Next-Generation Sequencing Based Approach to Identify Underlying Genetic Defects of Glanzmann Thrombasthenia

Glanzmann thrombasthenia (GT) is an autosomal recessive platelet function disorder characterized by mucocutaneous bleeding as the most common clinical phenotype. Patients with GT have normal platelet counts, platelet morphology but reduced platelet aggregation in response to various agonists. Homozygosity or compound heterozygosity for variants in the ITGA2B/ITGB3 genes is the genetic basis for GT. Establishing a molecular diagnosis is definitive and is important for predictive testing. Using multi-gene panels is an accurate, faster, and cost-effective mode as compared to Sanger sequencing in large genes. We used a targeted resequencing based approach to identify pathogenic variants in eight cases in seven families. These variants were validated using Sanger sequencing in patients as well as family members and were predicted probably pathogenic using in-silico prediction tools. The variants include three missense (3/7 = 43%) (ITGA2B:c.1028 T > C, ITGA2B:c.1186G > A, ITGB3:c.1388G > C), two deletions (ITGA2B:c.559delG, ITGA2B:c.3092delT), one duplication (ITGA2B:c.1424_1427dupAGGT) and nonsense variant (ITGA2B:c.2578C > T, p.Gln860Ter). Except for one case which was compound heterozygous, the rest of the cases were homozygous. We found two novel variants that are reported for the first time in GT. The targeted resequencing based approach revealed varied genetic variants in North Indian patients, including two novels ones. The high yield of our panel indicates its suitability for usage in larger cohorts for the genetic diagnosis of GT patients. This approach is cost-effective and less cumbersome as compared to Sanger sequencing for these large size genes with multiple exons. The information so obtained is helpful in prenatal testing, carrier analysis, and genetic counseling.     

CD40-mediated immune cell activation enhances response to anti-PD-1 in murine intrahepatic cholangiocarcinoma

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An updated systematic review and meta‐analysis of early outcomes after left atrial appendage occlusion

Background

Left atrial appendage occlusion (LAAO) is a promising intervention for stroke prevention in patients with non‐valvular atrial fibrillation (NVAF). Early outcomes following LAAO have been published in many studies with variable results.

Objective

This updated meta‐analysis aims to provide a summary of the early outcomes of LAAO.

Methods

Medline/Pubmed, Ovid Journals, Clinical trials, Abstract meetings, Cochrane databases were searched from January 1st, 1999 to November 30th, 2016.

Results

This meta‐analysis included 49 studies involving 12 415 patients. The median age was 73.5 years (IQR 72‐75 years) and 43% were males. Hypertension and diabetes were present in 36% and 15% of the population, respectively. There was a prior history of stroke and congestive heart failure in 14% and 18% of the population, respectively. The median CHADS₂ score was 2.9 (IQR 2.6‐3.3) and the median HASBLED score was 3.3 (IQR 3‐4). LAAO implantation was successful in 96.3% of patients (95.40‐97.08, I² = 76.1%). The pooled proportion of all‐cause mortality was 0.28% (0.19‐0.38, I² = 0%). The pooled proportion of all‐cause stroke was 0.31% (0.22‐0.42, I² = 9.4%), major bleeding requiring transfusion was 1.71% (1.13‐2.41, I² = 73.2%), and pericardial effusion was 3.25% (2.46‐4.14, I² = 79%). Sub analysis of randomized clinical trials comparing LAAO devices to warfarin showed lower mortality (P = 0.03) with similar bleeding risk (P = 0.20) with LAAO.

Conclusions

This meta‐analysis concludes that LAAO occlusion is a safe and effective stroke prevention strategy in patients with NVAF.     

Peripheral Vascular Complication from Coronary Angiography: a Case Report of Cholesterol Embolization

A 65-year-old man developed acute limb ischemia, severe abdominal wall and lower limb livedo reticularis following a coronary angiogram. The differential diagnoses of acute limb ischemia and multiple cholesterol emboli syndrome (MCES) are discussed. This work was performed at Long Island Jewish Medical Center, 270-05, 76^th Avenue, New Hyde Park, NY 11040.     

A COMPARISON OF TOPICAL MENTHOL TO ICE ON PAIN,EVOKED TETANIC AND VOLUNTARY FORCE DURING DELAYED ONSET MUSCLE SORENESS

Purpose/Background:

Pain can adversely affect muscle functioning by inhibiting muscle contractions. Delayed onset muscle soreness was used as a tool to ascertain whether a topical menthol-based analgesic or ice was more effective at reducing pain and permitting greater muscular voluntary and evoked force.

Methods:

Sixteen subjects were randomized to receive either a topical gel containing 3.5% menthol or topical application of ice to the non-dominant elbow flexors two days following the performance of an exercise designed to induce muscle soreness. Two days later, DOMS discomfort was treated with a menthol based analgesic or ice. Maximum voluntary contractions and evoked tetanic contractions of the non-dominant elbow flexors were measured at baseline prior to inducing muscle soreness (T1), two days following inducing DOMS after 20 (T2), 25 (T3) and 35 (T4) minutes of either menthol gel or ice therapy. Pain perception using a 10-point visual analog scale was also measured at these four data collection points. Treatment analysis included a 2 way repeated measures ANOVA (2 × 4).

Results:

Delayed onset muscle soreness decreased (p = 0.04) voluntary force 17.1% at T2 with no treatment effect. Tetanic force was 116.9% higher (p<0.05) with the topical analgesic than ice. Pain perception at T2 was significantly (p=0.02) less with the topical analgesic versus ice.

Conclusions:

Compared to ice, the topical menthol-based analgesic decreased perceived discomfort to a greater extent and permitted greater tetanic forces to be produced.

Level of Evidence:

Level 2b     

Corpus callosum abnormalities associated with greater externalizing behaviors in subjects at high risk for alcohol dependence

Subjects at high risk for alcoholism have a greater propensity for externalizing behaviors and brain volume reductions of possible neurodevelopmental origin. Morphometric deficits in the corpus callosum (CC), which might reflect this neurodevelopmental abnormality, have been reported in other externalizing disorders such as attention deficit hyperactivity disorder, but not in subjects at high risk for alcoholism. The objective of the current study was to evaluate the CC morphometry in subjects at high risk for alcoholism. Magnetic resonance images of the CC in high-risk subjects (n = 20) were compared with those of low-risk subjects matched to the high-risk subjects for age, sex, and handedness (n = 20). Mid-sagittal areas of the CC, genu, body, isthmus and splenium were measured based on Witelson's method with good inter- and intra-rater reliability. Externalizing behaviors were assessed using the Semi-Structured Assessment for Genetics of Alcoholism-II. Total CC, genu and isthmus areas were significantly smaller in high-risk than low-risk subjects after controlling for age and intracranial area. The total externalizing symptoms score had a significant negative correlation with genu and isthmus areas. Smaller CC areas and their negative association with externalizing behaviors may represent yet another marker of susceptibility to alcoholism in high-risk subjects.