Body

SEATTLE (November 16, 2018) - It's well established that secondhand smoke from cigarettes is a risk to anyone who suffers from asthma. New research being presented at the American College of Allergy, Asthma and Immunology (ACAAI) Annual Scientific Meeting shows it's possible for both children and adults with uncontrolled asthma to find their symptoms worsening due to cannabis allergy and exposure to marijuana smoke.

"A 6-year-old boy suffering with severe asthma had family members who frequently smoked marijuana in the house," says allergist Bryce Hoffman, MD, ACAAI member and lead author of the study. "Even though family members didn't smoke marijuana in the same room as the child, he was exposed to traces of smoke and plant material. It was not clear why his asthma was so severe and not responding to aggressive asthma therapies until we determined he was allergic to cannabis. After the cannabis was removed from the house, his asthma improved."

In addition to the young boy's allergies to cannabis, the study indicates his grandmother also had a history of hives after personal use of cannabis.

"Although the boy didn't have any clear allergic symptoms such as hives - like his grandmother - we know indoor allergens like pets and dust mites can make asthma worse without obvious allergic symptoms," says Dr. Hoffman. "This is different from secondhand tobacco smoke which worsens asthma by irritating the lungs in a non-allergic way. The takeaway is that cannabis allergy can make asthma worse even without direct use. Anyone using cannabis needs to consider that others living in their house who have asthma - particularly children - may be at risk of uncontrolled asthma."

If your child has asthma that isn't well controlled, see an allergist. An allergist can set your child on the right track for the long term to handle their allergies or asthma.

Over 30 years ago, Marsha and Allen Barnett lost their sons to a puzzling childhood disease that relentlessly attacked their nervous systems and sapped their energy. After five-year-old Chuckie died suddenly in 1981, doctors provided a name for the disease: Leigh syndrome. Leigh syndrome is a complex disorder typically caused by dysfunctional mitochondria, the tiny batteries inside all cells that generate our energy. Two years later, the same disease killed Michael, Chuckie's older brother, when he was 10 years old.

Earlier this year, Mrs. Barnett, who lives in southeastern Pennsylvania, received a phone call from a physician she knew, Marni J. Falk, MD, at Children's Hospital of Philadelphia (CHOP), where Barnett has long supported research in mitochondrial medicine. "She asked about Chuckie's and Michael's symptoms, then told me, 'I think we found the causal gene mutation,'" she said.

Falk, the Executive Director of CHOP's Mitochondrial Medicine Frontier Program, led a research team that identified the inherited mutation in the Barnett family, a change in one nuclear gene that arose spontaneously generations ago among both parents' Ashkenazi Jewish ancestors. Scores of different genes harbor mutations that may cause Leigh syndrome, by many different possible inheritance patterns. The mutation in this family was present on both copies of the same gene in both affected brothers, and was also seen in two other children in the study with Leigh syndrome who were not related to them.

The study team, a research collaboration involving multiple centers to prove that the gene mutation definitely impaired mitochondrial function, published its findings in the October 2018 issue of Human Molecular Genetics. Falk's co-study leader was Michio Hirano, MD, of Columbia University, and the study's co-first authors were Rebecca D. Ganetzky, MD, of CHOP, and Emanuele Barca, PhD, of Columbia University.

Leigh syndrome, named after a British neuropsychologist who first described it in 1951, involves metabolic strokes deep in the brain, with a loss of skills from stressors such as fever, illness and anesthesia. It has historically had a high mortality rate in childhood or adolescence. Over 90 different genes necessary for mitochondria to function properly are now known to cause it, with disease-causing gene variants rooted in DNA, either within a cell's nucleus or in the separate mitochondrial genome.

Impaired cellular energy production in Leigh syndrome causes patients to experience progressive weakening of their muscles, heart and central nervous system. Both Chuckie and Michael eventually lost control of their eye muscles, for instance.

Falk and colleagues analyzed data from four subjects affected with Leigh syndrome who did not have a specific genetic diagnosis: the Barnett boys and two unrelated patients from Ashkenazi families now living with Leigh syndrome who are followed by the CHOP Mitochondrial Medicine Frontier Program. The team identified a common causative mutation in the nuclear gene USMG5, a gene not previously associated with any human disease. USMG5 encodes a protein component of complex V, the molecular motor within the mitochondrial energy system that directly generates ATP, each cell's chemical energy currency.

The change in USMG5 is a founder mutation, one that originated by chance, most likely centuries ago in an unidentified individual from an Ashkenazi Jewish population, possibly in Eastern Europe. The mutation causes an autosomal recessive disease, so someone can carry the mutation in one of their pair of USMG5 genes without having disease symptoms. However, if both parents are mutation carriers--as is true of Marsha and Allen--each child has a 25 percent chance of inheriting the mutation on both copies of their gene, and being affected with Leigh syndrome. The youngest Barnett son, now 40 years old, does not have Leigh syndrome.

Nearly 30 years ago Marsha and Allen Barnett established a foundation to support research in mitochondrial disease, which subsequently supported the recruitment to CHOP of mitochondrial medicine pioneer Douglas C. Wallace, PhD, where he established the Center for Mitochondrial and Epigenomic Medicine in 2010. Wallace holds the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Disease.

Insights from the current research have implications for preventive medicine and genetic counseling, says Falk. The USMG5 mutation should be added to the list of mutations tested for at the time of prenatal genetic carrier screening in prospective Ashkenazi Jewish parents. The mutation is relatively common in the Ashkenazi population, where roughly one in 175 individuals are carriers. It should also be added to the list of genes to be evaluated in children with Leigh syndrome.

"What we've learned from these four children recognized to suffer from USMG5 deficiency will enable future children diagnosed with this condition to be very carefully monitored and managed when they face stressors such as fever or anesthesia, to avoid decompensation," said Falk. Decompensation is a rapid medical deterioration that may occur when a patient's system is stressed. In the longer run, Falk and other researchers are working to realize precision medicines for mitochondrial disease. In the future, children known to have this gene disorder may be able to receive treatments targeted to their specific disease.

"This work highlights the importance to families and medicine of continuing to work to solve cases that have never before been fully understood," says Falk. "The current revolution in genomic sequencing methods, combined with highly collaborative research investigations to validate genetic leads, continues to deepen our knowledge of mitochondrial disease, and with it, precision diagnosis, counseling, management, and therapies."

WEST LAFAYETTE, Ind. -- Diabetes can lead to ulcers that patients don't even feel or notice until the sight of blood. And because ulcers can't heal on their own, 14 to 24 percent of diabetics in the U.S. who experience them end up losing their toes, foot or leg.

Purdue University researchers have developed a shoe insole that could help make the healing process more portable for the 15 percent of Americans who develop ulcers as a result of diabetes.

"One of the ways to heal these wounds is by giving them oxygen," said Babak Ziaie, Purdue professor of electrical and computer engineering. "We've created a system that gradually releases oxygen throughout the day so that a patient can have more mobility."

Diabetic ulcers commonly result from high blood sugar damaging nerves, which takes away feeling from the toes or feet.

Without the ability to feel pain, hits and bumps tend to go unnoticed and skin tissue breaks down, forming ulcers. A lot of sugar in the bloodstream, along with dried skin as a consequence of diabetes, further slow the ulcer healing process.

"We typically treat ulcers by removing devitalized tissue from the surface of the wound, and by helping the patient to find ways to take the weight off the affected foot," said Desmond Bell, a podiatrist in wound management and amputation prevention at the Memorial Hospital in Jacksonville, Florida, and the founder of the Save a Leg, Save a Life Foundation.

"The gold standard for treating an ulcer is a patient wearing a total-contact cast, which provides a protective environment for the foot. If we could test how well this insole delivers oxygen to the wound site from within the cast, then this could be a way of aiding the healing process," he said.

Purdue researchers used lasers to shape silicone-based rubber into insoles, and then create reservoirs that release oxygen only at the part of the foot where the ulcer is located. A YouTube video is available at https://youtu.be/DX30YU5rmUM.

The work aligns with Purdue's Giant Leaps celebration, acknowledging the university's global advancements made in health, longevity and quality of life as part of Purdue's 150th anniversary. This is one of the four themes of the yearlong celebration's Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.

"Silicone is flexible and has good oxygen permeability," said Hongjie Jiang, a postdoctoral researcher in electrical and computer engineering. "Laser machining helps us to tune that permeability and target just the wound site, which is hypoxic, rather than poison the rest of the foot with too much oxygen."

According to the team's simulations, the insole can deliver oxygen at least eight hours a day under the pressure of someone weighing about 53-81 kilograms (117-179 pounds). But the insole can be customized to take on any weight, the researchers say.

The team envisions a manufacturer sending a patient a pack of pre-filled insoles customized to his or her wound site, based on a "wound profile" obtained from a doctor's prescription and a picture of the foot.

"This is mass-customization at low cost," said Vaibhav Jain, a recent graduate from Purdue's mechanical engineering master's program and a current research associate in electrical and computer engineering.

Next, the researchers want to create a way to 3D print the whole insole, rather than printing a mold first and then laser-machining a pattern. They also plan to test the insole on actual diabetic ulcers, to further gauge how well they advance the healing process.

"We're wanting to bring this technology to the user by addressing whichever technicalities would be required to simplify the manufacturing flow," Jain said.

The team published its work in the September issue of the Materials Research Society Communications, a journal by Cambridge Core. Funding for this work was provided by the NextFlex PC 1.0 Project.

A patent is pending on the insole technology. The team is currently seeking corporate partners.

Dublin, Ireland: Researchers investigating new treatments for neuroblastoma - one of the most common childhood cancers - have found that a combination of two drugs made tumours disappear in mice, making it more effective than any other drugs tested in these animals.

Professor Murray Norris, deputy director of the Children's Cancer Institute Australia for Medical Research, Sydney, Australia, told the 30th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland, today (Thursday) that the findings were unusual and highly significant. But he warned that it would be some time before the drug combination would be tested in children and, if successful, made available more widely to treat children with this disease, even though both drugs are currently undergoing clinical trial in a range of adult cancers.

Neuroblastoma is one of the most common childhood cancers and is the leading single cause of cancer deaths in children under five. It is frequently found in the adrenal glands on top of the kidneys. Despite using intensive treatment regimens, children with the most aggressive forms of neuroblastoma have less than 50% survival rates.

Prof Norris said: "To study neuroblastoma in the laboratory, we use a genetically modified neuroblastoma mouse model that closely recapitulates clinical features of the disease, and these mice spontaneously develop neuroblastomas within weeks after birth. We have found that when we combined CBL0137 and panobinostat to treat mice bearing neuroblastomas, the tumours disappeared and never came back during the entire experiment, whereas the tumours continued to grow in mice that received either no treatment or only single drug treatment.

"This is a highly significant finding as this drug combination is the most effective therapy that we have observed in this neuroblastoma mouse model. It is unusual to see this effect, especially in these mice where neuroblastoma develops within seven weeks of birth and is aggressive in nature. In fact, the CBL0137/panobinostat combination is more effective than any other current clinical chemotherapy combinations that our laboratory has tested in these mice."

CBL0137, which belongs to a new class of drugs called curaxins, attacks the structure of cancer cells but is a safe drug that does not damage DNA in normal cells. Prof Norris and his colleagues used RNA sequencing technology that can detect drug-induced changes in tumours, to see how the combination of CBL0137 and panobinostat stopped neuroblastoma growing.

"Our results suggest that these drugs work through two different mechanisms that offer a two-pronged attack. One of these mechanisms appears to be a direct attack on the cancer cells themselves, killing them by inhibiting DNA repair; then a second mechanism is involved in inducing a robust immune response. This is very exciting and will hopefully facilitate the clinical development of effective and non-toxic therapies for childhood cancer," he said.

"Unlike conventional chemotherapy drugs that interact with DNA, CBL0137 is non-DNA damaging and therefore is comparatively less toxic. Developing CBL0137 combination therapies has the potential to reduce acute and long-term side effects and increase the quality of life of children with cancer while extending the survival rates of these children. Another important implication is that the CBL0137/panobinostat combination can activate an immune response which may significantly boost the efficacy of immunotherapy drugs that are otherwise ineffective for neuroblastoma."

The researchers are continuing their laboratory work to investigate further how the combination of these two drugs activates the immune response, and to test CBL0137/panobinostat with other immunotherapy drugs in mice. A phase I clinical trial of CBL0137 in children with neuroblastoma and other difficult-to-treat childhood cancers is planned to start in 2019, following the completion of a phase I clinical trial of the drug in adults with solid cancers and previously treated blood cancers. The trial of CBL0137 alone in children will need to be completed successfully before a trial testing the combination of the two drugs can be planned, which means it will be a few years before it is known whether the treatment can be used more widely.

Further lab research by Prof Norris and his colleagues also showed that CBL0137 and panobinostat slowed the growth of aggressive childhood leukaemias in mice and significantly extended survival.

In addition to approving CBL0137 for phase I clinical trials in adults, the FDA has already approved panobinostat for multiple myeloma and it is being tested in clinical trials for a range of other cancers.

Co-chair of the EORTC-NCI-AACR Symposium, Dr James L. Gulley, who is Director of the Medical Oncology Service at the NIH / NCI Center for Cancer Research in the USA, and who is an expert in cancer immunotherapy but was not involved in this research, commented: "Although these are results from work conducted in mice, they are very interesting and suggest the exciting possibility that this drug combination might work more effectively than single agents in children with this rare but aggressive tumour. These are patients who desperately need better treatments. We await the results of the clinical trials with interest."

Although the absolute risk increase is small, the findings expand on current knowledge and quantify the risk of serious adverse events potentially linked to this group of drugs, say the researchers.

SGLT2 inhibitors are increasingly popular drugs for the treatment of type 2 diabetes. They lower blood glucose levels by increasing glucose loss through the kidneys, but concerns have been raised regarding their safety.

For instance, some studies have suggested that their use may be associated with serious complications, including lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infections, blood clots (venous thromboembolism) and acute pancreatitis.

To better understand these potential risks, an international research team analysed national registry data from Sweden and Denmark for 17,213 patients who started taking SGLT2 inhibitors and 17,213 patients who started taking GLP1 receptor agonists between July 2003 and December 2016.

Patients were aged 35 years or more with no previous prescriptions for any of the study drugs, no history of severe kidney problems (dialysis or transplantation) or pancreatic disorders, and median follow-up time for the studied outcomes was between 270 and 274 days.

The main outcomes were lower limb amputation, bone fracture, diabetic ketoacidosis, acute kidney injury, serious urinary tract infection, venous thromboembolism and acute pancreatitis.

After taking account of a large number of potentially influential factors including disease history, other medications and socioeconomic indicators, use of SGLT2 inhibitors was associated with a two-fold increased risk of both lower limb amputation (2.7 vs 1.1 events per 1000 person years) and diabetic ketoacidosis (1.3 vs 0.6 events per 1000 person years), compared with GLP1 receptor agonists.

But there was no significant risk increase for bone fracture, acute kidney injury, serious urinary tract infection, venous thromboembolism or acute pancreatitis.

Findings remained consistent after further analyses to test the strength of the results.

This is an observational study, so no firm conclusions can be drawn about cause and effect, and the researchers cannot rule out the possibility that other unmeasured factors may have affected the results.

However, the study used nationwide registry data from a large number of patients, and the findings are consistent with previous research in the field.

As such, the researchers conclude that SGLT2 inhibitors compared with GLP1 receptor agonists are associated with an increased risk oflower limb amputations and diabetic ketoacidosis but not with other serious adverse events of current concern. And they call for further analyses to accumulate more clinical data on the use of these drugs.

A 15-minute scan could help diagnose brain damage in babies up to two years earlier than current methods.

In a study of over 200 babies at seven hospitals across the UK and the USA, researchers found the brain scan, called magnetic resonance (MR) spectroscopy, predicted damage with 98 per cent accuracy.

Brain damage affects around one in 300 births in the UK, and is usually caused by oxygen deprivation. However, currently doctors are unable to accurately assess the extent of a newborn baby's brain damage.

Any child suspected of having some type of damage is given an MRI scan shortly after birth. This allows doctors to look at black and white pictures of the brain see if any areas of the brain look lighter than others, as this may suggest damage. Doctors then use this information to give parents an estimation of the extent of the damage, and the possible long-term disabilities their child may face.

However, this method is only between 60-85 per cent accurate, and relies heavily on the radiologist's individual judgement, meaning the prognosis can vary depending on who assesses the scan, and where the scan is done. Hence health professionals can only confirm if a child has lasting brain damage when they reach two years old, by assessing whether a youngster has reached their development goals such as walking and talking.

In the new study, led by Imperial College London, scientists used MR spectroscopy to assess the health of brain cells in an area called the thalamus, which coordinates a number of functions including movement, and is usually most damaged by oxygen deprivation.

The scan specifically tests for a compound called N-acetylaspartate - high levels of which are found in healthy brain cells, called neurons. A level of 9-10 is found in healthy neurons, whereas a level of 3-4 indicates damage.

The technology used is the same as that needed for an MRI scan, and only requires the baby to spend an additional 15 minutes in the scanner.

In the new trial, published in the journal Lancet Neurology, the scan was performed at the same time as the routine MRI scan when a baby was between four and 14 days old.

The scan does not carry any additional cost to the NHS, and the data can be easily analysed using special software by any radiographer.

Dr Sudhin Thayyil, study author and Director of the Centre for Perinatal Neuroscience in Imperial's Department of Medicine said: "At the moment parents have an incredibly anxious two-year wait before they can be reliably informed if their child has any long-lasting brain damage. But our trial - the largest of its kind - suggests this additional test, which will require just 15 minutes extra in an MRI scan, could give parents an answer when their child is just a couple of weeks old. This will help them plan for the future, and get the care and resources in place to support their child's long term development."

In the trial, funded by the National Institute for Health Research and the Medical Research Council, all of the babies had received so-called cooling therapy immediately after birth. This is now a routine treatment for newborns with suspected brain damage, and involves placing a baby on a special mat that reduces their body temperature by four degrees. Evidence has shown that cooling the body can help reduce the extent of brain damage, and reduce the risk of long term disabilities.

The babies then had their brain scan soon after this therapy, and detailed developmental assessment at two years of age. The results suggested the MR spectroscopy at two weeks accurately predicted the level of toddler's development at two years old.

Dr Thayyil added that the scan may also help scientists develop new treatments to tackle brain injury in babies: "At the moment, when doctors are trialling a new therapy that may boost development of children with brain damage, they must wait two years until they can assess whether the treatment is working. They also need to study a large number of babies. But with this new scan, they'll be able to assess this almost immediately, with a much smaller number of infants."

He added that the next step is to roll out the scan in more hospitals in the UK as a clinical tool. "Most NHS hospitals already have the facilities and software to perform this scan, it's just a case of increasing awareness and training."

"I remember the terror when we didn't hear a cry" - Christine's story

Christine Reklaitis gave birth to her daughter Georgiana in 2016, and took part in the trial at Imperial College Healthcare NHS Trust in London.

She said: "I had a healthy pregnancy, but during labour my midwife struggled to find Georgiana's heartbeat, and she was born shortly afterwards via emergency c-section.

I remember the terror when we didn't hear a cry after she was born, but thankfully she was breathing, and was whisked away to intensive care, and placed in an incubator. The doctors told us

they were going to cool her down, which we thought sounded unusual, but were told it would reduce her risk of brain damage.

We were asked to take part in a trial and quickly agreed. We felt our daughter's treatment benefitted from past studies, so we wanted to help develop future treatments.

After the first scan we were told the levels of a compound in her brain cells were low, but were incredibly relieved when a scan a few weeks later showed the levels had increased to normal levels.

She has since hit all her development goals, and is a normal two-year-old, and full of energy. We joke the cooling treatment stayed with her, as she never wants to wear a coat when we go outside.

We are so pleased we took part in this trial - and hope the research helps other families."

The global disease burden of meningitis remains unacceptably high, and progress lags substantially behind that of other vaccine-preventable diseases, warns a new analysis published in The Lancet Neurology.

The Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease study showed that meningitis deaths reduced by just 21% globally between 1990 - 2016, whereas other preventable diseases such as measles, tetanus, and diarrhoea due to rotavirus saw declines of 93.0%, 90.7%, and 57.9%, respectively, suggesting that progress in meningitis could have been substantially faster.

The number of actual cases of meningitis increased during that time period, from 2.5 million in 1990 to 2.82 million in 2016, due to increased population size.

The highest concentration of cases and deaths from meningitis was found in the sub-Saharan African countries that are collectively known as the "meningitis belt". This is despite huge progress in reducing meningococcal group A disease by 99% in the meningitis belt through the MenAfriVac vaccination programme.

Meningitis Research Foundation, co-authors of the analysis, state that to make faster progress, particular attention should be given to: developing vaccines with broader coverage against the bacterial causes of meningitis; making these vaccines affordable to the developing countries that are most affected; improving vaccine uptake; and improving interventions such as access to low-cost, rapid diagnostic tests and treatments.

Ongoing surveillance of the specific types of bacteria causing meningitis is said to be crucial to continue monitoring and reacting to meningitis burdens and trends throughout the world.

Bacterial meningitis is a deadly disease that strikes without warning and can leave survivors with lifelong after effects as serious as deafness, blindness and brain damage. The paper states that better support for disabled or impaired survivors of this disease is vital.

IHME's Dr. Nicholas J. Kassebaum, Professor of Health Metrics Sciences with the University of Washington, commented, "Declines in the incidence and mortality of meningitis have lagged far behind vaccine-preventable diseases, diarrhea and lower respiratory infections. It is likely that the growing number of meningitis survivors with lifelong disabilities are living in communities without the resources or programs to support them."

Study author Linda Glennie from Meningitis Research Foundation said, "This research shows that a huge number of people are still being affected by this dreadful disease. Vaccination is the only way to prevent meningitis and despite major progress over the last 20 years, large epidemics have occurred recently showing again that meningitis is very far from being defeated.

"Meningitis spreads around the world and we need a coordinated effort to defeat it. We need faster progress, similar to that achieved with measles, tetanus, and diarrhoea due to rotavirus. This year the World Health Organization launched an expert taskforce to develop a global roadmap to defeat meningitis by 2030, and MRF is delighted to be taking part. This taskforce is a crucial step towards defeating meningitis for good."

During the holiday season, it can be difficult for even the most determined of us to stick to a healthy diet. A piece of Halloween candy here, a pumpkin spice latte there, and suddenly we're left feeling like we forgot what vegetables taste like.

Our weight isn't the only aspect of our health that can fluctuate during times like these. According to a new article in the journal Nutrients, risk factors for cardiovascular disease closely track with changes in eating patterns, even only after a month or so.

"If you're inconsistent about what kinds of foods you eat, your risk factors for developing these diseases are going to fluctuate," said Wayne Campbell, a professor of nutrition science at Purdue University. "Even in the short term, your food choices influence whether you're going to have a successful or unsuccessful visit with your doctor."

Diet failure isn't an anomaly, it's the norm, and there are a variety of reasons for that. This can lead to repetitive attempts of adopting, but not maintaining, healthy eating patterns.

To assess how these diet fluctuations affect risk factors for diabetes and cardiovascular disease, such as blood pressure and cholesterol, Campbell's team looked to two previous studies (also led by Campbell at Purdue). The research study participants adopted either a DASH-style eating pattern (Dietary Approaches to Stop Hypertension) or a Mediterranean-style eating pattern.

"Our DASH-style eating pattern focused on controlling sodium intake, while our Mediterranean-style focused on increasing healthy fats," said Lauren O'Connor, the lead author of the paper. "Both eating patterns were rich in fruits, vegetables and whole grains."

Participants adopted a healthy eating pattern for five or six weeks and then had their risk factors measured. The study participants then returned to their normal eating patterns for four weeks and came back for a checkup. After adopting a healthy eating pattern again for another five or six weeks, participants had their risk factors assessed one last time.

The results look almost exactly as you'd expect: like a cardiovascular rollercoaster. How fast the participants' health started to improve after adopting a healthier diet is impressive, though. It only takes a few weeks of healthy eating to generate lower blood pressure and cholesterol.

"These findings should encourage people to try again if they fail at their first attempt to adopt a healthy eating pattern," Campbell said. "It seems that your body isn't going to become resistant to the health-promoting effects of this diet pattern just because you tried it and weren't successful the first time. The best option is to keep the healthy pattern going, but if you slip up, try again."

The long-term effects of adopting and abandoning healthy eating patterns on cardiovascular disease are unknown. Research on weight cycling suggests that when people who are overweight repeatedly attempt to lose weight, quit, and try again, that may be more damaging to their long-term health than if they maintained a steady weight. To know if long-term health effects of cycling between eating patterns raise similar concerns, further studies are needed.

[Background]

Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) and was estimated to be responsible for 745,000 deaths in 2012. Recently, highly efficient and direct-acting antiviral agents (DAAs) have been able to eliminate HCV from infected livers in more than 90% of cases. However, emergence of HCC at a rate of about 1% per year is now reported in HCV-infected livers. Therefore, new therapeutic strategies are needed to prevent HCV infection, HCC recurrence, and hepatocarcinogenesis.

Osteopontin (OPN) is a multifunctional cytokine and is involved in normal physiological processes, as well as in numerous pathological conditions, including inflammation, fibrogenesis, and carcinogenesis. In liver diseases, OPN plays an important role in acute liver injury, viral replication, liver repair, fibrosis, and HCC.

Recent work has identified CD44 as the most common marker for cancer stem cells (CSCs) in several human cancers. CD44 has a pivotal role in regulating the properties of CSCs, including their self-renewal, tumor initiation, metastasis, and chemoradioresistance, and OPN reportedly interacts with CD44.

In HCC, enrichment of several stem cell markers, including CD133, CD90, CD13, epithelial cell adhesion molecule (EpCAM), CD44, CD24, and oval cell marker OV6, is reported in certain side populations of CSCs. However, CSCs represent only a minor population of the cancer cells and there is currently no evidence for a role for CSCs in supporting HCV replication. Therefore, identifying the underlying mechanism of HCV pathogenesis and its relationship to CSCs is an important research challenge.

In this study, a group from Kanazawa University evaluated the significance of the OPN-CD44 axis for HCV replication in EpCAM+/CD44+ CSCs, and investigated the role of OPN in the regulation and maintenance of EpCAM+/CD44+ CSCs.

[Results]

EpCAM+/CD44+ CSCs showed marked HCV replication when compared with EpCAM?/CD44? cells. In addition, the levels of OPN mRNA and protein were higher
in EpCAM+/CD44+ CSCs than in EpCAM?/CD44? cells. OPN significantly enhanced HCV replication in EpCAM+/CD44+ CSCs and markedly suppressed interferon (IFN)-stimulated gene expression. Glycogen synthase kinase-3β inhibitor 6-bromoindirubin-3-oxime increased the EpCAM+/CD44+ CSC population and OPN expression and impaired IFN signaling via signal transducer and activator of transcription 1 (STAT1) degradation. Furthermore, OPN regulated stemness of EpCAM+/CD44+ CSCs, which led to inactivation of IFN signaling and enhanced HCV replication.

[Significance and future prospects]

The Kanazawa University group focused its attention on CSCs, as HCC is proposed to develop from CSCs, even though they represent a small part of the HCC cell population. However, HCV replication in CSCs is still poorly understood. This study showed the significance of the OPN-CD44 axis for HCV replication in EpCAM+/CD44+ CSCs.

The results of the Kanazawa University group highlight a new role for OPN in supporting HCV replication in EpCAM+/CD44+ CSCs through a reduction in STAT1 activation. They also provide evidence that OPN has the potential to maintain CSC phonotypes, and identify the OPN-CD44 pathway as a potential target for regulating HCV replication and stemness in HCC cells.

Dublin, Ireland: A new drug designed to make radiotherapy more effective in treating cancer has been given to patients while they are receiving radiation and shown to be safe, according to research presented today (Wednesday) at the 30th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland.

The drug, called 5-iodo-2-pyrimidinone-2'-deoxribose (IPdR), or ropidoxuridine, has the advantage that patients can take it in capsule form, as opposed to intravenously. When the drug enters the body, researchers believe it changes into an active form that can make cancer cells more susceptible to the effects of radiotherapy.

Results of US NCI trial #9882, presented by Dr Timothy Kinsella from the Department of Radiation Oncology at the Warren Alpert Medical School of Brown University and Rhode Island Hospital in the USA, show that the drug has minimal side effects when given to patients with a variety of gastrointestinal cancers during the course of their radiotherapy.

Dr Kinsella explained: "The aim of my research is to find better ways to treat patients with cancer, and specifically to develop ways to make radiation treatment safer and more effective.

"Previous research found a promising compound called iododeoxyuridine, or IUdR, that worked very well to improve the effectiveness of radiotherapy, but IUdR could only be given intravenously and proved to have many side effects for patients.

"As a result, this new drug, IPdR, was developed. It's a prodrug that can be taken as a capsule and, once inside the body, it's converted into the active drug, IUdR.

"This trial is the first to test it out in patients while they are receiving radiation therapy, and the results suggest that it's safe with minimal side effects."

Dr Kinsella and his colleagues tested the new drug in a group of 18 patients with advanced cancers including oesophageal, pancreatic, liver, bile duct, rectal and anal cancers. All had been referred for palliative radiotherapy.

Alongside their radiotherapy, patients were given a daily dose of the IPdR prodrug over 28 days. They were given blood tests to check on the levels of both the IPdR prodrug and the active IUdR drug at various points during their treatment. The dose of the prodrug was gradually increased, and patients were monitored for side effects.

Results of the trial suggest that IPdR can be safely given to patients up to a dose of 1200mg per day for 28 days without causing serious side effects. The results also suggest that this dose creates levels of the active IUdR drug in patients' blood that are high enough to have a radiosensitising effect.

Of the 18 patients on the trial, 14 could be assessed for any effect on their tumours with a CT or MRI scan 54 days after beginning the treatment. Among these patients, one had a complete response (disappearance of tumour), three showed a partial response (at least 30% reduction in the tumour targeted by radiotherapy), nine had stable diseases (no growth in the tumour) and one patient stopped treatment because of an infection and had progressive disease (at least 20% growth in the tumour).

Dr Kinsella added: "This clinical trial showed that when patients take IPdR at home before coming for radiation treatment, the level of IUdR in their bloodstream is high enough to make radiation more effective at killing cancer cells. It also showed that the dose of IPdR needed to achieve therapeutic levels of IUdR in the blood causes minimal side effects.

"However, this trial was with patients who had recurrent cancer and had already received a number of other cancer treatments. In newly diagnosed patients, it could be that we can safely use a higher dose and have a bigger effect on tumours."

Dr Kinsella and his colleagues are already studying the effects of IPdR in patients receiving whole brain radiotherapy for cancer that has spread to the brain. Following this trial, plans are in progress to study the drug in patients who have been newly diagnosed with glioblastoma, an aggressive form of brain cancer.

Professor Eric Deutsch, professor of radiation oncology and head of the radiation oncology department and research unit at the Institut Gustave Roussy, Villejuif, France, is a member of the EORTC-NCI-AACR Symposium scientific committee and was not involved with the research. He said: "Radiotherapy is a vital element in treating many forms of cancer. This research is investigating whether the IPdR drug could make radiotherapy even more effective for more patients.

"In treating cancer patients, we must always consider the risks and benefits of any therapy. In this study, the risks of the IPdR drug were minimal, and the benefit was that it can be taken by patients at home. We don't have enough evidence yet on whether IPdR can improve patient outcome, but we hope that this will become clearer as the research continues."

New research has linked adolescent obesity with up to a four-fold increased risk of pancreatic cancer later in life. The study's results also suggest that overweight and even higher weight within the "normal" weight range in men may increase pancreatic cancer risk in a graded manner. The findings are published early online in CANCER, a peer-reviewed journal of the American Cancer Society.

Pancreatic cancer is the sixth most common cause of cancer-related deaths in the world, and studies have linked adult obesity with an increased risk for its occurrence. To uncover any potential associations with adolescent weight, Zohar Levi, MD, of Rabin Medical Center and Tel Aviv University, and his colleagues analyzed 1,087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between the ages of 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through 2012 was identified by linkage to the Israeli National Cancer Registry.

Over a median of 23.3 years of follow up, 551 new cases of pancreatic cancer cases were identified, including 423 cancers among men and 128 cancers among women. Compared with normal weight (5th to

Among men, high-normal BMI (?75th to

"The overall population attributable fraction of pancreatic cancer due to adolescent overweight and obesity was 11 percent among this Israeli Jewish population," said Dr. Levi.

An accompanying editorial by Chanan Meydan, MD, of the Mayanei Hayeshua Medical Center in Israel, highlights systemic inflammation caused by obesity as a potential driver behind the development of pancreatic cancer.

People who experience major injuries requiring hospital admission, such as car crashes and falls, are at substantially increased risk of being admitted to hospital for mental health disorders, found a study in CMAJ (Canadian Medical Association Journal). As well, they are at much higher risk of suicide than people without such injuries.

"Major trauma was associated with a 40% increased rate of hospital admission for 1 or more mental health diagnoses," writes Dr. Christopher Evans, Department of Emergency Medicine, Queen's University, Kingston, Ontario, with coauthors. "The most common mental health diagnoses were alcohol abuse, other drug abuse disorders and major depressive disorders."

There is little evidence on the link between major injury and later mental health issues. This large study, based on more than 19 000 patients in Ontario, contributes to the literature on this important topic. Most participants who had experienced major trauma were male (70.7%), lived in urban areas (82.6%) and had accidental (89%) rather than intentional injuries.

Male sex, low socioeconomic status, rural residence, accidental injuries and surgery for these injuries were associated with higher admissions for mental health issues. Researchers found that children and youth under 18 years of age had the largest increase in admissions for 1 or more mental health issues after injury. Suicide is also higher in people with major physical injury, with 70 suicides per 100 000 patients per year compared to 11.5 suicides per 100 000 patients in the general population.

"Patients who suffer major injuries are at significant risk of admissions to hospital with mental health diagnoses in the years after their injury and of having high suicide rates during this period," write the authors.

The authors urge that mental health supports should be offered to all trauma victims, with special attention to high-risk patients, including children and youth.

"Mental health outcomes after major trauma in Ontario: a population-based analysis" is published November 12, 2018.

In the first large-scale analysis of cardiovascular complications linked to immune checkpoint inhibitors, Vanderbilt researchers have shown that heart and vessel complications include myocarditis, pericarditis, vasculitis and arrhythmias, and that they occur early in the course of treatment.

The study, published online Nov. 12 in The Lancet Oncology, augments previous work by Vanderbilt University Medical Center (VUMC) researchers who first reported in 2016 rare but fatal cardiac side effects from the most widely prescribed class of immunotherapies. The researchers used VigiBase, a global database of drug complications maintained by the World Health Organization, to track adverse cardiovascular reactions in the latest study.

"When the immune system wakes up to attack the cancer cells, in rare situations it can also attack the heart and vessels, and in some cases, this can result in fatalities," said Joe-Elie Salem, MD, PhD, a Vanderbilt Cardio-Oncology Fellow and the study's first author.

Fatalities occurred in half of myocarditis cases (inflammation of heart muscle), 21 percent of pericardial cases (inflammation of the sac that surrounds the heart) and 6 percent of vasculitis cases (inflammation of blood vessels). Fatalities with myocarditis occurred more often with combination therapy (65.6 percent) than monotherapy (44.4 percent). The new Vanderbilt study advises clinicians to monitor for pericardial disease and vasculitis.

Javid Moslehi, MD, director of the Cardio-Oncology Program at VUMC and the study's senior author, presented the study's findings Nov. 12 at the American Heart Association Scientific Sessions 2018 in Chicago. The cardiovascular complications can also occur simultaneously with neurological complications, including myasthenia gravis, Moslehi said.

"This study suggests a role for a multi-disciplinary group that will help us characterize these novel and diverse side-effects of immunotherapies and identify those at risk," said Douglas Johnson, MD, director of the melanoma program at Vanderbilt-Ingram Cancer Center and a study author.

Johnson, Moslehi and colleagues are forming an immuno-toxicity group with the hope of utilizing Vanderbilt resources like the REDCap database to track these toxicities. In addition, the group has established a web-based link for physicians nationally to report cases of cardiovascular complications related to immune checkpoint inhibitors, linking these cases to REDCap to collect data on the cases.

"We hope to leverage this unique collaboration and these studies that we have published over the past few years into something that is translatable to patient care," Moslehi said, explaining that the group will include clinicians from multiple specialties with expertise in treating complications that may occur.

While cardiovascular complications have been identified as most likely to result in fatalities, checkpoint inhibitors may also spur reactions in the lungs, liver and colon. Vanderbilt researchers detailed the incidence of these fatal reactions Sept. 13 in JAMA Oncology. With other complications, steroids are prescribed to relieve the resulting inflammation and can be effective.

The study just published in The Lancet Oncology focuses on cardiovascular complications, including myocarditis and pericarditis.

The researchers also found 18 cases of temporal arteritis with a risk for blindness occurring with vasculitis. Visual impairment and blindness occurred with one-third of those cases.

"There have been isolated cases of pericarditis and vasculitis related to immune checkpoint inhibitors described in the literature, but ours is the first comprehensive -- and by far largest -- case series," Salem said.

MADISON - Diets rich in fiber have long been associated with an array of positive outcomes, chief among them healthy hearts and arteries protected from the ravages of atherosclerosis, the accumulation of fatty plaques linked to heart attacks and strokes.

Figuring out just how the fiber we eat manages to protect our heart, however, has been challenging.

One clue has come from the revolution in understanding the effect the diverse microbial community that populates our guts has on our health. Our microbiome helps us process our food, particularly fiber. Perhaps these beneficial microbes somehow turned indigestible plant parts into heart health. But the link was uncertain.

In support of a microbial connection between fiber and heart health, researchers at the University of Wisconsin-Madison have identified a particular fatty acid as the mechanism behind certain protective effects of a high-fiber diet in a mouse model. Known as butyrate, this fatty acid is produced by certain bacteria in the gut as they digest plant fiber.

The scientists showed that mice that harbored the butyrate-producing bacteria Roseburia and that also ate a high-fiber diet suffered from less atherosclerosis and had reduced inflammation compared to mice without the bacteria. Mice that hosted Roseburia but that ate a low-fiber diet were not protected, because without fiber the bacteria produced little butyrate.

Mice fed a slow-release form of butyrate itself were also protected from atherosclerosis, pointing to the molecule as a key arbiter of the fiber-heart link.

The study was published recently in the journal Nature Microbiology by UW-Madison Professor of Bacteriology Federico Rey and postdoctoral researcher Kazuyuki Kasahara with collaborators at the Wisconsin Institute for Discovery, the University of California, Los Angeles and the University of Gothenburg in Sweden.

"Atherosclerosis has historically been considered a disease of lipid metabolism," says Rey, noting that controlling the disease has usually focused on lowering the levels of cholesterol and other fats in the blood. "But over the last few decades, it's been revised to be considered a chronic inflammatory disease."

So the key to reducing atherosclerosis may be reducing overall inflammation, especially in the bloodstream. Keeping inflammation down depends in part on having a strong gut barrier.

"One important function of the gut is to keep our friendly bacteria at a distance," says Kasahara.

When inflammatory molecules break off of beneficial bacteria and leech out of the gut and into the bloodstream, they can trigger widespread inflammation. To keep these molecules at bay, healthy gut cells form strong attachments to one another, creating an intact barrier. But that attachment can be broken up.

"When that attachment gets loose, the gut becomes leakier," say Rey. Leaky guts lead to more inflammation.

To study butyrate's effect on the gut and atherosclerosis, Kasahara colonized germ-free mice with specific communities of bacteria, either with or without the butyrate-producing Roseburia. Those mice were then fed diets either rich or lacking in fiber, which Roseburia processes into butyrate.

The researchers found that mice hosting Roseburia had lower levels of several markers of inflammation and a reduced extent of atherosclerosis -- but only if they ate a high-fiber diet. Without fiber, Roseburia levels plummeted and the mice were not protected from atherosclerosis. The researchers used mice genetically susceptible to atherosclerosis because mice do not naturally develop the disease.

To determine if butyrate was the true cause of Roseburia's protective effects, Kasahara fed the fatty acid to mice without any butyrate-producing bacteria. Because pure butyrate would quickly be taken up by cells in the upper intestine, Kasahara fed mice a slow-release version that made it intact to the lower guts.

The slow-release butyrate reduced the extent of fatty plaques by about a third, and reduced other markers of inflammation and atherosclerosis, suggesting that the fatty acid formed a major component of Roseburia's anti-atherosclerosis effects.

Previous work indicated that humans with cardiovascular disease harbor lower levels of Roseburia and other butyrate-producing bacteria. The new study is one of the first to identify a clear cause for a previously mysterious link between dietary fiber, microbiomes and health. However, the researchers caution that the results don't point to a butyrate as a new, simple supplement for heart health -- fiber from whole foods still appears to be the ideal way to support a healthy gut.

At least, that's what Rey has taken away from years of studying fiber's effects on health.

"My wife gives me a hard time because every bread I buy is sprouted, high-fiber, whole grains," he says. "And I eat oatmeal in the morning."

An analysis of major health research prizes, including the Canada Gairdner International Award, found that few Canadian-based scientists are winning these prestigious prizes. The article is published in CMAJ (Canadian Medical Association Journal).

The prestigious Gairdner award, which is often called the "pre-Nobel," has seen numbers of Canadian-based researchers decline over time since its inception in 1959 from 35 winners in the first three decades to 12 in the last 30 years. For other major prizes, only 11% were awarded to Canadian-based scientists.

Authors Dr. David Naylor, University of Toronto, and Robert Redelmeier, McMaster University, Hamilton, Ontario, suggest that the decline is due not to chance but to a "home-ice edge" in the early years of the Gairdner and a more thorough selection process in later decades. Funding patterns could also be a factor as government funding has been inconsistent.