脊髓性肌萎缩症生物标志物的研究进展

脊髓性肌萎缩(SMA)是一种高发生率并严重影响儿童生命健康的遗传性神经肌肉病。SMA的表型异质性高、对治疗药物的反应性也不同, 因此迫切需要寻找理想的生物标志物对患者的疾病严重程度、进展及预后和药物治疗的反应等方面进行有效的评估, 为患者制定完善的个性化治疗方案和多学科管理策略。近年来SMA生物标志物的研究取得重要进展, 本文就生物标志物在SMA疾病进展、预后、治疗效果等方面的研究进行综述。     

Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)

Large clonal expansions of peripheral CD8+ T cells carrying receptors for single epitopes of CMV and EBV are common in the elderly and may be associated with an immune risk phenotype predicting mortality. Here we show that the frequency of CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1), a marker of cells unable to undergo further clonal expansion, was markedly elevated in CD8+ T cells from old donors. Moreover, tetramer staining revealed that the elevated frequency of CMV-specific CD8+ T cells in the elderly was due to an accumulation of cells bearing this dominant negative receptor. The fraction of CMV-specific T cells able to secrete interferon-gamma after specific antigenic stimulation was significantly lower in the elderly than in the young, although the total number of functional cells was comparable. Therefore, the majority of the clonally expanded virus-specific CD8+ cells in the elderly was dysfunctional. Thus, T cell responses are altered in the aged by an accumulation of replicatively senescent dysfunctional T cells carrying receptors for persistent herpes viruses. The presence of clonal expansions of such virus-specific cells may shrink the available repertoire for other antigens and contribute to the increased incidence of infectious disease in the elderly.     

东方田鼠血清及其不同部分对日本血吸虫童虫的体外杀伤作用

目的 对东方田鼠血清及其不同部分对日本血吸虫童虫的体外杀伤的可能机制进行初步探讨。方法 将血清初步分离成含蛋白部分及分子量小于20kDa的小分子部分，并分别观察了东方田鼠全血清、去补体血清、蛋白及小分子血清成分对体外培养童虫的杀伤，此外，还观察了蜕皮素对东疗田鼠血清杀伤作用的影响。结果 东方田鼠热灭活去补体血清对童虫的杀伤显著低于正常血清；感染及正常东方田鼠血清小分子在第48h及72h表现出一定杀伤作用(30％)，而血清蛋白在24h就有显著杀伤，但杀伤作用略低于全血清；蜕皮素对东方田鼠血清的杀伤无明显影响。结论 补体在东方田鼠血清杀伤机制中有重要作用。血清蛋白为体外杀伤的主要成分，可能与小分子成分协同参与杀伤。     

Epac signaling is required for hippocampus-dependent memory retrieval

Previously we uncovered a critical role for norepinephrine and β₁-adrenergic signaling in hippocampus-dependent memory retrieval. Because the β₁ receptor couples to G_s, we examine here whether cAMP is also required for contextual memory retrieval. Using pharmacologic and genetic approaches to manipulate cAMP and downstream signaling, we demonstrate that cAMP and two of its targets, protein kinase A (PKA) and exchange protein activated by cAMP (Epac), are both required for retrieval. These findings demonstrate that cAMP signaling through Epac (as well as PKA) plays an essential role in cognition.     

Thrombolysis in postinfarction angina

Postinfarction angina carries a poor prognosis, with a 20-70% incidence of recurrent myocardial infarction (MI) or death within the subsequent 3-6 months. The pathophysiologic mechanisms causing postinfarction angina may include thrombus, complex coronary arterial lesions that form a nidus for thrombus formation, inadequate collateral supply following acute MI, or intimal endothelial dysfunction. The role of thrombus has been established in the pathophysiology of Q-wave MI, and thrombolytic treatment of patients presenting with acute transmural MI has been shown to salvage left ventricular function and to reduce mortality. However, thrombolytic therapy for the acute MI does not reduce the incidence of recurrent ischemia or infarction, as is evident from the 18-26% incidence of recurrent ischemia reported in the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) and Thrombolysis in Myocardial Infarction (TIMI) trials. In the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI) study the incidence of reinfarction was documented as 4% in the streptokinase group, which was actually significantly greater than in the placebo group (2%). In a randomized placebo-controlled study of thrombolysis for postinfarction angina, 29 patients were randomized to placebo (P group, n = 17) or to thrombolytic therapy (T group, n = 12). Patient groups were similar with respect to age, location of MI, ejection fraction, severity of coronary artery disease, and antianginal therapy. Patients underwent coronary angiography 6 +/- 1 days postinfarction. Filling defects consistent with intracoronary thrombus was seen in 11 of 12 T group patients and in 11 of 17 P group patients prior to treatment. Lysis occurred in 7 of 11 T patients and 1 of 11 P (p less than 0.02). Holter-detected silent ischemia was compared pre- and posttherapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Esophageal chest pain

The unequivocal diagnosis of esophageal chest pain requires the demonstration of simultaneous manometric changes and chest pain. Numerous provocative agents have been used to enhance the diagnostic value of esophageal manometry. Our aims were to: evaluate consecutively a large group of patients with proven noncardiac chest pain and normal baseline manometric studies, using edrophonium chloride, 10 mg, and determine the value of provocative testing in clinical practice. One hundred twenty patients with normal standard baseline esophageal manometries were studied using blinded testing with edrophonium chloride and followed clinically by questionnaire. A positive response of both chest pain and manometric changes was observed in 34%, a negative response in 49%, and an indeterminate response in 17% of patients. Baseline manometric features, including high-amplitude contractions, did not predict the response to edrophonium chloride. Following edrophonium chloride administration, the change in amplitude, duration, and number of repetitive contractions from baseline was significantly greater in positive responders. Edrophonium decreased the velocity of propagated contractions in positive responders (P less than 0.05), but not in nonresponders. Response to edrophonium chloride could not be predicted by patient age, sex, or clinical symptomatology. Seventy percent of patients in both groups had symptoms indistinguishable from ischemic heart disease. After making a specific diagnosis of esophageal chest pain, patients showed a marked clinical improvement, with a significant decrease in physical limitation, emergency room visits, hospital and CCU admissions, and in further cardiac testing. We conclude that provocative testing with edrophonium chloride will make it possible to definitively implicate the esophagus in over 30% of patients with normal baseline manometric findings and noncardiac chest pain.     

Isolated ventricular apical hypoplasia: A report of four cases and literature review

Isolated ventricular apical hypoplasia (IVAH) is a rare congenital cardiac anomaly, with clinical manifestations depending on the age of the patient, ranging from no symptoms in children to congestive heart failure or even malignant tachycardia in adults. Herein, we describe the clinical and anatomical findings in four cases with hypoplasia of the right or left ventricular apex, and we discuss the possible mechanisms and differential diagnosis of this malformation. Echocardiography is a rapidly accessible, low cost, noninvasive technique for the detection and evaluation of IVAH.     

Separating stimulus‐driven and response‐related LRP components with Residue Iteration Decomposition (RIDE)

When the lateralized readiness potential (LRP) is recorded in stimulus–response compatibility (SRC) tasks, two processes may overlap in the LRP, stimulus‐driven response priming and activation based on response selection rules. These overlapping processes are hard to disentangle with standard analytical tools. Here, we show that Residue Iteration Decomposition (RIDE), based on latency variability, separates the overlapping LRP components from a Simon task into stimulus‐driven and response‐related components. SRC affected LRP amplitudes only in the stimulus‐driven component, whereas LRP onsets were affected only in the response‐locked component. Importantly, the compatibility effect in reaction times was more similar to the effect in the onsets of the RIDE‐derived response‐locked LRP component than in the unseparated LRP. Thus, RIDE‐separated LRP components are devoid of distortions inherent to standard LRPs.