BigThink.com, September 27, 2010, by Max Miller — We spend one-third of our lives asleep—for an average American, that’s over 26 years—yet sleep remains one of the biggest mysteries of neuroscience. With brains scans, scientists have learned much about what happens in our heads during sleep, but they still can’t answer the simple question: why do we sleep? There are theories, of course (summarized in the takeaway below), but one thing is very clear: without sleep, our brain begins to malfunction.
Columbia University neuropsychologist Yaakov Stern tells Big Think that people’s abilities to perform simple tasks drops dramatically after 48 hours without sleep. But some people are affected more than others. What Stern’s research hoped to answer was why some brains are better able to cope with sleeplessness than others, with the hopes of potentially minimizing our biological need for sleep.
First, Stern located a neural network, mostly in the occipital and parietal lobes of the brain, that seemed to determine whether a person coped well or poorly without sleep. Then he used Transcranial Magnetic Stimulation (TMS) to stimulate these areas that were affected by sleep deprivation. “Our hope was that if we stimulated that area, we could improve people’s performance,” he tells Big Think. “And what we found, which was surprising to me was that, first of all, the stimulation to the occipital area did help people respond a little faster compared to some other area that had nothing to do with the network. And the people who benefited most from that stimulation were the people who had showed the most reduction in the network, which is another confirmation that we were finding something interesting.”
Stern’s studies may suggest future ways to mitigate sleep deprivation, but they don’t lead us any closer to understanding the function of sleep. Nor do they explain the nightly hallucinations we call dreams. Dreams occur mostly during REM sleep, a stage of sleep characterized by heightened brain activity. During a normal night of sleep, the brain cycles repeated back and forth between REM sleep and three stages of non-REM sleep: Stage 1, the twilight period between sleeping and waking which occurs only at the beginning of sleep; Stage 2, light sleep which accounts for 60% of night’s rest; and Stage 3, deep sleep, during which most sleep disorders occur.
In her Big Think interview, Shelby Harris, the director of the behavioral sleep medicine program at Montefiore Medical Center in the Bronx, told us that we normally cycle through these stages five or six times in a night and that REM sleep (and therefore dreaming) becomes more prevalent the long er we sleep. “That’s why people tend to remember their dreams in the morning a little bit better,” she explains. But what should we do with the fuzzy dream images that we do manage to hold onto? Are they really the “golden highway to the unconscious,” as Freud believed? Can we learn more about ourselves by trying to interpret them?
Harris doesn’t think so. As she explains in the video below, our understanding of dreams has changed dramatically in the past century. Freud and Jung believed that dreams are the way that the subconscious communicates with the conscious mind. If a person experiences anxiety or fear in a dream, analyzing the dream might help him understand why he is anxious in the first place and what he could do to mitigate that anxiety during the day. But modern theories don’t place as much stock in the actual content of the dreams. Harris thinks dreams are the brain’s method of sorting memories and experiences from the previous day, deciding which ones to retain and which ones to discard.
Though scientists haven’t found conclusive evidence for why our brains need so much sleep, there are some interesting theories:
Information processing theory — Several studies have suggested that REM sleep and/or non-REM sleep might be important for the brain’s ability to process and consolidate memories from the previous day, forming new neural networks and strengthening others. Related studies have also suggested that sleep helps clear away unimportant information, making room for new neural connections.
Damage reversal theory — During waking hours, neurons in the brain are subjected to the wear-and-tear of oxidative stress caused by free radicals; one theory holds that the cool-down period of sleep help to regulate homeostasis in the body and brain and to repair any damage that has occurred during waking.
Adaptive inactivity theory — Last year UCLA neuroscientist Jerome Siegel proposed that sleep might not be physiologically necessary to animals at all. He hypothesized that rather than serving some universally vital, but unknown, function in animals, sleep actually emerged because of its evolutionary benefits: sleep optimizes the timing and duration of behavior, conserving energy and protecting them from certain dangers. Across the animal kingdom there is wide variability in sleep duration, and Siegel suggests that ecological variables more so than biological needs dictate the timing and duration of sleep for different species.
— “Sleep viewed as a state of adaptive inactivity” (2009) published by Jerome Siegel in Nature
— Time magazine article about our biological need for sleep
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Can extreme cooling in intensive care bring people back from the dead? Plus, Jon Henley meets crime scene investigators who are solving murders by studying insects
Target Document and the eTMF
As most of our readers know by now, Target Health is committed to, and excels in, the “paperless clinical trial.” What this means is that we develop technology to make the clinical trial process both efficient and transparent. We anticipate that very shortly, both pharmaceutical companies and FDA will embrace virtual monitoring/inspection of clinical data and documents. Extensive source document verification (SDV) as we know it today, may be a thing of the past.
This week, Target Document Version 1.6 (TD 1.6), 21 CFR Part 11 compliant software, will be released. TD 1.6 completely fulfills all the needs of the eTMF for clinical sites, sponsors and regulators. When managed properly, you will never overnight or manually sign a document again. To “put our money where our mouth is,“ we invite all of our readers to read a ROI piece we wrote on cost savings for an 80 center study in ulcerative colitis. We will also guarantee that you will not only find TD 1.6 the most user-friendly document software out there, but it will also save you money.
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 also feel free to 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.
Artificial Ovary Could Help Infertile Women
Reproductive research: This artificial human ovary surrounds granulosa cell spheres, which are marked with fluorescent green dye. Credit: Brown University
Tissue engineering allows for complex three-dimensional 1) ___ construction.
Researchers at Brown University have created an “artificial human ovary” using a tissue engineering approach that they hope will one day allow scientists to mature human eggs in a laboratory. In the near term, an artificial 2) ___ will enable researchers to better explore the impact of environmental toxins or fertility-enhancing substances on human fertility. It could also aid the development of new forms of contraceptives and the study of ovarian cancer. Further down the line, it could also help women whose ovaries are damaged because of chemotherapy, radiation, or illness, according to a paper published in the current issue of Journal of Assisted Reproduction and Genetics. Today, those women have limited opportunities for 3) ___: either a hurried in-vitro fertilization cycle that leads to a handful of frozen eggs, or freezing ovarian tissue in the hopes that healthy eggs will someday be able to be matured.
An artificial ovary, where immature eggs could be 4) ___ by the thousands and then matured at will in the laboratory, would open up huge possibilities for the one in a 1,000 women who need it. The 5) ___ ovary marks the first time researchers have successfully created a three-dimensional environment that contains the three main types of ovarian cells: theca cells, granulosa cells, and the eggs, known as oocytes.
The artificial ovary could serve as a 6) ___ to help researchers better understand the ovarian aging process, the focus of much of his research. The Brown researchers’ innovation was using a honeycomb-shaped mold to support the egg. 7) ___ eggs are too large to be grown without some kind of support structure since if you try to grow it by itself in a dish, it basically collapses on itself. The researchers broke ovarian cells out of human tissue using enzymes, and poured them into a mold made of agar, a gelatinous substance usually derived from 8) ___. The different types of cells then assembled themselves into a honeycomb shape, with the theca and granulosa cells forming the structure. The egg cells, or oocytes, were inserted inside and bathed with hormones to stimulate the theca cells to produce androgen, and the granulosa cells to make estrogen. In that nonadhesive environment, the cells will 9) ___ to each other and self-assemble a three-dimensional structure, and it conforms to the shape of our mold. One of the challenges with maturation is, there are lot of things that go on locally that may affect the ability of oocytes to become 10) ___.
The research team now wants to go back and look more closely at how it functions. They want to identify various proteins involved in egg maturation, and to be able to explore whether those proteins can be altered as a means of contraception. They could also theoretically find something that might be important in the development of ovarian 11) ___. The work can also be used to test for 12) ___ effects from everyday products, such as plastics and insecticides, as well as medications. Source: MIT Technology Review, by Karen Weintraub
ANSWERS: 1) cell; 2) ovary; 3) childbirth; 4) harvested; 5) artificial; 6 model; 7) Human; 8) algae; 9) stick; 10) mature; 11) cancer; 12) toxic
Spanish Flu Pandemic
Influenza Fears, 1918, Photograph by Underwood and Underwood/Time & Life Pictures/Getty Images – Surgical masks provide a measure of protection against a killer flu for American baseball players in 1918. That year—the final year of World War I—the Spanish flu took 50 million lives worldwide, at least three times as many as during the war.
The 1918 flu pandemic (the Spanish Flu) was an influenza pandemic that spread widely across the world. Historical and epidemiological data are inadequate to identify the geographic origin. Most victims were healthy young adults, in contrast to most influenza outbreaks which predominantly affect juvenile, elderly, or weakened patients. The flu pandemic was implicated in the outbreak of encephalitis lethargica in the 1920s.
The pandemic lasted from March 1918 to June 1920, spreading even to the Arctic and remote Pacific islands. Between 50 and 100 million died, making it one of the deadliest natural disasters in human history. An estimated 50 million people, about 3% of the world’s population (1.6 billion at the time), died of the disease. 500 million, or 1/3 were infected.
Tissue samples from frozen victims were used to reproduce the virus for study. Among the conclusions of this research is that the virus kills via a cytokine storm (overreaction of the body’s immune system) which perhaps explains its unusually severe nature and the concentrated age profile of its victims. The strong immune systems of young adults ravaged the body, whereas the weaker immune systems of children and middle-aged adults resulted in fewer deaths.
Although the first cases were registered in the continental US, and the rest of Europe long before getting to Spain, the 1918 pandemic received its nickname “Spanish flu” because Spain, a neutral country in WWI, had no censorship of news regarding the disease and its consequences. Spanish King Alfonso XIII became gravely ill and was the highest-profile patient about whom there was coverage, hence the widest and most reliable news coverage came from Spain, thus giving the false impression that Spain was most affected.
The second wave of the 1918 pandemic was much deadlier than the first. The first wave had resembled typical flu epidemics; those most at risk were the sick and elderly, while younger, healthier people recovered easily. But in August, when the second wave began in France, Sierra Leone and the US, the virus had mutated to a much deadlier form. This has been attributed to the circumstances of the First World War. In civilian life, evolutionary pressures favor a mild strain; those who get really sick stay home, and those mildly ill continue with their lives, go to work and go shopping, preferentially spreading the mild strain. In the trenches the evolutionary pressures were reversed: soldiers with a mild strain remained where they were, while the severely ill were sent on crowded trains to crowded field hospitals, spreading the deadlier virus. So the second wave began and the flu quickly spread around the world again. It was the same flu, in that most of those who recovered from first-wave infections were immune, but it was now far more deadly, and the most vulnerable people were those who were like the soldiers in the trenches – young, otherwise healthy adults. Consequently, during modern pandemics, health officials pay attention when the virus reaches places with social upheaval, looking for deadlier strains of the virus.
After the lethal second wave struck in the autumn of 1918, new cases dropped abruptly – almost to nothing after the peak in the second wave. In Philadelphia for example, 4,597 people died in the week ending October 16, but by November 11 influenza had almost disappeared from the city. One explanation for the rapid decline of the lethality of the disease is that doctors simply got better at preventing and treating the pneumonia which developed after the victims had contracted the virus. Another theory holds that the 1918 virus mutated extremely rapidly to a less lethal strain. This is a common occurrence with influenza viruses as there is a tendency for pathogenic viruses to become less lethal with time, providing more living hosts.
Effect of Screening Mammography on Breast-Cancer Mortality in Norway
A challenge in quantifying the effect of screening mammography on breast-cancer mortality is to provide valid comparison groups. The use of historical control subjects does not take into account chronologic trends associated with advances in breast-cancer awareness and treatment. As a result, a prospective study, published in the New England Journal of Medicine (2010; 363:1203-1210), was performed to address this issue.
The Norwegian breast-cancer screening program was started in 1996 and expanded geographically during the subsequent 9 years. Women between the ages of 50 and 69 years were offered screening mammography every 2 years. The incidence-based rates of death from breast cancer was compared in four groups: two groups of women who from 1996 through 2005 were living in counties with screening (screening group) or without screening (nonscreening group); and two historical-comparison groups that from 1986 through 1995 mirrored the current groups.
For the study, data were analyzed from 40,075 women with breast cancer. The rate of death was reduced by 7.2 deaths per 100,000 person-years in the screening group as compared with the historical screening group (rate ratio, 0.72) and by 4.8 deaths per 100,000 person-years in the nonscreening group as compared with the historical nonscreening group (rate ratio, 0.82; P<0.001 for both comparisons), for a relative reduction in mortality of 10% in the screening group (P=0.13). Thus, the difference in the reduction in mortality between the current and historical groups that could be attributed to screening alone was 2.4 deaths per 100,000 person-years, or a third of the total reduction of 7.2 deaths.
According to the authors, the availability of screening mammography was associated with a reduction in the rate of death from breast cancer, but the screening itself accounted for only about a third of the total reduction.
Racial Differences in the Effects of Postnatal Environmental Tobacco Smoke on Neurodevelopment
According to an article published online in Pediatrics (20 September 2010), the 2001-2004 National Health and Nutrition Examination Survey was used to examine the association between postnatal environmental tobacco smoke exposure, measured as serum cotinine levels, and attention-deficit/hyperactivity disorder (ADHD) among children 4 to 15 years of age. The study further investigated the interactions of race and serum cotinine levels with ADHD.
The study found that the prevalence of ADHD increased as blood cotinine levels increased, and that the effects of blood cotinine levels on ADHD differed according to race. Compared with children of the same racial group with the lowest blood cotinine levels, the odds ratios were 2.72 for Mexican American children and 5.32 for children in other racial groups with the highest blood cotinine levels, with controlling for the effect of maternal smoking during pregnancy. However, no significant associations between blood cotinine levels and ADHD were observed among non-Hispanic white or non-Hispanic black children.
According to the authors, the findings of this study underscore the possibility of racial disparities in the effects of environmental tobacco smoke on behavioral problems in children and that these findings warrant further investigation.
A Genetic Association Study of Serum Acute-Phase C-Reactive Protein Levels in Rheumatoid Arthritis
The acute-phase increase in serum C-reactive protein (CRP) is used to diagnose and monitor infectious and inflammatory diseases. However, little is known about the influence of genetics on acute-phase CRP, particularly in patients with chronic inflammation. As a result, a study published in PLoS Medicine (7(9):e1000341), was performed to evaluate CRP in two independent sets of patients with chronic inflammation due to rheumatoid arthritis (total 695 patients).
A tagSNP approach captured common variation at the CRP locus and the relationship between genotype and serum CRP was explored by linear modeling. Erythrocyte sedimentation rate (ESR) was incorporated as an independent marker of inflammation to adjust for the varying levels of inflammatory disease activity between patients.
Results showed that common genetic variants at the CRP locus were associated with acute-phase serum CRP (for the most associated haplotype: p = 0.002, p<0.0005, p<0.0005 in patient sets 1, 2, and the combined sets, respectively), translating into an approximately 3.5-fold change in expected serum CRP concentrations between carriers of two common CRP haplotypes. For example, when ESR = 50 mm/h, the expected geometric mean CRP concentration was 43.1 mg/l for haplotype 1 and 14.2 mg/l (9.5–23.2) for haplotype 4.
According to the authors, the findings raise questions about the interpretation of acute-phase serum CRP. In particular, failure to take into account the potential for genetic effects may result in the inappropriate reassurance or suboptimal treatment of patients simply because they carry low-CRP-associated genetic variants. Since CRP is increasingly being incorporated into clinical algorithms to compare disease activity between patients and to predict future clinical events, the findings impact on the use of these algorithms. For example, where access to effective, but expensive, biological therapies in rheumatoid arthritis is rationed on the basis of a DAS28-CRP clinical activity score, then two patients with identical underlying disease severity could be given, or denied, treatment on the basis of CRP genotype alone. The accuracy and utility of these algorithms might be improved by using a genetically adjusted CRP measurement.
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FDA Approves First Oral Drug to Reduce MS Relapses
Multiple sclerosis (MS) is a chronic, often disabling, disease that affects the central nervous system including the brain, spinal cord, and optic nerves. The progress, severity, and specific symptoms of MS are unpredictable and vary from one person to another. Symptoms can be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. According to the National Multiple Sclerosis Society, there are about 400,000 people in the United States and 2.1 million people worldwide with MS.
The FDA has approved Gilenya capsules (fingolimod) to reduce relapses and delay disability progression in patients with relapsing forms of MS. Gilenya is the first in a new class of drugs that block some blood cells in lymph nodes, reducing their migration to the brain and spinal cord, which may help with reducing the severity of MS.
According to FDA, patients using Gilenya should be monitored for a decrease in heart rate upon starting the drug. Gilenya may also increase the risk of infections. Cases of serious eye problems (macular edema) have occurred in patients taking the drug and an ophthalmologic evaluation is recommended. The most frequent adverse reactions reported by patients taking Gilenya in clinical trials include headache, influenza, diarrhea, back pain, elevation of certain liver enzymes and cough.
The drug will be available in 0.5 milligram capsules. Gilenya is made by Novartis, Basel, Switzerland.
Reproductive research: This artificial human ovary surrounds granulosa cell
spheres, which are marked with fluorescent green dye.
Credit: Brown University
Tissue engineering allows for complex three-dimensional cell construction
MIT Technology Review, September 23, 2010, by Karen Weintraub — Researchers at Brown University have created an “artificial human ovary” using a tissue engineering approach that they hope will one day allow scientists to mature human eggs in a laboratory.
In the near term, an artificial ovary will enable researchers to better explore the impact of environmental toxins or fertility-enhancing substances on human fertility. It could also aid the development of new forms of contraceptives and the study of ovarian cancer.
Further down the line, it could also help women whose ovaries are damaged because of chemotherapy, radiation, or illness, according to a paper published in the current issue of Journal of Assisted Reproduction and Genetics. Today, those women have limited opportunities for childbirth: either a hurried in-vitro fertilization cycle that leads to a handful of frozen eggs, or freezing ovarian tissue in the hopes that healthy eggs will someday be able to be matured.
An artificial ovary, where immature eggs could be harvested by the thousands and then matured at will in the laboratory, would open up huge possibilities for the one in a 1,000 women who need it, says the paper’s first author, Stephan Krotz, who was a graduate student at Brown when he worked on the paper.
The artificial ovary marks the first time researchers have successfully created a three-dimensional environment that contains the three main types of ovarian cells: theca cells, granulosa cells, and the eggs, known as oocytes. The paper’s lead researcher is Sandra Carson, a professor of obstetrics and gynecology at Brown and Woman and Infants Hospital of Rhode Island.
Alan B. Copperman, director of infertility at Mt. Sinai Medical Center in New York, says clinical benefits are years and many scientific hurdles away, but he’s impressed by the research potential of the group’s work. “The concept of creating an artificial three-dimensional environment, and the fact that we can take out immature eggs and let them grow and mature into viable eggs, is really exciting,” he says.
Copperman says the artificial ovary could serve as a model to help researchers better understand the ovarian aging process, the focus of much of his research. “If we can establish a viable testing environment, we can learn more about how to optimize eggs, and discriminate good from bad eggs.”
The Brown researchers’ innovation was using a honeycomb-shaped mold to support the egg. Human eggs are too large to be grown without some kind of support structure. “If you try to grow it by itself, in a dish, it basically collapses on itself,” says Krotz, now a reproductive endocrinologist and fertility specialist at the Advanced Fertility Center of Texas.
The researchers broke ovarian cells out of human tissue using enzymes, and poured them into a mold made of agar, a gelatinous substance usually derived from algae. The different types of cells then assembled themselves into a honeycomb shape, with the theca and granulosa cells forming the structure. The egg cells, or oocytes, were inserted inside and bathed with hormones to stimulate the theca cells to produce androgen, and the granulosa cells to make estrogen.
“We took a different tack to rely on the inherent adhesiveness of cells to drive self-assembly,” says Jeffrey Morgan, codirector of the Center for Biomedical Engineering at Brown, who led this aspect of the research. “In that nonadhesive environment, the cells will stick to each other and self-assemble a three-dimensional structure, and it conforms to the shape of our mold.”
Researchers had assumed that, if allowed to self-assemble, cells would form a sphere, but Morgan says he showed that they can also create more complex forms with a little prompting.
Kim L. Thornton, a reproductive endocrinologist at Boston IVF, one of the nation’s largest fertility centers, says it’s tricky to re-create in a lab all of the activities that go on in a woman’s ovaries. “One of the challenges with maturation is, there are lot of things that go on locally that may affect the ability of oocytes to become mature,” she says. “We can’t duplicate all of those conditions” in a lab dish. However, Thornton says, the Brown model “is interesting, and it’s certainly promising.”
Carson says that now that the team has created the model, she wants to go back and look more closely at how it functions. She would like to identify various proteins involved in egg maturation, and be able to explore whether those proteins can be altered as a means of contraception. “We could also theoretically find something that might be important in the development of ovarian cancer,” she says.
The work can also be used to test for toxic effects from everyday products, such as plastics and insecticides, as well as medications–“anything we might be able to test against the control,” Carson says. “We’re not there yet, but I think this is going to be the most powerful use of the model.”