Extreme temperatures may increase preterm birth risk

Extreme hot or cold temperatures during pregnancy may increase the risk of preterm birth, according to study by researchers at the US National Institutes of Health. The study authors found that extremes of hot and cold during the first seven weeks of pregnancy were associated with early delivery. Women exposed to extreme heat for most of their pregnancies also were more likely to deliver early.

The researchers found more consistent associations with early delivery after exposure to extreme heat than to extreme cold weather. They theorized that, during cold spells, people are more likely to seek shelter and so could more easily escape the cold’s effects. But during extreme heatwaves, people are more likely to endure the temperature, particularly when the cost of or access to air conditioning is an impediment.

The study was published in Environmental Health Perspectives.

“Our findings indicate that it may well be prudent to minimize the exposure of pregnant women to extremes in temperature,” said the study’s senior author, Pauline Mendola, Ph.D., an epidemiologist in the Division of Intramural and Population Health Research at the NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

A pregnancy is considered full term at between 39 and 40 weeks. Preterm birth occurs before 37 weeks of pregnancy and increases the risk for infant death and long term disability. It is unknown why extremes of hot or cold might influence preterm birth risk. However, the researchers theorize that the stress of temperature extremes could hinder the development of the placenta or alter blood flow to the uterus, both of which could potentially lead to early labour.

To conduct the study, the researchers linked electronic medical records from 223,375 births at 12 clinical centres throughout the United States to hourly temperature records for the region surrounding each centre. The researchers noted that what constitutes a hot or cold temperature varies from person to person and place to place. To compensate for local climate variability and personal susceptibility, the researchers evaluated temperatures in the surrounding regions. They defined extreme cold temperatures as below the 10th percentile of average temperatures, and defined extreme heat as above the 90th percentile.

The researchers found that women who experienced extreme cold for the first seven weeks of their pregnancies had a 20% higher risk for delivering before 34 weeks of pregnancy, a nine percent increased risk for delivering from 34-36 weeks, and a three percent increased risk for delivering in weeks 37 and 38. Women whose first seven weeks of pregnancy coincided with extreme heatwaves had an 11% increase in risk before 34 weeks, and a four percent increased risk at 37 to 38 weeks.

Exposure to extreme heat during weeks 15-21 increased the risk for delivery at 34 weeks and at 34-36 weeks by 18 percent and for delivery from 37 to 39 weeks by four percent. Hot exposures during weeks 8-14 increased the risk for birth at 37 to 38 weeks by four percent.

Overall, exposure to extreme heat for the duration of pregnancy was associated with increases in risk for delivery at 34 weeks and 36-38 weeks by 6 to 21%.

An increase in the number of extreme hot days due to climate change could lead to increases in the preterm birth rate, the authors wrote. The authors added that their findings underscore the need for health professionals and policy makers to devise interventions for minimizing pregnant women’s exposure to extreme temperatures. The authors also called for more research to understand how temperature extremes might increase preterm birth risk.


Morning sickness linked to lower risk of pregnancy loss

A new analysis by researchers at the US National Institutes of Health has provided the strongest evidence to date that nausea and vomiting during pregnancy is associated with a lower risk of miscarriage in pregnant women. The study, appearing in JAMA Internal Medicine, was conducted by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and other institutions.

Nausea and vomiting that occurs in pregnancy is often called “morning sickness”, as these symptoms typically begin in the morning and usually resolve as the day progresses. For most women, nausea and vomiting subside by the 4th month of pregnancy. Others may have these symptoms for the duration of their pregnancies. The cause of morning sickness is not known, but researchers have proposed that it protects the foetus against toxins and disease-causing organisms in foods and beverages.

“It’s a common thought that nausea indicates a healthy pregnancy, but there wasn’t a lot of high-quality evidence to support this belief,” said the study’s first author, Stefanie N. Hinkle, Ph.D, a staff scientist in NICHD’s Epidemiology Branch. “Our study evaluates symptoms from the earliest weeks of pregnancy, immediately after conception, and confirms that there is a protective association between nausea and vomiting and a lower risk of pregnancy loss.”

For their study, Dr Hinkle and her colleagues analysed data from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial in which researchers tested whether taking daily low-dose aspirin prevents women who experienced one or two prior pregnancy losses from experiencing a future loss.

The authors looked at data from all the women in the study who had a positive pregnancy test. The women kept daily diaries of whether they experienced nausea and vomiting in the 2nd through the 8th week of their pregnancies and then responded to a monthly questionnaire on their symptoms through the 36th week of pregnancy. The study authors noted that most previous studies on nausea and pregnancy loss were not able to obtain such detailed information on symptoms in these early weeks of pregnancy. Instead, most of studies had relied on the women’s recollection of symptoms much later in pregnancy or after they had experienced a pregnancy loss.

In the EAGeR trial, a total of 797 women had positive pregnancy tests, with 188 pregnancies ending in loss. By the 8th week of pregnancy, 57.3% of the women reported experiencing nausea and 26.6% reported nausea with vomiting. The researchers found that these women were 50 to 75% less likely to experience a pregnancy loss, compared to those who had not experienced nausea alone or nausea accompanied by vomiting.


New treatment strategy could cut Parkinson’s Disease off at the pass

Researchers at Johns Hopkins report they have identified a protein that enables a toxic natural aggregate to spread from cell to cell in a mammal’s brain – and a way to block that protein’s action. Their study in mice and cultured cells suggests that an immunotherapy already in clinical trials as a cancer therapy should also be tested as a way to slow the progress of Parkinson’s disease, the researchers say.

A report on the study appears 30 September 2016 in the journal Science.

Ted Dawson, M.D., Ph.D., director of the Institute for Cell Engineering at the Johns Hopkins University School of Medicine and one of the study’s leaders, says the new findings hinge on how aggregates of -synuclein protein enter brain cells. Abnormal clumps of -synuclein protein are often found in autopsies of people with Parkinson’s disease and are thought to cause the death of dopamineproducing brain cells.

A few years ago, Dawson says, a researcher at Goethe University in Germany published evidence for a novel theory that Parkinson’s disease progresses as -synuclein aggregates spread from brain cell to brain cell, inducing previously normal -synuclein protein to aggregate, and gradually move from the “lower” brain structures responsible for movement and basic functions to “higher” areas associated with processes like memory and reasoning. “There was a lot of skepticism, but then other labs showed -synuclein might spread from cell to cell,” Dawson says. Intrigued, his research group began working with those of Valina Dawson, Ph.D., professor of neurology, and Han Seok Ko, Ph.D., assistant professor of neurology, to investigate how the aggregates enter cells.

The researchers knew they were looking for a certain kind of protein called a transmembrane receptor, which is found on the outside of a cell and works like a lock in a door, admitting only proteins with the right “key”. They first found a type of cells -synuclein aggregates could not enter – a line of human brain cancer cells grown in the laboratory. The next step was to add genes for transmembrane receptors one by one to the cells and see whether any of them allowed the aggregates in. Three of the proteins did, and one, LAG3, had a heavy preference for latching on to -synuclein aggregates over nonclumped -synuclein.

The team next bred mice that lacked the gene for LAG3 and injected them with -synuclein aggregates. “Typical mice develop Parkinson’s-like symptoms soon after they’re injected, and within six months, half of their dopamine-making neurons die,” Dawson says. “But mice without LAG3 were almost completely protected from these effects.” Antibodies that blocked LAG3 had similar protective effects in cultured neurons, the researchers found.

“We were excited to find not only how -synuclein aggregates spread through the brain, but also that their progress could be blocked by existing antibodies,” says Xiaobo Mao, Ph.D., a research associate in Dawson’s laboratory and first author on the study.

Dawson notes that antibodies targeting LAG3 are already in clinical trials to test whether they can beef up the immune system during chemotherapy. If those trials demonstrate the drugs’ safety, the process of testing them as therapeutics for Parkinsons’ disease might be sped up, he says.

For now, the research team is planning to continue testing LAG3 antibodies in mice and to further explore LAG3’s function.

Parkinson’s disease gradually strips away motor abilities, leaving people with a slow and awkward gait, rigid limbs, tremors, shuffling and a lack of balance. Its causes are not well-understood.


Precision medicine trial first of its kind to show benefit to patients

A clinical trial (MOSCATO 01) for types of advanced cancer is the first of its kind to show that precision medicine – or tailoring treatment for individual people – can slow down the time it takes for a tumour to grow back, according to research presented at the Molecular Analysis for Personalized Therapy (MAP) conference in London in September.

Results from the trial, which took place at the Gustave Roussy Cancer Campus in Paris, found that 199 out of 1110 patients with advanced cancer, who had their genes mapped and their treatment tailored, had around 30% longer before their cancer started growing again compared to any of the previous therapies the patients had tried. This ranged from between five and 32 months.

This trial involved patients who had no other treatment options left and who had already tried three or more cancer therapies. The team found potential faulty molecules to target for 411 of these patients and experimental drugs to hit the targets for 199 of these patients.

The patients on this trial had diverse types of advanced cancer including lung, breast, head and neck, prostate, bladder, bowel and stomach cancer.

The MAP conference is a joint initiative between Cancer Research UK, UNICANCER and ESMO.

Professor Jean Charles Soria, principal investigator of the trial from the Gustave Roussy Cancer Campus, said: “This is the first precision medicine trial to show that analyzing a person’s DNA improves treatment options for patients with late stage cancer. And these results are particularly exciting because in some cases we were testing experimental drugs, and found that we could slow down the growth of tumours in around one in five patients with advanced cancer.”

Dr Christophe Massard, head of the early drug development multidisciplinary committee at Gustave Roussy, said: “The great thing about this is that it’s not just for one type of cancer – patients with many different types of cancer could benefit from this in the future.” Dr Rowena Sharpe, head of precision medicine at Cancer Research UK, said:

“This is an exciting time for precision medicine and personalized treatment. It’s fantastic to see continued effort going into this area and it’s important that we make the most of the data that we already have. The MAP meeting brings together expertise from across the globe to find the best ways to improve precision medicine programs for cancer patients.”


Sixth sense may be more than just a feeling

With the help of two young patients with a unique neurological disorder, an initial study by scientists at the National Institutes of Health suggests that a gene called PIEZO2 controls specific aspects of human touch and proprioception, a “sixth sense” describing awareness of one’s body in space. Mutations in the gene caused the two to have movement and balance problems and the loss of some forms of touch. Despite their difficulties, they both appeared to cope with these challenges by relying heavily on vision and other senses.

“Our study highlights the critical importance of PIEZO2 and the senses it controls in our daily lives,” said Carsten G. Bönnemann, M.D., senior investigator at the US NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a co-leader of the study published in the New England Journal of Medicine. “The results establish that PIEZO2 is a touch and proprioception gene in humans. Understanding its role in these senses may provide clues to a variety of neurological disorders.”

Dr Bönnemann’s team uses cutting edge genetic techniques to help diagnose children around the world who have disorders that are difficult to characterize. The two patients in this study are unrelated, one nine and the other 19 years old. They have difficulties walking; hip, finger and foot deformities; and abnormally curved spines diagnosed as progressive scoliosis.

Working with the laboratory of Alexander T. Chesler, Ph.D., investigator at NIH’s National Center for Complementary and Integrative Health (NCCIH), the researchers discovered that the patients have mutations in the PIEZO2 gene that appear to block the normal production or activity of Piezo2 proteins in their cells. Piezo2 is what scientists call a mechanosensitive protein because it generates electrical nerve signals in response to changes in cell shape, such as when skin cells and neurons of the hand are pressed against a table. Studies in mice suggest that Piezo2 is found in the neurons that control touch and proprioception.

“As someone who studies Piezo2 in mice, working with these patients was humbling,” said Dr Chesler. “Our results suggest they are touch-blind. The patient’s version of Piezo2 may not work, so their neurons cannot detect touch or limb movements.” Further examinations at the NIH Clinical Center suggested the young patients lack body awareness. Blindfolding them made walking extremely difficult, causing them to stagger and stumble from side to side while assistants prevented them from falling. When the researchers compared the two patients with unaffected volunteers, they found that blindfolding the young patients made it harder for them to reliably reach for an object in front of their faces than it was for the volunteers. Without looking, the patients could not guess the direction their joints were being moved as well as the control subjects could.

The patients were also less sensitive to certain forms of touch. They could not feel vibrations from a buzzing tuning fork as well as the control subjects could. Nor could they tell the difference between one or two small ends of a calliper pressed firmly against their palms. Brain scans of one patient showed no response when the palm of her hand was brushed.

Nevertheless, the patients could feel other forms of touch. Stroking or brushing hairy skin is normally perceived as pleasant. Although they both felt the brushing of hairy skin, one claimed it felt prickly instead of the pleasant sensation reported by unaffected volunteers. Brain scans showed different activity patterns in response to brushing between unaffected volunteers and the patient who felt prickliness.

Despite these differences, the patients’ nervous systems appeared to be developing normally. They were able to feel pain, itch, and temperature normally; the nerves in their limbs conducted electricity rapidly; and their brains and cognitive abilities were similar to the control subjects of their age.

“What’s remarkable about these patients is how much their nervous systems compensate for their lack of touch and body awareness,” said Dr Bönnemann. “It suggests the nervous system may have several alternate pathways that we can tap into when designing new therapies.”

Previous studies found that mutations in PIEZO2 may have various effects on the Piezo2 protein that may result in genetic musculoskeletal disorders, including distal arthrogryposis type 5, Gordon Syndrome, and Marden-Walker Syndrome. Drs Bönnemann and Chesler concluded that the scoliosis and joint problems of the patients in this study suggest that Piezo2 is either directly required for the normal growth and alignment of the skeletal system or that touch and proprioception indirectly guide skeletal development.

“Our study demonstrates that bench and bedside research are connected by a twoway street,” said Dr Chesler. “Results from basic laboratory research guided our examination of the children. Now we can take that knowledge back to the lab and use it to design future experiments investigating the role of PIEZO2 in nervous system and musculoskeletal development.”

  • doi: 10.1056/NEJMoa1602812

Study finds key to nerve regeneration

Researchers at the University of Wisconsin- Madison have found a switch that redirects helper cells in the peripheral nervous system into “repair” mode, a form that restores damaged axons.

Axons are long fibres on neurons that transmit nerve impulses. The peripheral nervous system, the signalling network outside the brain and spinal cord, has some ability to regenerate destroyed axons, but the repair is slow and often insufficient.

The new study suggests tactics that might trigger or accelerate this natural regrowth and assist recovery after physical injury, says John Svaren, a professor of comparative biosciences at the UWMadison School of Veterinary Medicine. The finding may also apply to genetic abnormalities such as Charcot-Marie-Tooth disease or nerve damage from diabetes.

Svaren, senior author of a report published 30 August 2016 in The Journal of Neuroscience, studied how Schwann cells, which hug axons in the peripheral nervous system, transform themselves to play a much more active and “intelligent” role after injury.

Schwann cells create the insulating myelin sheath that speeds transmission of nerve impulses. In the repair mode, Schwann cells form a fix-up crew that adds house cleaning and stimulation of nerve regrowth to the usual insulating job.

Svaren and his graduate student, Joseph Ma, compared the activation of genes in Schwann cells in mice with intact or cut axons. “We saw a set of latent genes becoming active, but only after injury,” says Svaren, “And these started a program that places the Schwann cells in a repair mode where they perform several jobs that the axon needs to regrow.”

In the repair mode, but not in the normal one, Schwann cells start cleaning house, helping to dissolve myelin, which is essential for proper functioning but ironically deters regeneration after injury. “If you invite Schwann cells to a party,” says Svaren, “they will clean up the bottles and wash your dishes before they leave the house.”

This cleanup must happen within days of the injury, says Svaren, who directs the cellular and molecular neuroscience core at the Waisman Center on the UW-Madison campus.

The Schwann cells also secrete signals that summon blood cells to aid the cleanup, and they map out a pathway for the axon to regrow. Finally, they return to the insulator role to grow a replacement myelin sheath on the regenerated axon.

Unexpectedly, the Schwann’s transition into the repair form did not entail a reversion to a more primitive form, but rather was based on a change in the regulation of its genes. “Almost every other nervous-system injury response, especially in the brain, is thought to require stem cells to repopulate the cells, but there are no stem cells here,” Svaren says. “The Schwann cells are reprogramming themselves to set up the injuryrepair program. We are starting to see them as active players with dual roles in protecting and regenerating the axon, and we are exploring which factors determine the initiation and efficacy of the injury program.”

After the human genome was deciphered, epigenetics – the study of gene regulation – has moved to the forefront with the realization that genes don’t matter much until they are switched on, and that genetic switches are the fundamental reason why a skin cell doesn’t look like a nerve cell, and a nerve cells functions differently than a white blood cell.

In epigenetics, as elsewhere in biology, processes are often regulated through a balance between “stop” and “go” signals. In the Schwann cell transition, Svaren and Ma identified a system called PRC2 that usually silences the repair program. “This pathway amounts to an on-off switch that is normally off,” Svaren says, “and we want to know how to turn it on to initiate the repair process.”

The nature of the top-level gene-silencing system suggested drugs that might remove the silencing mark from the genes in question, and Svaren says he’s identified an enzyme that may “remove the brakes” and deliberately activate the repair program when needed in response to injury.

Even if the drug tests are promising, years of experiments will be necessary before the system can be tested in people. Furthermore, as Svaren acknowledges, “many factors determine how well an axon can regenerate. I am not saying this single pathway could lead to a cure-all, but we do hope it is an important factor.”

Svaren says it’s not clear how the current finding on peripheral nerves relates to damage to the brain and spinal cord, where a different type of cell cares for neurons. There are some similarities, however. In multiple sclerosis, for example, cleanup must precede the replacement of damaged myelin.

Ultimately, the study could open a new door on regeneration, even beyond one key sector of the nervous system. “We have thought of the Schwann cell as a static entity that was just there to make myelin, but they have this latent program, where they become the first responders and initiate many actions that are required for the axon to regenerate,” Svaren says.

 

Date of upload: 16th Nov 2016

                                  
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