Genetic and chromosomal alterations in Kenyan Wilms Tumor

Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub‐Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub‐Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment‐resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT‐associated genes and evaluated whole‐genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow‐up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment‐resistant. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.     

WONCA研究论文摘要汇编——基层抑郁症风险患者的连续性服务

背景目前已开展了对重性精神病患者进提供连续性服务的研究。目的探讨基层对有抑郁症风险患者提供连续性服务的水平,并与对心力衰竭患者的服务水平进行对比。方法采用抑郁症风险患者与心力衰竭患者对比的探索性研究。采用患者问卷评估服务的持续性,包含如下内容:(1)联系的服务提供者数(个人连续性);(2)诊所内服务提供者之间的合作(团队连续性)(6个项目,分数1~5分);(3)诊所外全科医师与服务提供者之间的合作(跨界连续性)(4个项目,分数1~5分)。结果大多数抑郁症风险患者在过去1年中寻遍整个服务提供界联系了几个服务提供者,曾遇到过高水平团队连续性服务及低水平跨界连续性服务。在诊所中可接触到的不同服务提供者要明显多于心力衰竭患者服务提供者(P<0.01)。抑郁症风险患者的服务提供者之间的合作更好一些,每项平均得分4.3分,心力衰竭患者得分为4.0分(P=0.03)。然而,跨界连续性服务方面正好相反:抑郁症风险患者每项平均得分3.5分,心力衰竭患者得分为4.0分(P=0.01)。结论抑郁症风险患者与心力衰竭患者之间的探索性对比显示:体验服务连续性方面的差距不大。对此还应行进一步分析。     

Traumatic Lingual Hematoma Resulting in Bilateral Temporal Mandibular Joint Dislocations

Background

Lingual hematoma (LH) is a relatively uncommon entity seen after both medical and traumatic etiologies. Regardless of the cause, the feared complication is acute airway obstruction.

Enhanced Dopamine-Dependent Hippocampal Plasticity after Single MK-801 Application

Dopaminergic hyperfunction and N-methyl-D-aspartate receptor (NMDAR) hypofunction have both been implicated in psychosis. Dopamine-releasing drugs and NMDAR antagonists replicate symptoms associated with psychosis in healthy humans and exacerbate symptoms in patients with schizophrenia. Though hippocampal dysfunction contributes to psychosis, the impact of NMDAR hypofunction on hippocampal plasticity remains poorly understood. Here, we used an NMDAR antagonist rodent model of psychosis to investigate hippocampal long-term potentiation (LTP). We found that single systemic NMDAR antagonism results in a region-specific, presynaptic LTP at hippocampal CA1-subiculum synapses that is induced by activation of D1/D5 dopamine receptors and modulated by L-type voltage-gated Ca²⁺ channels. Thereby, our findings may provide a cellular mechanism how NMDAR antagonism can lead to an enhanced hippocampal output causing activation of the hippocampus-ventral tegmental area-loop and overdrive of the dopamine system.     

Caged-in: Successful percutaneous closure of left atrial appendage with Watchman-FLX in the presence of proximal thrombus

Percutaneous mechanical closure of the left atrial appendage (LAA) is a valuable stroke prevention strategy in patients with atrial fibrillation and contraindication to oral anticoagulation. LAA thrombus is a common finding in patients with atrial fibrillation and frequently fails to resolve despite therapeutic anticoagulation. In this scenario, LAA occlusion device implant is generally discouraged due to the high risk of thrombus dislodgement and embolization; however, alternative management options are limited. We report the first case of a successful LAA occlusion device (Watchman-FLX) implant in the presence of a proximal thrombus.     

Corticotropin releasing factor-like peptides produce selective dilatation of the dog mesenteric circulation

Three synthetic peptides, ovine corticotropin-releasing factor, sauvagine, and urotensin I, contain homologous amino acid residues. In the anesthetized dog, all three produce marked and selective dilatation of the mesenteric circulation; none of the peptides influenced blood flow in the renal, femoral, carotid, or even celiac arteries. The mesenteric vasodilatation appeared to be unrelated to the common ability of these peptides to release corticotropin and beta-endorphin, and cannot be abolished or attenuated by conventional blocking agents or inhibitors. The unique action of these peptides suggests that there may be a related peptide in the intestine that acts to regulate intestinal blood flow. The peptides may also prove useful therapeutically in nonocclusive ischemia, if this unusual action is also present in humans.     

The relationship between lower body strength and obstructed gait in community-dwelling older adults

OBJECTIVES: To determine the relationship between lower body strength of community-dwelling older adults and the time to negotiate obstructed gait tasks. DESIGN: A correlational study. SETTING: The Biomechanics Laboratory, Deakin University, Australia. PARTICIPANTS: Twenty-nine women and 16 men aged 62 to 88 were recruited using advertisements placed in local newspapers. The participants were independent community dwellers, healthy and functionally mobile. MEASUREMENTS: Maximal isometric strength of the knee extensors and dynamic strength of the hip extensors, hip flexors, hip adductors, hip abductors, knee extensors, knee flexors, and ankle plantar flexors were assessed. The times to negotiate four obstructed gait tasks at three progressively challenging levels on an obstacle course and to complete the course were recorded. The relationship between strength and the crossing times was explored using linear regression models. RESULTS: Significant associations between the seven strength measures and the times to negotiate each gait task and to walk the entire course at each level were obtained (r = -0.38 to -0.55; P < .05). In addition, the percentage of the variance explained by strength (R(2)), consistently increased as a function of the progressively challenging level. This increase was particularly marked for the stepping over task (R(2) = 19.3%, 25.0%, and 27.2%, for levels 1, 2, and 3, respectively) and the raised surface condition (R2 = 17.1%, 21.1%, and 30.8%, for levels 1, 2, and 3, respectively). CONCLUSION: The findings of the study showed that strength is a critical requirement for obstructed locomotion. That the magnitude of the association increased as a function of the challenging levels suggests that intervention programs aimed at improving strength would potentially be effective in helping community-dwelling older adults negotiate environmental gait challenges.     

Oxidative stress and erythrocyte damage in Kenyan children with severe Plasmodium falciparum malaria

Anaemia causes significant morbidity in children with Plasmodium falciparum malaria, but the mechanism(s) are unclear. During malarial infection, increased reactive oxygen species (ROS) are generated that may contribute to erythrocyte damage and anaemia. This study measured the concentrations of alpha-tocopherol in plasma and erythrocyte membranes, and the percentage polyunsaturated fatty acid composition (%PUFA) (an indirect marker of ROS damage) in erythrocyte membranes in children with severe P. falciparum malaria from Kilifi, Kenya, and asymptomatic children from the same district. Malarial subjects were stratified into complicated malaria and malaria anaemia. Results demonstrated significant reductions in erythrocyte membrane alpha-tocopherol concentration (1.63 +/- 0.16 versus 3.38 +/- 0.18 micromol/mg protein; P < 0.001) and total %PUFA (30.7 +/- 0.49 versus 32.8 +/- 0.44% P < 0.005) for the malarial subjects (non-stratified) compared with controls. Malarial subjects showed a significant positive correlation between membrane alpha-tocopherol and haemoglobin concentrations (P < 0.005 r = 0.63 complicated malaria group; P < 0.05 r = 0.36 non-stratified data). There were no significant differences in plasma alpha-tocopherol concentration between malaria patients and controls. In conclusion, malarial infection may be associated with oxidative damage and reduced alpha-tocopherol reserve in the erythrocyte membrane, suggesting that local antioxidant depletion may contribute to erythrocyte loss in severe malaria. Erythrocyte membrane alpha-tocopherol appeared a better indicator of ROS exposure than plasma.     

The use of an implantable loop recorder in the investigation of unexplained syncope in older people

INTRODUCTION: Reveal is a patient activated implantable loop recorder device with an 18 month battery life now available to assist in the diagnosis of suspected syncope or arrhythmias. We present our experience using this device in older subjects referred to a dedicated falls and syncope clinic in whom usual clinical assessment had not satisfactorily identified an attributable diagnosis but where we still suspected a cardiovascular cause for syncope or falls. METHODS AND RESULTS: during the past 3 years 15 subjects (mean age 73 years, range 61-89 years) had Reveal implanted for symptoms of syncope alone (n=6; 40%) and unexplained falls (n=3; 20%) or symptoms of syncope and unexplained falls (n=6; 40%). Symptom duration was long (mean 48 months; range 4-200 months). Subjects had experienced significant morbidity, 6 subjects (40%) required A&E attendance or hospital admission and 4 (27%) experienced a fracture. Despite extensive and repeated investigations, which included 12-lead ECG, echocardiogram, 24-h ambulatory heart rate monitor, 24-h ambulatory blood pressure monitor, orthostatic blood pressure measurement, supine and erect carotid sinus massage, electroencephalogram, and passive and GTN head up tilt testing, the attributable diagnosis remained unexplained. Of the 15 subjects, 7 have activated the device at 4 (range 0-14) months after implantation. Bradycardia was identified in 3 and ventricular tachycardia in 1 subject. Two subjects did not activate the device during the 18 months it was in-situ. Four people had problems with device activation. This is comparable to rates noted using Reveal in younger subjects. CONCLUSION: Reveal offers additional diagnostic yield in complex elderly subjects with suspected cardiovascular causes of syncope or unexplained falls which have not been previously satisfactorily diagnosed despite extensive investigations.