UT Southwestern researchers find new way to combat multidrug-resistant bacteria in burn injuries

A new way to fight multidrug-resistant bacteria by blinding them rather than killing them proved highly effective in a model of burn injuries, UT Southwestern Medical Center research shows.

(A) Carboxy-functionalized polystyrene micro-beads of 1 μm diameter are activated using EDC/NHS, and covalently coupled to GST (control beads) or GST-MAM7 (inhibitor beads) using Sulfo-SMPB. This results in directional coupling of recombinant proteins to the bead surface via the cysteine-containing GST domain. (B) Schematic of GST-MAM7 bead mimicry of bacterial MAM7 presentation.

"In the United States, there are more than 1 million burn injuries and 100,000 hospitalizations annually. Up to 75 percent of the mortality in burn patients is associated with infections, which are particularly common in patients who suffer extensive burns - those that cover 40 percent or more of the body," said Dr. Steven Wolf, Section Chief for Burns and Professor of Surgery at UT Southwestern Medical Center.

Dr. Wolf, one of three senior authors of the study published today in Scientific Reports, is also a former Director of the Burn Center at the U.S. Army Institute of Surgical Research in San Antonio, Texas.

"Rather than killing the bacteria, we blinded them so they could not find the places where they normally stick to the host (body's) cells. If bacteria cannot bind, they cannot grow," said Dr. Wolf, who is also Surgery's Vice Chair for Research and holder of the Golden Charity Guild Charles R. Baxter, M.D. Chair.

The study done in rats targeted one of the most lethal pathogens: multidrug-resistant Pseudomonas aeruginosa, which is found in approximately 33 percent of all burn cases and in 59 percent of extensive burns. The researchers showed that topical application of an engineered adhesion inhibitor molecule - Multivalent Adhesion Molecule 7, or MAM7 - substantially decreased the bacterial levels in wounds in the first 24 hours after administration and prevented the spread of the infection to adjacent tissue for three more days. In addition, the experimental molecule aided wound healing and maintained normal inflammatory responses to the burn, the researchers report.

"Antibiotic-resistant bacteria are an increasingly prevalent problem in the clinic and hospital, so new ways to prevent and treat infections are direly needed. Antibiotics work by killing bacteria, which places microbes under extreme pressure to develop antibiotic resistance," said co-senior author Dr. Kim Orth, Professor of Molecular Biology and Biochemistry at UT Southwestern.

"Our approach doesn't target bacterial survival; rather it targets the microbes' ability to damage the host - its virulence. There is no reason for the bacteria to become resistant to this approach. Being unable to bind to wounded tissue is an inconvenience, and the bacteria move on," Dr. Orth said.

She compared the situation to the search for parking at a shopping mall.

"If all the parking spaces are filled, then the bacteria have no place to park," said Dr. Orth, a Howard Hughes Medical Institute Investigator who also holds the Earl A. Forsythe Chair in Biomedical Science and is a W.W. Caruth, Jr. Scholar in Biomedical Research at UT Southwestern.

The experimental molecule was developed in the Orth laboratory and grew out of the postdoctoral research project of the study's third senior author, Dr. Anne-Marie Krachler, now with the McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth).

When working at UT Southwestern, Dr. Krachler studied a group of adhesion molecules called adhesins that are created by bacteria to bind, or stick to cells in an early and crucial step in causing infection. Although most adhesins are specific to various pathogens, members of the adhesion family she identified - Multivalent Adhesion Molecules, including MAM7 - are used by most gram-negative bacteria, including the type used in this burn study.

In one UTSW experiment, Dr. Krachler detached MAM7 from the bacteria that produce it and showed that the lack of MAM7 made the bacteria much less able to cause infection. In 2013, Dr. Orth gave a UT Southwestern President's Lecture describing the molecular activity of MAM7. Dr. Wolf was in attendance, and approached Dr. Orth about a collaboration to test the efficacy of MAM7 using a fluorescent strain of antibiotic-resistant bacteria in a live animal model.

That led to the multiyear effort to develop the recombinant MAM7 inhibitor attached to a scaffold made of bacteria-sized polymer microbeads that was used in this study. UT Southwestern has an international patent application filed on the molecule.

"We attached lots of copies of MAM7 to the microbeads. In this study, we found that topically applied MAM7-coupled microbeads reach the cells' binding sites first and - for at least four days in this experiment - stay there, without hindering wound healing. The MAM7 adhesion inhibitors remain on the wounds and prevent the bacteria from binding to the tissue," Dr. Orth said.

In addition to burns, Dr. Krachler said, this strategy could work against diabetic ulcers and surgical wounds that can become infected.

"What's exciting about MAM7 is that the agent is so broad-spectrum. Most bacteria have their own specific type of adhesion molecules. For instance Vibrio uses one kind and Salmonella uses a different one and multidrug-resistant bacteria another, but almost all of them want to park in the same place.

"Antibiotics are amazing drugs, and they have saved countless lives since their discovery more than 80 years ago. But there is a challenge - the challenge of antibiotic resistance that has made many antibiotics ineffective. A material that targets virulence instead of killing bacteria could be a way to treat infections that are resistant to antibiotics," she said. "This is a trial in rats. A future goal is to use this strategy in patients."

Following the success of this proof-of-concept study, additional steps include testing whether the anti-adhesion strategy might also block infection of bacteria that can cause lethal infections during surgery, Dr. Orth said.

Ref : http://www.nature.com/articles/srep39341

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

A subset of lung tumours is exquisitely sensitive to a class of recently approved anti-cancer drugs. Researchers at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Vienna and the Ludwig Institute for Cancer Research in Oxford published this finding in the journal Nature Communications. It opens the way for new clinical trials in a type of cancer considered to be "undruggable" and may lead to a therapy for up to 10% of lung cancer patients.

(Vienna, 6th of December 2016) Lung cancer remains the leading cause of cancer-related deaths worldwide. In contrast to other tumour types, lung tumours present a high number of genomic alterations - this is a consequence of exposure to carcinogenic substances found in tobacco smoke, which is the main cause of lung cancer. About 10% of lung tumours carry mutations in a gene called ATM. However, there are no drugs available in the clinic to treat ATM mutant lung cancer.

With cutting edge high-throughput drug screens that analyse how the genetic makeup of the patient affects their response to drugs, the team of Sebastian Nijman, CeMM Adjunct PI and Group Leader at the Ludwig Institute for Cancer Research in Oxford made a surprising discovery: Cancer cells with ATM mutations are sensitive for drugs that inhibit an enzyme called MEK. The study was published in Nature Communications (DOI: 10.1038/NCOMMS13701)

MEK is part of a biochemical pathway which is responsible for supporting proliferation and survival of the cell, while ATM plays a central role during the DNA damage response. In ATM deficient lung cancer cells, Nijman's team found that MEK inhibition results in cells being unable to keep proliferating and leads to apoptosis. An unexpected finding, as MEK inhibitors have so far been approved for the treatment of a type of skin cancer but not for lung cancer.

"Normally lung cancer cells are resistant to MEK inhibition as they activate compensatory signals," Ferran Fece, one of the two first authors on the study and former PhD student at CeMM, explains. "In contrast, ATM mutant cells fail to do this and subsequently cannot cope with the blocking of MEK and die. We call this type of unexpected drug sensitivity synthetic lethality".

  Trametinib

Michal Smida, the other shared first author on the article and former PostDoc at CeMM, adds: "We knew that cancer mutations can lead to extreme sensitivity to some drugs. But finding these cancer Achilles' heels is very difficult as they are difficult to predict and extremely rare. We screened a large number of gene and drug combinations and got lucky."

The study constitutes a substantial contribution for the development of a future precision medicine: ATM mutations could be used as a potential biomarker to stratify lung cancer patients to receive a MEK inhibitor. ATM is found to be mutated in 8-10% of lung adenocarcinomas - given that this type of tumour is among the most prevalent for both men and women worldwide, a significant number of patients could benefit from a MEK inhibitor based treatment. 


More : http://www.nature.com/articles/ncomms13701

New Application of Existing Drug Offers Personalized Therapy for Lung Cancer

Moderate coffee consumption may offer protection against age-related cognitive decline

A new report from the Institute for Scientific Information on Coffee (ISIC), a not-for-profit organisation devoted to the study and disclosure of science related to coffee and health, highlights the potential role of coffee consumption in reducing the risk of cognitive decline. The report concludes that a moderate intake of coffee (3-5 cups per day) may provide protection against age-related cognitive decline and other neurodegenerative diseases such as Alzheimer's and Parkinson's.

The report provides a summary of the research presented at ISIC's symposium, titled 'Nutrition, Coffee and Age-Related Cognitive Decline', held during the European Union Geriatric Medicine Society's 2016 Congress in Lisbon, Portugal. The findings are particularly relevant given Europe's ageing population: the number of people aged 60 years or over is projected to rise to 217.2 million by 2030, therefore understanding and communicating diet and lifestyle factors that may limit age-related cognitive decline will help to improve the quality of life for this growing demographic.

The symposium speakers whose insights and research contributed to ISIC's report were:

• Professor Lisette de Groot, Professor of Nutrition and Ageing, Division of Human Nutrition at Wageningen University (The Netherlands)
• Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC) (Portugal)
• Dr Elisabet Rothenberg, Associate Professor of Nutrition at Kristianstad University (Sweden)

Key highlights about coffee from the report include:

• Research published in 2016 suggests that moderate coffee consumption can reduce the risk of developing Alzheimer's by up to 27%. Research has suggested that it is regular, long-term coffee drinking that is key to helping to reduce the risk of Alzheimer's Disease.
• The association between coffee consumption and cognitive decline is illustrated by a 'U-shaped' pattern in recent meta-analyses, with the greatest protection seen at an intake of approximately 3-5 cups of coffee per day.
• Although the precise mechanisms of action behind the suggested association between coffee and age-related cognitive decline are unknown, caffeine is likely to be involved. There are many other compounds in coffee, such as antioxidants and anti-inflammatory agents, which may also play a role. Caffeic acid, for example, is a polyphenol (antioxidant) found in coffee, and research suggests that these may be associated with improved cognitive function.

Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC), Portugal, commented:

"Healthcare professionals have an important part to play in providing patients with accurate research-based information, to help them to follow a healthy diet and lifestyle, and in turn, reduce their risk of age-related cognitive decline. Moderate coffee consumption could play a significant role in reducing cognitive decline which would impact health outcomes and healthcare spending across Europe."

In its Scientific Opinion on the safety of caffeine, the European Food Safety Authority (EFSA) concluded that intakes of up to 400mg of caffeine (the equivalent of up to 5 cups of coffee per day), from all sources, do not raise any concerns for healthy adults. One cup of coffee provides approximately 75-100mg caffeine.

 

Australian researchers have discovered remarkable evolutionary changes to insulin regulation in two of the nation's most iconic native animal species - the platypus and the echidna - which could pave the way for new treatments for type 2 diabetes in humans.

The findings, now published in the Nature journal Scientific Reports, reveal that the same hormone produced in the gut of the platypus to regulate blood glucose is also surprisingly produced in their venom.

The research is led by Professor Frank Grutzner at the University of Adelaide and Associate Professor Briony Forbes at Flinders University.

The hormone, known as glucagon-like peptide-1 (GLP-1), is normally secreted in the gut of both humans and animals, stimulating the release of insulin to lower blood glucose.

But GLP-1 typically degrades within minutes.

In people with type 2 diabetes, the short stimulus triggered by GLP-1 isn't sufficient to maintain a proper blood sugar balance. As a result, medication that includes a longer lasting form of the hormone is needed to help provide an extended release of insulin.

"Our research team has discovered that monotremes - our iconic platypus and echidna - have evolved changes in the hormone GLP-1 that make it resistant to the rapid degradation normally seen in humans," says co-lead author Professor Frank Grutzner, from the University of Adelaide's School of Biological Sciences and the Robinson Research Institute.

"We've found that GLP-1 is degraded in monotremes by a completely different mechanism. Further analysis of the genetics of monotremes reveals that there seems to be a kind of molecular warfare going on between the function of GLP-1, which is produced in the gut but surprisingly also in their venom," he says.

The platypus produces a powerful venom during breeding season, which is used in competition among males for females.

"We've discovered conflicting functions of GLP-1 in the platypus: in the gut as a regulator of blood glucose, and in venom to fend off other platypus males during breeding season. This tug of war between the different functions has resulted in dramatic changes in the GLP-1 system," says co-lead author Associate Professor Briony Forbes, from Flinders University's School of Medicine.

"The function in venom has most likely triggered the evolution of a stable form of GLP-1 in monotremes. Excitingly, stable GLP-1 molecules are highly desirable as potential type 2 diabetes treatments," she says.

Professor Grutzner says: "This is an amazing example of how millions of years of evolution can shape molecules and optimise their function.

"These findings have the potential to inform diabetes treatment, one of our greatest health challenges, although exactly how we can convert this finding into a treatment will need to be the subject of future research."

GLP-1 has also been discovered in the venom of echidnas. But while the platypus has spurs on its hind limbs for delivering a large amount of venom to its opponent, there is no such spur on echidnas.

"The lack of a spur on echidnas remains an evolutionary mystery, but the fact that both platypus and echidnas have evolved the same long-lasting form of the hormone GLP-1 is in itself a very exciting finding," Professor Grutzner says.

Platypus venom shows potential for new diabetes treatments

New treatment prevents chemotherapy-induced hearing loss in children with cancer

Investigators from Children's Hospital Los Angeles and 37 other Children's Oncology Group hospitals in the U.S. and Canada have determined that sodium thiosulfate prevents cisplatin-induced hearing loss in children and adolescents with cancer. Results of this randomized, controlled, phase 3 study, called ACCL0431, have been published in the early online edition of Lancet Oncology.

"This federally-funded, cooperative group study is the first to show that cisplatin-induced hearing loss can be reduced by about half in children and adolescents being treated for cancer," said David R. Freyer, DO, MS, director of the Survivorship & Supportive Care Program in the Children's Center for Cancer and Blood Diseases at Children's Hospital Los Angeles, who was lead author and chair of the study. "It is an important step toward developing a safe and effective strategy that will greatly improve quality of life for cancer survivors." Freyer is also professor of Clinical Pediatrics and Medicine at the Keck School of Medicine of USC.

Cisplatin is a chemotherapy medication widely used to treat a variety of cancers in both adults and children. Although effective, cisplatin frequently causes permanent hearing loss and tinnitus (ringing in the ears), resulting in functional disability for patients who receive it. For young children in particular, hearing loss is especially serious because it results in impaired language development, learning and social interactions. Preventing ototoxicity, while preserving chemotherapeutic efficacy, has been a long-standing goal of physicians, scientists, parents and survivors. Historically, there have been no proven treatments for preventing cisplatin-induced hearing loss tested under the rigorous conditions of ACCL0431. Without otoprotection, the only way to prevent hearing loss is to delete or decrease cisplatin doses, which could render the cancer treatment less effective.

In ACCL0431, 125 eligible participants between the ages of 1 to 18 years with newly-diagnosed cancer were enrolled over a 4 year period. The cancer diagnoses were hepatoblastoma, germ cell tumor, medulloblastoma, neuroblastoma, osteosarcoma, or other cancer types treated with cisplatin. Study participants were randomized to receive sodium thiosulfate or observation (control) during their chemotherapy. Their hearing was assessed at baseline, following completion of the chemotherapy regimen and 1 year later.

The investigators reported a significant reduction in the incidence of hearing loss in participants who were treated with cisplatin and sodium thiosulfate (29%) compared to those who received cisplatin alone (56%). The greatest benefit was seen in children younger than 5 years of age, who are most susceptible to, and also most affected by, cisplatin-induced hearing loss.

Other effects of sodium thiosulfate were carefully monitored in the study. Overall, sodium thiosulfate was tolerated well without any serious adverse events. Survival from the cancer was not affected by sodium thiosulfate among participants who had localized tumors. However, survival appeared to be lower among those with metastatic disease who received sodium thiosulfate. Additional research is needed to determine what role sodium thiosulfate should have in preventing hearing loss in specific subsets of patients being treated with cisplatin.

New drug treatment can override genetic fault that causes choroideremia

Researchers with funding from Fight for Sight have demonstrated that a new drug treatment for cystic fibrosis and Duchenne muscular dystrophy can override a genetic fault that causes choroideremia – a severe blinding disorder. Treatment with Ataluren restored the function of rab escort protein 1 (REP1) – a protein that is critical for vision – in skin cells from a patient with choroideremia and in a zebrafish model.

Ataluren

[Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy, Cystic Fibrosis, and potentially other genetic disorders involving prematurely truncated proteins. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union].

Choroideremia is a rare inherited retinal dystrophy caused by any number of faults in the CHM gene which encodes instructions for making REP1. Around 1 in 3 of these faults are nonsense mutations - single letter substitutions that generate a premature instruction for cells to stop assembling the protein.

REP1 is important for cells throughout the body to process protein correctly, but is particularly active in the retina. The loss of function caused by nonsense mutations in CHM damages both the light-detecting photoreceptor cells of the retina and the blood vessel layer (choroid) that supplies them.

Ataluren (PTC Therapeutics) is designed to weaken the cell’s recognition of nonsense mutations. The drug allows cells to misread an abnormal stop instruction, permitting full-length protein to be made that functions normally.

Dr Mariya Moosajee at UCL Institute of Ophthalmology is first author on the study, which is published in Human Molecular Genetics. She said:

In this study we have used two independent models of choroideremia. Patient-derived skin cells with absent REP1 function as a model for testing pharmacological therapy with Ataluren and related compounds; and the zebrafish as the only nonsense mutation animal model of choroideremia, enabling study of the whole retina in response to treatment.

In the zebrafish model, Ataluren prevented the onset of retinal degeneration and significantly reduced oxidative stress and programmed cell death. REP1 production increased by 23% and its biological function was restored from 0% to 98%. Although we did not see a measurable increase in REP1 production in the patient-derived cells, biological function was restored from 0% to 42%, indicating that some quantity of healthy REP1 was produced.

These results show the potential for this class of drug to rescue retinal function in choroideremia and other inherited retinal dystrophies due to nonsense mutations. The most obvious potential is in the earlier stages when the retina is still functional and able to produce restored protein when treated.

Ataluren is orally administered and has a demonstrably good safety profile. It has already had some success in clinical trials for other nonsense mutation-based inherited disorders. This could provide an alternative treatment to gene replacement therapy for some choroideremia patients.

Hallucinogenic drug offers relief for people with cancer-related anxiety or depression

In continuation of my update on psilocybin

In a small double-blind study, Johns Hopkins researchers report that a substantial majority of people suffering cancer-related anxiety or depression found considerable relief for up to six months from a single large dose of psilocybin -- the active compound in hallucinogenic "magic mushrooms."

The researchers cautioned that the drug was given in tightly controlled conditions in the presence of two clinically trained monitors and said they do not recommend use of the compound outside of such a research or patient care setting.

The Johns Hopkins team released its study results, involving 51 adult patients, concurrently with researchers from New York University Langone Medical Center, who conducted a similarly designed study on 29 participants. Both studies are published in the Journal of Psychopharmacology on Dec. 1.

The Johns Hopkins group reported that psilocybin decreased clinician- and patient-rated depressed mood, anxiety and death anxiety, and increased quality of life, life meaning and optimism. Six months after the final session of treatment, about 80 percent of participants continued to show clinically significant decreases in depressed mood and anxiety, with about 60 percent showing symptom remission into the normal range. Eighty-three percent reported increases in well-being or life satisfaction. Some 67 percent of participants reported the experience as one of the top five meaningful experiences in their lives, and about 70 percent reported the experience as one of the top five spiritually significant lifetime events.

"The most interesting and remarkable finding is that a single dose of psilocybin, which lasts four to six hours, produced enduring decreases in depression and anxiety symptoms, and this may represent a fascinating new model for treating some psychiatric conditions," says Roland Griffiths, Ph.D., professor of behavioral biology in the Departments of Psychiatry and Behavioral Sciences and of Neuroscience at the Johns Hopkins University School of Medicine. He notes that traditional psychotherapy offered to people with cancer, including behavioral therapy and antidepressants, can take weeks or even months, isn't always effective, and in the case of some drugs, such as benzodiazepines, may have addictive and other troubling side effects.

Griffiths says his team's new study grew out of a decade of research at Johns Hopkins on the effects of psilocybin in healthy volunteers, which found that psilocybin can consistently produce positive changes in mood, behavior and spirituality when administered to carefully screened and prepared participants. The study was designed to see if psilocybin could produce similar results in psychologically distressed cancer patients.

"A life-threatening cancer diagnosis can be psychologically challenging, with anxiety and depression as very common symptoms," says Griffiths. "People with this kind of existential anxiety often feel hopeless and are worried about the meaning of life and what happens upon death."

For the study, the investigators recruited 51 participants diagnosed with life-threatening cancers, most of which were recurrent or metastatic. They were chosen from a total of 566 individuals reached through flyers, web advertisements and physician referrals. Most participants had breast, upper digestive, GI, genitourinary or blood cancer, and each had been given a formal psychiatric diagnosis, including an anxiety or depressive disorder.

Half of the participants were female with an average age of 56. Ninety-two percent were white, 4 percent were African-American and 2 percent were Asian.

Each participant had two treatment sessions scheduled five weeks apart, one with a very low psilocybin dose (1 or3 milligrams per 70 kilograms) taken in a capsule and meant to act as a "control" placebo because the dose was too low to produce effects. In the other session, participants received a capsule with what is considered a moderate or high dose (22 or 30 milligrams per 70 kilograms).

To minimize expectancy effects, the participants and the staff members supervising the sessions were told that the participants would receive psilocybin on both sessions, but they did not know that all participants would receive one high and one low dose. Blood pressure and mood were monitored throughout the sessions. Two monitors aided participants during each session, encouraging them to lie down, wear an eye mask, listen to music through headphones and direct their attention on their inner experience. If anxiety or confusion arose, the monitors provided reassurance to the participants.

In addition to experiencing changes in visual perception, emotions and thinking, most participants reported experiences of psychological insight and often profound, deeply meaningful experiences of the interconnectedness of all people.

The researchers assessed each participant's mood, attitude about life, behaviors and spirituality with questionnaires and structured interviews before the first session, seven hours after taking the psilocybin, five weeks after each session and six months after the second session. Immediately after the sessions, participants completed questionnaires assessing changes in visual, auditory and body perceptions; feelings of transcendence; changes in mood; and more.

Structured clinical interviews, such as the Hamilton Depression Rating Scale and the Hamilton Anxiety Rating Scale, and patient questionnaires, like the Beck Depression Inventory and the State-Trait Anxiety Inventory, assessed depression and anxiety. Other questionnaires assessed quality of life, death acceptance, meaningful existence, optimism and spirituality -- generally defined as a search for the meaning of life and a connection to something bigger than one's self. To measure the changes in attitudes, moods and behavior over time, the researchers administered a questionnaire that assessed negative or positive changes in attitudes about life, mood and behavior.

With regard to adverse effects, Griffiths says 15 percent of participants were nauseated or vomited, and one-third of participants experienced some psychological discomfort, such as anxiety or paranoia, after taking the higher dose. One-third of the participants had transient increases in blood pressure. A few participants reported headaches following the session.

"Before beginning the study, it wasn't clear to me that this treatment would be helpful, since cancer patients may experience profound hopelessness in response to their diagnosis, which is often followed by multiple surgeries and prolonged chemotherapy," says Griffiths. "I could imagine that cancer patients would receive psilocybin, look into the existential void and come out even more fearful. However, the positive changes in attitudes, moods and behavior that we documented in healthy volunteers were replicated in cancer patients."

Up to 40 percent of people with cancer suffer from a mood disorder, according to the National Comprehensive Cancer Network.

Anticipating wide interest in the psilocybin research from scientists, clinicians and the public, the journal solicited 11 commentaries to be co-published with the study results written by luminaries in psychiatry, palliative care and drug regulation, including two past presidents of the American Psychiatric Association, a past president of the European College of Neuropsychopharmacology, the former deputy director of the U.S. Office of National Drug Control Policy, and the former head of the U.K. Medicines and Healthcare Products Regulatory Authority. In general, the commentaries were supportive of the research and of using these drugs in a clinical setting as tools for psychiatry.

Handful of nut consumption each day linked to reduced risk for wide range of diseases

A large analysis of current research shows that people who eat at least 20g of nuts a day have a lower risk of heart disease, cancer and other diseases.

The analysis of all current studies on nut consumption and disease risk has revealed that 20g a day - equivalent to a handful - can cut people's risk of coronary heart disease by nearly 30 percent, their risk of cancer by 15 percent, and their risk of premature death by 22 percent.

An average of at least 20g of nut consumption was also associated with a reduced risk of dying from respiratory disease by about a half, and diabetes by nearly 40 percent, although the researchers note that there is less data about these diseases in relation to nut consumption.

The study, led by researchers from Imperial College London and the Norwegian University of Science and Technology, is published in the journal BMC Medicine.

The research team analysed 29 published studies from around the world that involved up to 819,000 participants, including more than 12,000 cases of coronary heart disease, 9,000 cases of stroke, 18,000 cases of cardiovascular disease and cancer, and more than 85,000 deaths.

While there was some variation between the populations that were studied, such as between men and women, people living in different regions, or people with different risk factors, the researchers found that nut consumption was associated with a reduction in disease risk across most of them.

Study co-author Dagfinn Aune from the School of Public Health at Imperial said: "In nutritional studies, so far much of the research has been on the big killers such as heart diseases, stroke and cancer, but now we're starting to see data for other diseases.

"We found a consistent reduction in risk across many different diseases, which is a strong indication that there is a real underlying relationship between nut consumption and different health outcomes. It's quite a substantial effect for such a small amount of food."

The study included all kinds of tree nuts, such as hazel nuts and walnuts, and also peanuts - which are actually legumes. The results were in general similar whether total nut intake, tree nuts or peanuts were analysed.

What makes nuts so potentially beneficial, said Aune, is their nutritional value: "Nuts and peanuts are high in fibre, magnesium, and polyunsaturated fats - nutrients that are beneficial for cutting cardiovascular disease risk and which can reduce cholesterol levels.

"Some nuts, particularly walnuts and pecan nuts are also high in antioxidants, which can fight oxidative stress and possibly reduce cancer risk. Even though nuts are quite high in fat, they are also high in fibre and protein, and there is some evidence that suggests nuts might actually reduce your risk of obesity over time."

The study also found that if people consumed on average more than 20g of nuts per day, there was little evidence of further improvement in health outcomes.

The team are now analysing large published datasets for the effects of other recommended food groups, including fruits and vegetables, on a wider range of diseases.

Ref : http://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-016-0730-3

Combination treatment produces better outcomes in erythropoietin-refractory MDS patients, study shows

In continuation of my updates  lenalidomide

Patients with myelodysplastic syndromes (MDS) suffer from a reduction in the number of different types of blood cells, including red blood cells leading to the development of anemia. Many patients with lower-risk MDS benefit from treatment with recombinant-erythropoietin (rHuEPO), which stimulates blood cell production. However, patients who become refractory to rHuEPO have few effective treatment options.

 

Alan F. List, M.D., president and CEO of Moffitt Cancer Center, will present interim results from the phase 3 ECOG-ACRIN E2905 Intergroup Study at the American Society of Hematology Annual Meeting in San Diego. The study shows that lenalidomide in combination with epoetin alpha produced better outcomes and similar toxicity as lenalidomide alone in patients with erythropoietin-refractory, lower-risk myelodysplastic syndromes (MDS).

Early phase clinical trials have demonstrated that lenalidomide improves blood cell production in transfusion-dependent non-del(5q) MDS, leading to transfusion-dependence in 26 percent of patients. Additionally, data from a pilot trial suggested that lenalidomide in combination with epoetin alpha may overcome resistance and improve response rates in erythropoietin-refractory MDS patients.

This observation led to the initiation of a phase 3 trial to assess if lenalidomide combined with epoetin alpha improves the major erythroid response rate after 4 cycles of treatment when compared to lenalidomide alone in patients with low or intermediate-1 risk MDS who were unresponsive to rHuEPO treatment or were transfusion-dependent with serum erythropoietin levels greater than 500 mU/mL.

An interim analysis of 163 patients randomized to lenalidomide (n = 81) or lenalidomide + epoetin alpha (n = 82) showed that the study met the predefined stopping criteria. Lenalidomide + epoetin alpha treatment resulted in significantly better erythroid responses than lenalidomide alone among 116 evaluable patients, with a major erythroid response rate at 16 weeks of 33.3 percent for lenalidomide + epoetin alpha and 14.3 percent for lenalidomide alone. The treatment groups had similar rates and types of grade 3 or higher non-hematologic adverse events. Additionally, a biomarker analysis of responding patients suggested that the erythroid CD45 isoform may predict response to combination treatment.

More  at Medical News

CBD oil may reduce frequency and severity of seizures in patients with epilepsy, UAB study shows

Cannabidiol oil, also known as CBD oil, reduces the frequency and severity of seizures in children and adults with severe, intractable epilepsy, according to findings presented by researchers from the University of Alabama at Birmingham at the American Epilepsy Society 70th Annual Meeting.

UAB researchers presented eleven abstracts, or research findings, at the meeting. A key finding was that CBD provided a significant reduction in frequency of seizures for a majority of the patients in the study, and that approximately two-thirds of patients saw a greater than 50 percent reduction in severity.

"It is encouraging that both frequency and severity of seizures appear to improve in the majority of patients in our study, patients who have limited treatment options," said Jerzy P. Szaflarski, M.D., Ph.D., professor in the Department of Neurology and director of the UAB Epilepsy Center. "Our research adds to the evidence that CBD may reduce frequency of seizures, but we also found that it appears to decrease the severity of seizures, which is a new finding."

The results were based on an open-label study of 81 patients — 42 children and 39 adults — who experienced four or more seizures per month. UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April 2015. The studies, an adult study at UAB and a pediatric study at Children's of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly's Law.

After one month of beginning CBD therapy, 68 percent of the patients had experienced a greater than 25 percent reduction in seizure frequency; 58 percent had a greater than 50 percent reduction; 36 percent had a greater than 75 percent reduction and 9 percent were seizure-free. Those results were maintained at three and six months.

To assess seizure severity, researchers led by Jenifer DeWolfe, M.D., associate professor of neurology, used the Chalfont Seizure Severity Scale, a questionnaire given prior to therapy and re-administered at intervals throughout treatment. Fifty-seven patients were followed for three months: 67 percent experienced a more than 50 percent decrease in seizure severity, while 33 percent did not. Of 47 patients followed for six months, 64 percent had a greater than 50 percent decrease in seizure severity and 36 percent did not.

"These are encouraging results, but it is important to note that each patient may respond differently to CBD, and the dose for optimal seizures control varies," said Martina Bebin, M.D., professor of neurology and co-primary investigator of the CBD studies. "There appears to be an optimal CBD dose range where the patient achieves maximum benefit. If outside this CBD dosing range, the seizure frequency may not improve and may even increase. More research is needed, including determining why and how CBD helps some people with epilepsy but not others."

Among the other UAB abstracts presented at the AES meetings:

•CBD oil was associated with an improvement in mood, an effect independent of the extent of seizure reduction. Lead author Pongkiat Kankirawatana, M.D., professor of pediatrics, says CBD oil may have overall positive effects on mood, which should be further investigated in patients with epilepsy and other chronic conditions in controlled studies.

•A study led by Szaflarski and Bebin found that the optimum dose in both children and adults was between 20 and 25 mg/kg/day.

•Jane Allendorfer, M.D., assistant professor of neurology, found that CBD, in a selected group of patients with epilepsy who experienced overall improved seizure control, has the potential for positive cognitive effects that are associated with corresponding fMRI signal changes.

•One abstract reports on an interaction between warfarin, a drug used as an anticoagulant, and CBD. This underscores the importance of monitoring appropriate laboratory work in patients receiving CBD oil along with other medications, according to study lead Brannon Vines, M.D., a clinical neurophysiology fellow.

•Significant drug interactions were identified between CBD and commonly-used medications for epilepsy, including clobazam, rufinamide, topiramiate, zonisamide and eslicarbazepine. This study, led by neurology fellow Tyler Gaston, M.D., emphasizes the importance of monitoring anti-epilepsy drug levels during treatment with CBD.

•Electrical discharges measured by EEG decreased significantly after initiation and maintenance of CBD, particularly in pediatric patients, according to a study led by Leslie Grayson, M.D., a neurology fellow.

•Using fMRI imaging, Amber Gregory, a graduate student in psychology, showed that persons with epilepsy showed gains in working memory that were associated with a shift in neural recruitment as examined with functional MRI.

•An abstract aimed at examining associations between social determinants of health, such as age, gender and socioeconomic factors against health status, quality of life and mood states showed that higher age and low income were associated with lower health ratings among epilepsy patients, according to study led Magdalena Szaflarski, Ph.D., assistant professor of sociology.

The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.

The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants. 

For details read at the link

New anti-inflammatory drug reduces death of existing brain cells then repairs damage after stroke

Researchers at The University of Manchester have discovered that a potential new drug reduces the number of brain cells destroyed by stroke and then helps to repair the damage.

A reduction in blood flow to the brain caused by stroke is a major cause of death and disability, and there are few effective treatments.

A team of scientists at The University of Manchester has now found that a potential new stroke drug not only works in rodents by limiting the death of existing brain cells but also by promoting the birth of new neurones (so-called neurogenesis).  

This finding provides further support for the development of this anti-inflammatory drug, interleukin-1 receptor antagonist (IL-1Ra in short), as a new treatment for stroke. The drug is already licensed for use in humans for some conditions, including rheumatoid arthritis. Several early stage clinical trials in stroke with IL-1Ra have already been completed in Manchester, though it is not yet licensed for this condition.

In the research, published in the biomedical journal Brain, Behavior and Immunity, the researchers show that in rodents with a stroke there is not only reduced brain damage early on after the stroke, but several days later increased numbers of new neurones, when treated with the anti-inflammatory drug IL-1Ra.

Previous attempts to find a drug to prevent brain damage after stroke have proved unsuccessful and this new research offers the possibility of a new treatment.

Importantly, the use of IL-1Ra might be better than other failed drugs in stroke as it not only limits the initial damage to brain cells, but also helps the brain repair itself long-term through the generation of new brain cells.

These new cells are thought to help restore function to areas of the brain damaged by the stroke. Earlier work by the same group showed that treatment with IL-1Ra does indeed help rodents regain motor skills that were initially lost after a stroke. Early stage clinical trials in stroke patients also suggest that IL-1Ra could be beneficial.

The current research is led by Professor Stuart Allan, who commented: "The results lend further strong support to the use of IL-1Ra in the treatment of stroke, however further large trials are necessary."