FDA safety alert on unanticipated deaths with intragastric balloons


FDA is issuing an update to alert health care providers of five reports of unanticipated deaths that occurred from 2016 to present in patients with liquid-filled intragastric balloon systems used to treat obesity. Four reports involve the Orbera Intragastric Balloon System, manufactured by Apollo Endo Surgery, and one report involves the ReShape Integrated Dual Balloon System, manufactured by ReShape Medical Inc. All five reports indicate that patient deaths occurred within a month or less of b…

Read more at Medical Dialogues: FDA safety alert on unanticipated deaths with intragastric balloons http://speciality.medicaldialogues.in/fda-safety-alert-on-unanticipated-deaths-with-intragastric-balloons/

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Renal function and sodium intake: A review. 


Recent guidelines propose a dietary sodium intake of less than 2.0 g or even less than 1.5 g daily for patients with chronic kidney disease (CKD), report Japanese nephrologists at the Teikyo University School of Medicine in Tokyo. However, other topical studies have failed to find robust evidence to support this approach and have even indicated that a sodium intake of less than 1.5 g/d could be potentially harmful. In view of the ongoing controversy, the aim of the present quantitative review of the literature was to assess currently available evidence. Data were extracted from 36 studies (11 cross-sectional and 5 longitudinal observational studies, 20 intervention trials).
The key findings:
  • In observational studies, renal function as assessed by eGFR, albuminuria, urinary albumin-to-creatinine ratio, CKD, or ESRD yielded insufficient direct evidence for association with sodium intake.
  • Five longitudinal studies did not generate robust evidence that reduction of salt intake would prevent CKD or its progression.
  • The majority of intervention studies failed to provide sufficient information on design, results, and potential sources of bias, resulting in low quality scores.
  • According to intervention studies, eGFR and albuminuria or proteinuria increased with higher salt intake.
This review shows that there is currently no robust evidence to suggest that a long-term reduction of salt intake could or would prevent CKD or delay its progression, summarize the authors. However, they also stress that the present review is mainly based on studies investigating people with only low-grade renal impairment. Therefore, the current findings cannot be extrapolated to patients with moderate or severe chronic kidney disease.

BioMarin to Begin Phase 3 Gene Therapy Trials for Hemophilia A


BioMarin announced the results from their ongoing Phase 1/2 gene therapy studies evaluating  BMN 270 for patients with hemophilia A. Based on encouraging data, Phase 3 studies are being planned to start later this year.

Hemophilia A is a chronic, genetic disorder that results in impaired clotting mechanisms due to missing or reduced levels of Factor VIII. People with this rare disorder experience recurrent painful bleeding episodes, some of which can be life-threatening. Numerous orphan drugs have been approved and are available to treat the bleeding episodes and 2 orphan drugs – Advate and Kogenate – are approved for prophylactic use in patients with hemophilia A.

BMN 270 is an AAV 5 factor VIII vector designed to restore factor VIII plasma concentrations to levels that would essentially cure the person of the disorder.

In the Phase 1/2 study, patients with severe hemophilia A were given doses of BMN 270, 4e13 vg/kg or 6e13 vg/kg.

In the 6 patients given the 4e13 vg/kg dose, each has shown increased plasma levels of Factor VII and has experienced a dramatic reduction in bleeding episodes.  Three of the patients have been monitored for 32 weeks and 3 others monitored for 20 weeks. Results from those patients are shown in the table below.

Table 1:  Factor VIII Levels (%) of 4e13 vg/kg Dose Patients 

Week Mean Factor VII Levels (%) (mean) Range (low, high)
          4 (n=6)
 8
12
16
20
5
13
19
26
31
2, 10
3, 21
6, 32
5, 38
7, 45
          24 (n=3)
28
32
32
39
51
24, 42
32, 44
48, 54

Table 2:  Mean Annualized Bleeding Rate (ABR) and FVIII Infusions of 4e13 vg/kg Dose Patients Previously on Prophylaxis (N=6) up to 32 Weeks

Before BMN 270 Infusion** After BMN 270 
Infusion***
Annualized Bleeding Rate* (mean) 12.2 1.0
Annualized FVIII Infusions* (mean) 144.2 4.8

* Post infusion data were based on data after Factor VIII levels were above 5%
**Obtained from medical records.
***5 of 6 patients had 0 bleeds requiring Factor VIII infusions after Factor VIII levels were above 5%.

Similar trends were observed in the 7 patients receiving the higher dose (6e13 vg/kg). Those patients have been monitored for 52 weeks, the mean Factor VIII levels continue to be above 50%.

Based on the results, BioMarin plans to initiate 2 separate Phase 3 studies; a study with the 4e13 vg/kg dose and another with the 6e13 vg/kg dose. They are expected to start in the 4th quarter of 2017 and will enroll about 100 patients.

Hank Fuchs, M.D., President, Worldwide Research and Development at BioMarin said. “Given the low level of pre-existing immunity to AAV5, we expect that approximately 90 percent of patients would be treatment candidates for BMN 270 based on this criteria.”

BMN 270 was well-tolerated and no patients withdrew from the study. The most common adverse events across all dose cohorts were alanine aminotransferase (ALT) elevation in 11 patients; arthralgia, aspartate aminotransferase elevation, and headache in 7 patients each, and; back pain and fatigue in 5 patients each. One patient developed Grade 2 pyrexia with myalgia and headache within 24 hours of receiving BMN 270. The event resolved within 48 hours but was determined to be related to BMN 270.

Genetic Testing for the Healthy. 


Randomized trial examines genome sequencing in healthy patients

However, the use of genome sequencing in healthy individuals is controversial because no one fully understands how many patients carry variants that put them at risk for rare genetic conditions and how they and their doctors will respond to learning about these risks.

In a new paper published June 26 in the Annals of Internal Medicine by investigators at Harvard Medical School and Brigham and Women’s Hospital, along with collaborators at Baylor College of Medicine, report the results of the four-year, NIH-funded MedSeq Project, the first-ever randomized trial conducted to examine the impact of whole genome sequencing in healthy primary care patients.

In the MedSeq Project, 100 healthy individuals and their primary care physicians were enrolled and randomized so that half of the patients received whole genome sequencing and half did not.

Nearly 5,000 genes associated with rare genetic conditions were expertly analyzed in each sequenced patient, and co-investigators from many different disciplines, including clinical genetics, molecular genetics, primary care, ethics and law, were involved in analyzing the results.

Researchers found that among the 50 healthy primary care patients who were randomized to receive genome sequencing, 11 (22 percent) carried genetic variants predicted to cause previously undiagnosed rare disease.

Two of these patients were then noted to have signs or symptoms of the underlying conditions, including one patient who had variants causing an eye disease called fundus albipunctatus, which impairs night vision.

This patient knew he had difficulty seeing in low-light conditions but had not considered the possibility that his visual problems had a genetic cause.

Another patient was found to have a genetic variant associated with variegate porphyria, which finally explained the patient’s and family members’ mysterious rashes and sun sensitivity.

The other nine participants had no evidence of the genetic diseases for which they were predicted to be at risk. For example, two patients had variants that have been associated with heart rhythm abnormalities, but their cardiology workups were normal. It is possible, but not at all certain, that they could develop heart problems in the future.

“Sequencing healthy individuals will inevitably reveal new findings for that individual, only some of which will have actual health implications,” said lead author Jason Vassy, an HMS assistant professor of medicine at Brigham and Women’s and primary care physician at the VA Boston Healthcare System.

“This study provides some reassuring evidence that primary care providers can be trained to manage their patients’ sequencing results appropriately, and that patients who receive their results are not likely to experience anxiety connected to those results. Continued research on the outcomes of sequencing will be needed before the routine use of genome sequencing in the primary care of generally healthy adults can be medically justified,” Vassy said.

Primary care physicians received six hours of training at the beginning of the study regarding how to interpret a specially designed, one-page genome testing report summarizing the laboratory analysis.

Consultation with genetic specialists was available, but not required. Primary care physicians then used their own judgment about what to do with the information, and researchers monitored the interactions for safety and tracked medical, behavioral and economic outcomes.

The researchers noted that they analyzed variants from nearly 5,000 genes associated with rare genetic diseases. These included single genes causing a significantly higher risk for rare disorders than the low-risk variants for common disorders reported by direct-to-consumer genetic testing companies. No prior study has ever examined healthy individuals for pathogenic (high-risk) variants in so many rare disease genes.

“We were surprised to see how many ostensibly healthy individuals are carrying a risk variant for a rare genetic disease,” said Heidi Rehm, HMS associate professor of pathology at Brigham and Women’s and director of the Laboratory for Molecular Medicine at Brigham and Women’s.

“We found that about one-fifth of this sample population carried pathogenic variants, and this suggests that the potential burden of rare disease risk throughout our general population could be far higher than previously suspected,” said Rehm, a co-investigator on the study who directed the genome analysis. “However, the penetrance, or likelihood that persons carrying one of these variants will eventually develop the disease, is not fully known.”

Additionally, investigators compared the two arms of the study and found that patients who received genome sequencing results did not show higher levels of anxiety. They did, however, undergo a greater number of medical tests and incurred an average of $350 more in health care expenses in the six months following disclosure of their results. The economic differences were not statistically significant with the small sample size in this study.

“Because participants in the MedSeq Project were randomized, we could carefully examine levels of anxiety or distress in those who received genetic risk information and compare it to those who did not,” said Amy McGuire, director of the Center for Medical Ethics and Health Policy at Baylor College of Medicine.

“While many patients chose not to participate in the study out of concerns about what they might learn, or with fears of future insurance discrimination, those who did participate evinced no increase in distress, even when they learned they were carrying risk variants for untreatable conditions,” said McGuire, who supervised the ethical and legal components of the MedSeq Project.

There has also been great concern in the medical community about whether primary care physicians can appropriately manage these complicated findings. But when a panel of expert geneticists reviewed how well the primary care physicians managed the patients with possible genetic risk variants, the experts determined that only two of the 11 cases were managed inappropriately and that no harm had come to these patients.

MedSeq Project investigators note that the study’s findings should be interpreted with caution because of the small sample size and because the study was conducted at an academic medical center where neither the patients nor the primary care physicians are representative of the general population. They also stressed that carrying a genetic risk marker does not mean that patients have or will definitely get the disease in question. Critical questions remain about whether discovering such risk markers in healthy individuals will actually provide health benefits, or will generate unnecessary testing and subsequent procedures that could do more harm than good.

“Integrating genome sequencing and other -omics technologies into the day-to-day practice of medicine is an extraordinarily exciting prospect with the potential to anticipate and prevent diseases throughout an individual’s lifetime,” said senior author Robert C. Green, HMS professor of medicine at Brigham and Women’s Hospital, associate member of the Broad Institute of Harvard and MIT and leader of the MedSeq Project. “But we will need additional rigorously designed and well-controlled outcomes studies like the MedSeq Project with larger sample sizes and with outcomes collected over longer periods of time to demonstrate the full potential of genomic medicine.”

The MedSeq Project is one of the sites in the Clinical Sequencing Exploratory Research Consortium and was funded by the National Human Genome Research Institute, part of the National Institutes of Health.

The Genomes2People Research Program at Brigham and Women’s Hospital, the Broad Institute and Harvard Medical School conducts empirical research in translational genomics and health outcomes. NIH-funded research within G2P seeks to understand the medical, behavioral and economic impact of using genetic risk information to inform future standards. The REVEAL Study has conducted several randomized clinical trials examining the impact of disclosing genetic risk for a frightening disease. The Impact of Personal Genomics (PGen) Study examined the impact of direct-to-consumer genetic testing on over 1,000 consumers of two different companies. The MedSeq Project has conducted the first randomized clinical trial to measure the impact of whole genome sequencing on the practice of medicine. The BabySeq Project is recruiting families of both healthy and sick newborns into a randomized clinical trial where half will have their baby’s genome sequenced. Green directs the Program.

New material temporarily tightens skin. 


“Second skin” polymer could also be used to protect dry skin and deliver drugs.

Scientists at MIT, Massachusetts General Hospital, Living Proof, and Olivo Labs have developed a new material that can temporarily protect and tighten skin, and smooth wrinkles. With further development, it could also be used to deliver drugs to help treat skin conditions such as eczema and other types of dermatitis.

The material, a silicone-based polymer that could be applied on the skin as a thin, imperceptible coating, mimics the mechanical and elastic properties of healthy, youthful skin. In tests with human subjects, the researchers found that the material was able to reshape “eye bags” under the lower eyelids and also enhance skin hydration. This type of “second skin” could also be adapted to provide long-lasting ultraviolet protection, the researchers say.

“It’s an invisible layer that can provide a barrier, provide cosmetic improvement, and potentially deliver a drug locally to the area that’s being treated. Those three things together could really make it ideal for use in humans,” says Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES).

Anderson is one of the authors of a paper describing the polymer in the May 9 online issue of Nature Materials. Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, is the paper’s senior author, and the paper’s lead author is Betty Yu SM ’98, ScD ’02, former vice president at Living Proof. Langer and Anderson are co-founders of Living Proof and Olivo Labs, and Yu earned her master’s and doctorate at MIT.

Scientists at MIT and elsewhere have developed a new material that can temporarily protect and tighten skin, and smooth wrinkles. With further development, it could also be used to deliver drugs to help treat various skin conditions.

Mimicking skin

As skin ages, it becomes less firm and less elastic — problems that can be exacerbated by sun exposure. This impairs skin’s ability to protect against extreme temperatures, toxins, microorganisms, radiation, and injury. About 10 years ago, the research team set out to develop a protective coating that could restore the properties of healthy skin, for both medical and cosmetic applications.

“We started thinking about how we might be able to control the properties of skin by coating it with polymers that would impart beneficial effects,” Anderson says. “We also wanted it to be invisible and comfortable.”

The researchers created a library of more than 100 possible polymers, all of which contained a chemical structure known as siloxane — a chain of alternating atoms of silicon and oxygen. These polymers can be assembled into a network arrangement known as a cross-linked polymer layer (XPL). The researchers then tested the materials in search of one that would best mimic the appearance, strength, and elasticity of healthy skin.

“It has to have the right optical properties, otherwise it won’t look good, and it has to have the right mechanical properties, otherwise it won’t have the right strength and it won’t perform correctly,” Langer says.

The best-performing material has elastic properties very similar to those of skin. In laboratory tests, it easily returned to its original state after being stretched more than 250 percent (natural skin can be elongated about 180 percent). In laboratory tests, the novel XPL’s elasticity was much better than that of two other types of wound dressings now used on skin — silicone gel sheets and polyurethane films.

“Creating a material that behaves like skin is very difficult,” says Barbara Gilchrest, a dermatologist at MGH and an author of the paper. “Many people have tried to do this, and the materials that have been available up until this have not had the properties of being flexible, comfortable, nonirritating, and able to conform to the movement of the skin and return to its original shape.”

The XPL is currently delivered in a two-step process. First, polysiloxane components are applied to the skin, followed by a platinum catalyst that induces the polymer to form a strong cross-linked film that remains on the skin for up to 24 hours. This catalyst has to be added after the polymer is applied because after this step the material becomes too stiff to spread. Both layers are applied as creams or ointments, and once spread onto the skin, XPL becomes essentially invisible.

High performance

The researchers performed several studies in humans to test the material’s safety and effectiveness. In one study, the XPL was applied to the under-eye area where “eye bags” often form as skin ages. These eye bags are caused by protrusion of the fat pad underlying the skin of the lower lid. When the material was applied, it applied a steady compressive force that tightened the skin, an effect that lasted for about 24 hours.

In another study, the XPL was applied to forearm skin to test its elasticity. When the XPL-treated skin was distended with a suction cup, it returned to its original position faster than untreated skin.

The researchers also tested the material’s ability to prevent water loss from dry skin. Two hours after application, skin treated with the novel XPL suffered much less water loss than skin treated with a high-end commercial moisturizer. Skin coated with petrolatum was as effective as XPL in tests done two hours after treatment, but after 24 hours, skin treated with XPL had retained much more water. None of the study participants reported any irritation from wearing XPL.

“I think it has great potential for both cosmetic and noncosmetic applications, especially if you could incorporate antimicrobial agents or medications,” says Thahn Nga Tran, a dermatologist and instructor at Harvard Medical School, who was not involved in the research.

Living Proof has spun out the XPL technology to Olivo Laboratories, LLC, a new startup formed to focus on the further development of the XPL technology. Initially, Olivo’s team will focus on medical applications of the technology for treating skin conditions such as dermatitis.

Singapore scientists uncover how neural stem cells are activated intrinsically by spindle matrix proteins


Neural progenitor cells (green) in the rat olfactory bulb 

Neural stem cells (NSCs) are self-renewing and multipotent cells that give rise to the neurons and glia of the nervous system during an animal’s embryonic development. In a mammalian brain, only a small fraction of the adult NSCs are proliferative and a majority are in a nondividing state, also known as quiescence.

The balance between NSC proliferation and quiescence is essential for brain development and emerging evidence suggests that its imbalance is linked to neurodevelopmental disorders, such as microcephaly. On the other side, the population of quiescent NSCs in the brain increases with ageing, which is associated with declining brain function.

Understanding how endogenous NSCs can be activated has huge potential in regenerative medicine. However, it is poorly understood as to how NSCs switch between proliferation and quiescence in vivo.

A multicentre research team led by Duke-NUS Medical School (Duke-NUS)’s Neuroscience and Behavioural Disorders Programme has uncovered that spindle matrix proteins can play an intrinsic role in regulating neural stem cell (NSC) reactivation and proliferation.

This discovery is an early important step towards opening up avenues for further research that could lead to potential stem cell-based therapies for neurodevelopmental and neurodegenerative disorders such as microcephaly and Alzheimer’s disease.

Study

The study, published in Nature Communicationsis a first of its kind conducted on fruit flies (Drosophila melanogaster) that demonstrates a critical role of the spindle matrix complex containing chromator (Chro) functioning as an essential nuclear factor for controlling gene expression during NSC reactivation. The study suggests that Chro plays an important role in maintaining the balance between NSC proliferation and quiescence, as it is not only critical for NSC reactivation (exit from quiescence) but also essential for preventing re-entry into inactivation.

“In this study, we have uncovered that spindle matrix proteins play a novel role in regulating reactivation of neural stem cells. It may be in its early stage, but this should help to open up avenues for further research and the development of potent therapies for neurodevelopmental disorders in the future,” said lead author Hongyan Wang, an Associate Professor and Deputy Director of Duke-NUS’ Neuroscience and Behavioural Disorders Programme.

Chromator is required for activation of neural stem cells (NSCs). Upper panels show wild-type control Drosophila larval brains with proliferating NSCs (EdU+; in red). Lower panels show NSCs from chromator- mutant brains stay in a quiescent stage (EdU-). Note that cellular extension, a hallmark of quiescent NSCs, is indicated by a yellow arrowhead. NSCs are marked by nuclear Dpn (in blue) and cortical Mira (in green).

The team employed the state-of-art genomic technique for transcriptome analysis in vivo and identified binding-sites of Chro in NSCs. The main findings from these experiments suggest that Chro is a master nuclear factor that reactivates NSCs through regulating gene expression of key transcription factors that either promote or repress the proliferation of NSCs. The study also suggests that Chro functions downstream of Insulin/PI3k pathway, which is known to promote NSC reactivation and mutations of which are found in microcephalic patients.

“Our study demonstrates that some of the players such as transcription factors Grainy Head and Prospero act downstream of Chro and identifies the likely pathway by which NSCs are activated,” added Professor Wing-Kin Sung, who is from the National University of Singapore (NUS) School of Computing and a Senior Group Leader at A*STAR’s Genome Institute of Singapore (GIS).

Study reveals how to reprogram cells in our immune system


T cell
Scanning electron micrograph of a human T lymphocyte (also called a T cell) from the immune system of a healthy donor. 

When the immune system is imbalanced, either due to overly-active cells or cells that suppress its function, it causes a wide range of diseases, from psoriasis to cancer. By manipulating the function of certain immune cells, called T cells, researchers could help restore the system’s balance and create new treatments to target these diseases.

 Scientists at the Gladstone Institutes revealed, for the first time, a method to reprogram specific T cells. More precisely, they discovered how to turn pro-inflammatory cells that boost the immune  into anti-inflammatory cells that suppress it, and vice versa.

The researchers studied two types of cells called effector T cells, which activate the immune system to defend our body against different pathogens, and regulatory T cells, which help control the immune system and prevent it from attacking healthy parts of its environment.

“Our findings could have a significant impact on the treatment of autoimmune diseases, as well as on stem cell and immuno-oncology therapies,” said Gladstone Senior Investigator Sheng Ding, PhD, who is also a professor of pharmaceutical chemistry at the University of California, San Francisco.

By drawing on their expertise in drug discovery, Ding’s team identified a small-molecule drug that can successfully reprogram effector T cells into regulatory T cells. Their study, published in the renowned journal Nature, describes in detail a metabolic mechanism that helps convert one cell type into another.

This new approach to reprogram T cells could have several medical applications. For instance, in autoimmune disease, effector T cells are overly activated and cause damage to body. Converting these cells into regulatory T cells could help reduce the hyperactivity and return balance to the immune system, thus treating the root of the disease.

In addition, the study could improve therapies using . At least in theory, producing regulatory T cells could promote  and prevent the body from rejecting newly-transplanted cells.

“Our work could also contribute to ongoing efforts in immuno-oncology and the treatment of cancer,” explained Tao Xu, postdoctoral scholar in Ding’s laboratory and first author of the study. “This type of therapy doesn’t target the cancer directly, but rather works on activating the immune system so it can recognize  and attack them.”

Many cancers take control of regulatory T cells to suppress the immune system, creating an environment where tumors can grow without being detected. In such cases, the team’s findings could be used to transform regulatory T cells into effector T cells to strengthen the immune system so it can better recognize and destroy  .

Why Some People Respond to Stress by Falling Asleep


Why Some People Respond to Stress by Falling Asleep
Last month, my wife and I found ourselves in a disagreement about whether or not our apartment was clean enough for guests—the type of medium-sized disagreement that likely plagues all close relationships. In the midst of it, there was a lull and, feeling exhausted all of a sudden, I got up and left the living room. In the bedroom, I immediately fell face down into the sheets. The next thing I knew it was 20 minutes later and my wife was shaking me awake. I hadn’t meant to fall asleep; I just felt so fatigued in that moment that there was nothing else I could do.

This wasn’t new for me. A few weeks earlier, I had come into conflict with an acquaintance over some money. We were exchanging tense emails while I was at my office, and I began to feel the slow oozing onset of sleep, the same tiredness that came on when, as a child, I rode in the backseat of the car on the way home from some undesired trip. A sleepiness that overtakes the body slowly but surely and feels entirely outside of your control.

Though this has happened many times before, my response to conflict still seems strange to me. After all, as everyone knows from 9th grade biology class, when faced with stress—an acute threat—our bodies enter fight-or-flight mode. It’s supposed to be automatic: the adrenal cortex releases stress hormones to put the body on alert; the heart begins to beat more rapidly; breathing increases frequency; your metabolism starts to speed up, and oxygen-rich blood gets pumped directly to the larger muscles in the body. The point is to become energized, to prepare to face the source of the conflict head on, or, at the worst, be ready to run away, at top speed.

Of course, you don’t actually want the stress response system to be too reactive. If you were constantly in fight or flight mode, constantly stressed, it could actually have long-term effects on your neurochemistry, leading to chronic anxiety, depression, and, well, more sleeplessness. Even so, it seems like a good idea to sometimes be on high alert when dealing with stressful situations.

But that’s not what my body did. My body shut down.

If, during early development, a living thing comes to understand that it is helpless, it will continue to perceive a lack of control, no matter if the context changes.

I asked around, and found out that many others experience the same thing. For example, Dawn, a family counselor in Columbus, Ohio, told me that her husband Brad often “starts yawning in the middle of heated discussions, and will even lie down and go right to sleep.” One time their toddler son fell down the stairs (he was fine), and Brad left the room and went to bed. Brad has had this kind of stress response for all 24 years of their relationship; Dawn says she’s used to it by now.

Even though dozens of people told me similar stories, I began to wonder what was wrong with us—what was wrong with me. Why was my body, in the face of conflict, simply acquiescing? Where was the fight in me?

There’s a concept in psychology called “learned helplessness” used to explain certain aspects of depression and anxiety. It’s fairly old, having been first recognized and codified in the 1970s, but has remained largely relevant and accepted within the field. The name (mostly) explains it all: If, at a very early stage in development, a living thing comes to understand that it is helpless in the face of the world’s forces, it will continue to perceive a lack of control, and therefore actually become helpless, no matter if the context changes.

In the early studies, dogs were divided into two groups: The first half were subjected to electric shocks, but were given a way to stop the shocks (they just had to figure it out themselves). The second group of dogs received shocks but had no way to avoid, escape, or stop them. The experience, sadly, had long-term effects on the animals. When faced with stressful environments later on in life, the first group of dogs did whatever they could to try to deal with it; the second group simply gave up. They had been conditioned to respond to stress with acquiescence.

This type of learned helplessness isn’t limited to animals; many of the adults I spoke with all mentioned childhood anxiety stemming from uncontrollable situations.

“When I hit high school and stress levels became higher in my life (messy divorce between my parents and lots of moving), I began escaping into sleep,” says LeAnna, a 25-year-old from Washington state. “As an adult, I still have ‘go to sleep’ impulses whenever I feel overwhelmed.” Daniel, from Baltimore told me that “whenever there was any kind of ‘family strife’ I would just go to my room and sleep.” Daniel is now 51, and starts yawning any time he encounters a stressful situation.

“Our feelings are always in the past. This is something that’s really outlived its adaptive value.”

My parents divorced by the time I hit high school, but before they did, they fought a lot, usually in the kitchen beneath my bedroom. What I remember feeling most was powerlessness—not anger or sadness, but a shrug-your-shoulders, close-the-door, shut-your-eyes type of response because what was I going to do? Tell them to break it up?

That coping mechanism worked for me back then. I was able to compartmentalize those stressful experiences and move on with my life. I stayed in school and kept my grades up; I had friends and was relatively well-rounded. Things went well. But now, at 28, I still deal with interpersonal conflict by shutting the door and going to sleep. I act on feelings that are no longer relevant to the situation.

“Our feelings are always in the past,” says John Sharp, a psychiatrist at Harvard Medical School. “This is something that’s really outlived its adaptive value.” As an adult I should have control over my current situation, but I don’t. Am I like those lab dogs, shocked into helplessness?
At first glance, sleep might seem like quintessential avoidance, like burying your head in the pillow is no better than burying your head in the sand.

But I don’t feel as though I am not helping myself. After all, going to sleep isn’t like turning the lights off; the truth is that there’s a lot still going on while your eyes are closed. While we might be able to temporarily stave the flow of conflict by falling asleep, we’re not really escaping anything. In fact, sleep in some ways forces us to not only relive the emotional experience but to process and concretize it—by going to sleep I may be making the fight with my wife more real.

If you’re like me, you probably imagine memories work pretty simply: you have an experience, it gets stored somewhere, and then you retrieve it when you need it. But that leaves out a key step, memory consolidation, and that’s where sleep comes into play.

Here’s how it really works, according to Dr. Edward Pace-Schott, professor at Harvard Medical School’s Division of Sleep Medicine: When an experience is initially encoded as a memory, it rests in the brain’s short term storage facilities, where it is fragile, easily forgotten if other experiences come along quickly. In order for the experience to last, it needs to go through a process of consolidation, where it becomes integrated into other memories that you have. That’s why when you think of, say the 1993 baseball game between the Yankees and Orioles, you also think of bright green grass, the smell of peanuts and beer, your dad, and Bobby Bonilla, and not thousands of random bits and pieces.

Of course, not every experience is worth remembering. Only the highly intense experiences—positive or negative—are prioritized for storage later on. “Emotions put a stamp on a memory to say ‘this is important,’” says Pace-Schott. It makes sense: the color of the grocery store clerk’s shirt is significantly less essential than, say, your mother’s birthday.

If we didn’t shelve our memories appropriately, everything would be a jumble, and without consolidation, we would forget it all. Life would have no meaning, and more importantly (at least from an evolutionary standpoint) we would never learn anything—we’d be helplessly amorphous, easy prey.

“You can be driven to sleep simply by having a lot of emotional memories to process.”

Here’s the conundrum, though: the same experiences that are stamped as emotionally important can overwhelm your brain’s short term storage facilities. Dr. Rebecca Spencer, a professor at the University of Massachusetts Department of Psychology, likens it to a desk where “whatever is stressing you out is this big pile of papers, but there are also other memories piling up on you.” With more and more papers landing in front of you all day, you’ll never effectively get to them all. And emotionally rich experiences are all high priority messages, screaming to be dealt with right away. So what happens next?

“You can be driven to sleep simply by having a lot of emotional memories to process,” says Spencer. It takes sleep to provide the space needed to sift through the days’ experiences, and make permanent those that matter.

Studies show that sleep enhances your memory of experiences, and the effect is multiplied for experiences with the stamp of emotion. In fact, the memory-consolidation process that occurs during sleep is so effective that some scientists, including Pace-Schott and Spencer, have suggested that it could be used to treat PTSD. Spencer posits that keeping someone from sleep following a traumatic event could be good in the long run. “If you force yourself to stay awake through a period of insomnia,” Spencer says, “the [traumatic] memory and emotional response will both decay.”

On the flip side, when it comes to the majority of the negative things we experience in life—the things that aren’t necessarily traumatizing like, say, a fight with your significant other—we want to go to sleep, because that protects the memory and emotional response.

And Pace-Schott points out that sleep disruption may prevent consolidation of potentially therapeutic memories, sometimes termed ‘fear extinction’ memories. These are memories that can dull the effect of a traumatic experience by creating more positive associations with specific triggers.] This means that improving sleep quality following traumatic events may be crucial to preventing PTSD.

The nap following a fight with my wife should, ideally, teach me how to better manage interpersonal conflict.

Ever wonder why little kids nap so much? Researchers believe that it’s not just because they’ve been running around all day—it’s also due to the fact their short-term memory storage space is so small, and they constantly need to unload experiences and consolidate memories more often. One recent study, in fact, found that “distributed sleep” (a.k.a. napping) is critical for learning at an early age. The nap that follows a 4 year-old child getting burnt on a hot stove should help him learn from the experience.

Similarly, the nap following a fight with my wife should, ideally, teach me how to better manage interpersonal conflict. The benefits of sleep on memory don’t go away.

When we wake up from sleep, we feel different. It’s not just that time has passed; we’ve undergone a real chemical response. When we sleep, all the stress systems in our body are damped down, letting it relax, so that tenseness you felt, the sickness in your stomach, the frayed nerves, will all be gone in the morning. “It’s almost like we are different people when we wake up,” says Pace-Schott.

One particular neurochemical, called orexin, may hold the key to the puzzle. Orexin, which was discovered only about 15 years ago, is unique in that it plays a very clearly defined dual role in the body. First and foremost, it’s a crucial element in your daily sleep/wake rhythm. You get a boost of the stuff when you wake up, and it drops before you go to sleep. Studies in rats show that if you take all of an animal’s orexin away, it can no longer effectively control sleeping and waking. Since its discovery, orexin has become one of the key diagnostic criteria for determining narcolepsy—those with the sleep disorder essentially have none of the neurochemical.

And then there’s the second function: It’s part of the stress response system.

“The orexin system is absolutely hardwired into the sympathetic nervous system,” says Philip L. Johnson, a neuroscientist at the Indiana University School of Medicine. If everything is working normally, when you are faced with a stressful situation, your orexin system kicks in and triggers the stress responses that you expect: fight or flight.

In other words, the same exact neural pathway that handles wakefulness (we can’t even get out of bed without orexin kicking in) also handles a key aspect of our stress response.

Think about this: while narcoleptics do sometimes just nod off randomly, strong emotions are, most often, connected to onset of sleep. It’s counterintuitive, but it’s true, says Johnson. For many narcoleptics, strong emotions associated with stress can cause a complete collapse.

Of course, this should sound familiar—it’s not so different than what happens when Brad, LeAnna, Daniel, I, and so many others go head to head with stress. The science on this is still in its infancy, and it remains unclear exactly what’s going on at a chemical level here, but there does seem to be some connection.

In the meantime, sleep doesn’t seem too bad. The problem may still be there when you awake, but you’ll have a better understanding of it, and hopefully, a clear slate to handle it.

First U.S. Human Embryo Gene Editing Experiment Successfully “Corrects” a Heart Condition


IN BRIEF

A study published today in the journal Nature confirms earlier reports of the first-ever successful gene-editing of embryos in the U.S. Though controversial, the treatment could one day be used to address any of the 10,000 disorders linked to just a single genetic error.

CORRECTING MUTANT GENES

Last week, reports circulated  that doctors had successfully edited a gene in a human embryo — the first time such a thing had been done in the United States. The remarkable achievement confirmed the powerful potential of CRISPR, the world’s most efficient and effective gene-editing tool. Now, details of the research have been published in Nature.

The procedure involved “correcting” the DNA of one-cell embryos using CRISPR to remove the MYBPC3 gene. That gene is known to cause hypertrophic cardiomyopathy (HCM), a heart disease that affects 1 out of 500 people. HCM has no known cure or treatment as its symptoms don’t manifest until the disease causes sudden death through cardiac arrest.

How CRISPR Works: The Future of Genetic Engineering and Designer Humans
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The researchers started with human embryos created from 12 healthy female donors and sperm from a male volunteer who carried the MYBOC3 gene. The defective gene was cut out using CRISPR around the time the sperm was injected into the eggs.

 As a result, as the embryos divided and grew, many repaired themselves using the non-edited genes from the genetic materials of the female donors, and in total, 72 percent of the cells that formed appeared to be corrected. The researchers didn’t notice any “off-target” effects on the DNA, either.

The researchers told The Washington Post that their work was fairly basic. “Really, we didn’t edit anything, neither did we modify anything,” explained Shoukhrat Mitalipov, lead author and a researcher at the Oregon Health and Science University. “Our program is toward correcting mutant genes.”

A [CONTROVERSIAL] NEW ERA?

Basic or not, the development is remarkable.“By using this technique, it’s possible to reduce the burden of this heritable disease on the family and eventually the human population,” Mitalipov said in an OHSU press release.

However, gene editing is a controversial area of study, and the researchers’ work included changes to the germ line, meaning the changes could be passed down to future generations. To be clear, though, the embryos were allowed to grow for only a few days and none were implanted into a womb (nor was that ever the researchers’ intention).

In fact, current legislation in the U.S. prohibits the implantation of edited embryos. The work conducted by these researchers was well within the guidelines set by the National Academies of Sciences, Engineering, and Medicine on the use of CRISPR to edit human genes.

University of Wisconsin-Madison bioethicist Alta Charo thinks that the benefits of this potential treatment outweigh all concerns. “What this represents is a fascinating, important, and rather impressive incremental step toward learning how to edit embryos safely and precisely,” she told The Washington Post. “[N]o matter what anybody says, this is not the dawn of the era of the designer baby.”

Before the technique could be truly beneficial, regulations must be developed that provide clearer guidelines, according to Mitalipov. If not, “this technology will be shifted to unregulated areas, which shouldn’t be happening,” he explained.

More than 10,000 disorders have been linked to just a single genetic error, and as the researchers continue with their work, their next target is BRCA, a gene associated with breast cancer growth.

Mitalipov hopes that their technique could one day be used to treat a wide-range of genetic diseases and save the lives of millions of people. After all, treating a single gene at the embryonic stage is far more efficient that changing a host of them in adults.

Largely Ceded to GI Physicians, Surgeons Urged to Reclaim Endoscopy


Experts Describe Advantages of Developing Endoscopic Techniques for Practice

 

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New York—What do colonoscopy, polypectomy and endobiliary stenting all have in common? They are all endoscopic techniques first described by surgeons, along with control of hemorrhage, endoscopic retrograde cholangiopancreatography, percutaneous endoscopic gastrostomy/jejunostomy and control of variceal bleeding.

“It’s an old adage that general surgeons started endoscopy and gave it up to the gastroenterologists,” said Paresh C. Shah, MD, professor of surgery at NYU Langone School of Medicine, in New York City. “Unfortunately, that’s true, but we’re changing that and we need to be aggressive about it.”

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The American Board of Surgery has acknowledged the importance of surgical endoscopy through changes in residency training requirements for board eligibility. Starting in 2018, surgical residents will have to complete a flexible endoscopy curriculum and pass the Fundamentals of Endoscopic Surgery (FES) examination assessing their cognitive and technical skills. The FES program was developed by the Society of American Gastrointestinal and Endoscopic Surgeons.

But surgical endoscopy can expand and enhance practice for surgeons at any stage in their career, Dr. Shah explained at the 2016 Controversies, Problems & Techniques in Surgery annual meeting, noting that it was general surgeons again who played a role in promoting some of the more advanced endoscopic interventions, such as EndoCinch suturing, Stretta, anastomotic plication and peroral endoscopic myotomy (POEM).

“If we think of ourselves as gastrointestinal surgeons, we’re really obligated to look at the spectrum of what GI surgery is. Advanced endoscopy, therapeutic endoscopy, is nothing more than another form of GI surgery; it’s just one that happens within the lumen rather than outside.”

In the world of diagnostic endoscopy, some of the newer tools that surgeons have include microendoscopy and narrow-band imaging. “For those of you who do diagnostic upper and lower endoscopy, these are critical to have at your disposal,” Dr. Shah said. “They’ve impacted adenoma detection rate, early cancer detection, and clearly, postsurgical anatomy.”

As Jose Martinez, MD, pointed out, nobody understands postsurgical anatomy better than the surgeon who made it. “We do a lot of replumbing in the human body, and we know the plumbing doesn’t always work. We can end up with strictures or worse—a leak, fistula or perforations,” said Dr. Martinez, associate professor of surgery and chief of laparoendoscopic surgery at the University of Miami Miller School of Medicine.

Basic tools for interventional endoscopy include balloon dilation, bleeding control and feeding tubes. More advanced interventions—to manage complications that surgeons themselves may have created—include stents, clips, fibrin glue and endoscopic suturing.

Injection is an important skill to develop. “It allows you to do a lot of things in the GI tract, whether you’re injecting saline to lift the mucosa, tattoo to mark a lesion or epinephrine to control bleeding,” Dr. Shah said.

The application of clips, which have improved dramatically in recent years, also has myriad uses. “Closing small holes, mucosal defects; I use clips after endoscopic submucosal dissection (ESD) resections and peroral endoscopic myotomy, and they’re good for bleeding control,” Dr. Shah said.

When it comes to dealing with strictures, surgeons again have a number of tools at their disposal: stents, energy sources, balloons and dilators. “Many of these things were created for one purpose, but we’re using them in different ways to figure out how to best accomplish treatment for our patient,” Dr. Martinez said.

And then there are the very advanced endoscopic interventions: POEM, gastric POEM (G-POEM), ESD and endoscopic full-thickness resection (EFTR). “G-POEM changed our practice—I don’t do pyloroplasties anymore; and ESD and EFTR are now the avant- garde of what we can do endoluminally,” Dr. Shah said.

Incorporating Endoluminal Techniques

Jeffrey Marks, MD, long a promoter of flexible endoscopy, acknowledged that while the younger generation of surgeons might be more comfortable with it—especially the residents who will have to pass the FES and complete the flexible endoscopy curriculum in 2018 before sitting for their boards—more established surgeons can be a tougher sell.

“The hardest person to impress is the person outside fellowship and residency, someone in practice already. If they’re not doing flexible endoscopy, it’s hard to get them started,” said Dr. Marks, professor of surgery and director of surgical endoscopy at Case Western/University Hospitals, Cleveland Medical Center, in Ohio.

Drs. Marks and Shah recommend surgeons start with intraoperative assessment. “For one thing, the GI doctors aren’t going to want to come in to assess every anastomosis or bariatric bypass; also, the patient being asleep makes it easier—you don’t have to worry about them being uncomfortable—so it’s a great way to gain skills.”

Dr. Shah suggests having an endoscope involved in every case. “There is no downside to you doing your own intraoperative endoscopy, whether it’s foregut or colon.”

Once a surgeon has gained some comfort, some formal training can advance his or her competence. “Both the American College of Surgeons and the Society of American Gastrointestinal and Endoscopic Surgeons have hands-on courses for surgeons who have a basic skill set in flexible endoscopy to learn how to do more advanced therapies,” Dr. Marks said.

Dr. Shah also recommends working with GI colleagues to build one’s skill set for more advanced endoscopic procedures. “Most of them have more experience than you with the more advanced procedures,” he said.

This can be difficult politically in situations where gastroenterologists sense a turf war and resist sharing what they know, but the reality, according to Dr. Shah, is that most gastroenterologists are more than willing to turn over the more challenging and relatively less remunerative advanced endoscopic procedures. “It does not pay for them to do a two-hour procedure when they can do six screening colonoscopies in the same time. The reimbursement isn’t there for them, the interest isn’t there for them, and they don’t want to be responsible for potential complications.

“If you have a therapeutic or developmental endoscopist in your area or practice, partner with them,” he said. They’ll love to have that work with you. And if you don’t have a therapeutic endoscopist, there’s a very good opportunity for you to become that person for your GI community. They’ll be happy to do your pre-ops, screenings and post-ops, and to call on you when they need one of these more advanced therapeutic endoscopic procedures.”

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