Men can’t multitask, women have better memory, study led by Indian-origin scientist reveals.

Men can’t multitask and women have better memory because their brains are wired differently, a new study led by an Indian-origin scientist has found.

The research found striking differences in the neural wiring of men and women, which explains why males excel at certain tasks and females at others.

In one of the largest studies looking at the “connectomes” of the sexes, Ragini Verma, an associate professor in the department of radiology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues found greater neural connectivity from front to back and within one hemisphere in males.

This suggests male brains are structured to facilitate connectivity between perception and coordinated action.

In contrast, in females, the wiring goes between the left and right hemispheres, suggesting that they facilitate communication between the analytical and intuition.

“These maps show us a stark difference – and complementarity – in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others,” said Verma, who has a PhD in computer vision and mathematics from Indian Institute of Technology Delhi.

In the study, Verma and colleagues investigated the gender-specific differences in brain connectivity during the course of development in 949 individuals (521 females and 428 males) aged 8 to 22 years using diffusion tensor imaging.

DTI is water-based imaging technique that can trace and highlight the fiber pathways connecting the different regions of the brain, laying the foundation for a structural connectome or network of the whole brain.

Researchers found that females displayed greater connectivity in the supratentorial region, which contains the cerebrum, the largest part of the brain, between the left and right hemispheres.

Males, on the other hand, displayed greater connectivity within each hemisphere.

By contrast, the opposite prevailed in the cerebellum, the part of the brain that plays a major role in motor control, where males displayed greater inter-hemispheric connectivity and females displayed greater intra-hemispheric connectivity.

These connections likely give men an efficient system for coordinated action, where the cerebellum and cortex participate in bridging between perceptual experiences in the back of the brain, and action, in the front of the brain, researchers said in the journal Proceedings of National Academy of Sciences.

The female connections likely facilitate integration of the analytic and sequential processing modes of the left hemisphere with the spatial, intuitive information processing modes of the right side.

The authors observed only a few gender differences in the connectivity in children younger than 13 years, but the differences were more pronounced in adolescents aged 14 to 17 years and young adults older than 17.

Simple Test May Help Gauge Dopamine Loss in Parkinson’s.

The Triplets Learning Task (TLT) may help determine the extent of dopamine loss in patients with Parkinson’s disease (PD), results of a pilot study hint.

The TLT tests implicit learning, a type of learning that occurs without awareness or intent and that relies on the caudate nucleus, an area of the brain affected by dopamine loss.

The test is a sequential learning task that doesn’t require complex motor skills, which tend to decline in people with PD. In the TLT, participants see 4 open circles, see 2 red dots appear, and are asked to respond when they see a green dot appear. Unbeknownst to them, the authors note, the location of the first red dot predicts the location of the green target. Participants learn implicitly where the green target will appear, and they become faster and more accurate in their responses.

Katherine R. Gamble, psychology PhD student at Georgetown University in Washington, DC, and colleagues had 27 patients with mild to moderate PD receiving dopaminergic medication and 27 healthy controls matched for age and education take the TLT on several occasions.

Patients with PD implicitly learned the dot pattern with training, as did controls, but a loss of dopamine appeared to “negatively impact” that learning compared with healthy older adults, Gamble noted in an interview with Medscape Medical News.

“Their performance began to decline toward the end of training, suggesting that people with Parkinson’s disease lack the neural resources in the caudate, such as dopamine, to complete the learning task,” she added in a conference statement.

Gamble reported the findings here at Neuroscience 2013, the annual meeting of the Society for Neuroscience.

Implicit Learning

In this study, participants responded to 6 “epochs” of the TLT, for a total of 1500 trials. All patients had been diagnosed with PD by a neurologist, and all were receiving treatment with anti-PD medication when they took the test.

Their results showed “significant implicit sequence learning” on the TLT test, the researchers report. Learning increased over the first 5 epochs of training, they note; patients continued to respond more quickly to high- vs low-probability triplets, but this plateaued between periods 5 and 6.

“We suggest that in people with PD, learning is intact early in training because less affected regions of the brain (eg, the hippocampus) can support learning,” they conclude. “However, PD-related dopamine deficits appear later in training when the caudate becomes more important.”

The TLT “may be a noninvasive way to evaluate the level of dopamine deficiency in PD patients, and which may lead to future ways to improve clinical treatment of PD patients,” said Steven E. Lo, MD, associate professor of neurology at Georgetown University Medical Center and a coauthor of the study, in a statement.

The researchers are now testing how implicit learning may differ by different PD stages and drug doses.

Evaluating Dopamine Deficiency

Asked to comment on this pilot study, Lidia Gardner, PhD, assistant professor, Department of Neurology, University of Tennessee Health Science Center in Memphis, said the “simple implicit learning test might be potentially a useful tool for neuropsychologists. I would like to know if there is any correlation between the disease progression and the time required for TLT training.”

However, she told Medscape Medical News, “Until a strong correlation is established, most physicians would shy away from using it as a diagnostic tool for the loss of dopamine neurons. However, in addition to other clinical tests it could be useful.”

“Currently, the loss of dopamine neurons can be visualized with PET [positron emission tomography] using 18F-DOPA or other radio-tracers. This technique can give a relatively close assessment of dopamine neurons in PD patients. A simple and inexpensive test (in comparison to PET or SPECT [single-photon emission computed tomography]) is always welcome in healthcare administration,” Dr. Gardner said.

Improved detection of PTH imbalance may benefit dialysis patients.

New data demonstrate an association between lower levels of non-oxidized biologically active parathyroid hormone and increased mortality in hemodialysis patients, suggesting the need for improved assays.

“The current tests for parathyroid hormone levels overlook a key factor. When parathyroid hormone interacts with oxygen under conditions of stress such as end-stage kidney disease, it becomes biologically inactive,” researcherBerthold Hocher, MD, PhD, of the University of Potsdam in Germany, said in a press release.

Researchers conducted a prospective cohort study of 340 hemodialysis patients (224 men, 116 women; median age, 66 years) with end-stage CKD. They measured parathyroid hormone (PTH) levels using a third-generation intact parathyroid hormone electrochemiluminescence immunoassay system (ECLIA; Roche iPTH, Roche Diagnostics) directly and after prior removal of oxidized biologically inactive PTH using an antihuman oxidized parathyroid monoclonal antibody (Immundiagnostik AG).

During 5-year follow-up, 50% of the patients died. Cardiovascular diseaseaccounted for 60% of the deaths, according to the researchers, followed by infections (23%), cancer (11%) and unknown causes (6%).

Results revealed higher median non-oxidized biologically active PTH levels in those who survived (7.2 ng/L) vs. those who did not (5 ng/L; P=.002).

Survival was increased among patients in the highest tertile of non-oxidized biologically active PTH compared with the lowest (P=.0008). Additionally, in the highest tertile, median survival was 1,702 days compared with 453 days in the lowest tertile.

Data also showed that, after multivariable adjustment, older age appeared to increase risk for death, but higher levels of non-oxidized biologically active PTH decreased risk for death.

In an analysis of a subgroup of patients with intact PTH levels above the upper normal range of 70 ng/L at baseline, mortality appeared to be associated with oxidized biologically inactive PTH levels but not non-oxidized biologically active PTH levels.

“With more precise parathyroid hormone testing, health care professionals will have the information they need to improve clinical outcomes,” Hocher said. “The nephrology community has long recognized there is an issue with current testing approaches, and now we can solve this problem and improve patient care.”

Even a Little Physical Activity May Prevent Depression.

Even low levels of physical activity may reduce the risk of developing depression in individuals of all ages, new research suggests.

In 25 of 30 large studies examined in the systematic review, which included participants between the ages of 11 and 100 years, a “negative risk” was found between baseline physical activity (PA) and the future development of depression.

In addition, this inverse association was found in all levels of PA ― including less than 2.5 hours of walking per week.

“It was a little surprising that 25 of the studies found this protective effect, and that’s really promising,” lead author George Mammen, PhD candidate from the Faculty of Kinesiology and Physical Education Department at the University of Toronto in Ontario, Canada, told Medscape Medical News.

“We also did quality assessments on each study, and the majority were of high methodologic quality, which adds weight to the findings,” said Mammen.

He noted that the take-home message is that being active is important for more than just physical health.

“From a population health perspective, promoting PA may serve as a valuable mental health…strategy in reducing the risk of developing depression,” write the investigators.

The study was published in the November issue of the American Journal of Preventive Medicine.

Prevention Strategy Needed

Previous studies have shown a link between exercise and decreasing symptoms in patients with depression,including several reported by Medscape Medical News.

“However, with the high prevalence of depression worldwide and its burden on well-being and the healthcare system, intuitively, it would make more sense…to shift focus toward preventing the onset of depression,” the investigators write.

We need a prevention strategy now more than ever. Our health system is taxed. We need to…look for ways to fend off depression from the start,” added Mammen in a release.

After searching 6 of the top databases, including MEDLINE and PubMed, the researchers found 6263 worldwide citations of PA and depression. For this analysis, they selected 30 English-language studies that were published between January 1976 and December 2012.

All were prospective, longitudinal, and “examined relationships between PA and depression over at least two time intervals.” They had follow-up periods ranging from 1 to 27 years.

Results showed that 25 of the studies revealed a significant inverse effect between any PA reported at baseline and subsequent depression development.

Interestingly, 4 of these studies showed that women who reported baseline PA were less likely than men to develop depression.

“These studies postulate that psychological factors may explain these findings because women may benefit more from the social aspects of PA than men,” note the investigators.

Of the 5 studies that did not find a significant association between PA and depression, “only 1 was considered to be of high quality,” and 2 focused only on older adults.

Get Moving

Using data from the 7 studies that measured amounts of weekly PA participation, the researchers found that exercising more than 150 minutes per week was associated with a 19% to 27% decreased risk of developing depression.

Surprisingly, participating in less than 150 minutes per week of PA was associated with a 8% to 63% decreased depression risk compared with individuals who were sedentary. Still, the 63% decreased risk was found in one study of patients participating in 120 minutes of weekly PA.

CKD: Lower Salt Intake May Reduce Heart Risks.

A diet with restricted salt intake may help to reduce the risk for cardiovascular disease in patients with chronic kidney disease (CKD), as well as the risk for CKD progression, according to an article published online November 7 in the Journal of the American Society of Nephrology.

Emma J. McMahon, PhD candidate, University of Queensland, Australia, and colleagues conducted a double-blind, placebo-controlled randomized crossover trial involving 20 adult patients with stage 3 to 4 CKD. In the phase I portion of the LowSALT CKD study, the researchers evaluated the effects of high vs low sodium intake on several physiological measures, including ambulatory blood pressure, protein excretion, and body fluid status.

The researchers counseled patients to eat a low-sodium (1080 – 1440 mg/day) diet during the 1-week run-in period of the 6-week study, they then randomly assigned patients to either a high-sodium or low-sodium diet. Those on the high-sodium diet had a goal of 1080 to 1440 mg/day plus 2160 mg/day from a slow-release tablet. Those on the low-sodium diet had a goal of 1080 to 1440 mg/day plus a placebo capsule. Patients crossed over after an intermediate washout week.

The investigators found a mean reduction of 9.7/3.9 mm Hg in blood pressure in patients on the low-salt diet compared with the high-salt diet. The reductions were consistent during a 24-hour period with no significant difference between daytime and nighttime measurements. Researchers also found that patients had reductions in fluid volume, body weight, and protein in the urine while on the low-salt diet.

“If these findings are transferable to the larger CKD population and shown to be sustainable long-term, this could translate to markedly reduced risk of cardiovascular events and progression to end-stage kidney disease, and it could generate considerable health-care savings,” senior author Katrina J. Campbell, PhD, from Princess Alexandra Hospital, Queensland, said in a news release.

“These are clinically significant findings, with this magnitude of blood pressure reduction being comparable to that expected with the addition of an anti-hypertensive medication and larger than effects usually seen with sodium restriction in people without CKD,” McMahon noted in the release. “If maintained long-term, this could reduce risk of progression to end-stage kidney disease — where dialysis or transplant is required to survive — by 30%.”

“This study is salient because few intervention studies have evaluated dietary sodium reduction in patients with CKD, write Cheryl A.M. Anderson, PhD, MPH, and Joachim H. Ix, MD, both from the University of California San Diego School of Medicine, in an accompanying editorial. “The evaluation of other outcomes in addition to BP is an additional strength of the trial.”

Scientists identify clue to regrowing nerve cells.

Researchers atWashington University School of Medicine in St. Louis have identified a chain reaction that triggers the regrowth of some damaged nerve cell branches, a discovery that one day may help improve treatments for nerve injuries that can cause loss of sensation or paralysis. 

The scientists also showed that nerve cells in the brain and spinal cord are missing a link in this chain reaction. The link, a protein called HDAC5, may help explain why these cells are unlikely to regrow lost branches on their own. The new research suggests that activating HDAC5 in the central nervous system may turn on regeneration of nerve cell branches in this region, where injuries often cause lasting paralysis. 

Nerve cells with branches

“We knew several genes that contribute to the regrowth of these nerve cell branches, which are called axons, but until now we didn’t know what activated the expression of these genes and, hence, the repair process,” said senior author Valeria Cavalli, PhD, assistant professor of neurobiology. “This puts us a step closer to one day being able to develop treatments that enhance axon regrowth.” 

The research appears Nov. 7 in the journal Cell.

Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages. 

In the peripheral nervous system — the network of nerve cells outside the brain and spinal column — cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons. 

Working with peripheral nervous system cells grown in the laboratory, Yongcheol Cho, PhD, a postdoctoral research associate in Cavalli’s laboratory, severed the cells’ axons. He and his colleagues learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms. 

In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.

When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus.

When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.

“This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches,” Cavalli said. “We’re working on that now.”

Cavalli also is collaborating with Susan Mackinnon, MD, the Sydney M. Shoenberg Jr. and Robert H. Shoenberg Professor of Surgery, chief of the Division of Plastic and Reconstructive Surgery and a pioneer in peripheral nerve transplants. The two are investigating whether HDAC5 or other components of the chain reaction can be used to help restore sensory functions in nerve grafts.


Prostate Tops List of Most Inheritable Cancers.

One legacy that most men could do without is an inherited risk for prostate cancer, but a massive cohort study shows that for some men, genetic history hints at oncologic destiny.

Data on both identical (monozygotic) and fraternal (dizygotic) twins from the comprehensive birth-to-death registries in Denmark, Finland, Norway, and Sweden show that a man whose monozygotic twin has prostate cancer has a 32% risk for the disease himself, whereas a dizygotic twin whose brother has prostate cancer has only a 16% risk, said Jaakko Kaprio, MD, PhD, professor of genetic epidemiology at the University of Helsinki.

The estimated heritability of prostate cancer — the degree to which genes contribute to risk — was 58% (95% confidence interval, 52 – 63), which is the highest for any malignancy studied, Dr. Kaprio reported here at the American Society of Human Genetics 63rd Annual Meeting.

“These estimates for common cancers are greater than previously estimated. For rare cancers, such as testicular cancer, the concordance risk was substantial. We believe it provides an accurate estimate of familial risk prediction,” Dr. Kaprio toldMedscape Medical News.

Table. Cancers With Significant Heritability

Cancer Type Heritability Estimate, % 95% Confidence Interval
Prostate 58 52–63
Testicular 36 2–95
Breast 28 12–52
Kidney 23 11–42
Lung 25 12–44
Melanoma 39 8–81
Ovarian 28 15–47
Stomach 24 5–65
Uterine 24 14–87
Colon 16 2–63

The magnitude of the genetic contribution to prostate cancer found in this study is higher than the estimated 42% seen in a previous study of Nordic twins (N Engl J Med. 2000;343:78-85). Dr. Kaprio explained that this difference can be attributed to the fact that his team expanded the original cohort to include data from Norway, had 10 additional years of follow-up data, and had an aging cohort, with a resultant increase in incident cancers.

Dr. Kaprio’s team looked at data on 133,689 monozygotic and dizygotic pairs as part of the Nordic Twin Registry of Cancer. They used time-to-event analysis to estimate heritability and familial cancer risk.

What’s Going On?

This study raises important questions about the interplay between genetics and environment in cancer, said Richard Stevens, PhD, professor of cancer epidemiology at the University of Connecticut Health Center in Farmington.

“It’s a very strong study. The exciting thing about this study with prostate cancer is that it’s certainly saying something about mechanism that we don’t get,” he explained.

The study supports the presence of genetic polymorphisms in prostate cancer, and to a lesser degree breast cancer, that can cumulatively contribute to risk, he said.

“The specific polymorphisms we’re aware of — familial syndromes — account for very little breast cancer or prostate cancer. There are other genes where allelic variation and risk is moderate. There must be a lot of those genes with moderate risk; you put them together and it makes you more susceptible,” Dr. Stevens said.

UNC child neurologist finds potential route to better treatments for Fragile X, autism.

When you experience something, neurons in the brain send chemical signals called neurotransmitters across synapses to receptors on other neurons. How well that process unfolds determines how you comprehend the experience and what behaviors might follow. In people with Fragile X syndrome, a third of whom are eventually diagnosed with Autism Spectrum Disorder, that process is severely hindered, leading to intellectual impairments and abnormal behaviors.

In a study published in the online journal PLoS One, a team of UNC School of Medicine researchers led by pharmacologist C.J. Malanga, MD, PhD, describes a major reason why current medications only moderately alleviate Fragile X symptoms. Using mouse models, Malanga discovered that three specific drugs affect three different kinds of neurotransmitter receptors that all seem to play roles in Fragile X. As a result, current Fragile X drugs have limited benefit because most of them only affect one receptor.

“There likely won’t be one magic bullet that really helps people with Fragile X,” said Malanga, an associate professor in the Department of Neurology. “It’s going to take therapies acting through different receptors to improve their behavioral symptoms and intellectual outcomes.”

Nearly one million people in the United States have Fragile X Syndrome, which is the result of a single mutated gene called FMR1. In people without Fragile X, the gene produces a protein that helps maintain the proper strength of synaptic communication between neurons. In people with Fragile X, FMR1 doesn’t produce the protein, the synaptic connection weakens, and there’s a decrease in synaptic input, leading to mild to severe learning disabilities and behavioral issues, such as hyperactivity, anxiety, and sensitivity to sensory stimulation, especially touch and noise.

More than two decades ago, researchers discovered that – in people with mental and behavior problems – a receptor called mGluR5 could not properly regulate the effect of the neurotransmitter, glutamate. Since then, pharmaceutical companies have been trying to develop drugs that target glutamate receptors. “It’s been a challenging goal,” Malanga said. “No one so far has made it work very well, and kids with Fragile X have been illustrative of this.”

But there are other receptors that regulate other neurotransmitters in similar ways to mGluR5. And there are drugs already available for human use that act on those receptors. So Malanga’s team checked how those drugs might affect mice in which the Fragile X gene has been knocked out.

By electrically stimulating specific brain circuits, Malanga’s team first learned how the mice perceived reward. The mice learned very quickly that if they press a lever, they get rewarded via a mild electrical stimulation. Then his team provided a drug molecule that acts on the same reward circuitry to see how the drugs affect the response patterns and other behaviors in the mice.

His team studied one drug that blocked dopamine receptors, another drug that blocked mGluR5 receptors, and another drug that blocked mAChR1, or M1, receptors. Three different types of neurotransmitters – dopamine, glutamate, and acetylcholine – act on those receptors. And there were big differences in how sensitive the mice were to each drug.

“Turns out, based on our study and a previous study we did with my UNC colleague Ben Philpot, that Fragile X mice and Angelman Syndrome mice are very different,” Malanga said. “And how the same pharmaceuticals act in these mouse models of Autism Spectrum Disorder is very different.”

Malanga’s finding suggests that not all people with Fragile X share the same biological hurdles. The same is likely true, he said, for people with other autism-related disorders, such as Rett syndrome and Angelman syndrome.

“Fragile X kids likely have very different sensitivities to prescribed drugs than do other kids with different biological causes of autism,” Malanga said.

Blood Test May Predict Ketamine’s Antidepressant Effect.

Researchers have identified biomarkers that they hope will eventually help predict which patients with bipolar depression will respond to subanesthetic doses of ketamine.

An experimental blood test using pharmacometabolomics found patterns, or metabolic “fingerprints,” that differ between people whose bipolar depression improved with intravenous ketamine and those who did not get better. Pharmacometabolomics uses sophisticated chemistry techniques to quantify and analyze metabolites that the body produces in response to drugs.

“This work is telling us what we should measure [in the blood],” study coauthor Irving Wainer, PhD, from the National Institute on Aging‘s Intramural Research Program in Baltimore, Maryland, toldMedscape Medical News. “Then we’ll develop the technology to predict, pretreatment, which patients will respond to ketamine treatment and find ways to individualize and optimize treatment with ketamine.”

The research findings were presented here recently at the American Society of Anesthesiologists (ASA) 2013 Annual Meeting.

Rapid Antidepressant Effect

Recent studies of this investigational use of ketamine, a glutamateN-methyl-D-aspartate (NMDA) receptor antagonist, show that many patients with treatment-refractory bipolar depression ( Biol Psychiatry, 2012;71:939-946) or other types of major depression respond rapidly to intravenous infusion of ketamine — typically in several hours.

However, 1 in 3 patients do not respond to this treatment at all, said another author of the new study, Michael Goldberg, MD, an anesthesiologist from Cooper University Health Care in Camden, New Jersey.

“It’s not ethical to put everyone [with depression] on ketamine because it has risks. Hallucinations are common and may require other medications to counteract,” Dr. Goldberg told Medscape Medical News.

Knowing before ketamine administration who would be least likely to benefit would spare them from exposure to the drug and its common dissociative side effects, he said.

Toward that end, the researchers collected blood samples from 22 patients with bipolar disorder and major depression both before and after a single intravenous infusion of 0.5 mg/kg of ketamine or a placebo; the patients then were crossed over to the alternate therapy after a 1-week drug washout.

Patients also received treatment with either lithium (n = 16) or valproate (n = 6) as a mood stabilizer and responded to this therapy, according to Dr. Goldberg. Response to ketamine was identified 230 minutes after infusion using the Montgomery-Åsberg Depression Rating Scale.

The investigators analyzed the metabolomic patterns in the blood samples using liquid chromatography/quadruple time-of-flight mass spectometry and capillary electrophoresis/laser-induced fluorescence.

They also reportedly identified the compound that ketamine breaks down into, which they called 2S, 6S hydroxynorketamine.

Quick Turnaround Test

In the group receiving comedication with lithium, patients who did not respond to ketamine treatment (“nonresponders”) had significant post-treatment differences in 18 metabolites compared with ketamine responders, according to the abstract (P values not reported).

These included significantly increased levels of the fatty acids phenyllactic acid and monoglyceride and significantly decreased levels of trimethyl-L-lysine, lysophosphatidylethanolamine, and lysophosphatidylcholine.

The same trend was seen in the patients receiving valproate, but the number of patients in this group was not large enough to determine statistical significance, Dr. Goldberg stated.

Independently of the mood stabilizer, nonresponders also reportedly had significantly higher levels of the amino acid D-serine. In their abstract, the authors suggested a difference in the activity of the enzyme serine racemase between responders and nonresponders, possibly owing to an indirect change in NMDA receptor activity.

Although most patterns observed in metabolites were of fatty acids, some were metabolites of ketamine, Nagendra Singh, PhD, said during the oral presentation of the findings. Dr. Singh, who was not a coauthor of the study, will soon be joining Cooper University Health Care as a research associate.

Of 323 metabolites analyzed, only 2 were reportedly the same between the lithium and valproate groups.

“Two different mood stabilizers had very different metabolite patterns in their fatty acids, which was very interesting,” Dr. Singh said. “This clearly demonstrates that lithium and valproate affect fatty acids differently.”

The researchers speculated that patients with bipolar depression respond to ketamine on the basis of various endogenous factors, including fatty acid metabolism and the plasma levels of endogenous compounds involved in neurotransmission.

A limitation of the study, said Dr. Wainer, is that it was not designed prospectively for pharmacometabolomics. He described the pharmacometabolomic process as “time-consuming and costly.”

Dr. Wainer said his team plans to limit future analyses to 5 or 6 metabolites.

“Our goal is to develop the technology so that there will be on-site rapid turnaround of blood test results,” he said.

Not Ready for Routine Use

Commenting on the study for Medscape Medical News, Timothy Lineberry, MD, associate professor of psychiatry at Mayo Clinic, Rochester, Minnesota, said that identifying who will benefit from and have good response to ketamine is important.

Dr. Lineberry, who was not involved with the study, said that there are not yet enough research data for physicians to routinely use ketamine in clinical practice for this off-label purpose.

“There is also a need for identifying what are the psychological markers associated with response to ketamine and the particular diagnoses that will respond to treatment,” he added.

The next patient population in which Dr. Goldberg said their research team plans to study pharmacometabolomics after ketamine infusion is those with post-traumatic stress disorder.

Discovery of new gene regulator could precisely target sickle cell disease.

A research team from Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and other institutions has discovered a new genetic target for potential therapy of sickle cell disease (SCD). The target, called an enhancer, controls a molecular switch in red blood cells called BCL11A that, in turn, regulates hemoglobin production.

The researchers — led by Daniel Bauer, MD, PhD, and Stuart Orkin, MD, of Dana-Farber/Boston Children’s — reported their findings today in Science.

Prior work by Orkin and others has shown that when flipped off, BCL11A causes red blood cells to produce fetal hemoglobin that, in SCD patients, is unaffected by the sickle cell mutation and counteracts the deleterious effects of sickle hemoglobin. BCL11A is thus an attractive target for treating SCD.

The disease affects roughly 90,000 to 100,000 people in the United States and millions worldwide.

However, BCL11A plays important roles in other cell types, including the immune system’s antibody-producing B cells, which raises concerns that targeting it directly in sickle cell patients could have unwanted consequences.

The discovery of this enhancer — which regulates BCL11A only in red blood cells — opens the door to targeting BCL11A in a more precise manner. Approaches that disable the enhancer would have the same end result of turning on fetal hemoglobin in red blood cells due to loss of BCL11A, but without off-target effects in other cell types.

The findings were spurred by the observation that some patients with SCD spontaneously produce higher levels of fetal hemoglobin and enjoy an improved prognosis. The researchers found that these individuals possess naturally occurring beneficial mutations that function to weaken the enhancer, turning BCL11A’s activity down and allowing red blood cells to manufacture some fetal hemoglobin.

“This finding gives us a very specific target for sickle cell disease therapies,” said Orkin, a leader of Dana-Farber/Boston Children’s who serves as chairman of pediatric oncology at Dana-Farber Cancer Institute and associate chief of hematology/oncology at Boston Children’s Hospital. “Coupled with recent advances in technologies for gene engineering in intact cells, it could lead to powerful ways of manipulating hemoglobin production and new treatment options for hemoglobin diseases.”

“This is a very exciting study,” said Feng Zhang, PhD, a molecular biologist and specialist in genome engineering at the McGovern Institute for Brain Research at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, who was not involved in the study. “The findings suggest a potential new approach to treating sickle cell disease and related diseases, one that relies on nucleases to remove this regulatory region, rather than adding an exogenous gene as in classic gene therapy.”