A multi‐centre,single‐arm,open‐label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory,relapsed or chronic idiopathic thrombocytopenic purpura (R‐ITP1000 study)

The efficacy of a fixed‐dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 10⁹/l and ≤50 × 10⁹/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed‐up on weeks 1–8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 10⁹/l) or partial response (PR; platelet count >50 × 10⁹/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 10⁹/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m² four‐dose schedule in relapsed/chronic ITP.     

Evidence of a Major Reservoir of Non-Malarial Febrile Diseases in Malaria-Endemic Regions of Bangladesh

In malaria-endemic regions any febrile case is likely to be classified as malaria based on presumptive diagnosis largely caused by a lack of diagnostic resources. A district-wide prevalence study assessing etiologies of fever in 659 patients recruited in rural and semi-urban areas of Bandarban district in southeastern Bangladesh revealed high proportions of seropositivity for selected infectious diseases (leptospirosis, typhoid fever) potentially being misdiagnosed as malaria because of similarities in the clinical presentation. In an area with point prevalences of more than 40% for malaria among fever cases, even higher seroprevalence rates of leptospirosis and typhoid fever provide evidence of a major persistent reservoir of these pathogens.     

Chronic subthreshold subdural cortical stimulation for the treatment of focal epilepsy originating from eloquent cortex

Medically refractory epilepsy remains a major medical problem worldwide. Although some patients are eligible for surgical resection of seizure foci, a proportion of patients are ineligible for a variety of reasons. One such reason is that the foci reside in eloquent cortex of the brain and therefore resection would result in significant morbidity. This retrospective study reports our experience with a novel neurostimulation technique for the treatment of these patients. We identified three patients who were ineligible for surgical resection of the intracranially identified seizure focus because it resided in eloquent cortex, who underwent therapeutic trial of focal cortical stimulation delivered through the subdural monitoring grid. All three patients had a significant reduction in seizures, and two went on to permanent implantation, which resulted in long‐term reduction in seizure frequency. In conclusion, this small case report provides some evidence of proof of concept of the role of targeted continuous neocortical neurostimulation in the treatment of medically refractory focal epilepsy, and provides support for ongoing investigations into this treatment modality. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

Secreted Wingless-interacting molecule (Swim) promotes long-range signaling by maintaining Wingless solubility

Lipid-modified Wnt/Wingless (Wg) proteins can signal to their target cells in a short- or long-range manner. How these hydrophobic proteins travel through the extracellular environment remains an outstanding question. Here, we report on a Wg binding protein, Secreted Wg-interacting molecule (Swim), that facilitates Wg diffusion through the extracellular matrix. Swim, a putative member of the Lipocalin family of extracellular transport proteins, binds to Wg with nanomolar affinity in a lipid-dependent manner. In quantitative signaling assays, Swim is sufficient to maintain the solubility and activity of purified Wg. In Drosophila, swim RNAi phenotypes resemble wg loss-of-function phenotypes in long-range signaling. We propose that Swim is a cofactor that promotes long-range Wg signaling in vivo by maintaining the solubility of Wg.     

Alcohol dependence is related to overall internalizing psychopathology load rather than to particular internalizing disorders: evidence from a national sample

Background: Alcohol dependence is more prevalent among those with any one of several anxiety or depressive (“internalizing”) disorders than among those in the general population. However, because internalizing disorders are highly intercorrelated, it is ambiguous whether alcohol dependence is related to internalizing psychopathology components that are: (i) unique to a particular internalizing disorder (“specific”); versus (ii) shared across a number of internalizing disorders (“general”). To clarify this ambiguity, we employed structural equation and logistic models to decompose the specific versus general components of internalizing psychopathology and then related these components separately to alcohol dependence. Methods: The data were based on face‐to‐face interviews of U.S. community residents collected in the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; N = 43,093). Results: Both analytic approaches demonstrated that increases in the general internalizing psychopathology load are accompanied by increases in the prevalence of alcohol dependence. Once the general internalizing psychopathology load is accounted for, knowing whether a particular internalizing disorder is present or absent provides little additional information regarding the prevalence of alcohol dependence. Conclusions: The components of internalizing psychopathology that are associated with alcohol dependence are shared and cumulative among common anxiety and depressive disorders. These findings have the potential to influence clinical and scientific conceptualizations of the association between alcohol dependence and internalizing psychopathology.     

A murine model of mild traumatic brain injury exhibiting cognitive and motor deficits

Background

Mild traumatic brain injury (TBI) is a serious public health concern affecting more than 1.7 million people in the United States annually. Mild TBI is difficult to diagnose and is clinically associated with impaired motor coordination and cognition.

Methods

We subjected mice to a mild TBI (mTBI-1 or mTBI-2) induced by a weight drop model. We assessed brain injury histologically and biochemically, the latter by serum neuron-specific enolase and glial fibrillary acidic protein. Systemic and brain inflammation were measured by cytokine array. We determined blood–brain barrier integrity by cerebral vascular leakage of micromolecular and macromolecular fluorescent molecules. We evaluated mice using a rotarod device and novel object recognition to measure motor coordination and cognition, respectively.

Results

Mice undergoing mTBI-1 or mTBI-2 had significant deficits in motor coordination and cognition for several days after injury compared with controls. Furthermore, both mTBI-1 and mTBI-2 caused micromolecular leakage in the blood–brain barrier, whereas only mTBI-2 caused macromolecular leakage. Serum neuron-specific enolase and glial fibrillary acidic protein were elevated acutely and corresponded to the degree of injury, but returned to baseline within 24 h. Serum cytokines interleukin-6 and keratinocyte-derived chemokine were significantly increased within 90 min of TBI. Interleukin-6 levels correlated with the degree of injury.

Conclusions

The current study provides a reproducible model of mild TBI in mice that exhibits pathologic features of mild TBI in humans. Furthermore, our data suggest that serum cytokines, such as IL-6, may be effective biomarkers for severity of head injury.     

Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans: The Candidate Gene Association Resource Plus Study

Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10⁻⁸). Locus-wide analysis demonstrated significant associations (P_emp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.Type 2 diabetes (T2D) is a major public health problem affecting 25.8 million people in the U.S. (1). Marked racial differences in its prevalence have been observed, with African American (AfA) adults >40 years of age having nearly twofold higher prevalence than European Americans (27.1 and 15.5%, respectively) (2). In addition to socioeconomic and behavioral risk factors, genetic factors are likely contributors to T2D risk in AfA (3).Genome-wide association studies (GWAS) for T2D and related traits have successfully identified >50 loci with common genetic variants associated with T2D risk in primarily European-descent populations (4–14) and more recently in East and South Asians (15–21). The reported index single nucleotide polymorphisms (SNPs) at these loci have been replicated in multiple populations (22–24) but less successfully in AfA (25–27). Although differences in environment and lack of study power may partly account for the lack of transferability across ethnicities, differences in linkage disequilibrium (LD) patterns, effect sizes, and risk allele frequency also likely impact the replication of index SNPs. Although the long-range LD in European populations allows for the identification of T2D loci using less dense markers, causal variants are not distinguishable from other nearby SNPs in high LD. This issue prompts the need to examine T2D loci in other populations with different allelic and LD architecture, which may help fine mapping of the underlying functional variants (28).We performed a comprehensive evaluation of the LD region of T2D loci reported in European and Asian GWAS in a meta-analysis of six AfA GWAS. By testing the index and nearby SNPs, we evaluated the transferability of the previously reported loci for T2D association in AfA. We demonstrated that the reduced and differential LD structure in AfA facilitated fine mapping of regions potentially harboring causal variants at some T2D loci.     

Relationship between personality change and the onset and course of alcohol dependence in young adulthood

Aims To examine the reciprocal effects between the onset and course of alcohol use disorder (AUD) and normative changes in personality traits of behavioral disinhibition and negative emotionality during the transition between adolescence and young adulthood. Design Longitudinal–epidemiological study assessing AUD and personality at ages 17 and 24 years. Setting Participants were recruited from the community and took part in a day‐long, in‐person assessment. Participants Male (n = 1161) and female (n = 1022) twins participating in the Minnesota Twin Family Study. Measurements The effects of onset (adolescent versus young adult) and course (persistent versus desistent) of AUD on change in personality traits of behavioral disinhibition and negative emotionality from ages 17 to 24 years. Findings Onset and course of AUD moderated personality change from ages 17 to 24 years. Adolescent onset AUD was associated with greater decreases in behavioral disinhibition. Those with an adolescent onset and persistent course failed to exhibit normative declines in negative emotionality. Desistence was associated with a ‘recovery’ towards psychological maturity in young adulthood, while persistence was associated with continued personality dysfunction. Personality traits at age 11 predicted onset and course of AUD, indicating personality differences were not due to active substance abuse. Conclusions Personality differences present prior to initiation of alcohol use increase risk for alcohol use disorder, but the course of alcohol use disorder affects the rate of personality change during emerging adulthood. Examining the reciprocal effects of personality and alcohol use disorder within a developmental context is necessary to improve understanding for theory and intervention.