Wednesday, November 30, 2016

Justice for Martin Gottesfeld

Martin Gottesfeld, an activist jailed since February on charges stemming from a politically motivated cyberattack on Boston Children’s Hospital, has been on a hunger strike in prison for 49 days to bring attention to what he says is widespread mistreatment of children.

In a letter addressed to Attorney General Loretta Lynch and Department of Justice Inspector General Michael E. Horowitz, Gottesfeld calls on the DOJ to release him from solitary confinement and alleges that he’s being mistreated at Metropolitan Correctional Center, the prison in New York where he is currently housed. Gottesfeld provided the letter to The Huffington Post, which then forwarded the letter to the officials’ offices seeking comment.

The Office of the Inspector General said it could not comment on the allegations, and the DOJ did not respond.

Gottesfeld says he has lost 45 pounds since he began his hunger strike on Oct. 3 and that his kidneys are in constant pain, but instead of receiving proper medical care, he believes he’s being punished by the prison for participating in his hunger strike. In his letter, he says that as “a direct result” of his strike, prison staff moved him into solitary confinement, that the prison has barred him from making calls to his family and attorneys and has threatened to put him on “suicide watch.” He also says that one of the prison doctors threateningly told him that inmates who are housed at MCC in New York “are quickly forgotten.” All of which, Gottesfeld believes, is an attempt by the prison to break his hunger strike.

He also notes that the prison has defended how its treating him as medically necessary, but Gottesfeld claims that he’s not being medically monitored. He also claims that his cell is cold and has standing water leaking on the floor, which Gottesfeld says concerns him because his immune system is compromised due to the weeks of starvation he’s undergone. He says the conditions in his cell increase the odds of infection.

“The medically appropriate thing to do would be to place me in a clean hospital bed, hook me up to a heart monitor, and not to punish me,” Gottesfeld says.

MCC New York didn’t immediately respond to a request for comment…
Gottesfeld’s wife, Dana Gottesfeld, told HuffPost that for the last two days her husband has been drinking fluids again as a show of good faith as he awaits the Department of Justice’s response to his letter. 

Martin Gottesfeld has said he’ll continue his hunger strike unless two conditions are met: President-elect Donald Trump must promise to work toward ensuring American children are spared the kind of mistreatment he says has victimized Pelletier. And the office of Carmen Ortiz, the U.S. Attorney for Massachusetts, which is prosecuting Gottesfeld, must end its “political,” over-aggressive style of prosecution. (HuffPost catalogued Ortiz’s controversial record of targeting progressives in a July report that caused a political dust-up in Massachusetts.)

“The result of my hunger strike will serve as an appropriate backdrop to the upcoming Pelletier lawsuit, and accurately highlights the human rights records of Carmen Ortiz and Boston Children’s Hospital,” Gottesfeld said in a written statement provided to HuffPost. “The feats made public in those proceedings, which the courts would deny me the right to raise at my ‘trial,’ should be known to the world.”…

[from Gottesfeld’s letter]  Rolling Stone is working on a feature about my flight to protect these kids, the Huffington Post has published multiple articles, and television networks are also working on multiple pieces. Justina thanked me in her Rolling Stone Interview and said that I do not belong in jail. Reverend Mahoney, Director of the Christian Defense Coalition, to Rolling Stone he is praying for me, and the Pelletier family spoke in detail regarding the horrible abuses that paralyzed Justina and nearly took her life at Boston Children’s. Additionally, the Pelletier’s have sued the hospital so the totality of Justina’s suffering will be heard in open court. I take great comfort in knowing that the whole truth will inevitably be brought to light, further vindicating me.

As a direct result of my hunger strike, I am currently being punished at the DOJ facility MCC New York, despite never having been adjudicated of any crime by any court, nor even a prison disciplinary process. I am being held in solitary confinement, have not been able to call my family, nor my attorneys. I have been threatened with being placed on suicide watch, forcefully hydrated by IV, and force-fed. I am told if I don’t drink voluntarily, I can leave segregation. This is a clear and blatant attempt to break the hunger strike; there is no medical reason for restricting my calls to my wife, nor placing my in solitary.

One of the doctors here told me that inmates who come to MCC New York are quickly forgotten, but I know with all the journalists currently working on coverage, this thinly-veiled threat is simply not accurate in my case.

Further, while the reasons for these conditions are claimed to be medical, I am not being medically monitored. If I were to pass out at the wrong time, it could be several hours before I am discovered. My cell is cold, with standing water leaking on the floor, which given the compromising effects of starvation on my immune system, infection greatly increases the odds of a catastrophic and deadly infection.  The medically appropriate thing to do would be to place me in a clean hospital bed, hook me up to a heart monitor, and not to punish me.

I could be mere hours or days away from death, and I would like to call my wife, who I have not embraced in 9 months.


Sexual violence may reshape the female brain

“My independence, natural joy, gentleness and steady lifestyle I had been enjoying became distorted beyond recognition. I became closed off, angry, self-deprecating, tired, irritable, empty.” These chilling words, penned in a letter that a woman known only as “Emily Doe” read aloud in June to her attacker, former Stanford University student Brock Turner, offer a mere glimpse into the emotional devastation left by her rape. For Doe and others among the estimated one in three women who experience sexual violence, the damage can ripple throughout a lifetime.

But sexual violence may leave more than just emotional scars:  New research suggests sexual violence may change victim’s brains.

A recent study published in Scientific Reports found that sexual aggression from older male rats not only boosted the production of stress hormones in pubescent females, but it also disrupted their ability to learn various behaviors, including those needed to care for offspring. Females that struggled with maternal behaviors also had poorer survival of newly generated neurons in the hippocampus, a brain region crucial in memory and learning.

Women tend to be more sensitive to stress than men. Study lead author Tracey Shors of Rutgers University has wondered whether stress specifically from sexual violence changes the brain and learning in females. Despite growing openness to talking about sexual violence, “certainly it hasn’t been studied at a scientific level,” she says. “What does that actually do to the female brain?”
To find out, Shors and her colleagues developed the Sexual Conspecific Aggressive Response, or SCAR, a model of how stress from experiencing sexual aggression affects females. (Historically, lab models of stress have focused solely on its effects on males.) SCAR involves pairing a pubescent female rat with an adult male or adult female, or placing her alone in an unfamiliar cage for 30 minutes a day. An adult male caged with a pubescent female typically chases her genital region and pins and mounts her as she tries to escape.

After the experiment, Shors’ team measured levels of the stress hormone corticosterone in pubescent females’ blood. Sure enough, those that had been caged with adult males had higher corticosterone levels than those that hadn’t. The researchers also measured the pubescent females’ learning ability by using electrodes to stimulate their eyelids whenever a sound played, which trained them to eventually blink when they heard the tone, even without the stimulus. Pubescent females that had been paired with adult males did not learn this response as well as females that had not been exposed to them. The researchers also observed whether pubescent females exhibited maternal behaviors — like licking and grooming — when housed with two newborn pups. Those that had been caged with an adult male showed fewer maternal behaviors than the controls. “You have to learn new ways of thinking and behaving if you want your offspring to survive,” Shors says. “It has implications for not only women, but the species.”

What’s more, pubescent females that showed fewer maternal behaviors as a consequence had fewer newly generated cells in the hippocampus, necessary for learning about time. “If you’ve had a lot of trauma in your past, you might have difficulty paying attention to what’s happening in the present,” Shors says, which could explain the learning deficiencies her team observed.To be sure, we can’t completely generalize these findings to humans. J. Douglas Bremner of Emory University wonders whether adult male rats naturally display sexual aggression when trapped with younger females — “just a general question to make sure that the degree to which the model of this type of stress really corresponds to what it would be for humans,” he says. And as with any new model, SCAR “should be replicated by another group.”

Shors agrees SCAR can only go so far in explaining how sexual violence affects women and girls. She cautions against a fatalistic interpretation of the results — that just because a woman experiences sexual violence, she can’t learn maternal or other behaviors. Still, SCAR does highlight potential changes. Ultimately, Shors hopes the model will lead to effective interventions. Currently, Shors is providing MAP Training, an intervention that combines meditation and aerobic exercise, to women who have experienced sexual violence. “If we’re really going to help women with these experiences, we need to learn about how it’s changing their brain and behavior. If we do that, maybe we can design interventions that are more tailored to their needs and lives and experiences.”


The genetics of loneliness

So you’ve got a massive social circle, and some of them are actual friends, not just the Facebook kind. But you just can’t shake off that gnawing sense of isolation — like that awkward feeling that washes over you when swaying alone in the corner at a party, cocktail (or more) in hand. You’re probably not being dramatic, and it might not all be in your head. New research suggests that genetics plays a role. In a September Neuropsychopharmacology study, scientists reported that  14 to 27 percent of loneliness can be explained by our genes.

Other factors, like age and marital status, might also play a role. The researchers saw significant genetic similarities among individuals with high levels of loneliness, neuroticism and depressive symptoms, suggesting that people often inherit these traits together.

John Cacioppo of the University of Chicago, a study co-author, has proposed that we crave social contact in much the same way we feel hunger. Just as hunger alerts us to low blood sugar levels and drives us to seek food, loneliness alerts us to possible risks — indeed, earlier studies have cited loneliness as a risk factor for heart disease, cognitive decline and early death — and drives us to seek the company of others. Abraham Palmer, who led the study and whose lab at the University of California, San Diego studies the connection between genes and behavior, wanted to investigate whether genetics would influence how strongly someone feels these lonely urges…

“We’re not measuring whether someone has a lot of social contacts or not, but whether people perceive themselves as being lonely,” Palmer explains. To do that, Palmer and his team measured genetic variations, known as single-nucleotide polymorphisms, or SNPs, in the participants’ DNA and correlated them to their score on the three-question loneliness scale. They found that 14 to 27 percent of loneliness can be explained by genes we inherit. That falls below the 37 to 55 percent heritability that earlier studies had calculated, which could be because the method Palmer’s team used directly measures only common, not rare, genetic variations…

The remaining 73 to 86 percent might be due to life circumstances. Married participants felt less lonely than unmarried participants, and in fact, to Palmer’s surprise, loneliness declined with age. Biological sex had little influence on the tendency to feel lonely.

The researchers also saw strong genetic similarities among people who scored high on loneliness, neuroticism and depressive symptoms. In other words, someone who inherits one of these traits has probably also inherited the other two. Palmer’s team also saw weaker links between loneliness and schizophrenia, bipolar disorder and major depressive disorder.

Like with most psychiatric and personality traits, the researchers found that many genes collectively contribute to loneliness. But since each individual gene makes only a tiny contribution, they couldn’t pinpoint the exact genes involved. They recently launched a follow-up study with threefold the number of participants, which they hope will boost the signal strength of these genes enough so they can identify them.

To be sure, loneliness is a complex psychological state, which the three-question loneliness scale — a shortened version of the original 20-question scale — might not precisely measure, says Francis McMahon of the National Institute of Mental Health. “Are the questions really measuring what we think they’re measuring?” he wonders. Although the researchers noted a high correlation between the shortened and full-fledged scale, loneliness “isn’t like height, for example, or a disease diagnosis. It isn’t something that is necessarily always present,” he says. “It’s tough to measure.” But overall, he believes “it’s a very well-designed, well-executed study.”

And “genetics isn’t destiny,” Palmer says. “There are some people who have genetic tendencies to be one way or another, but the effects are never so strong … as to guarantee one person would be lonely and one person would not.” Still, “lots and lots of aspects of the human experience are influenced by genetics.” So if you find yourself frustrated over quips to “just get over it,” remember that your loneliness might be hardwired, at least to some extent.

Bacteria versus bacteria

As health experts continue to tackle the problem of antibiotic-resistant bacteria, a team of researchers in the United Kingdom has investigated a new bacteria-versus-bacteria approach to fighting dangerous pathogens.  

New approaches and novel drugs designed to take on bacteria resistant to antibiotics continue to emerge and offer new fronts in the battle against deadly infections. Still, the World Health Organization (WHO) calls antibiotic resistance one of the biggest threats to global health, food security, and development. Around the world, resistant forms of tuberculosis, pneumonia, and gonorrhea have become harder to treat, and thus, more likely to kill those infected. While health officials call for judicious antibiotic use and the development of new antibiotics to prevent and treat virulent bacterial infections, pathogens continue to develop new resistance mechanisms faster than researchers can outsmart them.  

Researchers at the Imperial College of London and Nottingham University Medical School in the UK recently studied a novel approach to treating multidrug-resistant shigellosis infections. Caused by the Shigella group of bacteria, these intestinal infections typically lead to diarrhea, fever, and stomach cramps within a day or two of exposure to the pathogen and symptoms can last for up to a week. Shigella is one of several bacteria associated with traveler’s diarrhea, particularly for those traveling to parts of Africa, Central America, South America, and Asia.  

Since 2013, the Centers for Disease Control and Prevention (CDC) in the United States has considered antibiotic-resistant Shigella as an urgent threat, with forms of the bacteria becoming increasingly resistant to first-line antibiotics such as ampicillin and trimethoprim-sulfamethoxazole. Cases of shigellosis infections resistant to the commonly used antibiotics, ciprofloxacin or azithromycin, though a bigger problem in developing countries, are appearing more frequently in the United States. While estimates vary on the number of shigellosis-related deaths occurring worldwide each year, a recent CDC advisory on travel-related health threats projects that 80 million to 165 million Shigella infections each year lead to 600,000 annual deaths.  

In the new study from the UK research team, published in the journal Current Biology, researchers conducted an experiment using Bdellovibrio bacteriovorus, a naturally occurring predatory bacterium, to fight Shigella bacteria. Predatory Bdellovibrio in natural environments are known to kill gram-negative bacterial pathogens and past studies have looked into the potential use of these bacteria as an antimicrobial agent. In their investigation, the researchers studied zebrafish larvae infected with a lethal dose of an antibiotic-resistant strain of Shigella flexneri, injecting them with Bdellovibrio as an antibacterial. In uninfected larvae, the predatory bacteria can live but is not pathogenic. In the infected larvae, the team found that Bdellovibrio work to reduce the number of Shigella, increasing the larvae’s chances for survival.  

"This study really shows what a unique and interesting bacterium Bdellovibrio is as it presents this amazing natural synergy with the immune system and persists just long enough to kill prey bacteria before being naturally cleared,” said co-lead author and Imperial College London researcher Serge Mostowy, PhD, co-lead author from Imperial College London, in a recent press release. “It’s an important milestone in research into the use of a living antibiotic that could be used in animals and humans."  

In their study, the authors note that Bdellovibrio worked with the hosts’ own immunity to impart full therapeutic benefits. Bdellovibrio live in a host long enough to prey on pathogens and can be engulfed and ultimately eliminated by a host’s neutrophils and macrophages. “This has been a truly ground-breaking collaboration that shows therapeutic Bdellovibrio in action inside the translucent living zebrafish,” said co-lead author and University of Nottingham professor Liz Sockett, PhD. “The predatory action of the Bdellovibrio breaks the Shigella-pathogen cells and this stimulates the white blood cells; redoubling their ‘efforts’ against the pathogen and leading to increased survival of the zebrafish ‘patients.’"  

The authors conclude that using Bdellovibrio bacteria as active antibacterial predators can be a beneficial approach to treating drug-resistant infections. With continued experiments they hope to better understand the “host immune response to this therapy, determine ways to modify predatory bacteria with immune-stimulatory properties, and examine the use of Bdellovibrio in more prolonged infections.”

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Tuesday, November 29, 2016

Chiropractic 101

Have you ever watched a good guitarist tuning his guitar? He picks up his instrument, and starts to play. Then he screws up his nose because he hears a “bung” note (that no-one else heard). Next thing you know he has stopped playing and is crouched down listening intently to one string as he gently and gradually adjusts the tuning peg. Then he carries on as if nothing happened. If you’ve seen a guitarist lately, you may even have noticed him pull out a little electric gizmo that he plugs his guitar into, which actually tells him when he’s found the right note!

So, what is he doing while he is winding or unwinding that small peg on the end of the guitar string? The amount of tension in the guitar string determines the note and hence the tune that plays when you pluck the string.

The skill of the musician is to be able to tune the guitar to make a beautiful noise.

Now try to imagine a funny looking guitar: This one has pegs at both ends of the string, so that you could change the tension in the string from either end of the guitar. There is also an extra peg right at the tip of the neck of the guitar which can also change the tension of all the strings.

What we have just described to you is an analogy for the relationship between your spinal column and your spinal cord. The “pegs” on the guitar are represented by small ligaments which actually hang the spinal cord within the spinal canal. These ligaments are few in number (about half a dozen at both ends of the spine), and only attach between specific vertebrae, and corresponding sections of the spinal cord (central nervous system).

When a specific command travels down the spinal cord from the brain to the body, or when sensory information is being transmitted back up the spinal cord to the brain; there is a “flash” of “electricity” that carries the messages. Quick body responses and sensory perceptions result.

At the same time though, there is also a low-grade “wave” of radio frequency traveling up and down your spinal cord that determines the “mood” or “tone” of your central nervous system. This affects your level of consciousness and awareness, your mood, and the slower metabolic and hormonal functions of your body.

Adjustments aim to remove any blockages to the fast acting messages traveling up and down the spinal cord; and at the same time rebalance the overall frequency at which the nervous system is operating.

Scientifically speaking, your spinal cord is a thick string of pizo-electric gel (electricity conducting jelly). The frequency it is working at is determined by the amount of tension and/or torsion being placed at either end of the “string”. Just like the guitar string, the tightness of the cord determines the tune that is being played.

Chiropractic Nervous SystemTRT differs from many of the other chiropractic techniques in that it focuses a lot of attention to the “tuning pegs”: The strategic and vital connection points between the spinal cord and spinal column. As we gently and methodically adjust these areas of your “guitar string” (spinal cord), we are changing the degree of tension in the central nervous system in an effort to change the notes that result.

Hence, the skill of the Chiropractor is to be able to tune your spinal cord to find some more beautiful notes. That is, a better level of tension.

When many people get up straight after an adjustment, they comment on how their vision seems clearer, the light or view seems sharper, their head feels lighter, there body feels looser etc. These are all reflections of your central nervous system now operating at a better frequency. The Integrator is the high-tech tool that we use to tune your nervous system.

EMG and disorders of consciousness

Lesenfants D, Habbal D, Chatelle C, Schnakers C, Laureys S, Noirhomme Q.
Electromyographic decoding of response to command in disorders of consciousness. Neurology. 2016 Oct 21. pii: 10.1212/WNL.0000000000003333. [Epub ahead of print]

To propose a new methodology based on single-trial analysis for detecting residual response to command with EMG in patients with disorders of consciousness (DOC), overcoming the issue of trial dependency and decreasing the influence of a patient's fluctuation of vigilance or arousal over time on diagnostic accuracy.
Forty-five patients with DOC (18 with vegetative/unresponsive wakefulness syndrome [VS/UWS], 22 in a minimally conscious state [MCS], 3 who emerged from MCS [EMCS], and 2 with locked-in syndrome [LIS]) and 20 healthy controls were included in the study. Patients were randomly instructed to either move their left or right hand or listen to a control command ("It is a sunny day") while EMG activity was recorded on both arms.
Differential EMG activity was detected in all MCS cases displaying reproducible response to command at bedside on multiple assessments, even though only 6 of the 14 individuals presented a behavioral response to command on the day of the EMG assessment. An EMG response was also detected in all EMCS and LIS patients, and 2 MCS patients showing nonreflexive movements without command following at the bedside. None of the VS/UWS presented a response to command with this method.

This method allowed us to reliably distinguish between different levels of consciousness and could potentially help decrease diagnostic errors in patients with motor impairment but presenting residual motor activity.

Volitional EMG response to motor command was detected in all 13 MCS+ cases, even though only six of them had presented a behavioral response on the day of the EMG assessment. An EMG response was also detected in all three of the patients emerging from a MCS and both of the patients with locked-in syndrome.

The researchers noted, however, that the locked-in patients in their study were in an incomplete locked-in state, meaning they showed residual motor abilities. Had they suffered from complete or classic locked-in syndrome, no signal could have been detected on EMG.

None of the 15 patients in a vegetative state showed any response on EMG. While two of the MCS- patients did show a response, the authors were unwilling to conclude on that basis that they retain awareness, as the results could have been false positives.

One of the patients initially diagnosed as being in a vegetative state showed no initial response on the EMG test, but when the patient later recovered enough to be clinically diagnosed as being MCS+, the EMG test was positive.

“The biggest limitation of the study,” Dr. Lesenfants said, “is that the technique is motor-dependent, whereas EEG or fMRI-based brain-computer interfaces could offer motor-independence and allow the detection of responses to command in patients without motor abilities. Perhaps some of these vegetative patients retain some awareness and we just do not see it on EMG. The problem with brain-computer interfaces, on the other hand, is that many patients who show awareness behaviorally do not show it on the imaging. There are too many false negatives.”

Maternal depression and children's brain structure

Lebel C, Walton M, Letourneau N, Giesbrecht GF, Kaplan BJ, Dewey D. Prepartum
and Postpartum Maternal Depressive Symptoms Are Related to Children's Brain
Structure in Preschool. Biol Psychiatry. 2015 Dec 15. pii: S0006-3223(15)01039-2. doi: 10.1016/j.biopsych.2015.12.004. [Epub ahead of print]

Perinatal maternal depression is a serious health concern with potential lasting negative consequences for children. Prenatal depression is associated with altered brain gray matter in children, though relations between postpartum depression and children's brains and the role of white matter are unclear.
We studied 52 women who provided Edinburgh Postnatal Depression Scale (EPDS) scores during each trimester of pregnancy and at 3 months postpartum and their children who underwent magnetic resonance imaging at age 2.6 to 5.1 years. Associations between maternal depressive symptoms and magnetic resonance imaging measures of cortical thickness and white matter structure in the children were investigated.
Women's second trimester EPDS scores negatively correlated with children's cortical thickness in right inferior frontal and middle temporal regions and with radial and mean diffusivity in white matter emanating from the inferior frontal area. Cortical thickness, but not diffusivity, correlations survived correction for postpartum EPDS. Postpartum EPDS scores negatively correlated with children's right superior frontal cortical thickness and with diffusivity in white matter originating from that region, even after correcting for prenatal EPDS.
Higher maternal depressive symptoms prenatally and postpartum are associated with altered gray matter structure in children; the observed white matter correlations appear to be uniquely related to the postpartum period. The reduced thickness and diffusivity suggest premature brain development in children exposed to higher maternal perinatal depressive symptoms. These results highlight the importance of ensuring optimal women's mental health throughout the perinatal period, because maternal depressive symptoms appear to increase children's vulnerability to nonoptimal brain development.

"We found an association between brain structure in the kids and maternal depressive symptoms, so, while we cannot say the depressive symptoms cause this, there is definitely something different structurally in the brains of kids whose moms were more depressed," Dr Lebel said.

"We know that prenatal and postpartum depression in moms has negative consequences for kids in terms of things like behavior and learning, and in fact, the kids have higher risks of mental health problems themselves, so the brain structure is of interest because it can tell us a little bit about potential mechanisms, help us understand why maternal depression is associated with such outcomes in kids," she said…

They found that cortical thickness in two areas of the right hemisphere was negatively correlated with second trimester maternal depressive symptoms, after controlling for the child's age, sex, gestational age, and weight at birth, as well as maternal postsecondary education.

One region was located in the right inferior frontal area and included much of the pars opercularis and pars triangularis and small sections of the precentral and rostral middle frontal areas…

In addition, structural patterns in the children's white matter were different.

"These types of changes suggest to us that the children whose mums were more depressed have a more mature pattern of brain structure. Their gray matter was thinner, and we know that with age, gray matter becomes thinner. So it looks like the kids whose mums were more depressed have this premature pattern of brain structure, almost like their brains are developing too soon," said Dr Lebel.

"Brain development is obviously a complicated process, and there is very likely a narrow window for an optimal time for stages of development to occur. Our findings may indicate that with brains developing almost a little bit too soon, these children are losing flexibility and adaptability that other kids might have…

"Overall, in our society, roughly 1 in 5 people will meet diagnostic criteria for depression in their lifetime. The prevalence of depression in women, overall, is double that of men. Among women who are pregnant or have recently given birth, the rate of depression doubles to roughly four times the rate of depression in men. These statistics suggest that undiagnosed and untreated depression among pregnant women is very common and is a significant public health concern," he said…

A question raised by this study concerns whether treatment of depression with medications might have prevented these alterations in brain development, Dr Krystal noted.

"Only one of the 52 women in this study was treated with antidepressants. We recognize that some antidepressant medications, such as paroxetine or mood stabilizing medications, such as lithium, appear to carry some risk for developmental effects when taken during pregnancy," he said.

"This new study suggests that the risk of developmental impact of maternal antidepressant medications must be weighed against the potential developmental impact of ineffectively treated maternal depression for the offspring.

"There are many forms of treatment for mood disorders that carry limited developmental risk for babies, including psychotherapy, neurostimulation treatments, such as transcranial magnetic stimulation of electroconvulsive therapy, or antidepressant medications that have very little developmental impact," said Dr Krystal.

Circumcision and SIDS

Elhaik E.  A “wear and tear” hypothesis to explain sudden infant death syndrome.  Front. Neurol., 28 October 2016 |

Sudden infant death syndrome (SIDS) is the leading cause of death among USA infants under 1 year of age accounting for ~2,700 deaths per year. Although formally SIDS dates back at least 2,000 years and was even mentioned in the Hebrew Bible (Kings 3:19), its etiology remains unexplained prompting the CDC to initiate a sudden unexpected infant death case registry in 2010. Due to their total dependence, the ability of the infant to allostatically regulate stressors and stress responses shaped by genetic and environmental factors is severely constrained. We propose that SIDS is the result of cumulative painful, stressful, or traumatic exposures that begin in utero and tax neonatal regulatory systems incompatible with allostasis. We also identify several putative biochemical mechanisms involved in SIDS. We argue that the important characteristics of SIDS, namely male predominance (60:40), the significantly different SIDS rate among USA Hispanics (80% lower) compared to whites, 50% of cases occurring between 7.6 and 17.6 weeks after birth with only 10% after 24.7 weeks, and seasonal variation with most cases occurring during winter, are all associated with common environmental stressors, such as neonatal circumcision and seasonal illnesses. We predict that neonatal circumcision is associated with hypersensitivity to pain and decreased heart rate variability, which increase the risk for SIDS. We also predict that neonatal male circumcision will account for the SIDS gender bias and that groups that practice high male circumcision rates, such as USA whites, will have higher SIDS rates compared to groups with lower circumcision rates. SIDS rates will also be higher in USA states where Medicaid covers circumcision and lower among people that do not practice neonatal circumcision and/or cannot afford to pay for circumcision. We last predict that winter-born premature infants who are circumcised will be at higher risk of SIDS compared to infants who experienced fewer nociceptive exposures. All these predictions are testable experimentally using animal models or cohort studies in humans. Our hypothesis provides new insights into novel risk factors for SIDS that can reduce its risk by modifying current infant care practices to reduce nociceptive exposures…

Circumcision contributes to the rise in allostatic load and increased risk for SIDS through multiple conduits. Circumcision produces crush and incisional injuries during amputation, resulting in damage to normal prepuce tissue, the associated nerves, and blood vessels. Wound healing manifested by hyperaemia and swelling at day 7 postoperative is observed in 70% of infants with minimally retractile prepuces seen in infants circumcised before 1 year of age with subsequent bacterial carriage of skin commensals. Circumcised males have increased pain responses to childhood immunization 4–6 months post-surgery  consistent with central sensitization. The abnormal development of sensory pathways in the developing nervous system elicited by the pain during critical postnatal periods is manifested in later life following nociceptive reexposure by abnormal sensory thresholds and pain responses that are not restricted to the original site of postnatal trauma. Neonatal nociceptive exposure induces long-term hypoalgesia or hyperalgesia depending on the nature and timing of the trauma and is consistent with surgery and pain adversely impacting neurodevelopment independent of anesthetic.

Post-circumcision, tactile hypersensitivity increases due to post-surgical and -traumatic mechanisms that contribute toward allostasis and the risk of SIDS. This is evident by the increase in toll-like receptor 4  associated with post-circumcision wound healing, which is also observed in post-surgical tactile hypersensitivity in males and dependent on testosterone . Following peripheral nerve injury, the purinergic receptors in the spinal cord microglial cells release BDNF  and mitogen-activated protein kinase p38  that contribute to neuropathic pain and tactile hypersensitivity. Due to their testosterone dependency, they are seen only in males. The testosterone surge occurring during the first 2- to 4-month period may increase susceptibility to the initial stages of infection and is consistent with the peak in SIDS mortality.

Male neonates subjected to circumcision can experience severe cardiorespiratory pain responses, including cyanosis, apnea, increased heart rate, and increased pitch (fundamental frequency) of cry (as high as 800–2000 Hz) associated with decreased heart rate variability, i.e., decreased vagotonia , a likely risk factor for SIDS. Other circumcision sequelae of sufficient severity to require emergency room evaluation or hospital admission and contribute toward allostasis include infection, urinary retention, inflammatory redness and swelling ascribed to healing, and amputation/necrosis of the glans. Behavioral abnormalities, such as eating disturbance and disturbed sleep, are also the consequence of pain exposure.

One mechanism by which circumcision may elicit SIDS concerns the inhibition of nerves involved in nociception processing that produces prolonged apnea while impairing cortical arousal. Neonatal surgery that traumatizes peripheral nerves with associated tactile hypersensitivity followed by a subsequent surgery later in development can increase spinal cord microglia signaling and elicit persistent hyperalgesia. It can also produce post-surgical hyperalgesia that subsequently alters postnatal development of the rostral rostroventral medulla (RVM), which controls the excitability of spinal neurons by spinally projecting neurons from the nucleus paragigantocellularis lateralis (PGCL) and the nucleus raphe magnus. Alterations in the RVM result in a descending inhibition of spinal reflex excitability on nociception . Inhibition of RVM neurons was shown to limit the duration of the laryngeal chemoreflex and produce prolonged apnea that contributes toward SIDS, particularly when combined with stimuli that inhibit respiration…

Another mechanism that can explain the SIDS toll following circumcision is the loss of ~1–2 ounces (oz) of blood out of a total of ~11 oz that a 3,000 gram male newborn has, the equivalent of ~1–2 blood donations in an adult. Excessive bleeding is highly common in circumcision with reports range from 0.1 to 35% in neonates. However, even moderate bleeding puts the infant as risk, and, being an inherent part of the procedure, it is not reported as a complication…

Fortunately, the prepuce has been well conserved throughout mammalian evolution, which attests to its functional importance, and allows carrying out animal studies. Our hypothesis can be tested by circumcising the prepuce of mammalian animal models and measuring whether an excess of SIDS is observed among cases when compared with untreated controls…

In humans, we can expect higher SIDS rates in Anglophone countries that adopted male neonatal circumcision in the nineteenth century, compared to Iberio-American that traditionally have opposed circumcision. We can also expect a higher incidence of SIDS in USA states where Medicaid, the most common health insurance, covers circumcision, compares to states where this procedure is not covered by Medicaid after accounting for culture and socioeconomic status.

Implausible, unreliable results found in leading journals (caveat emptor)

A systematic review and statistical analysis of 33 randomized controlled trials coauthored by a Japanese neurologist and published in such leading journals as the Archives of Internal Medicine, the Journal of the American Medical Association, and Neurology has found evidence of implausible, unreliable data in some or all of them.

Twelve of the papers, including the three published in Neurology, have already been retracted. The review and analysis of the 33 papers is being published online in the November 9 issue of
Neurology. Spurred by questions raised in journal correspondence regarding some of the papers, a group led by a New Zealand internist used advanced statistical methods to show that data in the papers failed by a wide margin to follow the degree of random variation in baseline and control-group variables expected.

Furthermore, the systematic analysis found, “There were multiple examples of inconsistencies between and within trials, errors in reported data, misleading text, duplicated data and text, and uncertainties about ethical oversight.”

The papers date from as far back as 1997 to as recently as 2012. Some have been cited over 300 times. They examine the effects of supplements and drugs (including alendronate and risedronate) on bone strength and function in elderly patients diagnosed with stroke, Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

The first author or coauthor of all 33 papers is Yoshihiro Sato, MD, PhD, a neurologist at Mitate Hospital in Japan. He has taken responsibility for the 12 articles retracted so far, conceding that they are “fraudulent.” In July, Neurology reported that in response to the journal's request for an explanation on one of the papers, Dr. Sato had said that he “accepts full responsibility for this fraudulent paper and maintains that none of the coauthors participated in any misconduct and appeared as authors on an honorary basis only.”

In response to an emailed request for comment from Neurology Today, Dr. Sato stated that 12 of the 21 papers not previously retracted are “valid.” Dr. Sato has published seven additional papers since 2013, beyond the span covered by the review, and many other reports with other study designs before 2013.

The questionable papers by Dr. Sato were identified in the course of conducting systematic reviews in osteoporosis. Dr. Sato's group stood out for having published a large number of randomized controlled trials that “collectively have substantially influenced relevant systematic reviews,” the paper stated.

Initial concerns had been raised in journal correspondence regarding some of the papers. For instance, a 2003 paper in the Journal of Neurology, Neurosurgery and Psychiatry about the efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson's disease prompted a letter from a British neurologist the following year.

“I was astonished to find that Dr. Sato and colleagues were able to identify 40 cases of neuroleptic malignant syndrome in patients with Parkinson's disease from a single institution over three years,” wrote Carl E. Clarke, MD, professor of clinical neurology at the University of Birmingham in the United Kingdom.

“At a recent neurosciences grand round in Birmingham, which has an interest in Parkinson's disease research, we could only recall two such cases in living memory,” Dr. Clarke wrote, noting that Dr. Sato and colleagues defended the high numbers as being drawn from a tertiary care hospital. The Neurology paper's first author, Mark J. Bolland, MBChB, PhD, associate professor of medicine at the University of Auckland, New Zealand, told Neurology Today that his group concluded that the data in Dr. Sato's papers were unreliable for two reasons.
“First, we used different statistical approaches that showed that the baseline data from the treatment groups presented in the papers were much more similar than expected if the groups had been formed by chance,” Dr. Bolland said in an email. “In other words, the likelihood that randomization resulted in the very similar treatment groups was very low. Second, we identified a very large number of concerns about the trials, including fairly incredible productivity and recruitment rates, implausibly positive outcome data, concerns about ethical oversight, plagiarism, and many logical and other errors in the papers.”…        
Although most of the techniques used by Dr. Bolland's group required analysis of many papers at once, some involved nothing more than close examination of the text for consistency, and could be applied to single papers. For instance, in one study, “participants were eligible for inclusion if they had sustained a stroke at least 3 months before the study began, but the mean duration of illness at baseline in both randomized groups was 90 days, or slightly less than 3 months, which appears implausible.”…

“Peer review, being a human process, is not perfect,” he said. “I wanted to alert our readership that we are on guard as much as possible, and to correct the literature.”

Asked to respond to Dr. Sato's assertion that 12 of the 33 papers are “valid,” Dr. Gross said: “I have no way of knowing if he's correct or not. The problem of course is when someone admits to fraudulent behavior, it's difficult to take at face value that some other papers are okay. I know what he said about the three papers he retracted in Neurology, and he wasn't willing to go much farther than that with us.”

Dr. Bolland's paper is careful not to call the 33 papers “fraudulent.”

“The statistical techniques we used cannot prove data are made-up,” he said. “Instead they assess how consistent the distribution of data is with the expected distribution. But made-up data is one reason why the distributions of data might be inconsistent with expectations.”…

Clifford Saper, MD, PhD, FAAN, the editor-in-chief of Annals of Neurology, said he found it especially concerning that the 33 papers had been published over such a long time span.

“There could be any number of cases out there that haven't yet been detected,” he said. “The problem is we don't know the percentage of people who get caught."

Even so, he said that he does occasionally see papers submitted in which the data look too good to be true.“When the error bars are too small and the statistics are too good, we get concerned,” Dr. Saper said. “It's really important that reviewers work as hard as they can on the statistics. If they have any questions at all, the editor's responsibility is to have a statistical consultant available.”,__Unreliable__Results.1.aspx

Monday, November 28, 2016

Homeopathic remedies

The Federal Trade Commission (FTC) has just announced its intent to pursue manufacturers of over-the-counter (OTC) homeopathy remedies who cannot back up health claims with scientific evidence.

Homeopathy products are based on an idea dating from the 1700s that symptoms of disease can be treated by minute doses of substances that produce similar symptoms when given in larger doses to healthy people. Most remedies are so diluted that they no longer contain detectable levels of the initial substance, according to the FTC. This is why proponents have generally claimed that homeopathy products are safe.

The US Food and Drug Administration (FDA) has allowed — with some limitations ― homeopathic remedies to be marketed over the counter without proof of efficacy or safety. It recently warned that homeopathic teething tablets and gels, used by some parents to relieve teething pain and symptoms, may pose risks to infants and children, including risk of seizures. The manufacturer subsequently stopped selling the products.

The FTC, by its own admission, has rarely challenged what could be misleading claims by homeopathic manufacturers. Both agencies signalled a potential change when they held separate public meetings in 2015 to examine the products.

On November 15, the FTC issued a new policy statement in which the agency says it "will hold efficacy and safety claims for OTC homeopathic drugs to the same standard as other products making similar claims," according to an FTC press release. The "companies must have competent and reliable scientific evidence for health-related claims, including claims that a product can treat specific conditions," the FTC said in the release.

Under the new policy, the FTC said that making a case for efficacy based on traditional theories ― without any modern scientific evidence ― would amount to a misleading claim that would be illegal.

The FTC enforcement policy will still give homeopathy makers some wriggle room — but it might not be welcomed by manufacturers. According to the FTC, they can get around a violation by clearly noting on the label or in ads that "there is no scientific evidence that the product works" or "that the product's claims are based only on theories of homeopathy from the 1700s that are not accepted by most modern medical experts."

The agency notes that homeopathy has grown from a small, multimillion dollar market to one with sales of more than $1 billion annually.

In a just-issued report summarizing its September 2015 workshop, the FTC said one manufacturer's chief executive estimated that more than 7000 homeopathic medicines are registered with the FDA, but that only 1000 are marketed routinely, and fewer than 100 are mass marketed. The $1 billion market is growing about 5% a year, said the executive. 

"It remains to be seen what if anything FDA will do regarding prescription homeopathic drug products and if the FTC's new policy and potential resulting enforcements actions will be challenged," wrote Riëtte van Laack, PhD, a food and drug law attorney in Washington, DC, in a blog post on November 15.

fMRI biomarkers predicting response to pivotal response treatment in autism

Yang D, Pelphrey KA, Sukhodolsky DG, Crowley MJ, Dayan E, Dvornek NC, Venkataraman A, Duncan J, Staib L, Ventola P. Brain responses to biological motion predict treatment outcome in young children with autism. Transl Psychiatry. 2016 Nov 15;6(11):e948.

Autism spectrum disorders (ASDs) are common yet complex neurodevelopmental disorders, characterized by social, communication and behavioral deficits. Behavioral interventions have shown favorable results-however, the promise of precision medicine in ASD is hampered by a lack of sensitive, objective neurobiological markers (neurobiomarkers) to identify subgroups of young children likely to respond to specific treatments. Such neurobiomarkers are essential because early childhood provides a sensitive window of opportunity for intervention, while unsuccessful intervention is costly to children, families and society. In young children with ASD, we show that functional magnetic resonance imaging-based stratification neurobiomarkers accurately predict responses to an evidence-based behavioral treatment-pivotal response treatment. Neural predictors were identified in the pretreatment levels of activity in response to biological vs scrambled motion in the neural circuits that support social information processing (superior temporal sulcus, fusiform gyrus, amygdala, inferior parietal cortex and superior parietal lobule) and social motivation/reward (orbitofrontal cortex, insula, putamen, pallidum and ventral striatum). The predictive value of our findings for individual children with ASD was supported by a multivariate pattern analysis with cross validation. Predicting who will respond to a particular treatment for ASD, we believe the current findings mark the very first evidence of prediction/stratification biomarkers in young children with ASD. The implications of the findings are far reaching and should greatly accelerate progress toward more precise and effective treatments for core deficits in ASD.

"We [currently] have no way to predict a child's outcome and to match a child to a particular intervention or determine which children have the best chance to respond to a particular treatment," Dr Ventola told Medscape Medical News.

The researchers investigated the accuracy of fMRI neurobiomarkers in predicting response to [pivotal response treatment] PRT in seven girls and 13 boys with ASD (mean age, 5.9 years).

PRT includes parental training and uses motivational play activities to boost the development of social communications skills.

For the study, the researchers used a well-validated biological motion fMRI paradigm that "robustly" engages the neural circuits supporting social motivation and social information processing.

They discovered a brain network in which the pretreatment brain activities that are engaged during biological motion viewing predicted response to PRT.

"Specifically, the network includes key brain regions supporting social information processing (the superior temporal sulcus region, fusiform gyrus, superior parietal lobule) and social motivation (orbitofrontal cortex, putamen, ventral striatum)," the researchers report.

"Critically," they note, the results were supported by multivariate pattern analysis, which utilized a standard cross validation framework, "suggesting that the patterns of brain activities across these brain regions may serve as robust predictive biomarkers, generalizable to new, unseen participants."

"This discovery might lead to further development of precision medicine in ASD," lead author Daniel Y. J. Yang, PhD, previously of Yale University, now with the Autism and Neurodevelopmental Disorders Institute, the George Washington University and Children's National Health System, in Washington, DC, told Medscape Medical News.
For example, pretreatment fMRI or electroencephalography "may be used to facilitate the fitting process when families want to identify appropriate and effective treatments for their children," he explained.

"For children who might not be able to benefit immediately from the treatment, theoretically, if we can increase the pretreatment activation and their brain readiness to respond (eg, by oxytocin), we can increase the treatment effectiveness for these children," Dr Yang said.

Nusinersen for spinal muscular atrophy

Biogen (NASDAQ:BIIB) and Ionis Pharmaceuticals (NASDAQ:IONS) announced that SPINRAZATM (nusinersen), an investigational treatment for spinal muscular atrophy (SMA), met the primary endpoint at the interim analysis of CHERISH, the Phase 3 study evaluating SPINRAZA in later-onset (consistent with Type 2) SMA. The analysis found that children receiving SPINRAZA experienced a highly statistically significant improvement in motor function compared to those who did not receive treatment. SPINRAZA demonstrated a favorable safety profile in the study.

“These results, along with our successful trial in infantile-onset SMA, reinforce the potential of SPINRAZA to benefit a broad range of SMA patients,” said Michael Ehlers, M.D., Ph.D., executive vice president, head of Research and Development at Biogen. “We will make regulators around the globe aware of this data and will continue working closely with them to bring SPINRAZA to families affected by SMA as quickly as possible.”

Biogen is preparing for the potential launch of SPINRAZA in the U.S. possibly as early as the end of 2016 or the first quarter of 2017.

Results From the CHERISH Interim Analysis

CHERISH is a fifteen-month study investigating SPINRAZA in 126 non-ambulatory patients with later-onset SMA (consistent with Type 2), including patients with the onset of signs and symptoms at greater than 6 months and an age of 2 to 12 years at screening.

Results from the primary endpoint of the pre-specified interim analysis demonstrated a difference of 5.9 points (p= 0.0000002) at 15 months between the treatment (n=84) and sham-controlled (n=42) study arms, as measured by the Hammersmith Functional Motor Scale Expanded (HFMSE). From baseline to 15 months of treatment, patients who received SPINRAZA achieved a mean improvement of 4.0 points in the HFMSE, while patients who were not on treatment declined by a mean of 1.9 points. The HFMSE is a reliable and validated tool specifically designed to assess motor function in children with SMA, and a change of three points or greater in the HFMSE has previously been identified as clinically meaningful. Data from the other endpoints analyzed were consistently in favor of children who received treatment. SPINRAZA demonstrated a favorable safety profile. The majority of the adverse events were considered to be either related to SMA disease, common events in the general population, or events related to the lumbar puncture procedure. No patients discontinued the study.

With the positive interim analysis, the CHERISH study will be stopped and participants will be able to transition into the SHINE open-label extension study to receive SPINRAZA. Full study results will be presented at future medical congresses.

“These data further validate the potential of SPINRAZA as a treatment for patients with SMA,” said B. Lynne Parshall, chief operating officer of Ionis Pharmaceuticals. “We are grateful to all the families and clinicians who have participated in all of the SPINRAZA studies. Without their commitment and support, this program would not have been able to progress so quickly.”

The U.S. Food and Drug Administration (FDA) recently accepted the company’s New Drug Application (NDA) for SPINRAZA as a treatment for SMA and communicated they plan to act early on the NDA under an expedited review. Additionally, the European Medicines Agency (EMA) recently validated Biogen’s Marketing Authorization Application (MAA) in the EU. The EMA’s Committee for Medicinal Products for Human Use (CHMP) granted Accelerated Assessment status and the FDA granted Priority Review to SPINRAZA. Biogen is initiating regulatory filings in other countries in the coming months.

Biogen initiated a global expanded access program (EAP) in infantile-onset SMA earlier this year. The company will continue to explore where and when the EAP may be broadened to include patients with later-onset SMA (consistent with Type 2).

The SPINRAZA Clinical Trial Program

SPINRAZA has been studied in both presymptomatic and symptomatic patients with SMA including patients likely to develop or diagnosed with SMA Types 1, 2, and 3.

The SPINRAZA Phase 3 program is comprised of two registrational studies, ENDEAR and CHERISH. ENDEAR is a thirteen-month study investigating SPINRAZA in 122 patients with infantile-onset SMA, including patients with the onset of signs and symptoms of SMA at up to six months of age. The endpoint pre-specified for the interim analysis of the study evaluated the proportion of motor milestone responders from the motor component of the Hammersmith Infant Neurological Examination (HINE). Given the results of the positive interim analysis, the ENDEAR study is being stopped and participants are able to transition into the SHINE open-label study, in which all patients will receive SPINRAZA.

Additionally, the SHINE open-label extension study for patients who previously participated in ENDEAR or CHERISH is open and is intended to evaluate the long-term safety and tolerability of SPINRAZA.

Two additional Phase 2 studies, EMBRACE and NURTURE, were designed to collect additional data on SPINRAZA. EMBRACE is studying a small subset of patients with infantile or later-onset SMA who do not meet the age and other criteria of ENDEAR or CHERISH. NURTURE is an open-label, ongoing study in pre-symptomatic infants who are up to six weeks of age at time of first dose to determine if treatment before symptoms begin would prevent or delay the onset of SMA symptoms. An interim analysis of NURTURE showed that infants treated for up to one year with SPINRAZA achieved motor milestones in timelines more consistent with normal development than what is observed in the natural history of patients with Type 1 SMA. Three infants experienced adverse events considered possibly related to SPINRAZA, all of which resolved. In addition, no infants have discontinued or withdrawn from the study and no new safety concerns have been identified. NURTURE is currently active and enrolling. All studies are being conducted on a global scale…
About SPINRAZA (nusinersen)

SPINRAZA is an investigational, potentially disease-modifying therapy for the treatment of SMA that was discovered and developed by Ionis Pharmaceuticals, a leader in antisense therapeutics. SPINRAZA is an antisense oligonucleotide (ASO) that is designed to alter the splicing of SMN2, a gene that is nearly identical to SMN1, in order to increase production of fully functional SMN protein.

ASOs are short synthetic strings of nucleotides designed to selectively bind to target RNA and regulate gene expression. Through use of this technology, SPINRAZA has the potential to increase the amount of functional SMN protein in infants and children with SMA.

Both the U.S. and EU have granted SPINRAZA Orphan Drug status. Additionally, both the U.S. and EU regulatory agencies have granted special status to SPINRAZA, including Fast Track Designation and Priority Review in the U.S. and Accelerated Assessment in the EU.

Biogen exercised its option to worldwide rights to SPINRAZA in August 2016.

Biogen and Ionis Pharmaceuticals acknowledge support from the following organizations for SPINRAZA: Cure SMA, Muscular Dystrophy Association, and SMA Foundation, intellectual property licensed from Cold Spring Harbor Laboratory and the University of Massachusetts Medical School.

Saturday, November 26, 2016

Maternal rheumatoid arthritis increases childhood epilepsy risk

Rom AL, Wu CS, Olsen J, Jawaheer D, Hetland ML, Christensen J, Ottesen B, Mørch LS. Parental rheumatoid arthritis and childhood epilepsy: A nationwide cohort study. Neurology. 2016 Nov 16. pii: 10.1212/WNL.0000000000003424. [Epub ahead of print]

To assess the influence of parental rheumatoid arthritis (RA) on risk of epilepsy.
We performed a nationwide cohort study including all singletons born in Denmark from 1977 to 2008 (n = 1,917,723) through individual linkage to nationwide Danish registries. The children were followed for an average of 16 years. Main outcome measures were adjusted hazard ratios (HRs) for epilepsy with onset in early childhood (29 days-4 years), late childhood (5-15 years), adolescence/adulthood (≥15 years), and at any age until the end of follow-up (December 31, 2010).
Compared to unexposed children, children exposed to maternal RA had an increased risk of early and late childhood epilepsy (adjusted HRs 1.34 [95% confidence interval (CI) 1.13-1.60] and 1.26 [95% CI 1.13-1.41]), while children exposed to maternal RA had no increased risk of epilepsy in adolescence/adulthood (HR 1.15 [95% CI 0.92-1.45]). Paternal RA was not associated with an overall risk of epilepsy in the offspring (HR 0.96 [95% CI 0.81-1.15]) or at any age. Children exposed to maternal RA in utero had a more pronounced increased risk of early childhood epilepsy than children exposed to mothers who were diagnosed with RA after childbirth (HR 1.90 [95% CI 1.26-2.86] vs HR 1.26 [95% CI 1.03-1.52], respectively [p = 0.16]).

Exposure to maternal RA was associated with an increased risk of childhood epilepsy, while exposure to paternal RA was not, which indicates that changes in the intrauterine environment may play a role.

Mouse model mimicking fetal brain abnormalities caused by Zika virus

A team of scientists led by researchers at the University of Georgia has developed a new mouse model that closely mimics fetal brain abnormalities caused by the Zika virus in humans.

This model, described in a paper published recently in the journal Development, may help scientists better understand how the Zika virus affects different cell types in the developing brain, which could hasten the creation of new treatments and diagnostics…

"A lot of the discussion about Zika has focused on microcephaly, and while that is certainly important, we found that the virus causes additional devastating damages to the developing brain as well," said Jianfu "Jeff" Chen, an assistant professor of genetics in UGA's Franklin College of Arts and Sciences.

Most notably, Chen and his colleagues, including postdoctoral fellow Qiang Shao and graduate student Stephanie Herrlinger, found that Zika infection leads to abnormal blood vessel formation in the brain and a leaky blood-brain barrier, which normally protects the brain from potentially harmful pathogens.

"In addition to neural progenitor cell disruption, which is a classical cause of human microcephaly, we also observed massive death of neuronal cells in our mouse model," Chen said. "This combined with the disruption of the vascular system and the blood-brain barrier results in microcephaly and extensive brain damage."

Therefore, he added, "It's not just that the brain is smaller than normal; it is severely injured as a result of the infection, and we need to understand all these effects if we are going to develop successful therapies."

The researchers created their model by injecting Zika virus that was isolated in Mexico from an infected mosquito into the brain of mouse embryos. They were then able to observe the neurological effects after the mice were born.

"A lot of scientists are looking for postnatal mouse models to study the effects of Zika virus infection, but the virus often causes premature birth in mice," Chen said. "The virus-infected pups in our model were carried to term, and they were born alive. This is important, because some infected babies were also born alive in humans, and establishing a postnatal mouse model will be a good start to understand potential neurological complications after virus infection."

Qiang Shao, Stephanie Herrlinger, Si-Lu Yang, Fan Lai, Julie M. Moore, Melinda A. Brindley, Jian-Fu Chen. Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage.  Development 2016 : doi: 10.1242/dev.143768


Zika virus (ZIKV) infection of pregnant women can result in fetal brain abnormalities. It has been established that ZIKV disrupts neural progenitor cells (NPCs) and leads to embryonic microcephaly. However, the fate of other cell types in the developing brain and their contributions to ZIKV-associated brain abnormalities remain largely unknown. Using intracerebral inoculation of embryonic mouse brains, we found that ZIKV infection leads to postnatal growth restriction including microcephaly. In addition to cell cycle arrest and apoptosis of NPCs, ZIKV infection causes massive neuronal death and axonal rarefaction which phenocopy fetal brain abnormalities in humans. Importantly, ZIKV infection leads to abnormal vascular density and diameter in the developing brain, resulting in a leaky blood-brain-barrier (BBB). Massive neuronal death and BBB leakage indicate brain damage, which is further supported by extensive microglial activation and astrogliosis in virally infected brains. Global gene analyses reveal dysregulation of genes associated with immune responses in virus-infected brains. Thus, our data suggest that ZIKV triggers a strong immune response and disrupts neurovascular development, resulting in postnatal microcephaly with extensive brain damage.

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