Intralymphatic Injections Safe for Grass Pollen Allergy

Intralymphatic injections of standard grass-pollen extract are well tolerated and could offer a new and convenient option for treating grass-pollen allergy, new research suggests.

The therapy involves ultrasound-guided injection into the right inguinal lymph node, and requires only three preseasonal doses, given 1 month apart, explained investigator Amber Patterson, MD, from Nationwide Children’s Hospital in Columbus, Ohio.

Intralymphatic immunotherapy is similar to subcutaneous immunotherapy “in that you do your course of treatment, but then you’re done,” without the monthly injections for 3 to 5 years, she explained.

In several European trials, it has been demonstrated that intralymphatic injections are effective against grass, birch, and cat.

“When I first read about this in Europe, I thought, ‘this is incredible, we need to be doing this here.’ It’s so nice to have options since a lot of people don’t do traditional allergy shots because it’s so inconvenient,” Dr Patterson told Medscape Medical News.

“The Europeans followed people 3 years out and saw sustained efficacy, so we’re banking on that,” she added.

Results from the study by Dr Patterson’s team were presented as a late-breaking poster here at the American Academy of Allergy, Asthma & Immunology 2015.

First Evidence

The double-blind trial involved 15 teenagers with grass-pollen-induced rhinoconjunctivitis, three of whom also reported mild intermittent asthma.

The patients were randomly assigned to receive three intralymphatic injections of either extract from North American grass pollen or placebo, administered at least 4 weeks apart and timed to be completed before the start of the grass-pollen season.

Escalating doses — 0.1 mL, 0.2 mL, and 0.5 mL — were administered with a 1.5-inch 25-gauge needle inserted into the subcapsular node space, Dr Patterson explained.

“The main aim was to show that we could take American extracts, which are standardized differently than European extracts, and that we could do this safely,” she said.

You hardly ever see this kind of compliance.

Patients were assessed for adverse safety events — such as erythema, pruritus, and edema — 2 and 5 hours after the injection and then 1 week later. There were no differences in safety scores between the treatment and placebo groups.

Of note, all the teenagers completed 100% of their injections, Dr Patterson reported. “When I told other allergists this, they were so surprised; you hardly ever see this kind of compliance.”

When she was asked about allergists’ access to ultrasound guidance for the injections, Dr Patterson explained that “we need to figure out the science first. Once that’s more established, we can figure out how to give the shots because it’s a pretty simple procedure.”

“It’s interesting,” said Hugh Sampson, MD, from Kravis Children’s Hospital at Mount Sinai in New York City, who was not involved in the study.

“It does seem safe and, if you can do it in three doses, you’re definitely going to get better compliance,” he told Medscape Medical News.

Complexities of Opioid-Induced Hyperalgesia Poorly Understood

Opioid-induced hyperalgesia is among the most pressing concerns in the national discussion of opioid addiction, underscored by the US Food and Drug Administration’s (FDA) call for clinical trials to better understand the risks, but the issue is mired in more complexities and confusion than many may even realize, an expert says.

Norman Harden, MD, from the Rehabilitation Institute of Chicago at Northwestern University in Illinois, presented a very popular talk on the issue at the American Academy of Pain Medicine (AAPM) 31st Annual Meeting.
“There is a wealth of animal research showing a direct association with increased opioid use and a hyperalgesic-like phenomenon in rats, so everyone has jumped on this assumption that the same type of linear response occurs in humans,” Dr Harden told the audience of pain specialists.

“But unfortunately there is limited data on whether it does translate to humans.”
Dr Norman Harden
At the crux of the confusion is the hypersensitivity to pain that can occur in patients in chronic pain with long-term, high-dose opioid use and whether the cause is from the opioids themselves or a tolerance that has developed to the opioids — or whether the symptoms represent allodynia and hyperalgesia, the central sensitization that normally occurs in chronic pain states.

A look at the potential mechanisms of hyperalgesia leads to a host of possibilities, including peripheral sensitization, central sensitization, disinhibition, or possibly sympathetic nervous system involvement.
“We have to ask, is this a disinhibition process; is it peripheral sensitization and inflammation; is it all of these mechanisms, and furthermore, is it subsets of these etiologies affecting some people but not others?” Dr Harden said.

“What we do know is that it is an incredibly complicated and probably heterogeneous process that differs between individuals.”

Issues of genotypes and endocrinopathy are hypothetically also parts of the puzzle as well, with some studies showing clues of hormonal changes associated with chronic pain perception, for instance.

“What we are seeing on the basis of largely uncontrolled case studies are significantly reduced levels of pregnenolone among chronic pain patients, which is at the ‘top of the pyramid’ of hormones,” Dr Harden said.

“The lower levels of certain hormones are reportedly seen in pain patients whether they are taking opioids or not, so perhaps it is the chronic pain, and not necessarily iatrogenic causes, that is behind this endocrinopathy.”

In a very preliminary effort to better understand the measures of pain to predict opioid-induced hyperalgesia, Dr Harden and his colleagues compared pain test responses among patients with chronic low back pain, including 10 who were receiving medium- to high-dose opioids (45 to 424 morphine milligram equivalency conversion) and 10 who were not taking opioids.

The study, presented at the meeting, showed no significant differences between the groups in terms of sensory tests for pain, assessed with the thermal quantitative sensory testing for warm and cold sensation and heat- and cold-induced pain, or other measures, such as thermal or mechanical wind-up or pinprick sensation.

Even more surprisingly, the one test that did show statistical significance, a pinprick wind-up test, showed a greater sensitivity not in the opioid group, as expected, but in the patients not taking opioids (P < .03).

“The people on opioids in fact had lower pain on this single test, and one interpretation of that would be that they’re getting an analgesic effect from the opioids, not hyperalgesia,” Dr Harden said. “This is 180 degrees from what we would have predicted if we had listened to and accepted (everything) about hyperalgesia in the last decade.”

This is 180 degrees from what we would have predicted if we had listened to and accepted (everything) about hyperalgesia in the last decade.Dr. Harden

Dr Harden stressed that the preliminary nature of the study should be emphasized, noting that the findings are part of what will eventually be a larger analysis.

The early findings appear to support, however, the assertion that hyperalgesia (central sensitization) in many cases may be part of the natural progression of chronic pain.

“We theorize pain drives changes in the central nervous system and that’s what our research corroborates,” Dr Harden said. “Maybe this is not an iatrogenic (opioid) hyperalgesia but ‘natural’ hyperalgesia that occurs in chronic pain.”

The one certainly, however, is that much more research needs to be done concerning the hyperalgesia phenomena in order to determine, for instance, how to prevent it, Dr Harden said.

“If we’re going to spend tens of millions to study hyperalgesia (as recommend by the FDA) we probably need to have a little understanding of just what it is and how it works; I can tell you we don’t. We have to do a lot of work to clarify this.”

Symptoms During Opioid Withdrawal

David Fishbain, MD, a professor of psychiatry and adjunct professor of neurological surgery and anaesthesiology at the University of Miami Miller School of Medicine in Florida, noted that a big factor in implicating opioid use in hyperalgesia has been observations in patient symptoms once they are tapered from the drugs.

“For years, pain centers have observed that when patients are detoxed from opioids, most of them, but not all, advise that their pain is better or same,” he told Medscape Medical News. “This indirectly supports the concept of opioid-induced hyperalgesia.”

Dr Harden agreed with the assertion. However, he pointed to an earlier uncontrolled study he conducted indicating that some patients do have a “halo effect” of resolved symptoms at first after detoxification, but that in some patients, the pain later gets worse.

Dr Fishbain agreed that much more research is necessary to better understand the phenomenon.

“There is some recent evidence that pain patients in general are hyperalgesic,” he said. “This then makes it very difficult to demonstrate hyperalgesia in pain patients on opioids because you do not know what the hyperalgesia is from.”

Well-designed clinical trials are needed to clarify the issue, he added.

“The issue of whether opioids induce hyperalgesia can only be settled with a prospective study where pain thresholds are measured before and after opioid treatment in humans, as has been done in rodents.”

Transfusion-Related Food Allergy Transmission Rare, Transient

Anaphylaxis can be induced by the passive transfer of immunoglobulin E (IgE) from blood products. Clinicians should be mindful of this rare mode of transmission in the evaluation of children who react to previously tolerated foods, according to the authors of a case study published online April 7 in the Canadian Medical Association Journal.

Joyce Cheung Yee Ching, MD, from the Department of Pediatrics, Rouge Valley Health System in Toronto, Ontario, Canada, and colleagues report the case of an 8-year-old boy who underwent multiple blood product transfusions as part of his treatment for medulloblastoma and subsequently experienced two separate allergic reactions to food caused by passive transfer of food-specific IgE from a pooled platelet transfusion.
In the first reported case of two separate allergic reactions to food, the patient initially experienced anaphylaxis within minutes of eating salmon. One week later, he developed an allergic reaction to peanuts. The patient tested positive for specific IgE to salmon and peanut by ImmunoCAP. In addition, skin prick testing was positive for peanut, salmon, mixed fish, and tree nut mix, the authors write.

Because the patient previously ate fish and nut products routinely without effect, the treating clinicians suspected passive transfer of IgE. “After being notified of our suspicion of passive transfer of allergy, Canadian Blood Services investigated the event and contacted all associated donors,” the authors write. One donor described a severe allergy to peanuts, tree nuts, shellfish and all fish, including salmon. Although there were no remaining donor blood products to test for specific IgE, the source of the passively transferred IgE was inferred to be a pooled platelet transfusion suspended in about 200 mL of plasma from the atopic donor, they write.

Less than 6 months after the initial allergic reactions, specific IgE to both salmon and peanut was undetectable and both foods had been successfully reintroduced into the patient’s diet, the authors report.

Passive transfer of allergy from blood products is unusual, the authors stress. First-line treatment with epinephrine is recommended for acute reactions, and the long-term prognosis is excellent. “However, it is unclear how best to avoid passive transfer of allergy from blood products,” they write. “Canadian and American blood service organizations do not defer donors for having a history of allergy, but donors are deferred if they have symptoms of allergies on the day of donation.” In addition, they explain, self-reported allergies by questionnaire at the time of donation have not been shown to correlate with or predict the actual serologic levels of IgE antibodies.

The clinicians did inform the hospital’s transfusion service of their suspicion of passive transfer of specific IgE, which “resulted in an understanding of the potentially transferred antibodies in our patient and the exclusion of the atopic donor from future donations.”
The authors conclude that “[t]here is no simple way to prevent these rare cases of passive transfer of IgE antibodies without losing safe donors.” Reporting suspected passive sensitization causing food allergy can lead to increased safety of the blood supply, they note. In addition, food allergy from passive transfer of IgE “is worth identifying to avoid unnecessarily prolonged avoidance of foods.”

Celiac Disease: Which Children Should Be Tested?

Serological screening studies indicate that celiac disease (CD) has a prevalence of 1% to 2% in Western populations and that the incidence is increasing across all age groups. Although many individuals develop symptomatic CD, others do not. In fact, researchers estimate that just 10% to 30% of patients with CD are ever diagnosed, in part because they may be asymptomatic.

For children, that lack of diagnosis can be critical: Young children with undiagnosed CD are particularly vulnerable to the effects of malabsorption and failure to thrive.
Because of that danger, some researchers and clinicians are pushing for widespread screening. Some experts go even further, suggesting that the entire pediatric population should be routinely screened for CD. Yet the cost and the need for invasive confirmatory biopsies leave others skeptical of that approach unless better, cheaper diagnostics become available

New data published in the March issue of the American Journal of Gastroenterology by Rok Seon Choung, MD, PhD, from the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, and colleagues, show that among a representative sample of nearly 15,000 Americans aged 6 years or older, the prevalence of confirmed CD was 0.8% (95% confidence interval [CI], 0.5% – 1.0%) in 2009 to 2012.

Extrapolating to the population at large, the data suggest that more than 1.5 million people in the United States have CD. Moreover, the analysis showed a near doubling in the prevalence among adults aged 50 years or older, rising from 0.17% (95% CI, 0.03 – 0.33%) in the 1988 to 1994 National Health and Nutrition Examination Survey to 0.44% (95% CI, 0.24% 0 0.81%) in the 2009 to 2012 survey. However, the adjusted prevalence is uneven among racial and ethnic groups, ranging from 1.0% of whites to 0.2% of blacks and 0.3% of Hispanics.

For Ritu Verma, MBChB, director of the Center for Celiac Disease and the Lustgarten Endowed Chair for Clinical Care of GI Motility Disorders at the Children’s Hospital of Philadelphia in Pennsylvania, those numbers and the consequences of undiagnosed CD lead to a straightforward conclusion: “The biggest plea I have for pediatricians is to just do the panel,” she told Medscape Medical News, referring to an antibody test panel that can help to determine whether a child likely has the disease.

However, other pediatric gastroenterologists, including Saeed Mohammad, MD, from Northwestern University Feinberg School of Medicine in Chicago, Illinois, feel that screening the entire population is just not feasible, and the cost of increased screening may not be justified.
“[CD] is more common in certain ethnic groups and less common in others,” he told Medscape Medical News. “Unless the cost of genetic testing drastically decreases, I believe the current system of screening children with risk factors for [CD] such as diabetes, Down syndrome, or autoimmune diseases, as well as testing for celiac-specific antibodies in children whose growth is faltering [and] those who have diarrhea or chronic abdominal pain, is the most cost-effective option with the greatest sensitivity.”

Moreover, he notes that children younger than 2 years should not be tested without high clinical suspicion, “and [diagnosis] should always be confirmed with endoscopy and biopsy,” he continued.

When and How to Test?

Classic symptoms of CD include prolonged abdominal pain, poor growth, chronic diarrhea, and abdominal distention. When children present with these symptoms, physicians may think of testing for CD, but unfortunately, there is no standardized celiac panel.

 The Children’s Hospital of Philadelphia, where Dr Verma practices, recommends a screening panel that includes total immunoglobulin A (IgA), antitransglutaminase (anti-tTG), and antiendomysial. Deaminated gliadin can be ordered in conjunction with anti-tTG. In addition, for children younger than 3 years, it may be advisable to test for antigliadin, she says.

Dr Verma would prefer that all children be screened for CD, but if that is not possible, then she encourages pediatricians to screen when they have even the slightest suspicion that the child might have CD.

She notes that many children who are diagnosed with CD in her clinic do not have a classic presentation. Thus, Dr Verma actively educates primary care physicians about CD and encourages them to consider the possibility of CD if they are treating a patient who does not seem to get better. The primary care physician can then order the simple celiac blood test.

Meanwhile, Boston Children’s Hospital in Massachusetts focuses their screening efforts on high-risk children. These would be children with classic symptoms of CD such as abdominal pain and chronic diarrhea, as well as those at known genetic risk for CD and children with type 1 diabetes.

Boston Children’s Hospital uses a similar celiac panel to the one used by the Children’s Hospital of Philadelphia. “We recommend that ‘high-risk’ children be screened with serologic celiac tests (specifically tissue transglutaminase IgA and a total IgA), even if they have no identifiable symptoms,” Dascha C. Weir, MD, associate director of the Celiac Program at Boston Children’s Hospital in Massachusetts, told Medscape Medical News.

A child who is strongly positive for all of these antibody tests likely has CD.

Dr Verma acknowledges that the tests can give false-negatives and provide a false sense of security to parents. They can also give a false-positive. This is why the definitive test for CD is upper endoscopy.

Dr Verma explained that physicians also need to take a dietary history. Some children do not eat a lot of gluten between the ages of 2 and 3 years, and therefore may not test positive on the celiac panel. Unfortunately, most pediatricians do not have the time to take a complete dietary history.

Moreover, the United States has a heterogeneous population, and some experts suggest that a one-size-fits-all screening approach may not be practical. That said, “care providers should have a low threshold to order celiac testing for children with gastrointestinal symptoms or nongastrointestinal symptoms,” Dr Weir emphasized.

Classic Symptoms Inadequate Cues

Regrettably, many primary care physicians have the false impression that children who lack classic symptoms of CD should not be screened for the disease. Unfortunately, relying on symptoms to trigger CD testing could miss a substantial proportion of affected children, according to recently published data from Sweden.

Daniel Agardh, MD, PhD, from Lund University in Sweden, and colleagues published their subanalysis of data from The Environmental Determinants of Diabetes in the Young (TEDDY) study online March 2 in Pediatrics. Whereas the primary goal of TEDDY is to identify genetic and environmental factors that contribute to the development of type 1 diabetes, Dr Agardh and colleagues used the birth cohort data to compare children who were positive for anti-tTGA with those who were negative for anti-tTGA.

They found that, compared with children who were negative for anti-tTGA, children positive for anti-tTGA were more likely to be symptomatic at 2 and 3 years of age, but not at 4 years of age. In addition, the researchers report that anti-tTGA levels correlate with severity of mucosal lesion in symptomatic and asymptomatic children, and some asymptomatic children had quite elevated levels of anti-tTGA. These children were diagnosed with CD because they were enrolled in the study, but likely would have been missed in standard practice.

Results from the study have led the experts to propose a two-tiered screening system by which all newborns are first specifically screened for genetic susceptibility such as HLA type and, if positive, then screened for celiac-specific antibodies. This screening protocol would be a departure from that used in the United States and would include much more comprehensive genetic screening.

“With awareness and availability of gluten-free foods increasingly entrenched within the mainstream of the North American lifestyle, the burden lies on the identification of all children who may benefit from treatment. The prospective data from TEDDY effectively demonstrate the utility of 2-tiered screening and constitute a step forward in devising a population-screening strategy that best offers the appropriate treatment at a stage in life where it may yield the most lifelong benefit,” writes Richard J. Noel, MD, PhD, from Duke University Medical Center in Durham, North Carolina, in an accompanying commentary in Pediatrics.

Dr Verma believes the study from Sweden advances the conversation, but does not take the concept of screening far enough. “I am glad that at least someone is thinking about screening people early,” Dr Verma said. “[but] if you are between 2 and 3 years of age, you should just have a celiac panel done.” She emphasized again that there are many atypical symptoms of CD, especially in children.

Genetic Risk Factors

The 2-tiered screening test may not yet be realistic for the United States.

Currently, children in the United States may be targeted for screening because they have a family history of CD or have Down syndrome, Turner syndrome, or Williams syndrome. The 2004 consensus guidelines from the National Institutes of Health indicate that patients with type 1 diabetes should also be screened for CD.

Although individuals who are homozygotic for HLA-DR3-DQ2 are at highest genetic risk for CD and tend to develop CD very early in life, HLA tests are not routinely performed in the United States, and therefore HLA status rarely triggers a CD test. According to Dr Weir, this is an evolving issue.

“Screening high-risk groups (such as family members or patients with predisposing conditions) for [CD] with serologic testing (tissue transglutaminase [immunoglobulin G and total immunoglobulin A] is widely accepted. However, in the USA, the use of HLA typing in screening children to identify who is at higher risk of [CD] has not been fully evaluated and is not currently recommended. However, as our understanding of the HLA typing and [CD] risk deepens, and as HLA testing becomes cheaper and more readily available, this may change,” Dr Weir noted.

The genetic basis of CD does mean that a diagnosis of CD has implications for the entire family. If a child tests positive for CD, the family (siblings, parents, and grandparents) should be tested for CD. In addition, siblings should be periodically retested to look for the development of CD.

Poor Growth May Point to CD

Another newly proposed screening strategy suggests children should be tested for CD if they have poor growth. Although CD does not always affect growth, most children who are diagnosed experience a decrease or slowing of growth before diagnosis. A new study suggests these children could be diagnosed earlier if they were being followed in a well-established growth-monitoring program.

Antti Saari, MD, from the University of Eastern Finland in Kuopio, and colleagues published the results of their longitudinal retrospective study on the relationship between growth and CD online March 2 and in the March issue of JAMA Pediatrics. They propose that screening for CD would include the use of several growth-monitoring parameters in combination. Furthermore, the parameters should be integrated into a computerized screening algorithm associated with an electronic health record system.

“I have sort of mixed feelings about [the study]…. I am personally of the belief that there should be mass screening of people,” stated Dr Verma. She explained that because not all of the children with CD have growth issues, the approach proposed by Dr Saari and colleagues would miss many children with CD.

Atypical Symptoms

Dr Verma described some of the atypical symptoms of CD. For example, anemia may be a sign of CD. As a consequence, Dr Verma recommends that children with unexplained anemia be tested for CD.

She added that chronic headaches, seizures, chronic constipation, elevated liver enzymes, chronic pancreatitis, alopecia, and tiredness can all be signs and symptoms of CD. Moreover, many patients who are originally diagnosed with irritable bowel syndrome are ultimately diagnosed with CD.

Parents should be counseled to have the blood work done before experimenting with a gluten-free diet. A gluten-free diet will eventually lower the levels of antibodies, thereby making the celiac panel unreliable. Moreover, physicians should keep in mind that children who consume low levels of gluten or consume occasional gluten may have lower antibody levels, even though they have CD.

A patient who tests positive on the celiac panel should be referred to a gastroenterologist. The gastroenterologist can decide whether endoscopy is required and can counsel the patient on the importance of a gluten-free diet. Patients must understand that the gluten-free diet is for life, and they need encouragement to adopt a gluten-free lifestyle.

Metabolic Syndrome, Insulin Resistance Affect Lung Function

Metabolic syndrome and insulin resistance appear to contribute to the pathogenesis of asthma in obese children and adolescents.

Erick Forno, MD, MPH, from the Children’s Hospital of Pittsburgh in Pennsylvania, and colleagues published the results of their cross-sectional study online March 4 in the Journal of Allergy and Clinical Immunology.
“To the best of our knowledge, this is the first study of insulin resistance or [metabolic syndrome] and lung function in a representative sample of US adolescents with and without asthma,” the authors write. “Among adolescents with and without asthma, we found that insulin resistance is associated with decreased FEV1 and FVC values and that [metabolic syndrome] is associated with lower FEV1/FVC ratios.”

The study used a representative sample of US adolescents and was performed by uniformly trained personnel using standardized procedures. The investigators reviewed data from 1429 adolescents aged 12 to 17 years enrolled in the 2007 to 2010 National Health and Nutrition Examination Survey, only 95 of whom had current asthma. The study did not control for diet or family history of diabetes.

The investigators found that both insulin resistance and metabolic syndrome are associated with significantly worsened lung function (2% – 10% decrease in FEV1/FVC) in adolescents who are overweight or obese. Specifically, metabolic syndrome was associated with a 2% decrease in lung function compared with healthy teenagers. Asthma alone was linked to a 6% reduction in lung function, and the combination of metabolic syndrome and asthma was associated with a 10% decrease. The results remained significant after controlling for other factors, including body mass index and waist circumference.

The study design precluded, however, the establishment of a temporal relationship among insulin resistance, metabolic syndrome, and lung function. The researchers analyzed only current asthma and did not identify adolescents who had low exacerbation risk but higher impairment before the study began.

Adolescents were classified as having metabolic syndrome if they met three of five criteria: fasting glucose levels of 110 mg/dL or higher, waist circumference in the 75th percentile or higher, fasting triglyceride levels of 100 mg/dL or higher, high-density lipoprotein levels of 50 mg/dL or lower, and systolic blood pressure in the 90th percentile or higher.

Although previous studies have been published on asthma and insulin resistance, the current study adds to the discussion by quantifying lung function.

“I think it really reinforces the need to screen for metabolic syndrome and insulin resistance,” emphasized Grace Kim, MD, from Seattle Children’s Hospital in Washington, to Medscape Medical News.
Dr Kim points out, however, that “they don’t really comment about people’s puberty status,” adding that “with puberty, kids are in a more insulin-resistant state.” Nor does the study examine visceral obesity.

Dr Kim explained that endocrinologists already know that children and adolescents who are overweight tend to have asthma. “They are finding what we know anecdotally,” she explained.

Insulin resistance may affect lung function via insulin growth factor 1, adiponectin, or leptin. Metabolic syndrome may affect lung function via increased protein turnover and consequent altered arginine metabolism.

Insulin resistance has been associated with hepatic steatosis and cardiovascular disease. Metabolic syndrome has been associated with asthma in adults, and one study linked it to reduced lung function.

Autoantibodies May Trigger First-Episode Psychosis

Children presenting with first-episode psychosis may have serum autoantibodies to the dopamine-2 receptor (D2R) and the N-methyl-D-aspartate (NMDA) receptor, suggesting that psychosis may be immune-mediated in some patients.

Investigators, led by Fabienne Brilot, PhD, head of the neuroimmunology group at the Children’s Hospital at Westmead, University of Sydney, Australia, found that children presenting with acute psychosis were significantly more likely to have positive immunoglobulin binding to either the DR2 or the NR1 subunit of the NMDA receptor than control children.

“Our identification of patients with D2R and NMDAR [NMDA receptor] antibodies, receptors heavily implicated in the pathogenesis of psychotic disease, strongly suggests that the presence of specific autoantibodies may define a biological subgroup of psychosis,” they write.

The research is published in the March 15 issue of Biological Psychiatry.

Improved Diagnosis, Treatment?
Building on recent investigations reporting the presence of autoantibodies against proteins expressed on the surface of cells in the central nervous system, Dr Brilot and colleagues examined serum samples taken during the acute presentation of 43 first-episode psychosis patients younger than 17 years.

In addition, they took serum samples from 43 pediatric control persons who were either healthy or had a neurologic or general medical condition. The samples were analyzed for the presence of immunoglobulin (Ig) G, IgM or IgA antibodies to D2R and the NR1 subunit of the NMDA receptor.

The presence of autoantibodies was detected using flow cytometry live cell–based assay and immunolabeling of murine primary neurons. Antibody binding was expressed as the mean fluorescence intensity (MFI), and a difference in MFI between patient and control serum samples of more than +3 standard deviations was considered positive.

The difference in the number of individuals with serum antibodies to D2R or NR1 between patients and control participants was significant, at 8 vs no participants (P < .001).

Positive D2R autoimmunoglobulin binding was found in three patients (IgG autoantibodies in three patients and IgM autoantibodies in one patient), whereas positive NMDA receptor binding was seen in six patients (IgG autoantibodies in five patients, and IgM and IgA autoantibodies in one patient each).

Crucially, further analysis confirmed the specificity of the antibody and that live cells are required to demonstrate autoantibody binding.

Dr Brilot is optimistic that the findings could point to future treatment options.

“It’s a very good moment in the field, because those autoantibodies in neurological disease have been shown to be very helpful in terms of diagnosis, but also in terms of treatment,” she said.

“There’s more and more data looking at how the antibody behaves with treatment and as a biomarker, but also at the cause of the disease,” she added.

Nevertheless, Dr Brilot acknowledged that psychosis is a “complex disease” and that there is still a long way to go before the precise role of the autoantibodies can be elucidated.

Autoantibodies, she said, are markers of the immune system being activated, but “is it the cause of psychosis? I don’t think that it is. I think we’re looking at subgroup.”

“In that subgroup…is it really only the antibodies that are the cause of this disease? Well, we don’t know. I think more studies are needed at this point,” she said.

Dr Brilot noted that this study was an important “first step” but that more research is needed.

“It’s the beginning, and that’s why its very interesting. It’s taking everything we know from the neurological field and trying to apply to the psychiatric field, where obviously we are in dire need of new treatment options,” she concluded.

Breakdown of Blood-Brain Barrier?

Commenting on the findings for Medscape Medical News, Scott Russo, PhD, associate professor of neuroscience, Icahn School of Medicine at Mount Sinai, New York City, described the results as “exciting.”

Dr Scott Russo

“There’s been a couple of other results that have shown similar things…and this is a really bona fide case where antibodies against the NMDA receptor can cause a number of symptoms that are classically associated with psychiatric illness, including things like cognitive dysfunction and memory loss,” he said.

Dr Russo, who was not involved in the research, explained that there are a few outstanding questions that need to be answered. The first centers on the size of the autoimmune antibodies, which are typically too large to cross the blood-brain barrier.

In neurologic conditions such as NMDA encephalitis, there is a breakdown of the blood-brain barrier that allows the autoantibodies to pass through. However, it is not clear how they could enter a healthy brain.

“So the question is, Is schizophrenia or psychosis one of these situations where we are seeing breakdown of the barrier and, thus, in a subset of patients that do overproduce these antibodies, combined with the breakdown of those vascular regions, you end up with a psychiatric phenotype?

“The other thing to consider really is that there is no functional study done yet to prove that the existence of these autoantibodies against the D2 receptor or NR1 receptor can cause the behaviors that we associate with schizophrenia or other mental illnesses,” he said.

“There’s really no translational animal model that I could find that would prove that there’s a functional connection between the two, because, at this point, you want to caution people that it is correlation, and it’s correlation really only in a small subset of patients.”

Dr Russo nevertheless believes that should these findings be replicated in further studies, there may be an opportunity to tackle psychosis at a crucial stage.

“For these types of illnesses, the key is finding it early and, from a research perspective, I think what you’d want is to prevent the longer-term damage that could occur from your body eating itself.”

“I think if you have multiple events over a lifetime, there’s probably going to be enough permanent damage that reverting back or treating becomes more difficult,” he concluded.

Why Vodka Red Bulls Are Bad News: Teens Drink More When Mixing Alcohol And Energy Drinks

Ostensibly, a vodka Red Bull seems like the end-all be-all of hard partying cocktails. You’ve got the energy drink that assures you won’t be the first of your friends to call it a night combined with the inhibition-lowering effects of alcohol. What could go wrong? From a health perspective, a lot.

Red Bull

A study conducted at Dartmouth’s Norris Cotton Cancer Center has found that American teenagers between the ages of 15 and 17 who have ever mixed energy drinks and alcohol are four times more likely to develop an alcohol use disorder compared to teens who have never experimented with this combination.

“These findings are concerning,” first author of the study Dr. Jennifer A. Emond said in astatement. “They highlight that mixed use of alcohol and energy drinks may signal the development of abusive drinking behaviors among adolescents.”

Emond and her colleagues used a sample of over 3,000 adolescents and young adults between the ages of 15 and 23 from across the United States. While a growing number of studies have focused on the negative outcomes of combining energy drinks and alcohol, these analyses have generally focused on undergraduate college students and rarely include high school students.

Out of 3,342 study participants, 9.7 percent of adolescents between the ages of 15 and 17 reported consuming an energy drink combined with alcohol. Adolescents who reported mixing energy drinks and alcohol not only increased their risk for binge drinking but were also four times more likely to meet the criteria for alcohol use disorder.

“Abusive alcohol use among adolescents is a dangerous behavior that can lead to injury, chronic alcohol use and abuse, and even death,” Emond added. “Identifying those most at risk for alcohol use is critical. Given that this is a sensitive issue, it’s possible that clinicians, parents, and educators might open dialogues about alcohol use with adolescents by starting the discussion on the topic of energy drinks.”

A similar study conducted by researchers from Australia found that the combination of energy drinks and alcohol increased a person’s desire to keep drinking. People under the age of 30 who consumed 60ml of vodka with a Red Bull Silver Edition energy drink had a stronger desire to continue drinking alcohol compared to people who consumed 60ml of vodka with club soda.

Clearly, the desire to drink more alcohol was accompanied by “a cycle of greater intoxication,” namely binge drinking. Other hazardous behaviors that can result from a greater urge to drink include drunk driving, risky sexual behavior, and alcohol-related violence.

IBM’s Watson to Guide Cancer Therapies at 14 Centers

‘Humans alone can’t do it,’ oncologist says.

Fourteen U.S. and Canadian cancer institutes will use International Business Machines Corp’s Watson computer system to choose therapies based on a tumor’s genetic fingerprints, the company said on Tuesday, the latest step toward bringing personalized cancer treatments to more patients.

Oncology is the first specialty where matching therapy to DNA has improved outcomes for some patients, inspiring the “precision medicine initiative” President Barack Obama announced in January.

But it can take weeks to identify drugs targeting cancer-causing mutations. Watson can do it in minutes and has in its database the findings of scientific papers and clinical trials on particular cancers and potential therapies.

Faced with such a data deluge, “the solution is going to be Watson or something like it,” said oncologist Norman Sharpless of the University of North Carolina Lineberger Cancer Center. “Humans alone can’t do it.”

It is unclear how many patients will be helped by such a “big data” approach, however. For one thing, in many common cancers old-line chemotherapy and radiation will remain the standard of care and genomic analysis may not make a difference.

Cloud-based Watson will be used at the centers – including Cleveland Clinic, Fred & Pamela Buffett Cancer Center in Omaha and Yale Cancer Center – by late 2015, said Steve Harvey, vice president of IBM Watson Health. The centers pay a subscription fee, which IBM did not disclose.

Oncologists will upload the DNA fingerprint of a patient’s tumor, which indicates which genes are mutated and possibly driving the malignancy. Watson, recognized broadly for beating two champions of the game show Jeopardy! in 2011, will sift through thousands of mutations and try to identify which is driving the tumor, and therefore what a drug must target.

Distinguishing driver mutations from others is a huge challenge. IBM spent more than a year developing a scoring system so Watson can do that, since targeting non-driver mutations would not help.

“Watson will look for actionable targets,” Harvey said, matching them to approved and experimental cancer drugs and even non-cancer drugs (if Watson decides the latter interfere with a biological pathway driving a malignancy).

But Watson has trouble identifying actionable targets in cancers with many mutations. Although genetic profiling is standard in melanoma and some lung cancers, where drugs such as Zelboraf (vemurafenib) from the Genentech unit of Roche Holding AG target the driver mutation, in most common tumors traditional chemotherapy and radiation remain the standard of care.

“When institutions do genetic sequencing, only about half the cases come back with something actionable,” Harvey said, often because it is impossible to identify the driver mutation or no targeted therapy exists.

For Superbugs, Fight Fire With Fire: Non-Toxic C. Diff Bacteria Ward Off Antibiotic-Resistant Strain

If you haven’t heard of Clostridium difficile, better known as C. difficile or C. Diff, you will soon. It’s one of the fastest growing superbugs, rivaling MRSA in both frequency and severity. Due to antibiotic resistance, a cure for C. difficile  has been elusive, but a recent study suggests that we’ve been looking in the wrong places and the only thing strong enough to fight off C. difficileis actually more C. difficile.

bacteria culture

According to a report published in the Journal of the American Medical Association, trials on 173 individuals with C. difficile infections showed that introducing a non-toxigenic C. difficile strain helped to dramatically cut the odds of repeat infections and is a promising start to finally getting an upper hand on this potentially fatal superbug.

In the study, conducted by researchers at Loyola University Health System in Illinois, patients with C. difficile infections were given spores of a non-toxin producing strain of C. difficile. Around 69 percent of the time the “friendlier” strain was able to occupy areas in the gut where the toxic C. difficile strain normally thrived. This inhibited the severe C. difficile from returning and only one in 50 of the patients experienced a recurrent C. difficile infection.

The research is still in its earliest stages, but the researchers are excited about the results. Although the patient remains infected with C. difficile, more importantly, the symptoms cease. The eventual goal of the research is to develop a treatment involving the digestion of “friendly” C. difficile spores to indefinitely prevent a patient once again falling ill from the infection.

“What we’re doing is establishing competition with the original, toxic strain,” Dr. Dale Gerding, one of the researchers involved in the study explained, as reported by the BBC. “I’m excited about this and looking forward to a phase-three [larger] trial. We think it’ll go a long way to reduce C. diff recurrence.”

C. difficile infections are almost exclusive to hospital settings, clinics, nursing homes and other health care facilities. The reason for this is that the bacteria take hold in individuals whose normal fauna of bacteria is disrupted due to antibiotic courses. Without the normal healthy bacteria standing in the way, the drug-resistant C. difficile can take hold and cause inflammation in the patient’s colon. According to the Centers for Disease Control and PreventionC. difficile infections are widespread and each year it’s linked to about 29,000 deaths in the United States.

Symptoms of C. difficile infections include frequent diarrhea, fever, loss of appetite, nausea, and abdominal pain and tenderness. These infections are commonly treated with antibiotics, but due to the bacteria’s evolved resistance to treatment the infection returns in around 20 percent of cases. Currently fecal transplants are the most effective way to treat repeat C. difficile infections, but the recent study suggests an equally effective and far less invasive approach to the condition.

People Judge Intelligence By The Sound Of Your Voice, Not Written Word

Intelligence cannot be directly observed, but yet we still judge how smart someone may be within moments of meeting. While you may think the best way to make a good impression is through witty, enthralling speech, a recent study has found evidence to suggest your intelligence is best conveyed not in what you say but in how you say it.


For the study, which is currently published in the Journal Psychological Science, a team of researchers from the University of Chicago videotaped MBA students while they were giving pitches. They then had prospective employers or professional recruiters either watch the video, listen to an audio of the speech, or simply read a transcript. Results showed the voice of the students had the biggest influence in whether or not they were hired, and adding video to the audio did not at all affect the students’ evaluations.

“What they show is that your intelligence is not necessarily something I can see on your body, but I think it’s a cue that we can pick up or hear in your voice,” explained Nicholas Epley, one of the researchers involved in the study, as reported by Time.

Epley recommends that we can use this data to our benefit, especially when it comes to trying to win over the favor of others and make a good first impression. According to Epley, although most of us may not want to speak out for the fear of appearing stupid, it’s actually the opposite that rings true. He recommends that in contexts such as a job interview, if you ever have the opportunity to speak to someone directly, take it.

“For conveying one’s intellect, it is important that one’s voice, quite literally, be heard,” the authors wrote.

This link between perceived intelligence and vocal pitch may have even bigger implications in how we understand human social interactions, especially in the new online setting.

Thanks to advances in technology, more and more human interactions take place in written form rather than verbal. That lack of verbal interaction has disturbed natural ways in which we socialize and has made it harder to judge the intelligence level of strangers. It may also explain why we treat strangers online differently than we do in person.

“I don’t think it’s any accident that people online seem to treat each other as mindless idiots,” Epley said.

Source: Scroader J, Epley N. The Sound of Intellect Speech Reveals a Thoughtful Mind, Increasing a Job Candidate’s Appeal. Psychological Science. 2015.

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Dana Dovey Dana Dovey
Dana Dovey is a reporter for Medical Daily and is currently based on the exotic Island of Long. read more
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