Localization and characterization of val‐opsin isoform‐expressing cells in the brain of adult zebrafish

In addition to vision, light information is used to regulate a range of animal physiology. Such nonimage‐forming functions of light are mediated by nonvisual photoreceptors expressed in distinct neurons in the retina and the brain in most vertebrates. A nonvisual photoreceptor vertebrate ancient long opsin (VAL‐opsin) possesses two functional isoforms in the zebrafish, encoded by valopa and valopb, which has received little attention. To delineate the neurochemical identities of valop cells and to test for colocalization of the valop isoforms, we used in situ hybridization to characterize the expression of the valop genes along with that of neurotransmitters and a neuropeptide known to be present at the sites of valop expression. Double labeling showed that the thalamic valop population coexpresses valopa and valopb. All the thalamic valop cells overlapped with a GABAergic cell mass that continues from the anterior nucleus to the intercalated thalamic nucleus. A novel valopa cell population found in the superior raphe was serotonergic in nature. A valopb cell population in the Edinger‐Westphal nucleus was identified as containing thyrotropin‐releasing hormone. Valopb cells localized in the hindbrain intermediate reticular formation were noncholinergic in nature (nonmotorneurons). Thus, the presence of valop cell populations in different brain regions with coexpression of neurotransmitters and neuropeptides and the colocalization of valop isoforms in the thalamic cell population indicate regulatory and functional complexity of VAL‐opsin in the brain of the zebrafish. J. Comp. Neurol. 522:3847–3860, 2014. © 2014 Wiley Periodicals, Inc.     

Sex differences in circadian timing systems: Implications for disease

Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic–pituitary–gonadal axis (HPG), the hypothalamic–adrenal–pituitary (HPA) axis, and sleep–arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions.     

Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-β (Aβ) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca(2+) imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of Aβ may underlie this impairment. Indeed, we found that acute treatment with the γ-secretase inhibitor LY-411575 reduces soluble Aβ levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Aβ can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble Aβ is crucial for hippocampal hyperactivity.     

Small molecule antagonist reveals seizure-induced mediation of neuronal injury by prostaglandin E2 receptor subtype EP2

With interest waning in the use of cyclooxygenase-2 (COX-2) inhibitors for inflammatory disease, prostaglandin receptors provide alternative targets for the treatment of COX-2-mediated pathological conditions in both the periphery and the central nervous system. Activation of prostaglandin E2 receptor (PGE(2)) subtype EP2 promotes inflammation and is just beginning to be explored as a therapeutic target. To better understand physiological and pathological functions of the prostaglandin EP2 receptor, we developed a suite of small molecules with a 3-aryl-acrylamide scaffold as selective EP2 antagonists. The 12 most potent compounds displayed competitive antagonism of the human EP2 receptor with K(B) 2-20 nM in Schild regression analysis and 268- to 4,730-fold selectivity over the prostaglandin EP4 receptor. A brain-permeant compound completely suppressed the up-regulation of COX-2 mRNA in rat cultured microglia by EP2 activation and significantly reduced neuronal injury in hippocampus when administered in mice beginning 1 h after termination of pilocarpine-induced status epilepticus. The salutary actions of this novel group of antagonists raise the possibility that selective block of EP2 signaling via small molecules can be an innovative therapeutic strategy for inflammation-related brain injury.     

Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain

P-glycoprotein, an ATP-driven drug efflux pump, is a major obstacle to the delivery of small-molecule drugs across the blood-brain barrier and into the CNS. Here we test a unique signaling-based strategy to overcome this obstacle. We used a confocal microscopy-based assay with isolated rat brain capillaries to map a signaling pathway that within minutes abolishes P-glycoprotein transport activity without altering transporter protein expression or tight junction permeability. This pathway encompasses elements of proinflammatory- (TNF-α) and sphingolipid-based signaling. Critical to this pathway was signaling through sphingosine-1-phosphate receptor 1 (S1PR1). In brain capillaries, S1P acted through S1PR1 to rapidly and reversibly reduce P-glycoprotein transport activity. Sphingosine reduced transport by a sphingosine kinase-dependent mechanism. Importantly, fingolimod (FTY720), a S1P analog recently approved for treatment of multiple sclerosis, also rapidly reduced P-glycoprotein activity; similar effects were found with the active, phosphorylated metabolite (FTY720P). We validated these findings in vivo using in situ brain perfusion in rats. Administration of S1P, FTY720, or FTY729P increased brain uptake of three radiolabeled P-glycoprotein substrates, ³H-verapamil (threefold increase), ³H-loperamide (fivefold increase), and ³H-paclitaxel (fivefold increase); blocking S1PR1 abolished this effect. Tight junctional permeability, measured as brain ¹⁴C-sucrose accumulation, was not altered. Therefore, targeting signaling through S1PR1 at the blood-brain barrier with the sphingolipid-based drugs, FTY720 or FTY720P, can rapidly and reversibly reduce basal P-glycoprotein activity and thus improve delivery of small-molecule therapeutics to the brain.     

Takotsubo cardiomyopathy has a unique cardiac biomarker profile: NT-proBNP/myoglobin and NT-proBNP/troponin T ratios for the differential diagnosis of acute coronary syndromes and stress induced cardiomyopathy

Background

Takotsubo cardiomyopathy (TC) usually is not recognized until heart catheterization reveals typical wall motion abnormalities in the absence of significant coronary artery disease. It was our aim to identify TC by its unique cardiac biomarker profile at an early stage and, preferably, with non-invasive procedures only.

Methods

Ratios of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and myoglobin, NT-proBNP and troponin T (TnT), NT-proBNP and creatinekinase-MB (CK-MB) were compared in patients with TC (n = 39), patients with ST-elevation myocardial infarction (STEMI, n = 48) and patients with non-ST-elevation myocardial infarction (NSTEMI, n = 34). Biomarkers were recorded serially at admission and at the three consecutive days. Optimal cut-off values to distinguish TC from STEMI and NSTEMI were calculated with receiver operator characteristic (ROC) curves.

Results

At admission a NT-proBNP (ng/l)/myoglobin (μg/l) ratio of 3.8, distinguished TC from STEMI (sensitivity: 89%, specificity: 90%), while a NT-proBNP (ng/l)/myoglobin (μg/l) ratio of 14 separated well between TC and NSTEMI (sensitivity: 65%, specificity: 90%). Best differentiation of TC and ACS was possible with the ratio of peak levels of NT-proBNP (ng/l)/TnT (μg/l). A cut-off value of NT-proBNP (ng/l)/TnT (μg/l) ratio of 2889, distinguished TC from STEMI (sensitivity: 91%, specificity: 95%), while a NT-proBNP (ng/l)/TnT (μg/l) ratio of 5000 separated well between TC and NSTEMI (sensitivity: 83%, specificity: 95%).

Conclusions

TC goes along with a singular cardiac biomarker profile, which might be useful to identify patients with TC among patients presenting with acute coronary syndromes (ACS).     

脑钠肽与超声心动图评价老年糖尿病并存高血压患者左心室舒张功能的研究

目的 探讨老年糖尿病并存高血压患者左心室功能的变化与脑钠肽(BNP)水平的关系. 方法 128例2型糖尿病患者按是否并存高血压分组,其中不伴高血压组63例,伴高血压组65例,对照组为62例健康查体者.测定各组BNP浓度.常规超声测定左心室结构指标,计算左心室质量指数(LVMI),脉冲多普勒测量二尖瓣口舒张早期血流速度(E)、舒张晚期血流速度(A),计算E/A值.定量组织多普勒技术(QTVI)测量左心室壁二尖瓣环6个位点(侧壁和后间隔、前壁和下壁、前间隔和后壁)处的舒张早期峰值运动速度(Em)和舒张晚期峰值运动速度(Am).计算6个位点平均Em、Am(MEm、MAm)和E/MEm比值. 结果 糖尿病不伴高血压组、伴高血压组LVMI[分别为(91.6±17.3)g/m2、(116.7±20.5)g/m2]、E/MEm(10.3±1.8和12.5±1.4)及BNP浓度[(47.7±29.4)ng/L、(105.7±32.5)ng/L]较对照组[分别为(78.7±19.5)g/m2、8.9±1.6、(20.8±11.63)ng/L]升高,差异有统计学意义(F值分别为11.54、13.83和9.75,P均＜0.05);不伴高血压组、伴高血压组MEm[《6.7±1.0)cm/s、(5.4±0.9)cm/s]较对照组[(5.4±0.9)cm/s]降低,差异有统计学意义(F=11.26,P＜0.05).糖尿病患者BNP浓度与E/A、MEm值呈负相关(r值分别为-0.42、-0.51,均P＜0.01),与LVMI和E/MEm值呈正相关(r值分别为0.48、0.58,均P＜0.01). 结论 糖尿病患者左心室舒张功能降低,并存高血压患者左心室舒张功能障碍更为严重.联合血浆BNP浓度和超声指标有助于准确评估老年糖尿病患者左心室舒张功能.     

射频导管消融治疗阵发性心房颤动患者的血浆B型利钠肽水平

目的 有研究表明,心房颤动(房颤)患者中的血浆B型利钠肽(brain natriuretic peptid,BNP)水平增高.研究为探讨血浆BNP水平对预测环肺静脉消融术(circumferential pulmonary vein ablation,CPVA)后房颤复发的意义.方法69例拟行CPVA治疗的阵发性症状性房颤患者,在 CPVA术前行血浆BNP浓度、经食管超声心动图检查.其中15例食管超声心动图发现心房血栓未行CPVA治疗,54例成功行CPVA治疗.所有患者均无临床心力衰竭症状,所有患者左室射血分数≥50％.平均随访3个月,所有患者随访期间若发作房颤均被要求记录发作持续的时间和次数.所有患者被要求随访期间每月至少做1次24 h Holter,按照是否复发房颤分为:成功组(39例)、失败组(15例).结果59.4％的患者BNP水平超过正常范嗣(0～144 ng/L),但69.6％的患者其BNP水平低于心力衰竭水平(＜500 ng/L).失败组患者BNP水平明显高于成功组(中位数371.6 ng/L与97.4 ng/L,p=0.001).失败组患者的左心房直径明显高于成功组[(53.3±15.1)mm与(45.2±11.2)mm,P=0.036].此外,Spearman's相关分析表明,血浆BNP水平与左心房直径存在明显相关性(r =0.574,P＜0.O1).结论阵发性房颤患者术前血浆BNP水平和左心房直径与射频消融术后房颤复发有相关性,术前BNP水平明显升高、左心房直径明显扩大的患者,CPVA术后复发的可能性高.术前低BNP水平的房颤患者,接受CPVA治疗成功率高,术前检查BNP水平有助于选择适合接受CPVA治疗的患者.     

Real-Time Changes in Connectivities During Neurofeedback

Introduction. Changes in quantitative EEG during and in response to neurofeedback (NF) training was explored in patients with traumatic brain injury (TBI). Data from 19 adults with a TBI of moderate mechanical nature, non-drug-related, and without severe posttraumatic stress disorder or seizure disorder were analyzed (14 male and 5 female).

Methods. EEG was evaluated before, during, and after ROSHI NF training. Data were collected as duplicate samples of 6 min each during eyes open and eyes closed conditions, but only the eyes closed condition was analyzed.

Results. Significant changes in connectivity occurred during and in response to NF training.

Conclusion. Results showed significant changes in real-time QEEG connectivity. An evaluation of a larger subject population will clarify gender differences in connectivity responses to NF training.