New study links neurological disorders in captive felids to improper diet

Findings from a recently published research study confirm what many scientists have long suspected. A high incidence of neurological disorders among captive felids in the United Arab Emirates (UAE), including demyelination of the spinal cord, correlates to copper and Vitamin A deficiencies, which is attributable to meat diets not properly supplemented nor based on mixed, whole carcass prey. The study was conducted by the Central Veterinary Research Laboratory (CVRL) in Dubai, UAE, with collaboration from Cheetah Conservation Fund (CCF), Namibia; Institute of Animal Nutrition, Vetsuisse Faculty Zurich; and Centre for Applied Biotechnology and Molecular Medicine, University of Zurich.

The study compared blood and tissue samples among captive felids, including cheetahs, lions and snow leopards, that were fed different diets. Thirty percent of the animals that did not receive supplements and existed primarily on a poultry muscle meat diet displayed clinical neurological signs such as ataxia, lack of coordination, swaying gait and moderate to severe hind limb weakness. Despite having normal appetites, these animals developed hind limb paresis and were eventually unable to stand. They either died or were euthanized, as damage is permanent and there is no treatment.

"The Role of Copper and Vitamin A Deficiencies Leading to Neurological Signs in Captive Cheetahs (Acinonyx jubatus) and Lions (Panthera leo) in the United Arab Emirates" was published in Food and Nutrition Sciences (2014, 5, 1978-1990). Claudia Kaiser, DVM, of the CVRL and the Institute of Animal Nutrition, Vetsuisse Faculty Zurich in Zurich, Switzerland, is the study's lead author. Dr. Kaiser worked with the CVRL from 2012 to 2013 and completed the study as her Doctoral thesis from Zurich University under the supervision of Prof. Annette Liesegang.

"We did this study because of all the post mortem findings of the previous years at the CVRL. Due to the fact that there was demyelinisation of the CNS in a lot of felids that were ataxic before euthanasia or natural death, we wanted to know if there was a correlation between the symptom and their nutrition. The results showed us that a supplemented diet is one of the key factors of keeping wild animals healthy in captivity," said Dr. Kaiser. "Captive animals cannot care for themselves, so it is our responsibility to optimize their lives in captivity."

According to Dr. Laurie Marker, Founder and Executive Director of CCF and one of the study's co-authors, cheetah myelopathy is the term used to describe ataxia, hind limb paralysis and pareses caused by degenerative lesions on the spinal cord. It's been found historically among some cheetahs kept in zoos, wildlife parks and private collections, but is now being reported with alarming frequency in the United Arab Emirates, where cheetahs are popularly kept as exotic pets and most often illegally taken from the wild. Cheetah myelopathy can lead to vision loss, muscle weakness, stiffness, spasms, loss of coordination, loss of sensation, pain and changes in bladder and bowel function. The majority of these cases are fatal.

"Many Emirates view cheetahs and other large felids as status symbols, but are often unfamiliar with the animal's proper care or diet. Big cats need the vitamins, minerals and trace elements found in bones, viscera, fur and feathers to remain healthy," said Marker. "Unfortunately, many cheetahs kept as pets are not fed whole carcasses with appropriate supplements, nor are they provided with the correct supplements to balance their diet. As a result, they experience debilitating health problems, and many will die prematurely."

With fewer than 10,000 wild cheetahs remaining and 50 to 70 percent of poached cubs dying en route to the Arabian Peninsula, there is little doubt the illegal trade in cheetahs is taking an already endangered species closer to the brink of extinction. "More education is needed to reduce the demand for cheetahs as exotic pets. If these wealthy exotic animal owners truly care about their animals, they would use their resources to educate others and help protect these majestic creatures where they belong, in the wild," added Dr. Marker.

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Cancer treatment potential discovered in gene repair mechanism

Case Western Reserve researchers have identified a two-pronged therapeutic approach that shows great potential for weakening and then defeating cancer cells. The team's complex mix of genetic and biochemical experiments unearthed a way to increase the presence of a tumor-suppressing protein which, in turn, gives it the strength to direct cancer cells toward a path that leads to their destruction.

If the laboratory findings are supported by tests in animal models, the breakthrough could hold the promise of increasing the effectiveness of radiation and chemotherapy in shrinking or even eliminating tumors. The key is to build up a "good" protein -- p53-binding protein 1 (53BP1) -- so that it weakens the cancer cells, leaving them more susceptible to existing cancer-fighting measures.

The breakthrough detailed appeared in the Nov. 24 online edition of the journal PNAS (Proceedings of the National Academy of Sciences).

"Our discovery one day could lead to a gene therapy where extra amounts of 53BP1 will be generated to make cancer cells more vulnerable to cancer treatment," said senior author Youwei Zhang, PhD, assistant professor of pharmacology, Case Western Reserve University School of Medicine, and member of the Case Comprehensive Cancer Center. "Alternatively, we could design molecules to increase levels of 53BP1 in cancers with the same cancer-killing end result."

The cornerstone of the research involves DNA repair -- more specifically, double-stand DNA repair. DNA damage is the consequence of an irregular change in the chemical structure of DNA, which in turn damages and even kills cells. The most lethal irregularity to DNA is the DNA double-strand break in the chromosome. DNA double-strand breaks are caused by everything from reactive oxygen components occurring with everyday bodily metabolism to more damaging assaults such as radiation or chemical agents.

The body operates two repair shops, or pathways, to fix these double strand breaks. One provides rapid, but incomplete repair -- namely, gluing the DNA strand ends back together. The problem with the glue method is that it leaves the DNA strands unable to transmit enough information for the cell to function properly -- leading to a high cell fatality rate.

The second shop, or pathway, uses information from intact, undamaged DNA to instruct damaged cells on how to mend broken double strands. During his study, Zhang and fellow investigators discovered a previously unidentified function of a known gene, UbcH7, in regulating DNA double-strand break repair. Specifically, they found that depleting UbcH7 led to a dramatic increase in the level of the 53BP1 protein.

"What we propose is increasing the level of 53BP1 to force cancer cells into the error-prone pathway where they will die," Zhang said. "The idea is to suppress deliberately the second accurate repair pathway where cancer cells would prefer to go. It is a strategy that would lead to enhanced effectiveness of cancer therapy drugs."

The next research step for Zhang and his team will be to test their theory in animal models with cancer. Investigators would study the effects of introducing the protein 53BP1 in lab mice with cancer and then applying chemotherapy and radiotherapy as treatment.

"Each cell in our bodies already contains these UbcH7 proteins that regulate 53BP1," Zhang said. "In patients with cancer, we want to induce more of 53BP1 proteins within their bodies to make their cancer cells vulnerable to radiation therapy and chemotherapy drugs."

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Malaria combination drug therapy for children

A drug combination of artemisinin-naphthoquine should be considered for the treatment of children with uncomplicated malaria in settings where multiple parasite species cause malaria according to Tim Davis from University of Western Australia, Fremantle, Australia and colleagues in new research published in this week's PLOS Medicine.

Malaria is a mosquito-borne parasitic disease that kills approximately 600,000 people every year. Several different parasite species cause malaria and in some settings, such as Papua New Guinea, two species, Plasmodium falciparum and Plasmodium vivax, are responsible for the majority of malaria infections. However, the two species respond differently to currently available anti-malarial drugs.

The authors compared the current recommended therapy for uncomplicated malaria in children in Papua New Guinea, artemether-lumefantrine, with a different combination therapy, artemisinin-naphthoquine. Using a randomized, controlled trial study design including 186 children with Plasmodium falciparum infections and 47 children with Plasmodium vivax infections, the researchers found that artemisinin-naphthoquine was non-inferior to (no worse than) artemether-lumefantrine for treating Plasmodium falciparum (a difference of 2.2% [95% confidence interval ?3.0% to 8.4%] for reappearance of infection within 42 days) but was more effective for treating Plasmodium vivax (a difference 70.0% [95% confidence interval 40.9%-87.2%] for reappearance of infection within 42 days).

The authors conclude, "[t]he efficacy, tolerability, and safety of three daily doses of artemisinin-naphthoquine suggest that this regimen should be considered together with other currently available effective [artemisinin combination therapies] for treatment of uncomplicated malaria in [Papua New Guinea] and similar epidemiologic settings with transmission of multiple Plasmodium species."

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Neonatal HBV vaccine reduces liver cancer risk

Neonatal HBV vaccination reduces the risk of liver cancer and other liver diseases in young adults in China, according to a study published by Chunfeng Qu, Taoyang Chen, Yawei Zhang and colleagues from the Cancer Institute & Hospital at the Chinese Academy of Medical Sciences, Qidong Liver Cancer Institute, China, and Yale School of Public Health and School of Medicine, USA in this week's PLOS Medicine.

The researchers report long-term outcomes from the Qidong Hepatitis B intervention Study (QHBIS), a randomized controlled trial of neonatal HBV vaccination that was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer (PLC) and other liver diseases. In this study, 41 rural towns (including a total of 77,658 newborns over the study period) were randomized to the intervention (HBV vaccination for all newborns) or control (no vaccination) groups, with two-thirds of the control group participants receiving a catch-up vaccination at age 10-14 years.

By collecting data on new cases of liver diseases over 30 years from a population-based tumor registry, the researchers estimated that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Based on survey data collected in 1996-2000 and 2008-2012 on HBsAg seroprevalence, an indicator of current hepatitis B virus (HBV) infection, they conclude that the efficacy of the catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared to neonatal vaccination (21% versus 72%). While these findings support the importance of neonatal HBV vaccination, the small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings.

The authors say: "Neonatal HBV vaccination significantly decreased HBsAg seroprevalence in childhood through young adulthood and subsequently reduced the risk of PLC and other liver diseases in young adults." They continue: "Our results also suggest that an adolescence booster should be considered in people who were born to HBsAg-positive mothers and completed HBV neonatal vaccination series."

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Nanotechnology used to engineer ACL replacements

Lindsey Vonn. Derrick Rose. Tom Brady. Mickey Mantle.

They have all fallen victim to the dreaded pop of the knee.

Connecting the femur to the tibia, the anterior cruciate ligament (ACL) rupture is one of the most devastating injuries in sports. No other injury has sidelined more athletes for a season or even the rest of a career. And ACL sprains and tears affect more people than just the pros. According to the American Association of Orthopaedic Surgeons, more than 250,000 ACL surgeries are performed annually in the United States, totaling up to more than $500 million in health care costs each year.

Not only is the ACL inelastic and prone to popping, it is incapable of healing itself, causing surgeons to rely on autografts for reconstruction. Most common is the bone-patellar tendon-bone (BPTB) graft, in which the surgeon removes part of the patellar tendon to replace the damaged ACL.

"BPTB autografts have a high incidence of knee pain and discomfort that does not go away," said Guillermo Ameer, professor of biomedical engineering at Northwestern University's McCormick School of Engineering and professor of surgery at the Feinberg School of Medicine. "By saving the patient's patellar tendon and using an off-the-shelf product, one may have a better chance of preserving the natural biomechanics of the knee."

Ameer and his research team are working to engineer such a product by combining three components: polyester fibers that are braided to increase strength and toughness, an inherently antioxidant and porous biomaterial previously created in Ameer's lab, and calcium nanocrystals, a mineral naturally found in human teeth and bones. His work is described in the paper "A biodegradable tri-component graft for anterior cruciate ligament reconstruction," which was published in the Nov. 21 issue of the Journal of Tissue Engineering and Regenerative Medicine. Eunji Chung, a postdoc at the University of Chicago and former graduate student in Ameer's lab, was the paper's first author.

During ACL reconstruction surgeries, tunnels are drilled into the femur and tibia bones to hold the new ligament in a fixed position. Ameer created a bone-like material by combining his antioxidant biomaterials with the calcium nanocrystals; he then embedded braided polyester fibers into it. The artificial ligament's bone-like ends healed to the native bone in the drilled tunnels, anchoring the ligament into place.

By studying an animal model, Ameer and his team noticed that the animal's natural bone and tissue cells migrated into the pores of the artificial ligament, populating it throughout and integrating with the bone tunnels. While longer-term studies are necessary to evaluate the potential use of the approach in humans, Ameer is optimistic about the results.

"The engineered ligament is biocompatible and can stabilize the knee, allowing the animal to function," Ameer said. "Most importantly, we may have found a way to integrate an artificial ligament with native bone."

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Children with autism who live with pets are more assertive

Dogs and other pets play an important role in individuals' social lives, and they can act as catalysts for social interaction, previous research has shown. Although much media attention has focused on how dogs can improve the social skills of children with autism, a University of Missouri researcher recently found that children with autism have stronger social skills when any kind of pet lived in the home.

"When I compared the social skills of children with autism who lived with dogs to those who did not, the children with dogs appeared to have greater social skills," said Gretchen Carlisle, research fellow at the Research Center for Human-Animal Interaction (ReCHAI) in the MU College of Veterinary Medicine. "More significantly, however, the data revealed that children with any kind of pet in the home reported being more likely to engage in behaviors such as introducing themselves, asking for information or responding to other people's questions. These kinds of social skills typically are difficult for kids with autism, but this study showed children's assertiveness was greater if they lived with a pet."

Pets often serve as "social lubricants," Carlisle said. When pets are present in social settings or a classroom, children talk and engage more with one another. This effect also seems to apply to children with autism and could account for their increased assertiveness when the children are living in a home with pets, Carlisle said.

"When children with disabilities take their service dogs out in public, other kids stop and engage," Carlisle said. "Kids with autism don't always readily engage with others, but if there's a pet in the home that the child is bonded with and a visitor starts asking about the pet, the child may be more likely to respond."

Carlisle also found that children's social skills increased the longer a family had owned a dog, yet older children rated their relationships with their dogs as weaker. When children were asked, they reported the strongest attachments to smaller dogs, Carlisle found.

"Finding children with autism to be more strongly bonded to smaller dogs, and parents reporting strong attachments between their children and other pets, such as rabbits or cats, serves as evidence that other types of pets could benefit children with autism as well," Carlisle said.

Carlisle surveyed 70 families who had children with autism between the ages of 8 and 18.The children were patients at the MU Thompson Center for Autism and Neurodevelopmental Disorders. Almost 70 percent of the families that participated had dogs, and about half of the families had cats. Other pets owned by participants included fish, farm animals, rodents, rabbits, reptiles, a bird and even one spider.

"Dogs are good for some kids with autism but might not be the best option for every child," Carlisle said. "Kids with autism are highly individual and unique, so some other animals may provide just as much benefit as dogs. Though parents may assume having dogs are best to help their children, my data show greater social skills for children with autism who live in homes with any type of pet."

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New treatment strategy allows lower doses of toxic tuberculosis drug without compromising potency

While an effective treatment is available for combating multidrug-resistant tuberculosis, it carries serious side effects for patients. New research conducted at the Center for Tuberculosis Research at the Johns Hopkins University School of Medicine shows that lower doses of the toxic drug bedaquiline -- given together with verapamil, a medication that's used to treat various heart conditions -- can lead to the same antibacterial effects as higher toxic doses of bedaquiline. The combination of the two drugs could potentially shorten treatment time, reduce the side effects of bedaquiline and improve patient outcomes for those suffering from TB.

The study will be published in the January 2014 issue of Antimicrobial Agents and Chemotherapy. The lead author is William Bishai, M.D., Ph.D., co-director of the Center for Tuberculosis Research.

"Using a mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses," says Shashank Gupta, Ph.D., a research fellow at Johns Hopkins. "A lower dose of bedaquiline will cause no or less severe side effects."

Two years ago, bedaquiline became the first drug in the last four decades to be approved by the U.S. Food and Drug Administration for the treatment of multidrug-resistant TB. The drug works by inhibiting an enzyme used by Mycobacterium tuberculosis to replicate and spread throughout the body. While it can be a lifesaving therapy against one of the world's deadliest diseases, bedaquiline can also cause serious side effects in the heart and liver. Therefore, strategies to reduce the dose of bedaquiline while retaining its antibacterial activity would provide significant benefits to patients.

"Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve multidrug-resistant TB treatment outcomes," says Gupta.

Bishai's team wondered whether giving verapamil in addition to lower doses of bedaquiline might do the trick. Verapamil is prescribed to patients with hypertension and other heart-related conditions, because it blocks cellular channels that affect the pumping of the heart and the dilation of blood vessels. Studies have revealed that the drug also inhibits bacterial efflux pumps that permit bacteria to survive within cells. Efflux pumps contribute to multidrug resistance, because they expel antibiotics and other compounds from cells. Blocking them could open the door for shortening the course of antibiotics and for restoring their activity against drug-resistant bacterial infections.

The researchers found that adding verapamil augmented the potency of bedaquiline and accelerated its ability to clear mycobacteria in mice. It also protected against the development of resistant mutants of the bacteria in the animals. The researchers demonstrated that supplementing bedaquiline with verapamil profoundly decreased the minimum inhibitory concentration of bedaquiline against various strains of TB. The minimum inhibitory concentration is the lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation in the lab. The presence of verapamil also decreased the minimum inhibitory concentration of another antimycobacterial drug, clofazimine, against TB.

The global burden of TB is enormous, with an estimated 8.6 million new cases in 2012. This included 450,000 people with multidrug-resistant disease that was associated with 170,000 deaths.

The results of this study can now be used to design a clinical trial in humans.

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Molecular network identified underlying autism spectrum disorders

Researchers in the United States have identified a molecular network that comprises many of the genes previously shown to contribute to autism spectrum disorders. The findings provide a map of some of the crucial protein interactions that contribute to autism and will help uncover novel candidate genes for the disease. The results are published in Molecular Systems Biology.

"The study of autism disorders is extremely challenging due to the large number of clinical mutations that occur in hundreds of different human genes associated with autism," says Michael Snyder, Professor at the Stanford Center for Genomics and Personalized Medicine and the lead author of the study. "We therefore wanted to see to what extent shared molecular pathways are perturbed by the diverse set of mutations linked to autism in the hope of distilling tractable information that would benefit future studies."

The researchers generated their interactome -- the whole set of interactions within a cell -- using the BioGrid database of protein and genetic interactions. "We have identified a specific module within this interactome that comprises 119 proteins and which shows a very strong enrichment for autism genes," remarks Snyder.

Gene expression data and genome sequencing were used to identify the protein interaction module with members strongly enriched for known autism genes. The sequencing of the genomes of 25 patients confirmed the involvement of the module in autism; the candidate genes for autism present in the module were also found in a larger group of more than 500 patients that were analyzed by exome sequencing. The expression of genes in the module was examined using the Allen Human Brain Atlas. The researchers revealed the role of the corpus callosum and oligodendrocyte cells in the brain as important contributors to autism spectrum disorders using genome sequencing, RNA sequencing, antibody staining and functional genomic evidence.

"Much of today's research on autism is focused on the study of neurons and now our study has also revealed that oligodendrocytes are also implicated in this disease," says Jingjing Li, Postdoctoral Fellow at the Stanford Center for Genomics and Personalized Medicine who helped to spearhead the work. "In the future, we need to study how the interplay between different types of brain cells or different regions of the brain contribute to this disease."

"The module we identified which is enriched in autism genes had two distinct components," says Snyder. "One of these components was expressed throughout different regions of the brain. The second component had enhanced molecular expression in the corpus callosum. Both components of the network interacted extensively with each other."

The working hypothesis of the scientists, which is consistent with other recent findings, is that disruptions in parts of the corpus callosum interfere with the circuitry that connects the two hemispheres of the brain. This likely gives rise to the different phenotypes of autism that result due to impairment of signaling between the two halves of the brain.

"Our study highlights the importance of building integrative models to study complex human diseases," says Snyder. "The use of biological networks allowed us to superimpose clinical mutations for autism onto specific disease-related pathways. This helps finding the needles in the haystack worthy of further investigation and provides a framework to uncover functional models for other diseases."

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Bats are a possible source of Ebola epidemic in West Africa

The outbreak of the Ebola virus disease occurring in West Africa may have originated from contact between humans and virus-infected bats, suggests a study led by researchers from the Robert Koch-Institute in Berlin, Germany. The report, published in EMBO Molecular Medicine, identifies insectivorous free-tailed bats as plausible reservoirs and expands the range of possible Ebola virus sources to this type of bats. The results also reveal that larger wildlife are not the source of infection.

Ebola virus disease epidemics are of zoonotic origin, transmitted to human populations either through contact with larger wildlife or by direct contact with bats. "We monitored the large mammal populations close to the index village Meliandou in south-eastern Guinea and found no evidence for a concurrent outbreak," says Fabian H. Leendertz of the Robert Koch Institute, who led the study. The second infection route appears more plausible as direct contact with bats is usual in the affected region.

Fruit bats are the commonly suspected Ebola virus reservoir as previous outbreaks in Africa show. Interviews with Meliandou locals revealed that exposure to fruit bats through hunting and consumption of meat in this area is common. Yet fruit bats seem an unlikely source of infection, as a food-borne transmission would have affected adults before or concurrently with the two-year-old boy -- the index case. This suggests a source of infection unrelated to food.

Another opportunity for infection was a large colony of free-tailed insectivorous bats housed in a hollow tree nearby the home of the index case. Villagers reported that children often used to play in and around the tree. This may have resulted in a massive exposure to bats.

The multidisciplinary team of researchers led a four-week field mission in Guinea in April 2014 to examine human exposure to bats, to survey local wildlife and to capture and sample bats in Meliandou and in neighbouring forests. The index village is not located in the forest but rather in an area heavily modified by humans representing "modern" African settings.

The virus that spread from Meliandou into other areas of Guinea and Sierra Leone, Liberia, Nigeria and Senegal, represents the largest ever-recorded Ebola outbreak killing 7,800 people (as of 17 December 2014).

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Heart drugs offer new hope to slow cardiac damage in muscular dystrophy

Early use of available heart failure drugs slows the progressive decline in heart function before symptoms are apparent in boys and young men with Duchenne muscular dystrophy (DMD), according to a new study published online by The Lancet Neurology.

Dr. Subha Raman, a cardiologist and professor at The Ohio State University Wexner Medical Center, led a team of DMD experts at multiple sites in a clinical trial that tested the combination of eplerenone and either an ACE inhibitor or an angiotensin receptor blocker (ARB) to decrease the progression of heart muscle disease, a leading cause of death in boys and young men with DMD.

"We believe this research offers evidence that supports the early use of these readily available medications," said Raman, who is also the lead author of the study.

Dr. Linda Cripe, a pediatric cardiologist and co-investigator at Nationwide Children's Hospital in Columbus, added, "This could quickly become standard of care for patients with DMD."

Raman and her team based this trial on their earlier lab findings that showed this combination of medicines reduced muscle damage and preserved function in an animal model of DMD. In this trial, researchers enrolled 42 boys with DMD who also showed evidence of early heart muscle damage by cardiac magnetic resonance imaging. In the double-blind study, the boys were randomized to receive one pill of either 25 milligrams of eplerenone or placebo daily for one year. All subjects received background therapy with either an ACE inhibitor or ARB as prescribed by their physician. Enrollment and follow-up visits were completed between March 2012 and July 2014.

The patients had cardiac MRIs before and again at six and 12 months after starting the study medicine. After 12 months, the team reported further decline in left ventricular function was significantly less in the eplerenone treatment group than in those on placebo. Raman noted that the results indicated at least six months of therapy was needed to realize benefit.

"We know that a sensitive measurement of heart function known as strain is abnormal well before complications like congestive heart failure and fatal arrhythmias occur in DMD. By impacting this earliest detectable change in heart function, we expect and hope to see even greater benefits with longer-term follow-up of these patients. Slowing the progression of heart disease should translate into improved quality of life for affected individuals and their families," Raman said.

DMD is a genetic disorder in which the body lacks dystrophin, a protein that helps keep muscle cells intact. It causes muscles to rapidly degenerate and weaken. DMD predominantly affects males. A majority of patients develop heart or respiratory failure, surviving into their 20s or early 30s.

This research was inspired by 26-year-old Ryan Ballou of Pittsburgh, a young man with DMD who, along with his father, started BallouSkies to raise awareness and funding for Raman's research of heart disease in muscular dystrophy patients. BallouSkies was the primary financial supporter of this clinical study.

"This research progressed much faster thanks to their support. The work we have accomplished in just a few years would have taken a decade or more if we had to seek funding from traditional grant mechanisms alone," Raman said.

Dr. John Kissel, a neurologist at Ohio State's Wexner Medical Center, added, "BallouSkies is a great example of how dedicated people working together can make a tremendous difference in fighting even the most serious conditions."

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Lung cancer metastases may travel through airways to adjacent or distant lung tissue

A new study by researchers in Canada supports the hypothesis that lung cancer, particularly adenocarcinoma, may spread through the airways. The putative occurrence of intrapulmonary aerogenous metastasis of lung cancer has staging, management, and prognostic implications.

Lung cancer is the most common and most lethal cancer worldwide. Its prognosis remains poor: The 5-year survival rate is 6-18%. Adenocarcinoma has surpassed squamous cell carcinoma as the leading histologic type, accounting for 30% of all cases of lung cancer. Hematogenous spread (i.e., carried by blood) is the most common mechanism of intrapulmonary metastasis. Although local venous spread can occur, systemic spread with secondary lung involvement is much more common.

"Cumulative evidence suggests that intrapulmonary aerogenous spread may exist and is underrecognized," say the authors of "Aerogenous Metastases: A Potential Game Changer in the Diagnosis and Management of Primary Lung Adenocarcinoma," published in the December 2014 issue of the American Journal of Roentgenology. "Aerogenous metastases must be differentiated from multiple synchronous lesions in the spectrum of lung adenocarcinoma, [and] imaging features are helpful in differentiating possible aerogenous spread of tumor."

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Tracing evolution of chicken flu virus yields insight into origins of deadly H7N9 strain

An international research team has shown how changes in a flu virus that has plagued Chinese poultry farms for decades helped create the novel avian H7N9 influenza A virus that has sickened more than 375 people since 2013. The research appears in the current online early edition of the scientific journal Proceedings of the National Academy of Sciences.

The results underscore the need for continued surveillance of flu viruses circulating on poultry farms and identified changes in the H9N2 virus that could serve as an early warning sign of emerging flu viruses with the potential to trigger a pandemic and global health emergency. The work focused on the H9N2 chicken virus, which causes egg production to drop and leaves chickens vulnerable to deadly co-infections. Scientists at St. Jude Children's Research Hospital and the China Agricultural University, Beijing, led the study.

Researchers used whole genome sequencing to track the evolution of the H9N2 chicken virus between 1994 and 2013. The analysis involved thousands of viral sequences and showed that the genetic diversity of H9N2 viruses fell sharply in 2009. From 2010 through 2013 an H9N2 virus emerged as the predominant subtype thanks to its genetic makeup that allowed it to flourish despite widespread vaccination of chickens against H9N2 viruses.

Evidence in this study suggests the eruptions set the stage for the emergence of the H7N9 avian virus that has caused two outbreaks in humans since 2013, with 115 confirmed deaths. The H9N2 infected chickens likely served as the mixing vessel where H9N2 and other avian flu viruses from migratory birds and domestic ducks swapped genes, researchers noted. The resulting H7N9 virus included six genes from the H9N2.

"Sequencing the viral genome allowed us to track how H9N2 evolved across time and geography to contribute to the H7N9 virus that emerged as a threat to human health in 2013," said Robert Webster, Ph.D., a member of the St. Jude Department of Infectious Diseases. He and Jinhua Liu, Ph.D., of the College of Veterinary Medicine at the China Agricultural University, are co-corresponding authors.

"The insights gained from this collaboration suggest that tracking genetic diversity of H9N2 on poultry farms could provide an early warning of emerging viruses with the potential to spark a pandemic," Webster said.

The analysis also provided insight into the creation of the H9N2 virus that emerged as the predominant subtype in 2010. Factors included widespread use of poultry vaccines and the natural tendency of flu to mutate, mix and swap genes.

Beginning in 1998, vaccinating poultry against H9N2 prevented flu outbreak for more than a decade. Vaccines work by recognizing and attaching to the spike-shaped hemagglutinin (HA) protein on the surface of the flu virus. That blocks the virus from infecting healthy cells. Changes in the HA gene that change the shape of the HA protein can reduce vaccine effectiveness and result in disease outbreaks. HA mutations occur naturally over time. Vaccines increase pressure for HA mutations that help the virus escape vaccine detection and cause infection.

Researchers at the China Agricultural University checked H9N2 vaccine effectiveness against the predominant H9N2 virus from 2010-11. Working in vaccinated and unvaccinated chickens, investigators found the vaccine neither protected vaccinated chickens from infection nor prevented spread of the virus in vaccinated chickens. Those failures suggest that due to HA mutations vaccines were less able to recognize the virus.

The tendency of flu viruses to swap genes also contributed to the enhanced ability of the predominant H9N2 subtype to spread. Researchers found that prior to the virus' emergence as the predominant H9N2 the virus had swapped genes with quail and duck influenza viruses.

The combination fueled the recent outbreaks of H9N2 on chicken farms by helping the virus escape vaccine detection and spread rapidly in vaccinated and unvaccinated poultry, said co-first author Juan Pu, Ph.D., a St. Jude visiting scientist from the China Agricultural University. The other first authors are Shuoguo Wang, Ph.D., of the St. Jude Department of Computational Biology, and Yanbo Yin, Ph.D., of Qingdao Agricultural University, Qingdao, China.

"The emergence of this dominant H9N2 virus was the first step in the genesis of the H7N9 viruses because it greatly increased the likelihood of reassortment between H9N2 and other flu subtypes," Liu said. Reassortment refers to the tendency of flu viruses to swap genes.

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Lyme disease enhances spread of emerging tick infection

Ninety-five percent of all Lyme disease cases are reported from 14 states (primarily on the East Coast and in the Midwest), and there are approximately 30,000 new cases reported each year. Babesiosis is found in similar regions, but 95% of cases are concentrated in the seven “core” Lyme disease states (Connecticut, Massachusetts, New Jersey, New York, Rhode Island, Minnesota, and Wisconsin).

Mice that are already infected with the pathogen that causes Lyme disease appear to facilitate the spread of a lesser-known but emerging disease, babesiosis, into new areas.

Research led by the Yale School of Public Health and published Dec. 29 in the journal PLOS ONE used laboratory experiments, mathematical models, and fieldwork data to find that mice infected with the agent that causes Lyme disease (Borrelia burgdorferi) are at increased risk for also transmitting Babesia microti, the pathogen responsible for babesiosis, and could be enhancing the geographic spread of this emerging disease. Both diseases are transmitted to humans through the bite of infected black-legged ticks (Ixodes scapularis).

The finding provides a possible answer as to why human babesiosis is only emerging in areas where Lyme disease is well established, said Maria Diuk-Wasser, senior author of the study, who performed the research in collaboration with Peter Krause's and Durland Fish's research groups while she was assistant professor at the Yale School of Public Health. Diuk-Wasser, who maintains an adjunct position and active collaboration with the Yale School of Public Health, is an associate professor at Columbia University. Other study collaborators were at the Yale School of Medicine, Tufts Medical Center, and the Royal Melbourne Institute of Technology.

"Ticks and natural hosts are commonly co-infected in nature, so understanding how these pathogens may influence each other's abundance and distribution is key for public health," Diuk-Wasser said. "We found that B. burgdorferi and B. microti co-occur in ticks more frequently than expected, resulting in enhanced human exposure to multiple infections that can cause more severe symptoms and sometimes make diagnosis more difficult."

Ninety-five percent of all Lyme disease cases are reported from 14 states (primarily on the East Coast and in the Midwest), and there are approximately 30,000 new cases reported each year. Babesiosis is found in similar regions, but 95% of cases are concentrated in the seven "core" Lyme disease states (Connecticut, Massachusetts, New Jersey, New York, Rhode Island, Minnesota, and Wisconsin). About 1,000 new cases of babesiosis are reported annually.

While the two diseases share some of the same symptoms, babesiosis is potentially fatal in immunocompromised patients and can be transmitted through blood transfusions in addition to tick bites, posing an additional public health threat.

Refined mathematical models may allow scientists to better predict areas that are at risk for B. microti expansion and to assess whether methods to reduce B. burgdorferi infection in ticks and mice may simultaneously reduce B. microti infection, Diuk-Wasser said.

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Sugar molecule links red meat consumption and elevated cancer risk in mice

While people who eat a lot of red meat are known to be at higher risk for certain cancers, other carnivores are not, prompting researchers at the University of California, San Diego School of Medicine to investigate the possible tumor-forming role of a sugar called Neu5Gc, which is naturally found in most mammals but not in humans.

In a study published in the Dec. 29 online early edition of the Proceedings of the National Academy of Sciences, the scientists found that feeding Neu5Gc to mice engineered to be deficient in the sugar (like humans) significantly promoted spontaneous cancers. The study did not involve exposure to carcinogens or artificially inducing cancers, further implicating Neu5Gc as a key link between red meat consumption and cancer.

"Until now, all of our evidence linking Neu5Gc to cancer was circumstantial or indirectly predicted from somewhat artificial experimental setups," said principal investigator Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine and member of the UC San Diego Moores Cancer Center. "This is the first time we have directly shown that mimicking the exact situation in humans -- feeding non-human Neu5Gc and inducing anti-Neu5Gc antibodies -- increases spontaneous cancers in mice."

Varki's team first conducted a systematic survey of common foods. They found that red meats (beef, pork and lamb) are rich in Neu5Gc, affirming that foods of mammalian origin such as these are the primary sources of Neu5Gc in the human diet. The molecule was found to be bio-available, too, meaning it can be distributed to tissues throughout the body via the bloodstream.

The researchers had previously discovered that animal Neu5Gc can be absorbed into human tissues. In this study, they hypothesized that eating red meat could lead to inflammation if the body's immune system is constantly generating antibodies against consumed animal Neu5Gc, a foreign molecule. Chronic inflammation is known to promote tumor formation.

To test this hypothesis, the team engineered mice to mimic humans in that they lacked their own Neu5Gc and produced antibodies against it. When these mice were fed Neu5Gc, they developed systemic inflammation. Spontaneous tumor formation increased fivefold and Neu5Gc accumulated in the tumors.

"The final proof in humans will be much harder to come by," Varki said. "But on a more general note, this work may also help explain potential connections of red meat consumption to other diseases exacerbated by chronic inflammation, such as atherosclerosis and type 2 diabetes.

"Of course, moderate amounts of red meat can be a source of good nutrition for young people. We hope that our work will eventually lead the way to practical solutions for this catch-22."

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Breast reconstruction using patient's own tissues yield higher satisfaction rates

For women who have undergone mastectomy, breast reconstruction using the patient's own tissues -- rather than implants -- provides higher satisfaction scores, reports a study in the January issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

But the findings may at least partly reflect differences in the characteristics of women choosing different options for breast reconstruction, according to the study by plastic surgeon Dr. Yassir Eltahir and colleagues of University Medical Center Groningen, the Netherlands.

Higher Satisfaction Score with Autologous Breast Reconstruction

The researchers used the recently developed "BREAST-Q" questionnaire to analyze patient satisfaction and quality of life after breast reconstruction. The BREAST-Q was designed to gauge these important outcomes from the patient's point of view.

The study included BREAST-Q surveys completed by 92 women who had breast reconstruction between 2006 and 2010. Forty-seven women underwent autologous reconstruction, with the patient's own tissues -- generally "donor" flaps from the abdomen -- used to create the new breast. The remaining 45 women underwent alloplastic reconstruction, using implants.

The results suggested that women choosing reconstruction with their own tissues were more satisfied with the results. Scores for satisfaction with the reconstructed breasts averaged about 75 (on a 100-point scale) after autologous reconstruction versus 65.5 for implant-based reconstruction.

Overall patient satisfaction scores were also higher with autologous reconstruction: about 82 versus 74.5. Scores for various aspects of quality of life -- including psychosocial, sexual, and physical well-being -- were not significantly different between groups.

Significant Differences in Patient Characteristics 

The researchers also noted some important differences between the two groups of patients. Women choosing autologous reconstruction were older: 51 versus 44 years. Autologous reconstruction was performed on a delayed basis, an average of 21 months after mastectomy; whereas implant-based reconstruction was usually performed immediately.

Women receiving implant reconstruction were also more likely to undergo reconstruction of both breasts. Many of these women underwent preventive double mastectomy because of high genetic risk of breast cancer.

Women undergoing autologous reconstruction were more likely to receive radiation therapy, had a higher average body weight, and were less educated. Complication rates were similar between groups, although the autologous reconstruction group had a higher rate of secondary corrective surgeries.

Women have several options for breast reconstruction after mastectomy, in terms of the type of reconstruction and immediate versus delayed reconstruction. Studies comparing the outcomes of autologous versus implant-based reconstruction have reported conflicting results. The new study, using the validated BREAST-Q questionnaire, suggests higher patient satisfaction rates for women undergoing reconstruction using their own tissues.

But the findings may reflect differences in patient characteristics between groups. For example, younger women undergoing immediate implant reconstruction may have higher expectations, compared to women who have waited several months for delayed autologous reconstruction. The researchers plan further studies to evaluate some of the questions raised by their preliminary results.

Meanwhile, Dr. Eltahir and coauthors emphasize that both methods of breast reconstruction provided good outcomes, with similar scores for quality of life. "The study found no ideal breast reconstruction suitable for all patients," the researchers write. "However, [it] may inform patients and medical teams in making decisions about breast reconstruction."

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Report on remission in patients with MS three years after stem cell transplant

Three years after a small number of patients with multiple sclerosis (MS) were treated with high-dose immunosuppressive therapy (HDIT) and then transplanted with their own hematopoietic stem cells, most of the patients sustained remission of active relapsing-remitting MS (RRMS) and had improvements in neurological function, according to a study published online by JAMA Neurology.

MS is a degenerative disease and most patients with RRMS who received disease-modifying therapies experience breakthrough disease. Autologous (using a patient's own cells) hematopoietic cell transplant (HCT) has been studied in MS with the goal of removing disease-causing immune cells and resetting the immune system, according to the study background.

The Hematopoietic Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) study examines the effectiveness of early intervention with HDIT/HCT for patients with RRMS and breakthrough disease. The article by Richard A. Nash, M.D., of the Colorado Blood Cancer Institute at Presbyterian/St. Luke's Medical Center, Denver, and coauthors reports on the safety, efficacy and sustainability of MS disease stabilization though three years after the procedures. Patients were evaluated through five years.

Study results indicate that of the 24 patients who received HDIT/HCT, the overall rate of event-free survival was 78.4 percent at three years, which was defined as survival without death or disease from a loss of neurologic function, clinical relapse or new lesions observed on imaging. Progression-free survival and clinical relapse-free survival were 90.9 percent and 86.3 percent, respectively, at three years. The authors note that adverse events were consistent with the expected toxic effect of HDIT/HCT and that no acute treatment-related neurologic adverse events were seen. Improvements in neurologic disability, quality-of-life and functional scores also were noted.

"In the present study, HDIT/HCT induced remission of MS disease activity up to three years in most participants. It may therefore represent a potential therapeutic option for patients with MS in whom conventional immunotherapy fails, as well as for other severe immune-mediated diseases of the central nervous system. Most early toxic effects were hematologic and gastrointestinal and were expected and reversible. Longer follow-up is needed to determine the durability of the response," the authors conclude.

Editorial: Moving Targets for Stem Cell Transplantation for Patients with MS

In a related editorial, M. Mateo Paz Soldán, M.D., Ph.D., of the University of Utah, Salt Lake City, and Brian G. Weinshenker, M.D., of the Mayo Clinic, Rochester, Minn., write: "This study and another phase 2 single-arm study leave little doubt that high-dose immunotherapy is able to substantially suppress inflammatory disease activity in patients with MS who have active disease in the short term. There is some evidence for long-term suppression of MS. Lessons have been learned about how treatment-related morbidity and mortality may be reduced. However, deaths have occurred, even in small studies, and aggressive regimens have resulted in lymphomas associated with Epstein-Barr virus."

"Nash et al show evidence of prolonged depletion of memory CD4+ cells, depletion of CD4+-dominant T-cell receptor clones and evidence of 'immune reset'; however, clinical or radiologic evidence of relapse trumps immunologic evidence of immune reset, and this study raises concern that those end points have not been adequately achieved. The jury is still out regarding the appropriateness and indication of HCT for MS," the authors conclude.

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How economic insecurity impacts diabetes control among patients

Difficulty paying for food and medications appears to be associated with poor diabetes control among patients in a study that examined the impact of economic insecurity on managing the disease and the use of health care resources, according to a report published online by JAMA Internal Medicine.

Increased access to health insurance offered by the Patient Protection and Affordable Care Act may not improve diabetes control among low-income patients because of social determinants of health, which are outside the scope of medical practice, such as difficulty paying for food, medications, housing or utilities (material need insecurities), according to the study background.

Seth A. Berkowitz, M.D., M.P.H., of Massachusetts General Hospital, Boston, and coauthors sought to determine the association between material need insecurities and diabetes control and the use of health care resources. Their study of 411 patients included data from June 2012 through October 2013 collected at a primary care clinic, two community health centers and a specialty treatment center for diabetes in Massachusetts.

The study found that, overall, 19.1 percent of patients reported food insecurity; 27.6 percent cited cost-related medication underuse; 10.7 percent had housing instability; 14.1 percent had trouble paying for utilities (energy insecurity); and 39.1 percent of patients reported at least one material need insecurity. Poor diabetes control (as measured by factors including hemoglobin A1c, low-density lipoprotein cholesterol level or blood pressure) was seen in 46 percent of patients.

According to the study results, food insecurity was associated with greater odds of poor diabetes control and increased outpatient visits but not increased emergency department(ED)/inpatient visits. Cost-related medication underuse was associated with poor diabetes control and increased ED/inpatient visits but not outpatient visits. Housing instability and energy (utilities) insecurity were associated with increased outpatient visits but not with diabetes control or with ED/outpatient visits. Having an increasing number of economic insecurities was associated with poor diabetes control and increased health care use.

"Health care systems are increasingly accountable for health outcomes that have roots outside of clinical care. Because of this development, strategies that increase access to health care resources might reasonably be coupled with those that address social determinants of health, including material need insecurities. In particular, food insecurity and cost-related medication underuse may be promising targets for real-world management of diabetes mellitus," the study concludes.

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Year of birth significantly changes impact of obesity-associated gene variant

“Looking at participants in the Framingham Heart Study, we found that the correlation between the best known obesity-associated gene variant and body mass index increased significantly as the year of birth of participants increased,” says Harvard Medical School instructor James Niels Rosenquist of the Massachusetts General Hospital Department of Psychiatry, lead author of the report.

Investigators working to unravel the impact of genetics versus environment on traits such as obesity may also need to consider a new factor: when individuals were born. In the current issue of PNAS Early Edition a multi-institutional research team reports finding that the impact of a variant in the FTO gene that previous research has linked to obesity risk largely depends on birth year, with no correlation between gene variant and obesity in study participants born in earlier years and a far stronger correlation than previously reported for those born in later years.

"Looking at participants in the Framingham Heart Study, we found that the correlation between the best known obesity-associated gene variant and body mass index increased significantly as the year of birth of participants increased," says James Niels Rosenquist, MD, PhD, of the Massachusetts General Hospital (MGH) Department of Psychiatry, lead author of the report. "These results -- to our knowledge the first of their kind -- suggest that this and perhaps other correlations between gene variants and physical traits may very significantly depending on when individuals were born, even for those born into the same families."

The authors note that most studies of interactions between genes and the environment have looked at differences within specific birth cohorts -- groups born during a particular span of years -- which would not account for changes in the larger environment that take place over time. To investigate whether different conditions experienced by different age groups might alter the impact of a gene variant, they analyzed data from participants in the Framingham Offspring Study -- which follows the children of participants in the original study -- gathered between 1971, when participants ranged in age from 27 to 63, and 2008.

Looking at the relationships between participants' body mass index (BMI), as measured eight times during the study period, the FTO variants they had inherited and when they were born revealed that the previously reported association between a specific FTO variant and BMI was seen, on average, only in participants born in later years. While there was no correlation between the obesity-risk variant and BMI for those born before 1942, in participants born after 1942 the correlation was twice as strong as reported in previous studies. While this study was not able to identify the environmental differences that combine with FTO variant to increase the risk of obesity, the authors note that post-World War II factors such as increased reliance on technology rather than physical labor and the availability of high-calorie processed foods are likely contributors.

"We know that environment plays a huge role in the expression of genes, and the fact that our effect can be seen even among siblings born during different years implies that global environmental factors such as trends in food products and workplace activity, not just those found within families, may impact genetic traits," says Rosenquist, an instructor in Psychiatry at Harvard Medical School. "Our results underscore the importance of interpreting any genetic studies with a grain of salt and leave open the possibility that new genetic risk factors may be seen in the future due to different genetically-driven responses to our ever-changing environment."

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Complications after thigh lift surgery common, but usually minor

Performed as part of body contouring procedures in patients with massive weight loss, a procedure called medial thigh lift carries a substantial risk of complications, reports a study in the January issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS).

"Wound complications in medial thighplasty are common, but most are minor and can be managed without reoperation," according to the new research by ASPS member surgeon, Dr. Jeffrey Adam Gusenoff and colleagues of University of Pittsburgh. The study is the first detailed look at complications after thigh lift surgery, performed as part of body contouring surgery after bariatric (weight reduction) surgery.

After Thigh Lift, Most Patients Have Mild Complications
 
Dr Gusenoff and coauthors analyzed their experience with medial thigh lift in 106 patients with massive weight loss, mainly after bariatric surgery. The patients were 90 women and 16 men, average age 45 years. Most patients undergoing bariatric surgery for severe obesity are left with excess, sagging skin folds of the thigh and other areas.

Overall, 68 percent of patients experienced some type of complication after thigh lift surgery. The complication rate varied with the extensiveness of surgery: from 43 percent for patients undergoing the least-extensive "horizontal thighplasty," to 64 percent with an intermediate "short-scar thighplasty," to 74 percent with the most-extensive "full-length vertical thighplasty."
But while complications were frequent, they usually weren't serious. The most common issues were minor wound healing problems: problems with wound closure (dehiscence) and fluid collections (seromas). Most of these were managed without any further surgery.

Six percent of patients had complications requiring additional surgery. Another 14 percent underwent further surgery to improve their cosmetic results.

New Findings on Risk Factors for Complications
 
Leg swelling (edema) developed in 22 percent of patients -- most undergoing the most-extensive type of thigh lift surgery. In all but two cases, the edema cleared up within a year after surgery.

Edema occurred mainly in patients undergoing the most extensive type of thigh lift, while seromas were more likely in patients with high blood pressure. Infections were more common in older patients, those with low thyroid function, and those undergoing liposuction at the same time as thigh lift.

With the increased use of bariatric surgery, the numbers of patients seeking body contouring surgery after massive weight loss have increased sharply. Thigh lift surgery has demonstrated functional and cosmetic benefits for patients, but concerns about complications may limit the use of this procedure.

The new study -- the largest series of patients undergoing thigh lifting surgery reported to date -- shows a high overall rate of complications, especially after the more-extensive procedures. However, most of these complications are relatively minor wound-healing issues, resolving without the need for further surgery. Swelling is also common, and also resolves over time in most cases.

"Despite these considerable challenges, massive weight loss patients also stand to benefit immensely from contouring procedures," Dr Gusenoff and colleagues conclude. The researchers believe their results will be useful in counseling patients as to what to expect after thigh lift surgery. They also outline some steps that may help to reduce the risk of common complications, and call for further studies to compare the outcomes of different surgical techniques.

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What are mechanisms of zooxanthella expulsion from coral?

Coral bleaching, which often results in the mass mortality of corals and in the collapse of coral reef ecosystems, has become an important issue around the world, with the number of coral reefs decreasing annually. Associate Professor Kazuhiko Koike and Ms. Lisa Fujise of the Graduate School of Biosphere Science at Hiroshima University and their collaborators have proposed mechanisms that might cause coral bleaching and damage. This research group demonstrated that corals more actively digest and expel damaged symbiotic zooxanthellae under conditions of thermal stress, and that this is likely to be a mechanism that helps corals to cope with environmental change. On the other hand, if the stressful conditions prevail, accumulation of the damaged symbiotic zooxanthellae may not maintain the expulsion, which will gradually accumulate in coral tissues. These researchers consider that this loss of zooxanthellae and the accumulation of damaged cells results in coral bleaching. These results were published as an article in PLOS ONE.

The symbiosis between corals and zooxanthellae (dinoflagellate genus Symbiodinium) form the foundation of coral reef biology. The aforementioned research group demonstrated that the expulsion of zooxanthellae at 27°C (non-thermal stress conditions) is part of a regulatory mechanism that maintains zooxanthellal density and a stable carbon concentration with expulsion of digested or normal forms of symbionts. However, at 30°C (moderate thermal stress), Symbiodinium were damaged, and corals selectively digested the damaged cells or immediately expelled them without digestion by exocytosis, which is most likely to reflect an adaptive mechanism in response to moderate thermal stress to avoid the accumulation of damaged cells. However, under thermal stress, the accumulation of damaged cells may exceed the increased rate of expulsion of digested zooxanthella. More photosynthetically damaged zooxanthellae were observed upon prolonged exposure to thermal stress, and were released by corals without digestion, therefore preventing their accumulation. This response may be an adaptive strategy to moderate stress to ensure survival, but the accumulation of damaged Symbiodinium, which causes subsequent coral deterioration, may occur when this response cannot cope with the magnitude or duration of environmental stress, and this might be a possible mechanism underlying coral bleaching during prolonged moderate thermal stress.

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Study sheds light on what causes cells to divide

A time series of a single E. coli cell from birth to division.

When a rapidly-growing cell divides into two smaller cells, what triggers the split? Is it the size the growing cell eventually reaches? Or is the real trigger the time period over which the cell keeps growing ever larger?

A novel study published online in the journal Current Biology has finally provided an answer to this long unsolved conundrum. And it's not what many biologists expected.

"How cells control their size and maintain stable size distributions is one of the most fundamental, unsolved problems in biology," said Suckjoon Jun, an assistant professor of physics and molecular biology at UC San Diego, who headed the research study with Massimo Vergassola, a professor of physics. "Even for the bacterium E. coli, arguably the most extensively studied organism to date, no one has been able to answer this question."

Finding a solution was more than a basic-science pursuit for the scientists, who pointed out that learning more about the triggers of cell division would enable researchers to better understand such processes as the runaway cell division that leads to cancer. To conduct the study, Jun and his colleagues developed a tiny device to isolate and physically manipulate individual genetic materials.

"It turned out that we can use this device to also follow the life history of thousands of individual bacterial cells for hundreds of generations," he said. "We looked at the growth patterns of the cells very, very carefully, and realized that there is something really special about the way the cells control their size."

"In our study, we monitored the growth and division of hundreds of thousands of two kinds of bacterial cells, E. coli and B. subtilis, under a wide range of tightly controlled steady-state growth conditions," said Jun. "This produced statistical samples about three orders of magnitude, or a thousand times better, than those previously available. We could thus pursue an unprecedented level of quantitative analysis."

The scientists found through their development of mathematical models that matched their experimental data that the growth of cells followed the growth law, essentially exponential growth based on a constant rate. But they also found to their surprise that cell size or the time between cell divisions had little to do with when the cells divided. Instead, to keep the distribution of different sized cells within a population constant, the cells followed what the researchers termed "an extraordinarily simple quantitative principle of cell-size control."

"Specifically, we showed that cells sense neither space nor time, but add constant size irrespective of their birth size," said Jun. "This 'adder' principle automatically ensures stability of size distributions."

"E. coli and B. subtilis are one billion years divergent in evolution, and they are the textbook examples of the diversity of molecular details for biological controls in different bacterial species. Thus, their sharing the same quantitative principle for size maintenance is a textbook level discovery."

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For facial transplantation patients, blink assessment is essential

Face transplantation can dramatically enhance a patient's quality of life after severe facial trauma, but lack of attention to eyelid function and vision can leave patients with impaired vision, corneal exposure, eyelid retraction that occurs when the upper or lower eyelid pulls away from the eyeball, and other eyelid-related complications. A new retrospective study led by researchers at NYU Langone Medical Center makes the case for careful blink assessment in planning facial transplant procedures, as well as during and after transplant, and post-transplant revision surgeries. Their work appears online in the January 2015 issue of Plastic and Reconstructive Surgery.

The research team, led by senior author Eduardo D. Rodriguez, MD, DDS, the Helen L. Kimmel professor and chair of the Department of Plastic Surgery at NYU Langone, and Director of its Institute of Reconstructive Plastic Surgery, underscore the importance of being extremely methodical in assessing eyelid function because loss of the protective blink reflex can not only compromise vision, but lead to blindness over time. Blinking is a complex facial function that has not been carefully addressed in the facial transplantation literature before this manuscript.

"There is no guarantee that the eyelids will function normally after transplantation," explains Dr. Rodriguez. "Careful and methodical preparation prior to facial transplantation, and attentiveness to post-surgical eyelid function, is essential to preserving vision in these cases."

In the paper, "Eyelid Transplantation: Lessons from a Total Face Transplant and the Importance of Blink," Dr. Rodriguez and his co-investigators report on a patient with a severe injury to the central and lower face caused by a gunshot injury. They describe what procedures they used to preserve and restore blinking function, which can be damaged from the trauma and during surgery. Nerve injury also can occur with tissue handling and during dissection of vital structures.

This particular patient, Richard Lee Norris of Virginia, whose case has been well documented in professional literature and by media outlets worldwide, had one of the most extensive and comprehensive face transplants reported to date, involving total face, double jaw, and tongue transplantation. Slow-motion video analysis of blinking, especially involuntary or "reflex" blinking, was done before face transplantation and up to several months after the surgery.

Visual acuity was evaluated prior to transplantation, eye movement was also assessed preoperatively, and again, six months following transplantation. Evaluation of the eye socket in surgical planning and postoperatively was also performed.

Before the first surgery, the patient had complete eyelid closure in both eyes, equivalent to 100 percent normal voluntary blinking function, but involuntary blinking was impaired in the left eye with diminution on the right (40 percent) following the initial injury. After the surgery, reflex blinking of the right eye improved to 70 percent. The left eye fared well as reflex blink was preserved to the same degree from before the transplant (90 percent). Six months after transplantation, the patient had normal visual acuity and eye movement in both eyes. Involuntary blinking improved to 90 percent in the right eye and 100 percent in the left eye.

"This is the first article addressing blinking in the facial transplant setting," commented Dr. Rodriguez. "We have to work carefully to preserve the underlying muscle, the eyelids structures and their innervation. Blinking may seem like a simple, automatic function to many people. However, if you can't blink, your corneas are susceptible to the extremes of weather and exposure of the corneas while you sleep due to incomplete closure. This ultimately results in painful corneal exposure and potential scarring over part of the pupil which will ultimately impair vision."

The research team hopes that this retrospective study stimulates more meticulous attention to the eye in facial transplantation.

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Mechanism of toxin's inflammatory effect on lungs found

A study released Dec. 23 describes a never-before-seen mechanism by which a bacterial toxin leads to severe inflammation in asthma and other acute and chronic pulmonary diseases. Researchers from The University of Texas Health Science Center at San Antonio said the discovery could result in development of therapeutic strategies that improve health in individuals who suffer from airway diseases.

The offending party is the Mycoplasma pneumoniae Community Acquired Respiratory Distress Syndrome (CARDS) toxin. The CARDS toxin, discovered at the Health Science Center in 2006, is considered the first major bacterial respiratory toxin discovered since the days of diphtheria and pertussis.

Persistent and harmful

M. pneumoniae is a common and persistent infection in the lungs and airway. Once there, it produces the CARDS toxin and a cascade of harmful effects. Specifically, CARDS toxin reacts with NALP3, a key molecule that regulates inflammatory pathways, leading to excessive activation of pro-inflammatory reactions.

"Inflammation is important for self-protection from infection and any injury, but when a microbial factor such as the CARDS toxin controls inflammation, bad things happen," said study author Joel B. Baseman, Ph.D., professor of microbiology and immunology in the School of Medicine at the UT Health Science Center and director of the Center for Airway Inflammation Research (cAIR). "Through this mechanism, CARDS toxin triggers exaggerated and prolonged inflammation that results in tissue injury, airway narrowing, mucus hypersecretion, wheezing and coughing."

Multiple infections

"Because M. pneumoniae infections occur so frequently in children and adults and CARDS toxin is such a powerful inducer of inflammation, it is likely that co-infections involving M. pneumoniae, CARDS toxin and other respiratory pathogens result in enhanced severity of disease," said Santanu Bose, Ph.D., study co-author and associate professor at Washington State University.

"Now that we have identified this pathway of disease development, our goal is to prevent the wide range of airway pathologies caused by CARDS toxin with drugs, vaccines and protective antibodies," said study co-author Thirumalai R. Kannan, Ph.D., associate professor/research in the Department of Microbiology and Immunology at the UT Health Science Center and also a member of cAIR. "We are undertaking those studies now."

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Reprogramming stem cells may prevent cancer after radiation

The body has evolved ways to get rid of faulty stem cells. A University of Colorado Cancer Center study published in the journal Stem Cells shows that one of these ways is a "program" that makes stem cells damaged by radiation differentiate into other cells that can no longer survive forever. Radiation makes a stem cell lose its "stemness." That makes sense: you don't want damaged stem cells sticking around to crank out damaged cells.

The study also shows that this same safeguard of "programmed mediocrity" that weeds out stem cells damaged by radiation allows blood cancers to grow in cases when the full body is irradiated. And by reprogramming this safeguard, we may be able to prevent cancer in the aftermath of full body radiation.

"The body didn't evolve to deal with leaking nuclear reactors and CT scans. It evolved to deal with only a few cells at a time receiving dangerous doses of radiation or other insults to their DNA," says James DeGregori, PhD, investigator at the CU Cancer Center, professor of Biochemistry and Molecular Genetics at the CU School of Medicine, and the paper's senior author.

DeGregori, doctoral student Courtney Fleenor, and colleagues explored the effects of full body radiation on the blood stem cells of mice. In this case, radiation increased the probability that cells in the hematopoietic stem cell system would differentiate. Only, while most followed this instruction, a few did not. Stem cells with a very specific mutation were able to disobey the instruction to differentiate and retain their "stemness." Genetic inhibition of the gene C/EBPA allowed a few stem cells to keep the ability to act as stem cells. With competition from other, healthy stem cells removed, the stem cells with reduced C/EBPA were able to dominate the blood cell production system. In this way, the blood system transitioned from C/EBPA+ cells to primarily C/EBPA- cells.

Mutations and other genetic alterations resulting in inhibition of the C/EBPA gene are associated with acute myeloid leukemia in humans. Thus, it's not mutations caused by radiation but a blood system reengineered by faulty stem cells that creates cancer risk in people who have experienced radiation.

"It's about evolution driven by natural selection," DeGregori says. "In a healthy blood system, healthy stem cells out-compete stem cells that happen to have the C/EBPA mutation. But when radiation reduces the heath and robustness (what we call 'fitness') of the stem cell population, the mutated cells that have been there all along are suddenly given the opportunity to take over."

Think about it in terms of chipmunks and squirrels: reducing an ecosystem's population of chipmunks may allow squirrels to flourish -- especially if the way in which chipmunks are reduced changes the ecosystem to favor squirrels, similar to how radiation changes the body in a way that favors C/EBPA-mutant stem cells).

These studies don't just tell us why radiation makes hematopoietic stem cells (HSCs) differentiate; they also show that by activating a stem cell maintenance pathway, we can keep it from happening. Even months after irradiation, artificially activating the NOTCH signaling pathway of irradiated HSCs lets them act "stemmy" again -- restarting the blood cell assembly line in these HSCs that would have otherwise differentiated in response to radiation.

When DeGregori, Fleenor and colleagues activated NOTCH in previously irradiated HSCs, it kept the population of dangerous, C/EBPA cells at bay. Competition from non-C/EBPA-mutant stem cells, with their fitness restored by NOTCH activation, meant that there was no evolutionary space for C/EBPA-mutant stem cells.

"If I were working in a situation in which I was likely to experience full-body radiation, I would freeze a bunch of my HSCs," DeGregori says, explaining that an infusion of healthy HSCs after radiation exposure would likely allow the healthy blood system to out-compete the radiation-exposed HSC with their "programmed mediocrity" (increased differentiation) and even HSC with cancer-causing mutations. "But there's also hope that in the future, we could offer drugs that would restore the fitness of stem cells left over after radiation."

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Protein identified as possible universal therapeutic target for many infections, including Ebola

A protein called GRP78 could be a universal therapeutic target for treating human diseases like brain cancer, Ebola, Influenza, Hepatitis and superbug bacteria such as MRSE and MRSA, according to a Virginia Commonwealth University-led pre-clinical study published this month in the Journal of Cellular Physiology.

By using a drug combination of the clinically tested OSU-03012 (AR-12) and FDA approved Phosphodiesterase 5 Inhibitors (Viagra, Cialis) to target GRP78 and related proteins, researchers prevented the replication of a variety of major viruses in infected cells, made antibiotic-resistant bacteria vulnerable to common antibiotics and found evidence that brain cancer stem cells were killed. Data were obtained in multiple brain cancer stem cell types, and using Influenza, Mumps, Measles, Rubella, RSV, CMV, Adenovirus, Coxsakie virus, Chikungunya, Ebola, Hepatitis, E. coli, MRSA, MRSE and N. gonorrhoeae, among others.

"Basically, we've got a concept that by attacking GRP78 and related proteins: (a) we hurt cancer cells; (b) we inhibit the ability of viruses to infect and to reproduce; and (c) we are able to kill superbug antibiotic-resistant bacteria," said the study's lead investigator, Paul Dent, Ph.D., Professor in the Department of Biochemistry and Molecular Biology at VCU School of Medicine, and Universal Chair for Signal Transduction.

GRP78 is part of a family of proteins called chaperones. The job of a chaperone is to help shape chains of amino acids into proteins and then to keep those proteins active in the correct 3D shape. The OSU/Viagra drug combination attacks GRP78 and other chaperones, thereby killing cancer cells. After learning of the drug combination's effect on GRP78 in cancer cells, Dent and his team began to target GRP78 for infectious diseases such as viruses and bacteria.

The chaperone proteins are very important in cancer cells or virus infected cells because these cells make extra protein compared to normal / uninfected cells. The team found that the OSU/Viagra drug combination reduced infectivity via reduced viral receptor expression on the surface of target cells and the prevention of virus replication in infected cells. The drug combination was able to reduce expression of viral receptors for Ebola, Marburg, Hepatitis A, B and C, and Lassa fever viruses. In cancer cells the drug combination reduced the expression of oncogene receptors, too.

In bacteria, the drug combination reduced expression of the equivalent GRP78 protein, in bacteria called Dna K, and induced cell death in pan-antibiotic resistant forms of E. coli, MRSE, MRSA and N. gonorrhoeae.

"The findings open an avenue of being able to treat viral infections, infections that certainly most people would say we'll never be able to treat; they prove that GRP78 is a "drugable" target to stop viruses from reproducing and spreading," Dent said. "And in the case of bacteria, we have a new antibiotic target, Dna K, that if we're careful and only use the OSU drug in hospitals, we've got something that can help to treat the superbugs."

Dent said that the next steps have already been taken and are leading to new discoveries: "we know in mice that the OSU/Viagra treatment can kill tumor cells but doesn't harm normal tissues like the liver and the heart. Of even more importance we've just discovered that the OSU/Viagra combination can reduce the levels of proteins called "pumps" in the mouse brain. Pumps are responsible for making tumor cells resistant to chemotherapy and for stopping life-saving brain cancer chemotherapy from entering into the brain and killing cancer."

VCU researchers previously have found Viagra drug combinations to be beneficial in many ways. In 2010, for example, Rakesh Kukreja, Ph.D., scientific director of the VCU Pauley Heart Center and the Eric Lipman professor in cardiology in the VCU School of Medicine, in collaboration with Dent, found that Viagra improved the effectiveness of the breast cancer treatment Doxorubicin while protecting the heart from harm caused by the chemotherapy. In 2013 and 2014 Dr. Dent obtained similar data with Viagra and conventional chemotherapy in bladder, pancreatic and pediatric brain cancer cells. Based on work from Dent's group, in the spring of 2015 a new phase I clinical trial will open at VCU Massey Cancer Center combining the colon cancer drug regorafenib with Viagra for all solid tumor patients.

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Binge drinking disrupts immune system in young adults, study finds

Binge drinking in young, healthy adults significantly disrupts the immune system, according to a study led by a researcher now at Loyola University Chicago Stritch School of Medicine.

Depending on their weight, study participants drank four or five shots of vodka. Twenty minutes after reaching peak intoxication, their immune systems revved up. But when measured again, at two hours and five hours after peak intoxication, their immune systems had become less active than when sober.

The study by Majid Afshar, MD, MSCR, and colleagues is published online ahead of print in Alcohol, an international, peer-reviewed journal.

Binge drinking increases the risk of falls, burns, gunshot wounds, car accidents and other traumatic injuries. One-third of trauma patients have alcohol in their systems.

In addition to increasing the risk of traumatic injuries, binge drinking impairs the body's ability to recover from such injuries. Previous studies have found, for example, that binge drinking delays wound healing, increases blood loss and makes patients more prone to pneumonia and infections from catheters. Binge drinkers also are more likely to die from traumatic injuries. The study led by Dr. Afshar illustrates another potentially harmful effect of binge drinking

Drinkers generally understand how binge drinking alters behavior. "But there is less awareness of alcohol's harmful effects in other areas, such as the immune system," said Elizabeth Kovacs, PhD, a co-author of the study and director of Loyola's Alcohol Research Program.

The National Institute on Alcohol Abuse and Alcoholism defines binge drinking as drinking enough to reach or exceed a blood alcohol content of .08, the legal limit for driving. This typically occurs after four drinks for women or five drinks for men, consumed in two hours. One in six U.S. adults binge drinks about four times a month, and binge drinking is more common in young adults aged 18 to 34, according to the Centers for Disease Control and Prevention.

Dr. Afshar led the study while at the University of Maryland, where he completed a fellowship before joining Loyola. The study included eight women and seven men with a median age of 27. Each volunteer drank enough shots of vodka -- generally four or five -- to meet the definition of binge drinking. (A 1.5 oz. shot of vodka is the alcohol equivalent of a five-ounce glass of wine or 12-ounce can of beer.) Dr. Afshar and colleagues took blood samples at 20 minutes, two hours and five hours after peak intoxication because these are times when intoxicated patients typically arrive at trauma centers for treatment of alcohol-related injuries.

The blood samples showed that 20 minutes after peak intoxication, there was increased immune system activity. There were higher levels of three types of white blood cells that are key components of the immune system: leukocytes, monocytes and natural killer cells. There also were increased levels of proteins called cytokines that signal the immune system to ramp up.

Two hours and five hours after peak intoxication, researchers found the opposite effect: fewer circulating monocytes and natural killer cells and higher levels of different types of cytokines that signal the immune system to become less active.

Dr. Afshar is planning a follow-up study of burn unit patients. He will compare patients who had alcohol in their system when they arrived with patients who were alcohol-free. He will measure immune system markers from each group, and compare their outcomes, including lung injury, organ failure and death.

Dr. Afshar is a pulmonologist, critical care physician and epidemiologist. He is an assistant professor in the Division of Pulmonary and Critical Care Medicine and in the Department of Public Health Sciences of Loyola University Chicago Stritch School of Medicine.

Loyola's nationally recognized Alcohol Research Program investigates such issues as how heavy drinking hinders the body's ability to recover from burns and trauma; how alcohol abuse damages bones; and whether teen binge drinking can increase the risk of mood disorders later in life.

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Enzyme's alter ego helps activate the immune system

Already known to cut proteins, the enzyme SPPL3 turns out to have additional talents, according to a new study from Johns Hopkins. In its newly discovered role, SPPL3 works without cutting proteins to activate T cells, the immune system's foot soldiers. Because its structure is similar to that of presenilin enzymes, which have been implicated in Alzheimer's disease, the researchers believe their findings could shed more light on presenilin functions, in addition to providing new insight into how the immune system is controlled.

A summary of their findings was published on Dec. 22, 2014 in the journal Molecular and Cellular Biology.

"No one could have predicted that SSPL3 was involved in T cell activation," says Joel Pomerantz, Ph.D., an associate professor of biological chemistry at The Johns Hopkins University. "It walks like a duck and quacks like a duck, but its duck-like abilities don't come into play here."

T cells are immune system cells that kill invading cells and help activate other immune cells. When a foreign protein binds to a receptor protein on the outside of a T cell, a signal relay system is activated. It finishes when a protein called NFAT moves to the nucleus and turns on a number of genes to fully prepare the T cell for battle. Some of what happens in between is known, but Pomerantz and his team wanted to find more players in the process.

The researchers looked for proteins that could increase NFAT's activity and found SPPL3, an enzyme that proved essential to NFAT's activation but had never before been implicated in immune system function. Further tests properly placed SPPL3 within the sequence of events that lead to NFAT activation.

SPPL3 lives in the membrane of the endoplasmic reticulum (ER), a ruffled, membrane-bound compartment inside the cell that helps process new proteins, where it seems to encourage interactions between STIM1 and Orai1, two known components of the NFAT signal relay system. But SPPL3 turned out to accomplish this without using its enzymatic, or protein-cutting, abilities. It also encourages the release of calcium from the ER, which contributes to the signaling system, though it is unclear whether this is something it does directly or indirectly.

"SPPL3 is a relatively uncharacterized protein that had never before been implicated in immune system function," says Pomerantz. "It opens up a whole new set of scientific questions."

Pomerantz thinks that SPPL3 could be used as a drug target to either enhance the activation of T cells in immunodeficient individuals or to suppress it in those with overactive immune systems. He also plans to study the ability of SPPL3 to mediate the influx of calcium into the cell and the release of calcium from the ER, since calcium is integral to the functioning of many cell signaling networks.

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