis of a portion of U.S. patients. Pregnant women and people with chronic health conditions have been at risk.

A similar pattern was seen in the 1918 pandemic, in which death rates were highest among young adults. That may be due at least partly to the fact that people over age 60 may have some immunity to the new virus, from exposure to older H1N1 viruses that are more similar to the new swine flu than the other recent H1N1 varieties, according to the CDC.

Unsure of the course the disease will take, officials are preparing for the worst. Over the next eight to 10 weeks, CDC and WHO officials plan to track the spread of the disease in the southern hemisphere, where winter and flu season are setting in. They are watching to see if the virus mutates as it mixes with other circulating seasonal flu viruses, becoming more virulent or resistant to antiviral drugs such as Tamiflu. Last winter, one variety of H1N1 developed such a resistance while the more recent version hasn’t so far.

The CDC has shipped kits to influenza laboratories in more than 100 countries to allow them to test for the new H1N1 virus. Among the questions that agency scientists plan to monitor are whether many people are hospitalized for long periods with pneumonia, whether the virus causes secondary bacterial pneumonia, and who is affected most — children or adults, primarily healthy people or those with underlying diseases, Dr. Schuchat said.

U.S. and global officials are also pushing ahead to prepare a vaccine against the H1N1 virus, even though they haven’t decided whether or not to go ahead with mass production of shots. The U.S. government said last week it’s setting aside $1 billion for clinical studies and the production of two bulk ingredients to be placed in a federal stockpile in case vaccine production goes ahead.

Alessandro Vespignani, a professor of informatics at Indiana University who has modeled scenarios for the spread of H1N1 flu, predicts a second wave would strike more than the hundreds of thousands of people he expects to be hit by the first wave. “It’s good we had the first wave,” he said. “It gives us time to understand more about the disease.”

Experts Debunk Four Common Myths About Swine Flu 

By JOSEPH BROWNSTEIN
ABC News Medical Unit

May 28, 2009-

Since it first caught public attention a little over a month ago, swine flu has captured numerous headlines, in addition to generating a lot of new, cautionary information for people to learn.

According to the World Health Organization, the virus has infected 13,398 people and caused 95 deaths. The WHO has stated that countries should begin preparing for a possible pandemic and this week vaccine manufacturers for the United States began receiving sample viruses from which to make a swine flu vaccine.

While swine flu has not yet had a major impact here, concerns remain over the effect the virus might have when flu season begins in earnest next fall.

It should be no surprise that a number of myths have emerged about how to avoid the virus and what all of this means.

Below we look at four common myths to help you understand what to expect from this strain of influenza virus.

1. Swine flu is more benign than seasonal flu.

According to the WHO, 95 people worldwide have died of confirmed cases of swine flu.

However, seasonal flu claimed an average of 36,000 lives annually in the 1990s, according to a study by the Centers for Disease Control and Prevention that was published in the Journal of the American Medical Association.

While many believe that swine flu is waning and these numbers may lead people to believe that swine flu is not as bad as seasonal flu, the situation can be deceiving.

Swine flu emerged at the end of the traditional flu season. With more people spending time outdoors and schools getting out for the summer, the virus is not nearly as likely to spread as it would be during the regular flu season, which begins in the fall and typically peaks in February.

As influenza expert Dr. William Schaffner of Vanderbilt University said in an interview with ABC News:

“All that early discussion about mildness should be modified as the information has evolved,” he said. “It’s not a harmless infection. We anticipate that whatever it does this summer, it’s likely to be a major player in the fall, and when something this new and unpredictable shows up, we are well-advised to do our best to prepare for it.”

Get Your Questions Answered at the ABC News OnCall+ Swine Flu Center

Swine flu may not create a major hazard, similar to 1976, when many were worried but the virus had a relatively small impact. For that reason, the CDC will prepare a vaccine for swine flu but will monitor the virus before making the separate decision of whether to deploy it.

2. You can get swine flu from eating or handling pork.

To date, no evidence has been found to link eating or handling pork to contracting swine flu.

“By eating pork or handling pork products you won’t [contract] H1N1,” said Ed Hsu, an associate professor of health informatics at the University of Texas Health Science Center and a contributor to ABC News’s OnCall+ Swine Flu site. “There is no scientific evidence or literature or any studies that suggest that one contracts H1N1 virus through eating pork or handling pork products.”

Additionally, USDA guidelines say to cook pork products to an internal temperature of at least 160 degrees Fahrenheit, in order to kill pathogens that live on raw pork. That temperature would kill the swine flu virus.

3. If you got a seasonal flu shot you are protected from swine flu.

While a strain of H1N1 virus is one of the three flu viruses contained in the annual flu vaccine, it does not match the strain of swine flu that has been making people sick, and so the vaccine will likely not provide full protection against the flu.

“It’s unclear at this time whether previous flu shots or having had the flu in the past will protect you from swine flu,” said Dr. Christopher Ohl, an associate professor of infectious diseases at Wake Forest University Baptist Medical Center.

“Certainly, to have full protection is not going to be possible,” he said. “However, it may be that some partial protection may be provided by earlier shots or having had the flu.”

Seasonal flu vaccine development is well under way, but the first viruses from which manufacturers will make swine flu vaccines are only being delivered this week.

The CDC expects those to be made and tested at the end of June and then made so that they can be available in the fall, when flu season begins.

At that time, CDC officials will be tracking the swine flu to see if they need to deploy the swine flu vaccine.

So, to be fully protected against flu strains likely to be around next flu season, you will likely need more than one vaccination.

4. When the World Health Organization’s pandemic alert level rises, it means the swine flu is becoming deadlier.

The pandemic alert level is not a measure of swine flu’s deadliness. Rather, it’s a measure of how widespread the disease has become.

As the WHO notes, Level 5 — the current level for swine flu — indicates that the disease has spread from person to person and a pandemic is considered “imminent.”

At this point, the WHO advises countries to be prepared for a possible pandemic.

A pandemic is not considered to be under way unless the pandemic alert level is raised to Level 6.

As the WHO notes on its Web site, “While most countries will not be affected at this stage, the declaration of Phase 5 is a strong signal that a pandemic is imminent and that the time to finalize the organization, communication and implementation of the planned mitigation measures is short.”

20090528-9

Human Microbiome Project (HMP) 

Overview 

Within the body of a healthy adult, microbial cells are estimated to outnumber human cells by a factor of ten to one. These communities, however, remain largely unstudied, leaving almost entirely unknown their influence upon human development, physiology, immunity, and nutrition. To take advantage of recent technological advances and to develop new ones, the NIH Roadmap has initiated the Human Microbiome Project (HMP) with the mission of generating resources enabling comprehensive characterization of the human microbiota and analysis of its role in human health and disease.

Traditional microbiology has focused on the study of individual species as isolated units. However many, if not most, have never been successfully isolated as viable specimens for analysis, presumably because their growth is dependant upon a specific microenvironment that has not been, or cannot be, reproduced experimentally. Among those species that have been isolated, analyses of genetic makeup, gene expression patterns, and metabolic physiologies have rarely extended to inter-species interactions or microbe-host interactions. Advances in DNA sequencing technologies have created a new field of research, called metagenomics, allowing comprehensive examination of microbial communities, even those comprised of uncultivable organisms. Instead of examining the genome of an individual bacterial strain that has been grown in a laboratory, the metagenomic approach allows analysis of genetic material derived from complete microbial communities harvested from natural environments. In the HMP, this method will complement genetic analyses of known isolated strains, providing unprecedented information about the complexity of human microbial communities.

By leveraging both the metagenomic and traditional approach to genomic DNA sequencing, the Human Microbiome Project will lay the foundation for further studies of human-associated microbial communities. Broadly, the project has set the following goals:

  • * Determining whether individuals share a core human microbiome
  • * Understanding whether changes in the human microbiome can be correlated with changes in human health
  • * Developing the new technological and bioinformatic tools needed to support these goals
  • * Addressing the ethical, legal and social implications raised by human microbiome research.

Notably, however, the utility of the techniques and technologies pioneered by the HMP will not be limited to studies of human health but will be applicable to the study of microbes in a wide range of biological processes. Microbes profoundly shape this planet and all life on it, and yet the test tube of the laboratory is rarely reflective of how they actually exist in the environment. The ability to study native microbial communities represents a fundamental shift in microbiology and is one whose implications can only be imagined.

Finally, the NIH Human Microbiome Project is only one of several international efforts designed to take advantage of metagenomic analysis to study human health. The HMP expects to continue the practice established by the Human Genome Project of international collaboration to generate a rich, comprehensive, and publicly available data set. This information will be available worldwide for use by investigators and others in efforts to understand and improve human health. For more information on the Human Microbiome Project, e-mail HMPinformation@mail.nih.gov or visit http://www.hmpdacc.org.

U.S. Department of Health and Human Services

NATIONAL INSTITUTES OF HEALTH NIH News

National Human Genome Research Institute (NHGRI)

For Release: Thursday, May, 28, 2009 

Genomic Research Lays Groundwork for New Approaches for Treating, Preventing Skin Diseases 

The health of our skin — one of the body’s first lines of defense against illness and injury — depends upon the delicate balance between our own cells and the millions of bacteria and other one-celled microbes that live on its surface. To better understand this balance, National Institutes of Health researchers have set out to explore the skin’s microbiome, which is all of the DNA, or genomes, of all of the microbes that inhabit human skin. Their initial analysis, published today in the journal Science, reveals that our skin is home to a much wider array of bacteria than previously thought. 

The study also shows that at least among healthy people, the greatest influence on bacterial diversity appears to be body location. For example, the bacteria that live under your arms likely are more similar to those under another person’s arm than they are to the bacteria that live on your forearm. 

“Our work has laid an essential foundation for researchers who are working to develop new and better strategies for treating and preventing skin diseases,” said Julia Segre, Ph.D., of the National Human Genome Research Institute (NHGRI), who was the study’s senior author. “The data generated by our study are freely available to scientists around the world. We hope this will speed efforts to understand the complex genetic and environmental factors involved in eczema, psoriasis, acne, antibiotic-resistant infections and many other disorders affecting the skin.” 

Drawing on the power of modern DNA sequencing technology and computational analysis, the research team from NHGRI, the National Cancer Institute (NCI) and the NIH Clinical Center uncovered a far more diverse collection of microbes on human skin than had been detected by traditional methods that involved growing microbial samples in the laboratory. 

The NIH study involved taking skin samples from 20 sites on the bodies of 10 healthy volunteers. “We selected skin sites predisposed to certain dermatological disorders in which microbes have long been thought to play a role in disease activity,” said study coauthor Maria Turner, M.D., senior clinician in NCI’s Dermatology Branch. 

The researchers extracted DNA from each sample and sequenced the 16S ribosomal RNA genes, which are a type of gene that is specific to bacteria. The researchers identified more than 112,000 bacterial gene sequences, which they then classified and compared. The analysis detected bacteria belonging to 19 different phyla and 205 different genera, with diversity at the species level being much greater than expected. 

To gauge how much the skin microbiome differs among healthy people, the researchers studied many different parameters. They found considerable variation in the number of bacteria species at different sites, with the most diversity being seen on the forearm (44 species on average) and the least diversity behind the ear (19 species on average). 

The research also generated information that may prove useful in efforts to combat the growing problem of methicillin-resistant Staphylococcus aureus (MRSA), a bacterium that can cause serious, even life-threatening, infections. While it is known that a significant proportion of people have colonies of S. aureus inside their noses, the NIH team checked to see where else on the body surface that these bacteria thrive. They found that the crease of skin outside the nose is the site with the microbial community most similar to that found inside the nose. 

“Not only does our work shed new light on understanding an important aspect of skin biology, it provides yet another example of how genomic approaches can be applied to study important problems in biomedical research,” said NHGRI’s Scientific Director Eric D. Green, M.D., Ph.D., who is a co-author of the study. “This also demonstrates what can be achieved through efforts that pull together researchers from across NIH.” 

NIH recently launched the Human Microbiome Project, a part of the NIH Roadmap for Medical Research, to discover what microbial communities exist in different parts of the human body and to explore how these communities change with disease. In addition to skin and nose, that project is sampling the digestive tract, the mouth, and the vagina.

The skin sites selected for the Science study represent three microenvironments: oily, moist and dry. The oily sites included between the eyebrows, beside the nose, inside the ear, back of the scalp, and upper chest and back. Moist areas were inside the nose, armpit, inner elbow, webbed area between the middle and ring fingers, side of the groin, top fold of the buttocks, behind the knee, bottom of the foot and the navel. Dry areas included the inside surface of the mid-forearm, the palm of the hand and the buttock. Researchers found that dry and moist skin had a broader variety of microbes than did oily skin. Oily skin contained the most uniform mix of microbes.

To look for changes that may occur in the skin microbiome over time, the researchers sampled some volunteers twice, with the samples being taken about four to six months apart.  Most of the resampled volunteers were more like themselves over time than they were like other volunteers. However, the stability of the microbial community was dependent on the site surveyed. The greatest stability was found in samples from inside the ear and nose, and the least stability was found in samples from behind the knee. 

“Our results underscore that skin is home to vibrant communities of microbial life, which may significantly influence our health,” said the study’s first author, Elizabeth Grice, Ph.D., who is a postdoctoral fellow at NHGRI.

20090528-6

Des Tobin MD

Department of Biomedical Sciences at the University of Bradford

 Professor of Cell Biology.

By Desmond J. Tobin MD, University of Bradford, UK  —  Adult human skin extends to approximately 2 m2 in area, is around 2.5 mm thick on average and has an average density of 1.1. Together these provide for a 5-6 kg mass value for skin or to put it another way skin constitutes an impressive 6% of our total body weight. As such the skin exceeds all other organs in total mass, if we exclude the muscle, bone, adipose and blood systems from this limited definition of organ.’ The skin invests the body to provide a vast physical barrier at the interface with the external environment and is designed to protect us against a range of insults including: desiccant (temperature, electrolyte/fluid balance), mechanical, chemical and microbial. Further protection is provided by the ultraviolet radiation (UVR)-absorbing pigmentation system and the complex immuno-regulatory sentinel networks, which sense tissue micro-environments for foreign or abnormally expressed components. It is only by thinking of the skin in holistic terms can we accommodate, and then tackle, the difficulties in modern clinical dermatology, dermato-pathology, and dermato-pharmacology that will hopefully guide us to development of targets for therapeutic intervention.

Conventionally, the skin is described as consisting of two broad tissue types; the epidermis – an external stratified, non-vascularized, epithelium of between 75 and 150 µm (up to 600 µm thick on palms/soles), and an underlying connective tissue called the dermis – consisting of mixture of fibroblasts producing dense fibrous/elastic components and the erroneously termed ground substance. The dermis may be up to 4 mm thick (e.g. adult back) but is usually less than 2 mm and houses many of the skin’s business centers including; its vascular, neural and lymphatic systems and its multiple accessory appendages. The latter include its excretory and secretary glands (Sebaceous, Eccrine and Apocrine glands), its keratinizing structures (Hair follicles and Nails), and its sensory nerve receptors of Meissner’s corpuscles (touch), Pacinian corpuscles (pressure), Pilo-Ruffini corpuscles (mechanoreceptors), free terminals, hair follicle endings etc. There is considerable variation in the presence and density of these appendages between different body sites. Finally, anatomists include a third skin layer, the sub-cutis or hypodermis consisting of fatty connective tissue that connects the dermis to underlying skeletal components. Interested readers keen on learning more about the cell biology and physiology of skin can consult specialized texts.

20090528-7

Fig. 1 High-resolution light microscopy view of a portion of normal

human skin showing epidermis and dermis (D). SC, S. corneum;

SG, S. granulosum; SS, S. spinosum; SB, S. basale.

Scale bar = 30 µM.

20090528-8

Fig. 2 Cartoon of normal human skin showing epidermis (E), dermis (D), subcutaneous fat layer (SCFL), and skin appendages including hair follicle (HF) with hair shaft (HS), sebaceous gland (SG), eccrine sweat gland (ESG), Meissner’s corpuscle (MC), Pacinian corpuscle (PC), blood vessels (BV), sweat gland pore (P), nerve fiber (NF), free nerve ending (FNe). 

By Des Tobin MD, University of Bradford, UK  —  It is only appropriate that the immune function should be strongly represented in the organ that is most directly responsible for separating physically the self from the non-self. However, the skin not only provides immune protection for itself, but also helps protect the whole body. More stimulation of the immune system is likely to occur at this biological interface (between you and your external environment) than any other area of your body. Biological aggressors like bacteria, viruses, mould, yeast, fungus and chemical insults that threaten our health can gain entry to our bodies via the skin and its numerous ports of entry (e.g. hair follicle canals, sweat gland pores etc.) However, unless the skin itself is damaged (e.g. wounds, abrasions or disease) or the host is compromised (e.g. immuno-suppressed), most of these threats are repelled by our skin.

Immunodermatology, the study of the skin immune system (SIS), has grown enormously over the last couple of decades and we have made great strides in the dissection of the skin immunological networks involved in both physiologic and pathologic circumstances.45 The make up of the SIS can be most simply described in terms of its components, i.e. cellular and humoral components or alternately whether we are looking at its innate (pre-existing) or adaptive (subsequent to prior exposure to an immune response generating stimulus) immunity. In the last few years it has become clear that practically all cell types residing in and transiting through skin can exhibit immune functionality. The better characterized cellular components include keratinocytes, lymphocytes (various subpopulations in skin), Langerhans cells (and other skin dendritic cells), monocytes and macrophages, endothelial cells of blood and lymphatic vessels, mast cells (containing a battery of mediators of both immune and neuroendocrine responses), neutrophils, eosinophils, and basophils. Innate components include free radicals, anti-microbial peptides including defensins and cathelicidins, cytokines, chemokines, neuropeptides, adhesion molecules and a wide range of pro- and anti-inflammatory mediators. Immunoglobulins or antibodies are additional potent proteins that are secreted from activated B-lympocytes and can neutralize threats to the body. Given the surface location of skin, it is not surprising that the physiology and pathology of skin can be affected by ultraviolet sunlight and so the sub-field of photo-immunology has yielded several important findings. Prominent among these is the general immuno-suppressive effect of sunlight with its associate killing of Langerhans cells or altering their function. Our increasing longevity will require us to depend even more on the skin immune system immuno-surveillance function to prevent and limit tumor growth etc.

There are also may congenital and acquired disorders with associated skin manifestations, as well as immune or autoimmune related disorders. Examples, of the latter include so-called immunobullous or blistering diseases, Lichen planus and graft-versus-host disease, Lupus erythematosus, psoriasis etc. Moreover, how the skin handles xenobiotics also involves immunological mechanisms, and the degree to which individuals may exhibit an allergic or atopic tendency will determine whether they will develop atopic dermatitis, allergic contact dermatitis etc. The last decade or so has witnessed the development of new immuno-modulatory drugs (both biologics and chemicals) for manipulating skin immune response and so managing treatment of skin disease.

The hair follicle has its own unique immune system principally characterized by its so-called immune privileged status, where its lower regions are immuno-silent during parts of the hair growth cycle. This appears to be an adaptation to protect this critical mini-organ during its hair cycle-dependent dramatic tissue remodeling events.

To read this entire paper, go to the following website of the Royal Society of Chemistry:

http://www.rsc.org/delivery/_ArticleLinking/DisplayHTMLArticleforfree.cfm?JournalCode=CS&Year=2006&ManuscriptID=b505793k&Iss=1

DOD Helping to Get Skin Harvesting Kit to Market

20090528-5

GoogleNews.com, May 27, 2009  —  As the Obama administration continues to fight wars in Iraq and Afghanistan, the Pentagon is working on medical technology that can help soldiers recover and rehabilitate faster than ever before. Shrapnel wounds and burns caused by explosions often require grafting the damaged areas with regrown skin cells. To make this process easier and faster, Avita Medical out of Nedlands, Australia has created a kit called ReCell for harvesting autologous skin cells by clinicians even in the field. The Pentagon believes in effectiveness of this technology so much that a grant of $1.45 million has been provided to Avita by the United States Armed Forces Institute of Regenerative Medicine (AFIRM) to speed up FDA approval.

ReCell is an innovative single-use medical device for harvesting autologous skin cells. Developed as an ‘off the shelf’ kit, ReCell enables a thin split thickness biopsy, taken at the time of procedure, to be processed into an immediate cell population for delivery onto the wound surface. Once processed, the cell suspension is available for immediate use and can cover a wound up to 80 times the area of the donor biopsy.

ReCell enables the delivery of keratinocytes, melanocytes, fibroblasts and Langerhans cells harvested from the epidermal-dermal junction for application onto a wound surface in order to promote effective wound healing. Melanocyte repopulation may result in the reintroduction of pigmentation into hypopigmented areas.

ReCell has been generally used to treat smaller wounds such as small burns and scalds, donor sites, glabrous injuries, mild to moderate scars, hypopigmentation (hypopigmented scars, iatrogenic hypopigmentation and Vitiligo) and prophylactically in cosmetic rejuvenation procedures.

As the ReCell device enables cell processing at the site of treatment without the use of specialised laboratory staff, the process is both cost and time efficient.

Advantages include:

  Improved wound healing time and scar quality.

  Repopulation of melanocytes to reduce hypopigmentation.

  On-site processing for immediate application.

  Increased viability through immediate harvest and application.

  Ability to be processed by clinician not specialised laboratory staff.

Eli Greenblat

May 27, 2009

Shares in Avita Medical rallied nearly 25 per cent this morning after the biotechnology company announced it had won $US1.45 million ($2 million) in funding from the United States Armed Forces Institute of Regenerative Medicine (AFIRM) to accelerate approval of the company’s ReCell skin healing technology.
 
The intent from Avita and AFIRM, an arm of the US government, is to fast-track the skin healing technology for approval in the US so it can be used in commercial applications as well as by the armed forces to help care for soldiers hurt in the heat of battle.
 
Avita was awarded the grant following a highly competitive approval process that saw the Australian company compete against project submissions from over 25 other companies and universities.
 
Shares in Avita jumped nearly 25 per cent on the news to a high of 13.5 cents and were up 2.1, or 21.2 per cent, at 12 cents this afternoon.
 
The award of the AFIRM grant may also accelerate the US FDA approval process for ReCell – an important milestone in Avita’s commercialisation of the product, the company said.

ReCell is a spray-on treatment for burns victims that promises better healing and end results for patients than traditional skin graft procedures.

The technology was developed by Fiona Wood, a former Australian of the Year.
 
The AFIRM funding will provide capital for a 100-patient, multicentre trial of ReCell. Up to 10 US investigational sites will participate and the study site collection process will begin in the coming weeks.
 
Avita Medical chief executive William Dolphin said the grant from the US Armed Forces, which closely follows the funding of a medico-economic study by the French Ministry of Health, was another compelling endorsement of ReCell.
 
“The selection process was based on the identification of high impact, highly innovative technologies with the greatest likelihood of delivering clinical benefit. ReCell is a disruptive technology which we believe will redefine the clinical treatment of burns, scar remodeling and other skin defects and injuries.
 
“The underlying technology has enormous application in the field of regenerative medicine and tissue engineering.”

egreenblat@theage.com.au

20090528-4

New evidence of how the elevated glucose levels that occur in

diabetes damage blood vessels may lead to novel strategies for

blocking the destruction, Medical College of Georgia researchers say.

(Credit: Image courtesy of Medical College of Georgia)
Medical College of Georgia (2009, May 12). New Evidence Of How High Glucose Damages Blood Vessels Could Lead To New Treatments. ScienceDaily   –   New evidence of how the elevated glucose levels that occur in diabetes damage blood vessels may lead to novel strategies for blocking the destruction, Medical College of Georgia researchers say.

They found a decreased ability of blood vessels to relax resulted from increased activity of a natural mechanism for altering protein form and function, says Dr. Rita C.Tostes, physiologist in the MCG School of Medicine. 

The researchers suspect increased modification of proteins by a glucose-derived molecule is a player in vascular problems associated with hypertension, stroke and obesity as well. 

One aftermath of high glucose levels is low levels of the powerful vasodilator nitric oxide in blood vessels, a shortfall that increases the risk of high blood pressure and eventual narrowing of the vessels, researchers reported at the American Society of Hypertension 24th Annual Scientific Program in San Francisco during a joint session with the Council for High Blood Pressure. 

“We know diabetes is a major risk factor for cardiovascular disease and we think this is one of the reasons,” Dr. Tostes says. 

Diabetes increases the risk of cardiovascular disease such as heart disease and stroke, even when glucose, or blood sugar, levels are under control. In fact, about 75 percent of people with diabetes die from some form of heart or blood vessel disease, according to the American Heart Association. 

Most of the glucose in the body goes directly into cells where it’s modified to produce the energy source ATP. However about 5 percent of all glucose is converted to another sugar moiety, O-GlcNAc, one of the sugar types that can modify proteins. 

Inside the blood vessel walls of healthy mice, MCG researchers found increased activity by O-GlcNAc competes with another mechanism for modifying proteins called phosphorylation. In blood vessels, phorphorylation modifies the enzyme that produces nitric oxide, called nitric oxide synthase, so that it makes more of the blood vessel dilator. But add more O-GlcNAc to the mix and it seems to beat phosphorylation to the punch so there is the opposite result. The longer O-GlcNAc levels were high, the worse the resulting problem, says Victor Lima, a graduate student at the University of Sao Paulo working with Dr. Tostes.

An animal model of hypertension seemed to confirm the finding that the more O-GlcNAc, the more blood vessels contract because these animals had higher O-GlcNAc levels. “Now we are trying to see why this is happening and what comes first. Is increased blood pressure leading to changed O-GlcNAc or are augmented levels of O-GlcNAc contributing to the change we see in the vasculature of hypertensives?” Dr. Tostes says. “If we know how this changes vascular function, we can understand some of the dysfunction that we see in diabetes.”

To make sure they were targeting the O-GlcNAc sugar and not dealing with other effects of glucose on blood vessels, the researchers blocked the enzyme OGA, an enzyme that normally removes O-GlcNAc from proteins so they can revert to their normal state. 

If the findings continue to hold true, drugs similar to those they use in the lab to inhibit OGA or OGT, the enzyme that adds O-GlcNAc to the protein, could one day help reduce the significant cardiovascular risk associated with diabetes, Mr. Lima says. “I think it looks very promising,” Dr. Tostes adds.

Future studies will include blocking the pathway for adding O-GlcNAc in hypertensive animals to study the impact on blood pressure and vascular function.

20090528-3

Green teas have undergone less processing than black teas, and have a much lighter flavour. The health benefits of green tea are seemingly endless. Since the leaves are not fermented, the taste is pleasantly fresh and herbal. The pictured variety here is called Dragonwell tea. Photo supplied by Adagio Teas

Mayo Clinic (2009, May 27). Green Tea Extract Shows Promise In Leukemia Trials. ScienceDaily– Mayo Clinic researchers are reporting positive results in early leukemia clinical trials using the chemical epigallocatechin gallate (EGCG), an active ingredient in green tea. The trial determined that patients with chronic lymphocytic leukemia (CLL) can tolerate the chemical fairly well when high doses are administered in capsule form and that lymphocyte count was reduced in one-third of participants. 

“We found not only that patients tolerated the green tea extract at very high doses, but that many of them saw regression to some degree of their chronic lymphocytic leukemia,” says Tait Shanafelt, M.D., Mayo Clinic hematologist and lead author of the study. “The majority of individuals who entered the study with enlarged lymph nodes saw a 50 percent or greater decline in their lymph node size.” 

CLL is the most common subtype of leukemia in the United States. Currently it has no cure. Blood tests have enabled early diagnosis in many instances; however, treatment consists of watchful waiting until the disease progresses. Statistics show that about half of patients with early stage diseases have an aggressive form of CLL that leads to early death. Researchers hope that EGCG can stabilize CLL for early stage patients or perhaps improve the effectiveness of treatment when combined with other therapies. 

The research has moved to the second phase of clinical testing in a follow-up trial — already fully enrolled — involving roughly the same number of patients. All will receive the highest dose administered from the previous trial. 

These clinical studies are the latest steps in a multiyear bench-to-bedside project that began with tests of the green tea extract on cancer cells in the laboratory of Mayo hematologist Neil Kay, M.D., a co-author on this article. After laboratory research showed dramatic effectiveness in killing leukemia cells, the findings were applied to studies on animal tissues and then on human cells in the lab.  

In the first clinical trial, 33 patients received variations of eight different oral doses of Polyphenon E, a proprietary compound whose primary active ingredient is EGCG. Doses ranged from 400 milligrams (mg) to 2,000 mg administered twice a day. Researchers determined that they had not reached a maximum tolerated dose, even at 2,000 mg twice per day. 

The findings appear online May 26 in the Journal of Clinical Oncology. The study was sponsored by Mayo Clinic, the CLL Global Research Foundation, CLL Topics (including contributions by individual CLL patients) and the Commonwealth Foundation for Cancer Research. Medication for the study was provided by Polyphenon E International. Others on the research team were Timothy Call, M.D.; Clive Zent, M.D.; Betsy LaPlant; Deborah Bowen; Michelle Roos; Charla Secreto; Asish Ghosh, Ph.D.; Brian Kabat; Diane Jelinek, Ph.D.; and Charles Erlichman, M.D., all of Mayo Clinic; and Mao-Jung Lee, Ph.D., and Chung Yang, Ph.D., both of Rutgers University.

Next Page →