Body

Charcot Marie Tooth and Dejerine-Sottas syndrome are groups of diseases that involve the breakdown of the myelin sheath covering nerve axons.

As this myelin sheath breaks down, people who have these disorders suffer nerve damage in the arms and legs--those with Dejerine-Sottas disease may never walk or may lose the ability to walk by the time they are teenagers.

Researchers have known that a protein called PMP22, which is important for nerve myelin, is likely involved in the disease. But because the protein is so small and part of the cell membrane, it's difficult to study. Now, an interdisciplinary team from the University of Michigan and Vanderbilt University have used a cutting-edge technique called ion mobility-mass spectrometry (IM-MS) to show that an unstable, mutant version of the PMP22 protein associates with another mutant PMP22, forming a stable complex called a "dimer."

"If you get one of these mutations in your PMP22 gene, that leads to the creation of this mutant protein. Then, our results indicate that the mutant protein produced is likely going to dimerize," said Brandon Ruotolo, lead author on the new study and a professor of chemistry at U-M. "Because it's stable, it's not going to re-form into monomeric protein that is then going to give you normal myelin sheath production."

Their results, published in the Proceedings of the National Academy of Sciences, provide a new view into how these diseases work, and could one day provide a target for therapeutics.

Vanderbilt researcher Charles Sanders began studying PMP22 in 2000. It was a protein known to be involved in these neurological diseases, but few were studying it. There are other diseases related to problems with protein folding, Sanders says. Typically, misfolding proteins cause disease in two ways: one is that when they misfold, they are degraded and can't complete the job they're meant to do. A second is that a protein clumps up, gumming up the cell and preventing it from doing its job properly.

"With PMP22, it's never been completely clear how it causes disease. It's definitely related to problems with folding, but how does this really work? What Brandon's results suggest is that when this protein is unstable, it doesn't fold correctly, but instead of getting degraded, it forms this misfolded dimer," Sanders said. "We still don't know exactly what it then does to cause these diseases, but it's an interesting and unusual observation that makes these diseases different from all of the other protein-folding diseases."

Over the years, Sanders' lab has done a series of measurements to quantitate the stability of mutant forms of PMP22. His lab has also collaborated with U-M researcher Melanie Ohi to study the healthy function of PMP22, work that started while Ohi was on the faculty at Vanderbilt.

"We were able to see what we called myelin-like assemblies that allowed us to get some idea of what this protein might actually be doing in the context of a membrane. When we came to U-M, our goal was to get a high-resolution structure, which is really hard because this is a really small protein," Ohi said. "We needed to figure out if the protein Dr. Yadav was making for structural studies was forming larger oligomers and, surprisingly, PMP22 works well for Brandon's technique."

Currently an associate professor in U-M's Life Sciences Institute, Ohi met Ruotolo, whose lab specializes in using IM-MS to capture native structures of biomolecules as well as how they assemble.

To view these proteins using this kind of mass spectrometry, Ruotolo's lab transfers the protein into the gas phase using a technique called nano-electrospray ionization. The technique works by aersolzing protein-containing solutions into tiny charged droplets. The solvent carrying the protein quickly dries--this process happens over just milliseconds--which leaves the charged protein behind. These charged proteins are then drawn into a vacuum environment inside the mass spectrometry instrument.

Once inside the instrument, ions encounter a chamber pressurized with a small amount of background gas. Within this chamber, the instrument uses an electric field to pull the ionized proteins through a series of electrodes in the presence of the background gas. This separates the ions according to their size. A subsequent device uses a chamber operated under strict vacuum conditions to separate the same ions according to their mass. This way, the researchers are able to view both the structures of the proteins, and separate PMP22 dimers from monomers in order to evaluate them independently.

The researchers then heat the ionized proteins and measure their size, repeating this step several times in order to measure the changes in size as the proteins unfold. This tells the researchers how stable the proteins are--and in particular, the stability of the misfolded dimer proteins.

The researchers say developing therapeutics to interfere with these mutants clumping together is further down the road, but knowing how and where the protein self-associates provides a road map for a new venue of research.

"Not only is this a big step forward in what we know about the protein, mass spectrometry has such fabulous capabilities that this opens the door for a whole unbelievable set of things that we could do in the future with this protein," Sanders said. "With the sort of techniques that Brandon works with, you could imagine eventually extending this to drug discovery, using this basic method as an assay for finding compounds that correct these defects."

Philadelphia, April 20, 2021 - Intestinal epithelial tight junctions (TJs) act as a functional and structural barrier against harmful antigens that promote intestinal inflammation in inflammatory bowel disease (IBD) and other inflammatory conditions of the gut. A defective intestinal TJ barrier, sometimes known as "leaky gut," plays an important role in exacerbating and prolonging intestinal inflammation. New research reported in The American Journal of Pathology, published by Elsevier, shows that the probiotic Lactobacillus acidophilus (L. acidophilus) strain known as LA1 can generate a rapid and sustained enhancement of this defective intestinal barrier and effectively treat intestinal inflammation by preserving and restoring the intestinal barrier.

The use of probiotics has emerged as a therapy for a number of intestinal disorders, including IBD and necrotizing enterocolitis; however, specific probiotic bacteria with true beneficial effects on intestinal disease need to be identified. In this study researchers used high-throughput screening to assess over 20 probiotic bacteria to determine their ability to increase intestinal barrier function, using both a cell culture model of the intestinal epithelial lining and live mice.

The probiotic bacterial species L. acidophilus, specifically the LA1 strain, produced a rapid and marked increase in intestinal TJ barrier; other strains within L. acidophilus had no effect. The researchers found that this particular strain interacted with intestinal cells in a unique way to activate pathways that tightened the intestinal barrier, treating intestinal inflammation. It attaches to the intestinal epithelial membrane surface by directly interacting with the toll-like receptor-2 complex, which alerts the intestine to trigger an immune response.

The researchers also performed in vivo proof-of-concept studies in live mice to investigate the effect of LA1 and another strain, LA3, in the enhancement of mouse intestinal barrier and the therapeutic efficacy of LA1 in maintaining intestinal barrier and protecting against induced colitis. They found that LA1, but not LA3, caused rapid and marked enhancement of small intestine and colonic epithelial barrier in mice. Treatment studies after the onset of colitis found that LA1 was also effective in the healing of intestinal barrier and colitis.

"Our data indicate that LA1 is able to prevent colonic inflammation formation and promote colitis healing," said lead investigator Thomas Ma, MD, PhD, Penn State College of Medicine, Hershey Medical Center, Hershey, PA, USA. "The implications of the present findings are that this bacterial strain can be used in a wide variety of intestinal permeability disorders, including IBD, coeliac disease, alcoholic liver disease, non-alcoholic fatty liver disease, and necrotizing enterocolitis, to treat inflammation associated with the leaky gut."

L. acidophilus is found in various brands of yogurt including Chobani, Dannon, Siggi's, Stonyfield, and Yoplait.

DALLAS, April 19, 2021 — Gender-affirming hormone therapy (GAHT) was associated with blood pressure changes in both transgender men and women, according to new research published today in Hypertension, an American Heart Association journal. Given the higher burden of heart attack, stroke and other cardiovascular conditions among transgender men and women, blood pressure screening and monitoring are important, especially after beginning hormone therapies.

Although doctors have prescribed gender-affirming hormone therapy to transgender men and women for more than 25 years, researchers and health care professionals know little about rates of hypertension and how the effects on blood pressure change over time. Previous research has shown that transgender men were almost five times as likely to report having a heart attack compared to cisgender women. Conversely, transgender women were more than two-and-a-half times more likely to have reported a heart attack than cisgender women, yet they did not have a significant increase in heart attack incidence when compared with cisgender men. However, a systematic review conducted in 2020 found most of the studies examining gender-affirming hormones and blood pressure had sample sizes that were too small to detect statistically significant differences in blood pressure.

“There are many important gaps in our knowledge about the effects of hormone therapy for transgender people. This study examined the time course and magnitude of the effects of gender-affirming hormones on blood pressure,” said senior study author Michael S. Irwig, M.D., an associate professor of medicine at Harvard Medical School and director of transgender medicine at Beth Israel Deaconess Medical Center in Boston.

To conduct the largest and longest observational study of its kind, the researchers followed 470 patients who began GAHT at a medical center in the Washington, D.C. area from 1/1/2007 to 6/1/2015. Participants were all at least 17 years old and non-cisgender. Of the 470 patients, 247 were transfeminine and 223 were transmasculine. About 27% of the participants were non-white, and 16% self-identified as Latinx. Researchers measured each patient’s blood pressure before beginning GAHT to establish a baseline and continued measurements at subsequent clinical visits for up to 57 months.

The study found:

Within two to four months of beginning hormone therapy, transgender women saw an average decrease of 4.0 mm Hg in their systolic blood pressure, but transgender men saw an average increase of 2.6 mm Hg.
The prevalence of stage 2 hypertension (at least 140/90 mm Hg) dropped from 19% to 10% in the transfeminine group within two to four months of beginning hormone therapy.
The use of testosterone in transgender men could lead to an increased risk for heart attack or stroke if they also have untreated high blood pressure.

In addition, the results indicated that some patients experienced different blood pressure effects compared to the majority of those with the same gender identity. Some transgender women and transgender men saw blood pressure rates trend in the opposite direction of their peers. The study authors highlight this is an area that requires further research, noting individuals taking the same medication may react in different ways.

The study has several limitations. Most patients were on the same formulation of intramuscular testosterone or oral estrogen, so the effects of other formulations need further study. Additionally, the study did not have a large enough sample to detect statistically significant changes in blood pressure measures among Black or Latinx patients.

Monitoring blood pressure and other preventive screening measures are particularly important in transgender and LBGTQ communities. A 2020 Scientific Statement from the American Heart Association indicates transgender adults had lower physical activity levels than their cisgender counterparts, and transgender women may be at increased risk for cardiovascular disease due to behavioral and clinical factors (such as the use of gender-affirming hormones like estrogen). The statement indicates that it is paramount to include LGBTQ health in clinical training and licensure requirements for health care professionals in order to better address cardiovascular health disparities in the LGBTQ community.

Anyone sexually active under age 30 should be offered testing for chlamydia and gonorrhea, according to a new guideline from the Canadian Task Force on Preventive Health Care published in CMAJ (Canadian Medical Association Journal).

Chlamydia and gonorrhea are the most commonly reported sexually transmitted bacterial infections (STIs) in Canada and are treatable with antibiotics. Without treatment, these infections can lead to pelvic inflammatory disease, pain and possibly infertility.

"If people are under 30 and sexually active, it's a good idea to get tested," says Dr. Ainsley Moore, a family physician and associate clinical professor, Department of Family Medicine, McMaster University, and chair of the task force chlamydia and gonorrhea working group. "Many people are asymptomatic and may not seek treatment so we're recommending opportunistic testing -- that is, at any health care visit."

The guideline recommends that health care providers in Canada offer routine testing for chlamydia and gonorrhea annually to all sexually active patients younger than 30 who are not known to belong to a high-risk group. Sexual activity is defined as anyone who has had oral, vaginal or anal intercourse.

Why is the task force recommending screening?

1 in 20 sexually active individuals 15-29 years old will get chlamydia.

Reported rates for this age group are 1.0%-1.9% (chlamydia) and 0.2%-0.3% (gonorrhea).

Many people are asymptomatic or do not seek care and are not included in reported cases.

True rates of chlamydia in 15- to 29-year-olds may be as high as 5%-7%.

Rising rates of chlamydia and gonorrhea in people aged 25-29 years since 2000.

Screening may reduce pelvic inflammatory disease in females.

This recommendation does not apply to pregnant people, people known to the clinician to be at increased risk based on sexual behaviours, or patients seeking care for a possible STI. Clinicians should consult national, provincial, or local guidance when providing care for these individuals.

Current practice in Canada recommends screening sexually active people who are not at high risk up to age 25.

"This recommendation to extend screening to age 30 reflects increasing rates of infection among Canadians aged 25 to 29 years," says Dr. Donna Reynolds, a member of the working group, family physician and an assistant professor at the University of Toronto. "As it's an easy test, usually a urine test or vaginal swab, it can be done at any visit to a physician, nurse practitioner or sexual health clinic."

The recommendations also consider the potential for anxiety and embarrassment around screening for STIs.

"Although we recommend this as routine, clinicians know to expect feelings of fear, anxiety or embarrassment on the part of some patients and be ready to discuss these," says task force member Dr. Brenda Wilson, a public health physician and professor at Memorial University, St. John's, Newfoundland.

The guideline recommends also screening males as the primary source of infection for females, for whom the health consequences can be greater.

"Screening males, who are often without symptoms, may reduce transmission and complications in females and may improve health equity for females," says Dr. Moore.

Target Audiences

Clinicians - The guideline is aimed at clinicians in primary care, sexual health and student clinics and other settings.

Public - As the guideline is aimed at people younger than 30, an infographic, Instagram campaign and frequently asked questions will help explain why it's a good idea to get tested.

The task force engaged Canadians to understand their values and preferences around screening to inform recommendations. They expressed a strong preference for screening.

The College of Family Physicians of Canada, the Nurse Practitioner Association of Canada and the Canadian Association of Perinatal and Women's Health Nurses have endorsed the guideline.

In a related commentary http://www.cmaj.ca/lookup/doi/10.1503/cmaj.210604, Drs. Troy Grennan, BC Centre for Disease Control, Vancouver, British Columbia, and Darrell Tan, University of Toronto, write a "potential benefit of the authors' recommendations is its potential to normalize conversations about sexual health and STIs between clinicians and patients, which have long been marred by stigma and shame. Offering screening may help patients feel that they 'have permission' to discuss health issues that may seem difficult to talk about."

The commentary authors note that the lack of high-quality evidence on the topic should spur researchers to engage in future studies to inform guidelines and clinical practice.

What The Study Did: This population-based study of multiple databases from Canada found no association between epidural labor pain relief and risk of autism spectrum disorders in children.

Authors: Elizabeth Wall-Wieler, Ph.D., of the University of Manitoba in Winnipeg, Canada, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2021.0376)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

What The Study Did: This study examined the association of paternal drinking before pregnancy with the risk of birth defects in children among couples in China.

Authors: Xiaotian Li, M.D., Ph.D., of Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapediatrics.2021.0291)

Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding and support.

Scientists have for the first time captured the complex dynamics of particle movement in granular materials, helping to explain why mixed nuts often see the larger Brazil nuts gather at the top. The findings could have vital impact on industries struggling with the phenomenon, such as pharmaceuticals and mining.

Many people will have the experience of dipping their hands into a bag of mixed nuts only to find the Brazil nuts at the top. This effect can also be readily observed with cereal boxes, with the larger items rising to the top. Colloquially, this phenomenon of particles segregating by their size is known as the 'Brazil-nut effect' and also has huge implications for industries where uneven mixing can critically degrade product quality.

Now, for the first time, scientists at The University of Manchester have used time-resolved 3D imaging to show how the Brazil nuts rise upwards through a pile of nuts. The work shows the importance of particle shape in the de-mixing process.

A common difficulty with examining granular materials is following what happens to particles on the inside of the pile, which cannot easily be seen. This new research published in the journal Scientific Reports makes a key breakthrough in our understanding by utilising advanced imaging techniques at the new National Research Facility for Lab-based X-ray Computed Tomography (NXCT), based in The Henry Royce Institute.

Regius Professor Philip Withers said: "In this work, we followed the motion of the Brazil nuts and peanuts through time-lapse X-ray Computed Tomography as the pack was repeatedly agitated. This allowed us to see for the first time the process by which the Brazil nuts move past the peanuts to rise to the top."

The team captured the unique imaging experiment on video showing the temporal evolution of the nut mixture in 3D. Peanuts are seen to percolate downwards whilst three larger Brazil nuts are seen to rise upwards. The first Brazil nut reaches the top 10% of the bed height after 70 shear cycles, with the other two Brazil nuts reaching this height after 150 shear cycles. The remaining Brazil nuts appear trapped towards the bottom and do not rise upwards.

Dr Parmesh Gajjar, lead author of the study, adds: "Critically, the orientation of the Brazil nut is key to its upward movement. We have found that the Brazil nuts initially start horizontal but do not start to rise until they have first rotated sufficiently towards the vertical axis. Upon reaching the surface, they then return to a flat orientation.

"Our study highlights the important role of particle shape and orientation in segregation. Further, this ability to track the motion in 3D will pave the way for new experimental studies of segregating mixtures and will open the door to even more realistic simulations and powerful predictive models. This will allow us to better design industrial equipment to minimise size segregation thus leading to more uniform mixtures. This is critical to many industries, for instance ensuring an even distribution of active ingredients in medicinal tablets, but also in food processing, mining and construction."

Advanced materials is one of The University of Manchester's research beacons - examples of pioneering discoveries, interdisciplinary collaboration and cross-sector partnerships that are tackling some of the biggest challenges facing the planet. #ResearchBeacons

Chronic lower-limb edema (CLE) -- the permanent accumulation of fluid in the leg -- often occurs in elderly people. The condition leads to various physical and mental problems, including difficulty in walking or moving, fatigue and anxiety. One cause of CLE is the lack of physical activity, which is associated with a decrease in muscle pump action. The latter refers to the leg muscle's acting as a blood pump: when contracted, the muscle squeezes veins together, forcing blood to flow. The question whether muscle pump action systematically changes with age has not been thoroughly investigated; now, Junko Sugama from Kanazawa University and colleagues have addressed this issue. In addition, they studied how leg posture affects muscle pump action.

For their study, Sugama and colleagues recruited a total of 76 healthy volunteers in three age categories: young, middle-aged and old, with average ages of 24, 47 and 72 years, respectively. They investigated blood flow in the subjects' lower legs by means of magnetic resonance imaging (MRI). The latter is a technique enabling visualizing the morphology of muscles and veins at a given position along the leg. The scientists made MRI cross-section images at 21 positions in the calf region; combining the images made it possible to obtain information on blood flow in the leg.

To examine the effect of leg motion, subjects were asked to perform plantar flexion (moving the foot so that it becomes aligned to the leg) every 2 seconds during one minute. MRI images were recorded before and after the exercise. The procedure was performed for three different body positions: supine (lying with face and torso facing upwards), sitting and standing.

The scientists found that for all postures, blood flow increased after the exercise, implying that the latter promotes muscle pump action. The blood flow velocity increased most for the standing posture (90-135%), followed by the supine (55-90%) and sitting (30-40%) postures. Generally, no difference in muscle pump action was found for the different age groups -- but Sugama and colleagues point out that the majority of their elderly volunteers had exercise habits.

The researchers suggest that measuring muscle pump action by nurses is useful for deciding whether intervention exercise is necessary to prevent CLE, but that MRI is not the most suitable tool for doing so -- an easier device allowing measurement at the bedside would be required.

Although additional studies need to be done, for example adapting the measurement equipment so that it can be applied to elderly people with reduced walking ability, the scientists could conclude that for their set of subjects, "no difference was found in the changes in muscle pump action with age", and that "elderly people may be able to maintain their muscle pump action when they have exercise habits".

[Background]

Edema

Edema, sometimes spelt oedema, is the medical term for the accumulation of fluid in tissue, resulting in local swelling. It occurs most often in the legs or arms. General symptoms include the swollen area to feel heavy, skin feeling tight, and junctures being hard to move. The work of Junko Sugama from Kanazawa University and colleagues addresses an aspect of chronic edema in the lower limb (leg); they looked at whether leg muscle pumping capability changes with age, and whether exercise habits can prevent chronic edema in the leg.

Magnetic resonance imaging

Magnetic resonance imaging (MRI) is an imaging technique widely used in medicine for obtaining images of physiological process and the anatomy of the body. Images are generated by applying strong magnetic fields, magnetic-field gradients and radio waves. The underlying physical principle is that certain atomic nuclei, when subject to a magnetic field, can absorb the energy from the radio waves; detecting where this absorption happens results in a mapping of the absorbing atoms. In medical contexts, the absorbing nuclei are mostly hydrogen nuclei, and MRI scans provide mappings of water and fat in the body. A main advantage of the method is that it does not involve X-rays or ionizing radiation; disadvantages include discomfort for the person undergoing the imaging procedure. Sugama and colleagues used the method to map blood flow in the leg.

The research is conducted by Kazan University's Open Lab Gene and Cell Technologies (Center for Precision and Regenerative Medicine, Institute of Fundamental Medicine and Biology) and Republic Clinical Hospital of Kazan. Lead Research Associate Yana Mukhamedshina serves as project head.

Spinal cord injury mechanisms include primary and secondary injury factors. Primary injury is mechanical damage to the nervous tissue and vasculature with immediate cell death and hemorrhage. Secondary damage leads to significant destructive changes in the nervous tissue due to the development of excitotoxicity, death of neurons and glial cells, inflammatory reactions, and the formation of a glial scar, which prevents the restoration of nerve connections. It should be noted that secondary trauma during this period leads to more serious clinical consequences than the original primary trauma. In this regard, there is an urgent need to develop a panel of diagnostic biomarkers to determine the severity of injury. Therefore, over the past two decades, there has been a growing interest in the development of new, reliable and practical tools for diagnosing the degree of spinal cord injury and predicting the outcome of the disease.

This paper demonstrates the importance of measuring serum cytokine concentrations as a quick and affordable means of accurately classifying the severity of spinal cord injury in patients, eliminating the risks and complications associated with the use of repeated cerebrospinal fluid sampling. But more research is needed to integrate those findings into the universal standard of care for spinal cord injury screening and diagnosis.

The need for predictive biomarkers is multifaceted. First, health care decisions will become more personalized and tailored to each case, which will minimize ineffective interventions and facilitate patient follow-up. Second, such tools would be useful in the provision of medical care for patients with spinal cord injury in developing countries that lack modern medical resources. Third, it will significantly accelerate research into spinal cord injury at both the preclinical and clinical levels.

Results will allow the development of a test system for assessing the prognostic course of traumatic spinal cord injury, as well as recommendations and suggestions for the use of the most effective therapy option. They will also contribute to the development of new early biomarkers of neurodegenerative diseases.

Boston - Transgender people have a higher burden of cardiovascular disease and hypertension than cisgender people. However, while doctors have prescribed gender-affirming hormone therapy to transgender men and women for more than 25 years, little is known about how this treatment may impact rates of hypertension in this patient population or how the effects of hormone therapy on blood pressure may change over time.

In the largest and longest observational study of its kind, physician-researchers from Beth Israel Deaconess Medical Center (BIDMC) found that gender-affirming hormone therapy (GAHT) was associated with blood pressure changes in both transgender men and women. Given the higher burden of heart attack, stroke and other cardiovascular conditions among transgender men and women, these new findings underscore the importance of monitoring blood pressure and other preventive screening measures in transgender patients especially after beginning hormone therapies. The study appears in Hypertension, a journal of the American Heart Association.

"There are many important gaps in clinicians' knowledge about the effects of hormone therapy for transgender people," said senior author Michael S. Irwig, MD, Director of Transgender Medicine at BIDMC. "Our study sought to address these gaps by recruiting a racially and ethnically diverse pool of participants to examine the time course and magnitude of the effects of gender-affirming hormones on blood pressure."

Irwig and colleagues followed 470 patients who began GAHT at two medical centers in the Washington, D.C. between 2007 and 2015. Participants were all at least 17 years old and non-cisgender. Of the 470 patients, 247 were transfeminine and 223 were transmasculine; about 27 percent of patients were non-white. Researchers measured each patient's blood pressure before beginning GAHT to establish a baseline and continued measurements at subsequent clinical visits for up to 57 months.

Within two to four months of beginning hormone therapy, transgender women saw an average decrease of 4.0 mm Hg in their systolic blood pressure, while transgender men saw an average increase of 2.6 mm Hg. The prevalence of stage 2 hypertension (at least 140/90 mm Hg) dropped from 19 percent to 10 percent in the transfeminine group within two to four months of beginning hormone therapy. The use of testosterone in transgender men could lead to an increased risk for heart attack or stroke if they also have untreated high blood pressure.

In addition, the results indicated that some patients experienced different blood pressure effects compared to the majority of those with the same gender identity. Some transgender women and transgender men saw blood pressure rates trend in the opposite direction of their peers. The study authors highlight this is an area that requires further research, noting individuals taking the same medication may react in different ways.

"Further research is needed to understand how different formulations may affect different people and to find out if there are any disparities among Black or Latinx patients," said Irwig, who is also Associate Professor of Medicine at Harvard Medical School. "A 2020 Scientific Statement from the American Heart Association indicates that it is paramount to include LGBTQ health in clinical training and licensure requirements for health care professionals so that physicians can better address cardiovascular health disparities in the LGBTQ community."

PHILADELPHIA - A new gene therapy for one of the most common forms of congenital blindness was safe and improved patients' vision, according to initial data from a clinical trial led by researchers at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania.

The therapy delivers working copies of GUCY2D to the eyes of patients who have severe vision impairments caused by mutations in the gene. Each of the first three treated patients experienced improvement in some aspects of vision, without serious side effects, according to the new study, published in the journal iScience.

"We found sustained improvements in both day and night vision, even with a relatively low dose of the gene therapy," said study lead author Samuel G. Jacobson, MD, PhD, a professor of Ophthalmology in the Perelman School of Medicine.

The GUCY2D gene is one of about 25 different human genes whose mutations cause problems in the retina, leading to severe vision impairment from birth or early childhood. This family of inherited retinal disorders, collectively known as Leber congenital amaurosis (LCA), accounts for a considerable portion of blindness in children worldwide.

Normal copies of GUCY2D encode an enzyme in the key pathway that light-sensitive rod and cone cells in the retina use to convert light into electrochemical signals. A lack of this enzyme blocks the recovery of this pathway, preventing the reset needed for further signaling. As a result, the signal from rod and cone cells becomes very weak -- which equates to severe vision loss.

Even in adults who have lived for decades with this condition, it is often the case that many light-sensing retinal cells remain alive and intact despite their dysfunction. Thus, adding functional copies of GUCY2D via a gene therapy could get those cells working again and restore some vision.

In 2019, Jacobson and co-investigator Artur V. Cideciyan, PhD, a research professor of Ophthalmology in the Perelman School of Medicine, began the first clinical trial of a GUCY2D gene therapy, a solution of a harmless virus that carries the gene and is injected beneath the retina -- initially in just one eye per patient. They are following each patient for two years after treatment. In the new report, they described their findings after nine months in the first three patients treated.

The first patient experienced a substantial increase in light-sensitivity in rod cells, which are more light-sensitive than cone cells and are chiefly responsible for low-light or "night vision." This patient also showed improved pupil responses to light.

The second patient showed a smaller but sustained increase in light-sensitivity in rod cells, starting about two months after the gene therapy.

The third patient showed no improvement in rod cell sensitivity, but did show significantly improved visual acuity over the nine-month follow-up period, an improvement that the researchers tied to better function in the patient's cone cells, the predominant cells for daylight and color vision.

"These initial results from the first-ever trial of a GUCY2D gene therapy are very encouraging and will inform our ongoing and future trials of this therapy," said Cideciyan.
There were no serious adverse side effects, and any side effects that occurred in the patients' retinas resolved.

The gene therapy dose used in these first three patients was the lowest of the doses the researchers plan to use in the study, so they are hoping to see continued safety and greater efficacy in later-enrolled patients who will receive higher doses.

DALLAS - April 19, 2021 - Treating people with Type 2 diabetes with a new once-a-week injectable insulin therapy proved to be safe and as effective as daily insulin injections, according to the results of two international clinical trials published online today in Diabetes Care. The studies suggest that the once-weekly treatment could provide a convenient alternative to the burden of daily insulin shots for diabetes patients.

Starting and maintaining insulin treatment remain a challenge for millions of patients worldwide with Type 2 diabetes. Fear of injections and the inconvenience and burden of injectable therapy contribute to the barriers against insulin therapy initiation and adherence. The effectiveness and safety of ongoing insulin treatment are also highly dependent on other factors, such as the accuracy of dosages, timing, and glycemic targets. Health care providers believe that reducing the frequency of treatment administration with advances, such as the once-weekly insulin used in these phase 2 trials, may decrease the reluctance to initiate insulin therapy while improving long-term adherence, glucose control, and ultimately, patient well-being.

Insulin, which has been the foundation of diabetes treatment for 100 years, is an effective glucose-lowering agent and is safe when used at the correct dose," says Ildiko Lingvay, M.D., M.P.H., M.S.C.S., a professor of internal medicine and population and data sciences at UT Southwestern. "Insulin treatment is burdensome, requires frequent injections, and continues to carry a certain stigma. The development of an effective and safe insulin that can be administered once a week is a huge advance in the field."

Lingvay, who is a consultant for Novo Nordisk, is the lead author of one of the studies, which involved 205 patients from seven countries (the U.S., Croatia, Germany, Hungary, Poland, Slovakia, and Spain). The clinical trial consisted of a two-week screening period, 16 weeks of treatment, and a five-week follow-up to evaluate three different ways to adjust and optimize the insulin dose and determine which one presented the best balance between effectively lowering glucose while minimizing low-glucose events.

She also is an author of the second study that included 154 patients from five countries (the U.S., Canada, the Czech Republic, Germany, and Italy). This trial followed the same 23-week time frame and evaluated practical aspects of insulin use as well as the best ways to transition from a daily regimen to the new weekly insulin injections. The researchers determined that starting with a higher first dose - called a loading dose - allowed patients to reach their optimal glucose target faster.

"These two studies served as the steppingstones for a large phase 3 clinical trial program that is currently ongoing at UT Southwestern and other sites, which is designed to evaluate the efficacy of once-weekly insulin administration in patients with either Type 1 or Type 2 diabetes," Lingvay says. "A weekly insulin is a game-changer that will decrease the treatment burden for patients while also improving compliance. This treatment will also decrease the burden on those who care for patients with diabetes requiring insulin. For example, for patients who need help injecting, those living in long-term care facilities, and those with memory problems, a once-weekly insulin will facilitate treatment and decrease the burden on the care providers."

BOSTON - At the end of 2020, experts led by allergists at Massachusetts General Hospital (MGH) examined all information related to possible allergic reactions to COVID-19 vaccinations. Now the team has published updated insights based on their experience overseeing more than 65,000 employees who have become fully vaccinated since that time. The group's latest findings are published in the Journal of Allergy and Clinical Immunology: In Practice.

"Our main goal is to enable as many individuals as possible to receive a COVID-19 vaccine safely and avoid unnecessary vaccine hesitancy due to a lack of knowledge around allergic reactions to vaccines," says lead author Aleena Banerji, MD, clinical director of the Allergy and Clinical Immunology Unit at MGH.

In addition to updated guidance on the Pfizer-BioNTech and Moderna COVID-19 vaccines, this guidance also includes the Janssen COVID-19 vaccine, which had not yet been authorized for emergency use at the end of 2020.

With additional clinical data and authorization of the third COVID-19 vaccine in the United States, the investigators propose modified approaches to the evaluation of patients with a history of allergies. This includes clear and simple initial questions to identify individuals who are eligible for all COVID-19 vaccines without needing an allergist evaluation.

"With more time and experience, we have been able to significantly narrow the group of patients with prior allergies who require an allergist assessment before COVID-19 vaccination," says senior author Kimberly G. Blumenthal, MD, MSc, co-director of the Clinical Epidemiology Program within MGH's Division of Rheumatology, Allergy and Immunology. "We now advise that only the rare individuals who have had a recent severe allergic reaction to polyethylene glycol, an ingredient in the vaccines, see an allergist or immunologist for evaluation, which may include skin testing." Individuals with severe allergies to foods, oral drugs, latex, bee stings or venom can safely receive the COVID-19 vaccines.

The team noted that severe allergic reactions to the vaccines remain exceedingly rare. Vaccine clinics should continue to observe higher-risk individuals for 30 minutes after vaccination, and they should have staff trained in recognizing and managing allergic reactions that may occur.

A lot about the human brain and its intricacies continue to remain a mystery. With the advancement of neurobiology, the pathogenesis of several neurodegenerative diseases (ND) has been uncovered to a certain extent along with molecular targets around which current therapies revolve. However, while the current treatments offer temporary symptomatic relief and slow down the course of the disease, they do not completely cure the condition and are often accompanied by a myriad of side effects that can impair normal daily functions of the patient.

Light stimulation has been proposed as a promising therapeutic alternative for treating various ND like Alzheimer's disease (AD), Parkinson's disease (PD), cognitive and sleep disorders. Light therapy consists of controlled exposure to natural daylight or artificial light of specific wavelengths. While neurologists worldwide have begun testing its use in clinical practice, less remains understood about the mechanisms behind how light affects neurological function.

Thus, in a review article now published in Chinese Medical Journal, researchers from China comprehensively summarize the growing knowledge on the mechanism of action, effectiveness, and clinical applications of LT in the treatment of ND. Neurologist and author Dr. Chun-Feng Liu explains how their work can advance our understanding of novel emerging therapies for ND. "While light therapy has been investigated in mental and sleep disorders, comprehensive knowledge on its use in neurodegenerative diseases in lacking. We therefore sought to shed light on the potential therapeutic methods and implications of light therapy," he states.

Our body function is tuned to a circadian or day and night rhythm. The clock that controls this rhythm is housed in the hypothalamus region of the brain. The genes expressed in this region are crucial in maintaining the circadian rhythm. Thus, a malfunction of these genes can disrupt the rhythmic cycle. These defects have been associated with neurodegenerative, metabolic and sleep disorders. External stimuli such as light, physical activity and food intake can help reset the clock and restore normal circadian rhythms, thus alleviating symptoms.

Another mechanism by which the clock controls circadian rhythms is through the secretion of the melatonin (MT) hormone. MT secreted by the pineal gland in the brain is known to control sleep patterns as it is secreted in higher amounts in the night than the day. Light stimulation in this case suppresses the secretion of MT during the day time and thus reduces drowsiness.

Interestingly, different tissue and organs in the body may respond differentially to light stimulation. Furthermore, different biomolecules expressed in circulating immune cells and stem cells are sensitive to specific wavelengths of light and thus elicit different responses by promoting the secretion of neurotrophic factors that can rescue neuronal functions.

Next, the researchers go on to discuss the application of light stimulation in specific neurodegenerative disorders. In case of AD, a progressive dementia, sleep disturbance has been associated with an increased expression of biomarkers that promote disease progression. Patients with AD often experience confusion, emotional distress and hyperactivity after dusk and through the night. Preliminary clinical studies on AD mouse models as well as patients with AD suggest that light stimulation helps restore memory and cognition and decreases the burden of the pathogenic amyloid-β protein in the brain. Furthermore, LT has been shown to improve sleep quality and duration in patients with sleep disorders while bright environments help reduce anxiety and aggressive behaviors in patients with dementia.

In case of PD, patients suffer from motor impairment, tremors and posture imbalance and also display non-motor symptoms such as insomnia, depression and fatigue that can collectively impair their quality of life. While LT has been shown to decrease non-motor symptoms to some extent, evidences on its direct benefits towards motor-function however are limited.

The use of LT in other neurodegenerative disorders is currently at preclinical stages and needs to be pursued further. Overall, LT offers a safe and cost-effective alternative for treatment of ND. Additional studies and large scale clinical trials in this direction can help establish its effectiveness as a potential therapeutic strategy.

Explaining the long term clinical applications of LT, Dr. Liu says, "The light box or light therapy lamp will help improve the sleep quality of patients with sleep disorders. Light stimulation will also likely have therapeutic effects on neurodegenerative diseases and seasonal depression. Further studies are needed to elucidate its effectiveness."

This review not only advances our understanding on how LT functions in resetting the circadian rhythm and associated neurological symptoms but also highlights its applications in routine clinical practice.

Scientists at VCU Massey Cancer Center have identified a protein that operates in tandem with a specific genetic mutation to spur lung cancer growth and could serve as a therapeutic target to treat the disease.

Mutations in the p53 gene are found in more than half of all cancers, but it remains difficult to effectively target the gene with drugs even decades after its discovery. Though previous research has shown that p53 acts as a tumor suppressor and initiates cancer cell death in its natural state, a new study led by Sumitra Deb, Ph.D., suggests that gain-of-function (GOF) mutations -- a type of mutation where the changed gene has an added function -- turn p53 into an oncogene, causing cells to replicate uncontrollably and contribute to cancer development.

Recently published in Nature Communications, the researchers determined that mutant p53 genes are empowered by a specific protein, PLK3, to copy their genetic code and promote tumor cell proliferation through a process called transactivation.

Using preclinical models of lung cancer driven by p53 GOF mutations, Deb and his research team discovered that PLK3 activates an amino acid called serine 20 (S20), a cellular building block they found to play an important role in cancer cell replication.

By inhibiting PLK3 in GOF p53 mutant cells, they observed a decrease in the function of S20 along with overall reductions in transactivation and tumor cell formation.

"Our research indicates that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions, raising the possibility of targeting p53-driven cancer cells using PLK3 inhibitors," said Deb, a member of the Cancer Biology research program at Massey and professor in the Department of Biochemistry and Molecular Biology at the VCU School of Medicine.

Deb's team will continue to explore the potential for PLK3 inhibitors to be effective drugs in the treatment of lung cancer and potentially other forms of disease with the same genetic mutation.