Platelet transfusions increase mortality for some blood cell disorders

People hospitalized with certain rare blood cell disorders frequently receive a treatment that is associated with a twoto fivefold increase in death, according to a new study that reviewed hospital records across the United States. The study authors recommend that for these rare disorders, doctors should administer the treatment, a platelet transfusion, only in exceptional circumstances.

The Johns Hopkins-led study, published 14 January 2015 in Blood, the journal of the American Society of Hematology, is the first US-wide review of nearly 100,000 combined hospital admissions for three rare blood cell disorders: thrombotic thrombocytopenic purpura (TTP), heparin-induced thrombocytopenia (HIT) and immune thrombocytopenic purpura (ITP).

“Because these conditions are so rare, they’re difficult to study,” says Aaron Tobian, M.D., Ph.D., an associate professor of pathology at the Johns Hopkins University School of Medicine and an expert in transfusion medicine. “There was some suggestion that transfusion may be harmful in these conditions, but it really was not known until now. Our study is the first one to show that platelet transfusions are frequently administered to patients with ITP, HIT and TTP, and that they’re associated with higher odds of arterial blood clots and mortality in TTP and HIT.”

All three conditions are immune system disorders marked by low levels of platelets that help seal up damaged blood vessels. TTP is a life-threatening condition in which clots form in small blood vessels, resulting in a low overall platelet count. It occurs in less than one out of every 100,000 people per year. ITP is a less serious tendency to bleeding, seen in about one in every 20,000 children and one in every 50,000 adults, which often clears up on its own. HIT is a life-threatening reaction to the drug heparin, given to patients to prevent the formation of blood clots. For unknown reasons, in about 1% to 5% of patients given heparin, the immune system responds by producing clots rather than suppressing them.

Because the disorders are rare, haematologists have little to go on when deciding how to treat them. When a panel of experts convened by the AABB — formerly known as the American Association of Blood Banks – issued guidelines for platelet transfusions in November 2014, it made no recommendation on treatments for ITP, TTP and HIT.

To fill the data gap, Tobian, who served on that expert panel, and several Johns Hopkins colleagues turned to the Nationwide Inpatient Sample, a US federal database that contains billing records for about 20% of all patients treated and discharged at about 1,000 US community hospitals in 47 states. The database, which does not reveal patients’ identities, contains information on about 8 million inpatient hospitalizations per year nationwide. The Johns Hopkins-led study covered the years 2007 to 2011.

“The Nationwide Inpatient Sample is an incredible resource, especially for studying uncommon diseases,” says Ruchika Goel, M.D., M.P.H., a clinical fellow in paediatric haematology oncology at The Johns Hopkins Hospital and the study’s lead author.

“Our analysis found no significantly increased risks from platelet transfusions in ITP,” Goel says. “But in TTP, a platelet transfusion increased the odds of a potentially lethal arterial blood clot more than fivefold and doubled the odds of a heart attack.” In HIT, platelet transfusions increased the risk of bleeding fivefold and the risk of an arterial clot more than threefold.

In TTP, the odds of dying in the hospital doubled when the patient was given a platelet transfusion. In HIT, the odds of dying were five times greater with a platelet transfusion. doi: blood-2014-10-605493
 

Locking mechanism found for ‘scissors’ that cut DNA

Researchers at Johns Hopkins have discovered what keeps an enzyme from becoming overzealous in its clipping of DNA. Since controlled clipping is required for the production of specialized immune system proteins, an understanding of what keeps the enzyme in check should help explain why its mutant forms can lead to immunodeficiency and cancer. A summary of the results are published in the journal Cell Reports on 24 December 2014.

The immune system relies on the formation of specialized proteins – antibodies – that can recognize and immobilize foreign invaders like viruses and bacteria. Since storing individual blueprints for each of these proteins would require huge amounts of DNA, the body instead mixes and matches different chunks of sequence to produce roughly 300 trillion possibilities. This mixing and matching, called recombination, requires that DNA be clipped by the enzyme RAG.

“Recombination is essential for the immune system’s ability to recognize and fight new enemies, but too much clipping can cause harmful chromosome rearrangements,” says Stephen Desiderio, M.D., Ph.D., director of the Institute for Basic Biomedical Sciences and the senior researcher for the study. “We now know that RAG has a built-in lock that prevents it from getting out of hand as it clips DNA.”

To keep the system efficient, each immune cell makes only a single antibody and only does so after being activated. Several years ago, Desiderio’s group found that this level of control is enforced by a segment of RAG called the PHD. The PHD binds to a chemical tag called H3K 4me3, which is only found on DNA that is actively being rewritten as RNA. This prevents RAG from recombining DNA that is not active.

When the PHD segment was mutated and nonfunctional, RAG couldn’t cut, suggesting that the binding of the PHD to H3K4me3 was required for RAG’s function. But when the PHD was deleted entirely, RAG was just fine. To understand what was happening, Desiderio’s team looked for mutations that would bring function back to the mutant PHD. They found that when 13 amino acids were deleted in front of the mutant PHD segment, RAG cut even better than it normally does.

Alyssa Ward, a graduate student in Desiderio’s laboratory, says that the system works like the bolt on a door. The PHD piece is the lock, H3K4me3 is the key and the deleted piece is the actual bolt. When all of the pieces are normal, H3K4me3 unlocks the PHD segment, which moves the bolt so that the door can open – i.e., so that RAG can cut. If there is a mutation in the PHD, the key won’t fit the lock, so the door remains bolted. But, if the lock or bolt is removed entirely, the door can open and close freely.

Desiderio says that these results have implications for many other proteins that interact with DNA. “It was previously thought that H3K4me3 was simply a docking site for proteins,” he says. “This study shows that it is also a key that activates them.”

The team is now making a line of mice with the overactive RAG so they can see what effects it has in an animal. They hope that the overactive RAG will give them clues to how the enzyme is normally controlled, and to what goes wrong in those immunodeficiencies and cancers linked to mutations in RAG.
 


Added fructose is a principal driver of type 2 diabetes

Recent studies have shown that added sugars, particularly those containing fructose, are a principal driver of diabetes and pre-diabetes, even more so than other carbohydrates. Clinical experts writing in Mayo Clinic Proceedings challenge current US dietary guidelines that allow up to 25% of total daily calories as added sugars, and propose drastic reductions in the amount of added sugar, and especially added fructose, people consume.

“At current [US guideline] levels, added-sugar consumption, and addedfructose consumption in particular, are fuelling a worsening epidemic of type 2 diabetes,” said lead author James J. DiNicolantonio, PharmD, a cardiovascular research scientist at Saint Luke’s Mid America Heart Institute, Kansas City.

The net result of excess consumption of added fructose is derangement of both overall metabolism and global insulin resistance say the authors. Other dietary sugars not containing fructose seem to be less detrimental in these respects. Indeed, several clinical trials have shown that compared to glucose or starch, isocaloric exchange with fructose or sucrose leads to increases in fasting insulin, fasting glucose, and the insulin/glucose responses to a sucrose load. “This suggests that sucrose (in particular the fructose component) is more harmful compared to other carbohydrates,” added Dr DiNicolantonio.

Dr DiNicolantonio and his co-authors, James H O’Keefe, MD, Saint Luke’s Mid America Heart Institute, Kansas City, and Sean C. Lucan, MD, MPH, MS, a family physician at Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, examined animal experiments and human studies to come to their conclusions.

Data from recent trials suggest that replacing glucose-only starch with fructosecontaining table sugar (sucrose) results in significant adverse metabolic effects. Adverse effects are broader with increasing baseline insulin resistance and more profound with greater proportions of added fructose in the diet.

The totality of the evidence is compelling to suggest that added sugar, and especially added fructose (usually in the form of high-fructose corn syrup and table sugar), are a serious and growing public health problem, according to the authors.

While fructose is found naturally in some whole foods like fruits and vegetables, consuming these foods poses no problem for human health. Indeed, consuming fruits and vegetables is likely protective against diabetes and broader cardiometabolic dysfunction, explained DiNicolantonio and colleagues. The authors propose that dietary guidelines should be modified to encourage individuals to replace processed foods, laden with added sugars and fructose, with whole foods like fruits and vegetables.

The World Health Organization recommends that added sugars should make up no more than 10% of an entire day’s caloric intake, with a proposal to lower this level to 5% or less for optimal health. Such levels are more in line with what the authors would recommend.
 


Researchers show link between gene switches and autoimmune diseases

Investigators with the US National Institutes of Health have discovered the genomic switches of a blood cell key to regulating the human immune system. The findings, published in Nature (16 Feb 2015), open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis.

Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases, for example, the joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families.

“We now know more about the genetics of autoimmune diseases,” said US National Institute of Allergy and Infectious Diseases (NIAMS) Director Stephen I. Katz, M.D., Ph.D. “Knowledge of the genetic risk factors helps us assess a person’s susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual.”

Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.

The senior author of the paper, John J. O’Shea, M.D., is the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases. His lab team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of NIH Director, Francis S. Collins, M.D., Ph.D., in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute, and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction.

Dr. O’Shea’s team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease.

“Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” said Dr O’Shea. “From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets – their key proteins – and thereby where we are most likely to find genetic alterations that confer disease susceptibility.”

Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokine and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

But the researchers’ most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs. Additional experiments provided further evidence for a central role for SEs in rheumatoid arthritis. When the scientists exposed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs to alter the activities of important T cell genes.

“Three types of data – the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug – are all pointing to the importance of super-enhancers,” said lead author, Golnaz Vahedi, Ph.D., a postdoctoral fellow in Dr O’Shea’s lab. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”

doi: 10.1038/nature14154
 


Study shows adult neurogenesis helps maintain proper connections
in brain


For decades, scientists thought that neurons in the brain were born only during the early development period and could not be replenished. More recently, however, they discovered cells with the ability to divide and turn into new neurons in specific brain regions. The function of these neuroprogenitor cells remains an intense area of research. Scientists at the US National Institutes of Health (NIH) report that newly formed brain cells in the mouse olfactory system play a critical role in maintaining proper connections. The results were published in the 8 October 2014 issue of the Journal of Neuroscience.

“This is a surprising new role for brain stem cells and changes the way we view them,” said Leonardo Belluscio, Ph.D., a scientist at NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and lead author of the study.

The olfactory bulb is located in the front of the brain and receives information directly from the nose about odours in the environment. Neurons in the olfactory bulb sort that information and relay the signals to the rest of the brain, at which point we become aware of the smells we are experiencing. Olfactory loss is often an early symptom in a variety of neurological disorders, including Alzheimer’s and Parkinson’s diseases.

In a process known as neurogenesis, adult-born neuroprogenitor cells are generated in the subventricular zone deep in the brain and migrate to the olfactory bulb where they assume their final positions. Once in place, they form connections with existing cells and are incorporated into the circuitry.

Dr Belluscio, who studies the olfactory system, teamed up with Heather Cameron, Ph.D., a neurogenesis researcher at the NIH’s National Institute of Mental Health, to better understand how the continuous addition of new neurons influences the circuit organization of the olfactory bulb. Using two types of specially engineered mice, they were able to specifically target and eliminate the stem cells that give rise to these new neurons in adults, while leaving other olfactory bulb cells intact. This level of specificity had not been achieved previously.

According to Dr Belluscio, it is generally assumed that the circuits of the adult brain are quite stable and that introducing new neurons alters the existing circuitry, causing it to re-organize. “However, in this case, the circuitry appears to be inherently unstable requiring a constant supply of new neurons not only to recover its organization following disruption but also to maintain or stabilize its mature structure. It’s actually quite amazing that despite the continuous replacement of cells within this olfactory bulb circuit, under normal circumstances its organization does not change,” he said.

Dr Cameron added: “It’s very exciting to find that new neurons affect the precise connections between neurons in the olfactory bulb. Because new neurons throughout the brain share many features, it seems likely that neurogenesis in other regions, such as the hippocampus, which is involved in memory, also produce similar changes in connectivity.”

doi: 10.1523/ JNEUROSCI.2463-14.2014


                                  
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