Science Weekly: At the edge of physics

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Physics in the world’s most extreme locations; the UK election’s impact on science. Plus: Do wildlife documentaries infringe animals’ privacy?

Target Health Unveils a Novel Approach to eSource for Clinical Trials

Target Health is pleased to announce the publication of The Final eFrontier in the online May edition of Applied Clinical Trials. The article discusses the feasibility of totally paperless clinical trials including the eClinical Trial Record. Target e*CTR™ (patent pending) is Target Health’s novel solution to eSource and is now running in the background in one of our ongoing clinical trials. A phase III program will be implemented with one of our clients within 6 months. There will be no onsite monitoring of data against source documents and we anticipate that onsite monitoring visits will be dramatically reduced. Analysis of current EDC data are underway to assess aspects of risk-based monitoring.

Target e*CTR™ joins Target Health suite of clinical trial software including:

  • Target e*CRF®, EDC with 18 NCE approvals
  • Target Document®, Paperless TMF and much more
  • Target Encoder®, MedDRA and WHODRUG coding from any database
  • Target e*CTMS®, Clinical Trial Management System
  • Target Newsletter™, Updates status of clinical trials to Investigators
  • The next version of Target e*CRF®, Target e*Studio™, will be fully integrated with Target e*CTR™, CDISC’s SDTM and ADaM standards as well allowing users to build EDC applications easily and inexpensively.

 

For more information about Target Health contact Warren Pearlson (212-681-2100 ext 104). For additional information about software tools for paperless clinical trials, please feel free to also contact Dr. Jules T. Mitchel or Ms. Joyce Hays. Target Health’s software tools are designed to partner with both CROs and Sponsors. Please visit the Target Health  website at: www.targethealth.com

New Nerve Cells Even in Old Age

After birth the brain loses many 1) ___ cells and this continues throughout life. Most neurons are formed before 2) ___, after which many excess neurons degenerate. However, there are some cells that are still capable of division in old age, at least in the brains of mice. According to scientists from the Max Planck Institute of Immunobiology in Freiburg, different types of neuronal stem cells exist that can create new neurons. While they divide continuously and create new 3) ___ in young animals, a large proportion of the cells in older animals persist in a state of dormancy. However, the production of new cells can be reactivated, for example, through physical activity or epileptic 4) ___. What happens in mice could also be applicable to humans as neurons that are capable of dividing also occur in the human brain into adulthood. The research is published in the journal Cell Stem Cell. The proverb “You can’t teach an old dog new tricks“ corresponds to the view that the brain loses learning and memory capacity with advancing age, has prevailed for a long time. However, neuronal stem cells that exist in the hippocampus, a region of the brain that plays a central role in learning and memory functions can produce new nerve cells throughout 5) ___. It is known from tests on mice that the newly formed cells are integrated into the existing networks and play an important role in the learning capacity of animals. Nonetheless, the formation of new cells declines with 6) ___ and the reasons for this were unknown up to now. Together with colleagues from Dresden and Munich, the Freiburg researchers have now succeeded in explaining for the first time why fewer new neurons are formed in the adult mouse 7) ___. They managed to identify different populations of neuronal stem cells, thereby demonstrating that the hippocampus has active and dormant or inactive neuronal 8) ___ cells. The precise factors that influence the reactivation of 9) ___ stem cells are not yet clear. The cells can, however, be stimulated to divide again. The scientists observed more newborn hippocampal neurons in physically active mice than in their inactive counterparts. Pathological brain activity, for example that which occurs during epileptic seizures, also triggers the division of the neuronal stem cells. The different stem cell populations are easy to distinguish under the microscope. The first group comprises cells which lie perpendicular to the surface of the hippocampus. Most of these radial stem cells are dormant. As opposed to this, over 80% of the cells in the group of horizontal stem cells – cells whose orientation runs parallel to the hippocampus surface – continuously form new cells; the remaining 20% are dormant but sporadically become 10) ___. The activity of genes such as Notch, RBP-J and Sox2 is common to all of the cells. Radial and horizontal stem cells differ not only in their arrangement, apparently they also react to different stimuli. When the animals are physically active, some radial stem cells abandon their dormant state and begin to divide, while this has little influence on the horizontal stem cells. The result is that more radial stem cells 11) ___ in active mice. The horizontal stem cells, in contrast, are also influenced by epileptic seizures. It would appear that neuronal stem cells are not only found in the brains of mice. The presence of neurons that are formed over the course of life has also been demonstrated in the human 12) ___. Therefore, scientists suspect that different types of active and inactive stem cells also arise in the human brain. It is possible that inactive stem cells in humans can also be activated in a similar way to inactive stem cells in mice.

ANSWERS: 1) nerve; 2) birth; 3) neurons; 4) seizures; 5) life; 6) age; 7) brain; 8) stem; 9) dormant; 10) activated; 11) divide; 12) hippocampus

Biology

The word biology is formed by combining the Greek bios, meaning “life“, and the suffix “logy“, meaning “science of“, “knowledge of“, “study of“. The earliest humans must have had and passed on knowledge about plants and animals to increase their chances of survival. This may have included knowledge of human and animal anatomy and aspects of animal behavior (such as migration patterns). However, the first major turning point in biological knowledge came with the Neolithic Revolution about 10,000 years ago. Humans first domesticated plants for farming, then livestock animals to accompany the resulting sedentary societies. The history of biology traces the study of the living world from ancient to modern times. Although the concept of biology as a single coherent field arose in the 19th century, the biological sciences emerged from traditions of medicine and natural history reaching back to ancient Egyptian medicine and the works of Aristotle and Galen in the ancient Greco-Roman world. The pre-Socratic philosophers asked many questions about life but produced little systematic knowledge of specifically biological interest – though the attempts of the atomists to explain life in purely physical terms would recur periodically through the history of biology. However, the medical theories of Hippocrates and his followers, especially humorism, had a lasting impact. The philosopher Aristotle was the most influential scholar of the living world from classical antiquity. Though his early work in natural philosophy was speculative, Aristotle’s later biological writings were more empirical, focusing on biological causation and the diversity of life. He made countless observations of nature, especially the habits and attributes of plants and animals in the world around him, which he devoted considerable attention to categorizing. In all, Aristotle classified 540 animal species, and dissected at least 50. He believed that intellectual purposes, formal causes, guided all natural processes. Aristotle, and nearly all Western scholars after him until the 18th century, believed that creatures were arranged in a graded scale of perfection rising from plants on up to humans: the scala naturae or Great Chain of Being. Aristotle’s successor at the Lyceum, Theophrastus, wrote a series of books on botany – the History of Plants – which survived as the most important contribution of antiquity to botany, even into the Middle Ages. Many of Theophrastus’ names survive into modern times, such as carpos for fruit, and pericarpion for seed vessel. Pliny the Elder was also known for his knowledge of plants and nature, and was the most prolific compiler of zoological descriptions. A few scholars in the Hellenistic period under the Ptolemies – particularly Herophilus of Chalcedon and Erasistratus of Chios – amended Aristotle’s physiological work, even performing experimental dissections and vivisections. Claudius Galen became the most important authority on medicine and anatomy. Though a few ancient atomists such as Lucretius challenged the teleological Aristotelian viewpoint that all aspects of life are the result of design or purpose, teleology (and after the rise of Christianity, natural theology) would remain central to biological thought essentially until the 18th and 19th centuries. Ernst W. Mayr argued that “Nothing of any real consequence happened in biology after Lucretius and Galen until the Renaissance.“ The ideas of the Greek traditions of natural history and medicine survived, but they were generally taken unquestioningly in medieval Europe. This ancient work was further developed in the Middle Ages by physicians and scholars such as Avicenna. During the European Renaissance and early modern period, biological thought was revolutionized in Europe by a renewed interest in empiricism and the discovery of many novel organisms. Prominent in this movement were Vesalius and Harvey, who used experimentation and careful observation in physiology, and naturalists such as Linnaeus and Buffon who began to classify the diversity of life and the fossil record, as well as the development and behavior of organisms. Microscopy revealed the previously unknown world of microorganisms, laying the groundwork for cell theory. Over the 18th and 19th centuries, biological sciences such as botany and zoology became increasingly professional scientific disciplines. Lavoisier and other physical scientists began to connect the animate and inanimate worlds through physics and chemistry. Explorer-naturalists such as Alexander von Humboldt investigated the interaction between organisms and their environment, and the ways this relationship depends on geography?laying the foundations for biogeography, ecology and ethology. Naturalists began to reject essentialism and consider the importance of extinction and the mutability of species. Cell theory provided a new perspective on the fundamental basis of life. These developments, as well as the results from embryology and paleontology, were synthesized in Charles Darwin’s theory of evolution by natural selection. The end of the 19th century saw the fall of spontaneous generation and the rise of the germ theory of disease, though the mechanism of inheritance remained a mystery. In the early 20th century, the rediscovery of Mendel’s work led to the rapid development of genetics by Thomas Hunt Morgan and his students, and by the 1930s the combination of population genetics and natural selection in the “neo-Darwinian synthesis”. New disciplines developed rapidly, especially after Watson and Crick proposed the structure of DNA. Following the establishment of the Central Dogma and the cracking of the genetic code, biology was largely split between organismal biology – the fields that deal with whole organisms and groups of organisms?and the fields related to cellular and molecular biology. By the late 20th century, new fields like genomics and proteomics were reversing this trend, with organismal biologists using molecular techniques, and molecular and cell biologists investigating the interplay between genes and the environment, as well as the genetics of natural populations of organisms.

Magnetic Stimulation Scores Modest Success as Antidepressant

According to an article published in the Archives of General Psychiatry (2010;67:507-516), some depressed patients who don’t respond to or tolerate antidepressant medications may benefit from a non-invasive treatment that stimulates the brain with a pulsing electromagnet. This first industry-independent, multi-site, randomized, tightly controlled trial of repetitive transcranial magnetic stimulation (rTMS) found that it produced significant antidepressant effects in a subgroup of patients, with few side effects. Active rTMS treatment accounted for remissions in 14% of antidepressant-resistant patients actively treated, compared to about 5% for a simulated treatment. The treatment aims to jump-start underactive mood-regulating circuitry by targeting the top left front part of the brain with an electromagnetic coil that emits 3,000 pulses over a 37-minute session. It can be safely administered in a doctor’s office with few side effects – unlike more invasive brain stimulation treatments, such as electroconvulsive therapy (ECT). Following a decade and a half of studies yielding mixed results, the FDA cleared an rTMS device for treatment of mildly treatment resistant depression in 2008, based on data submitted by the manufacturer. The field has been awaiting the results of the NIMH-funded multi-site trial to provide more definitive evidence of efficacy. Lack of a convincing simulation control treatment that mimics transient tapping and twitching sensations produced by the magnet weakened confidence in findings of some previous rTMS studies. To address these concerns, the new study sought to blind patients, treaters and raters with a simulation control treatment that produced the same head-tapping sensation and scalp twitching as the active treatment. A metal insert below the magnet blocked the magnetic field from entering the brain, while electrodes touching the scalp delivered the tapping sensation. This simulation was so convincing that even the treaters could not confidently guess the randomization above chance level. A sample of 190 patients who had previously failed to respond to antidepressant medications received at least three weeks of randomized, controlled magnetic stimulations on weekdays for three weeks, with the rTMS magnet aimed at their brain’s left prefrontal cortex. Those who showed improvement received up to an additional three weeks of such blinded treatment. Thirteen (14%) of 92 patients who received the active treatment achieved remission, compared to 5 (about 5%) of 98 patients who received the simulation treatment. Patients who received active rTMS were significantly more likely to reach remission, particularly if they had been moderately, rather than severely, treatment resistant. The remission rate climbed to nearly 30 percent in an open-label phase of this study in which there was no simulation control. Patients who responded to active treatment received up to three weeks of additional blinded, controlled rTMS until they achieved remission or stopped showing a meaningful response – so the number of responders did not differ significantly from the number of remitters. These patients who remitted then received a combination of medications intended to help maintain the treatment effect. Despite failing to respond to medications in the past, most remained in remission for several months. Study participants who failed to improve during the blinded phase entered a course of open-label rTMS. Among those who had been in the active rTMS group, 30% achieved remission during this second phase. This suggests that some patients might require as many as 5-6 weeks of daily rTMS treatment. Most patients who remitted required 3-5 weeks of treatment.

ONCOLOGY

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Trends Suggest Increase in Cancers of the Lower Stomach for Younger Whites In U.S.

 

Cancers of the upper and lower parts of the stomach are thought to have different causes. Cancers of the upper stomach may be related to acid reflux, whereas a major cause of lower stomach cancers is infection with the bacterium Helicobacter pylori (H. pylori). Most stomach cancers are diagnosed in people 65 years of age or older. In the United States, stomach cancer is higher among African-Americans, Asian-Americans, and Hispanics. According to an article published in the Journal of the American Medical Association (2010;303:1723-1728), cancer of the lower stomach has decreased overall in American adults but has increased in whites age 25-39. The study analyzed data from NCI’s Surveillance, Epidemiology and End Results (SEER) program, which collects cancer incidence and survival data from population-based registries that cover 26% of the U.S. population. The study identified 39,003 cases of lower stomach cancer diagnosed from 1977 through 2006, and then compared changes in incidence rates during this 30-year period in groups defined by age, race, and other factors. Results showed that the overall incidence rates (cases per 100,000 people) of lower stomach cancers declined over the 30-year study period for all races. Specifically, rates dropped from 5.9 to 4.0 among whites, from 13.7 to 9.5 among blacks, and from 17.8 to 11.7 among other racial groups. However, among whites, different age groups had markedly different incidence rate trends. Even though incidence rates fell from 20 to 13 among people age 60-84, and from 3 to 2 among those ages 40-59, they increased from 0.27 to 0.45 among those ages 25-39. In contrast, incidence rates of lower stomach cancer declined for nearly all age groups among blacks and people of other races. Because infection of the stomach lining by H. pylori is a primary cause of lower stomach cancer, changes in infection patterns during the last 50 years might explain the difference in incidence trends between younger and older whites. The declines in lower stomach cancer seen in the older cohorts are consistent with observed declines in H. pylori infection, reflecting improved hygiene and less crowding during childhood, when the infections are typically acquired. The increase in younger cohorts may indicate a change in the age at infection or even a reversal of the long-term decline in the prevalence of the infection. According to the authors, it may also be possible that a new carcinogenic process is emerging, perhaps unmasked by eradication of H. pylori. Apart from H. pylori infection, nutritional exposures, such as consuming salt and salt-preserved foods, have been implicated as risk factors for lower stomach cancer. Tobacco smoking is another risk factor for both upper and lower stomach cancers.

GENETICS

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Study Provides New Leads Into Genetics of Cleft Lip and/or Palate

Among whites, isolated clefts occur in an estimated 1 in every 1,000 live births. The frequency seems to be even higher in some Asian countries, such as China and the Philippines, but lower among people of African descent. Though usually correctable with several surgeries, families undergo tremendous emotional and economic hardship during the process, and children often require many other services, including complex dental care and speech therapy. Families and physicians have long hoped for ways to prevent the problem before a baby is born, but solutions have been difficult to find. Isolated clefts arise early during fetal development from disruptions in the dynamic but still poorly understood interplay of genes, diet, and environment. According to an article published online by the journal Nature Genetics (May 2010), a consortium of scientists have identified two human genes that, when inherited in a slightly altered form, may play a role in causing cleft lip and/or palate (roof of the mouth), one of the world’s most common congenital malformations. The finding is unique in the study of congenital malformations because of how the discoveries were made. They come from the largest genome-wide association, or GWA, study to date on cleft lip and/or palate. GWA studies allow researchers to survey the DNA of people with a shared condition to measure hundreds of thousands of different points across the genome that can be indicative of a nearby gene alteration. By working as a consortium and through the consent of more than 1,900 affected families from eight countries, the authors were able to detect variations close to genes called MAFB and ABCA4. The variations suggest that altered forms of these genes may be related to clefting. Had the researchers worked alone with their limited numbers of DNA samples, they likely would have lacked the needed statistical power to identify genes that are less frequently altered or have modest effects on the risk of developing a cleft. As is standard for GWA studies, the discoveries were independently replicated by studying 1,965 more affected families from 12 countries, or a total of 8,115 people. The study later obtained additional DNA from participants born with a cleft, sequenced portions of the MAFB and ABCA4 genes, and identified protein-altering changes in some of these samples. Interestingly, they also found in studies with mice that MAFB is expressed early in the development of the head and face, including during the fusion of the roof of the mouth, an indication the Mafb protein is needed for the normal development of the palate. The authors also confirmed in the GWA study the role of two previously reported genetic findings. About 70% of babies born with a cleft lip/or palate have the isolated form, meaning they have no other associated birth defects.

TARGET HEALTH excels in Regulatory Affairs and works closely with many of its clients performing all FDA submissions. TARGET HEALTH receives daily updates of new developments at FDA. Each week, highlights of what is going on at FDA are shared to assure that new information is expeditiously made available.

FDA Changes Process for Medical Device Advisory Committees

The FDA has announced that it will change the way its expert panels review and discuss data and information during public hearings on medical devices under review for premarket approval, effective May 1, 2010. The changes were prompted by an increasing number of medical device advisory panel meetings in recent years. In 2008, there were 10 panel meetings covering 14 major topics. In 2009, there were 17 meetings on 20 topics, and 2010 is on track to surpass those numbers, according to the FDA’s Center for Devices and Radiological Health (CDRH). The increased activity has created challenges for CDRH and the way it operates panel meetings. In accord with current agency policy and guidance for advisory committees, the changes address staffing issues, voting procedures, and other items related to information presentation and flow of discussion. In the past, panel discussions have not always reflected a panel’s final vote on approvability. Now, instead of voting on the approvability of premarket approval applications, including conditions of approval, the panel will vote on the safety and effectiveness of a device and the device’s risk versus its benefit. According to FDA, by making this change in voting procedure, panel members will address key scientific issues during their discussions, which will be reflected in their votes. FDA added that the change also will allow panel members to address issues related to their area of expertise instead of regulatory issues that may be unfamiliar to them. In addition, panels will vote by ballot instead of by a show of hands. While the votes will be publicly tallied so that panel members can be identified by their vote, the ballot process allows each panel member to cast his or her vote without immediate influence by other votes. There are many issues involved in the FDA’s review of a medical device. Historically, the FDA’s presentations to panels included comments on approvability. With the changes, the FDA’s presentations will continue to include reviews of the agency’s data analysis, but will no longer include comments on approvability. Before the changes, the agency medical device reviewers presented a unified, consensus analysis of supporting data. Now, reviewers will present together with data and analysis, the range of scientific opinion in the group. This move will allow more in-depth discussion on safety and effectiveness and risk versus benefit of the device under consideration. The FDA and CDRH will continue to evaluate panel procedures and make changes when necessary. A detailed description of changes to panel operations can be found here.

For more information about our expertise in Medical Affairs, contact Dr. Mark Horn. For Regulatory Affairs, please contact Dr. Jules T. Mitchel or Dr. Glen Park.

Target Health (www.targethealth.com) is a full service eCRO with full-time staff dedicated to all aspects of drug and device development. Areas of expertise include Regulatory Affairs, comprising, but not limited to, IND (eCTD), IDE, NDA (eCTD), BLA (eCTD), PMA (eCopy) and 510(k) submissions, Management of Clinical Trials, Biostatistics, Data Management, EDC utilizing Target e*CRF®, Project Management, and Medical Writing.

 Target Health has developed a full suite of eClinical Trial software including 1) Target e*CRF® (EDC plus randomization and batch edit checks), 2) Target e*CTMS™, 3) Target Document®, 4) Target Encoder®, 5) Target Newsletter®, 6) Target e*CTR™ (electronic medical record for clinical trials). Target Health ‘s Pharmaceutical Advisory Dream Team assists companies in strategic planning from Discovery to Market Launch. Let us help you on your next project.

 


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