ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile

Here, we describe novel mechanisms limiting a toxic cytosolic Ca²⁺ rise during adenosine 5′-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca²⁺ signalling in mouse pancreatic acinar cells. Measurements of ATP in isolated cells after adenovirus-mediated expression of firefly luciferase revealed that the cytosolic ATP concentration fell from approximately 1 mM to near zero after treatment with oligomycin plus iodoacetate. ATP depletion resulted in the inhibition of Ca²⁺ extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca²⁺ influx. Alternative inhibition of Ca²⁺ extrusion by carboxyeosin had a much smaller effect on Ca²⁺ influx. The coordinated metabolic inhibition of Ca²⁺ influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also suppressed acetylcholine (ACh)-induced Ca²⁺ oscillations, which was due to the inhibition of Ca²⁺ release from internal stores. This could be particularly important for limiting Ca²⁺ toxicity during periods of hypoxia. In contrast, metabolic control of Ca²⁺ influx and Ca²⁺ release from internal stores spectacularly failed to prevent large toxic Ca²⁺ responses induced by bile acids—activators of acute pancreatitis (a frequent and often fatal disease of the exocrine pancreas). The bile acids taurolithocholic acid 3-sulphate (TLC-S), taurochenodeoxycholic acid (TCDC) and taurocholic acid (TC) were used in our experiments. Neither Ca²⁺ release from internal stores nor Ca²⁺ influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

淫羊藿苷调节雄性大鼠生殖功能

目的:探讨淫羊藿苷在环磷酰胺诱导的大鼠睾丸生精障碍动物模型中的作用,研究淫羊霍苷对睾丸功能的影响.方法:分为空白对照组、阴性对照组、模型组、淫羊藿苷治疗组;H-E染色观察睾丸组织结构变化,TUNEL方法检测睾丸生殖细胞凋亡,放射免疫法检测血清睾酮.结果:睾丸H-E染色切片观察显示模型组睾丸生精小管直径缩小,间距增宽,生精上皮变薄,生殖细胞数量减少,生精小管多未见精子形成,与空白对照组比较其生精小管结构变化显著;淫羊藿苷治疗组与模型组比较生精小管壁增厚,含有精子的生精小管明显增多.睾丸生精小管中生殖细胞凋亡的观察模型组与空白对照组比较其生殖细胞凋亡增多,变化显著;淫羊藿苷治疗组与模型组比较生精小管中生殖细胞凋亡数量明显减少.模型组与空白对照组比较血清睾酮明显降低;淫羊藿苷治疗组与模型组比较其血清睾酮明显增加.结论:淫羊藿苷对环磷酰胺诱导生精障碍的睾丸具有改善睾丸生精小管结构、减少生殖细胞凋亡、促进精子发生和间质细胞分泌睾酮的功能.     

Non-fibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors

Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.     

The contribution of dementia to the disablement process and modifying factors

The objective of this study was to examine the impact of dementia on disability progression and mortality, and to analyze the modifying effect of risk factors and extra-individual factors. A sample of 3,403 participants in the PAQUID study was followed for 10 years. Disability was assessed on a 4-grade scale: no disability, disabled only on the Rosow-Breslau scale, disabled on the Rosow-Breslau scale and on instrumental activities of daily living (IADL) scales, and disabled on the Rosow-Breslau, IADL and activities of daily living (ADL) scales. A Markov model was used to estimate the effect of explanatory variables on disability and mortality. Controlling for age, gender, education, place of residence, medical care and informal support, dementia had a strong significant effect on progression to IADL and then to ADL disability. Dementia did not increase the risk of death, once disability was taken into account, except from the lowest disability grade.     

Adult trkB Signaling in Parvalbumin Interneurons is Essential to Prefrontal Network Dynamics

Inhibitory interneurons expressing parvalbumin (PV) are central to cortical network dynamics, generation of γ oscillations, and cognition. Dysfunction of PV interneurons disrupts cortical information processing and cognitive behavior. Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling regulates the maturation of cortical PV interneurons but is also implicated in their adult multidimensional functions. Using a novel viral strategy for cell-type-specific and spatially restricted expression of a dominant-negative trkB (trkB.DN), we show that BDNF/trkB signaling is essential to the integrity and maintenance of prefrontal PV interneurons in adult male and female mice. Reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) resulted in deficient PV inhibition and increased baseline local field potential (LFP) activity in a broad frequency band. The altered network activity was particularly pronounced during increased activation of the prefrontal network and was associated with changed dynamics of local excitatory neurons, as well as decreased modulation of the LFP, abnormalities that appeared to generalize across stimuli and brain states. In addition, our findings link reduced BDNF/trkB signaling in prefrontal PV interneurons to increased aggression. Together our investigations demonstrate that BDNF/trkB signaling in PV interneurons in the adult mPFC is essential to local network dynamics and cognitive behavior. Our data provide direct support for the suggested association between decreased trkB signaling, deficient PV inhibition, and altered prefrontal circuitry.SIGNIFICANCE STATEMENT Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase B (trkB) signaling promotes the maturation of inhibitory parvalbumin (PV) interneurons, neurons central to local cortical dynamics, γ rhythms, and cognition. Here, we used a novel viral approach for reduced BDNF/trkB signaling in PV interneurons in the medial prefrontal cortex (mPFC) to establish the role of BDNF/trkB signaling in adult prefrontal network activities. Reduced BDNF/trkB signaling caused pronounced morphologic alterations, reduced PV inhibition, and deficient prefrontal network dynamics. The altered network activity appeared to manifest across stimuli and brain states and was associated with aberrant local field potential (LFP) activities and increased aggression. The results demonstrate that adult BDNF/trkB signaling is essential to PV inhibition and prefrontal circuit function and directly links BDNF/trkB signaling to network integrity in the adult brain.     

West syndrome: a university hospital based study from Oman.

Forty-four children (20 male: 24 female) with West syndrome (infantile spasms, mental retardation/regression and hypsarrhythmia) diagnosed at Sultan Qaboos University Hospital (Pediatric Neurology Division of the Department of Child Health) are reported, with thirty-four (77.3%) children constituting the symptomatic group. All children were followed up for an initial 1 year at this hospital. Thirty-seven cases (84%) still continue their follow-up with us. The age of onset ranged from 1 to 14 months (mean, 6.0 months). Developmental delay before the onset of infantile spasms was noted in 29 (65.9%) children. Brain computed tomography was abnormal in 29 (65.9%). Sodium valproate and vigabatrin were the most often used drugs, though other antiepileptic drugs were also used. Nine (24.5%) children achieved good seizure control, out of which five have normal development. Only one child could be weaned off antiepileptic drugs completely. There was one death in the whole series, related to aspiration pneumonia.     

Syndrome of cerebrospinal fluid hypovolemia following lumbar puncture cerebrospinal fluid leak in a patient with idiopathic intracranial hypertension

An 11-year-old girl presented with headache of 3 months' duration. There was bilateral disc edema. The cerebrospinal fluid pressure was 50 cm of water with normal cerebrospinal fluid cytology and biochemistry. She developed severe headache (different and disabling), dizziness, vomiting, and backache on sitting up 6 hours after lumbar puncture, and lying supine relieved all of her symptoms. Intravenous fluids, analgesics, and complete bed rest did not relieve her symptoms over the next 72 hours. She was completely relieved of her symptoms on receiving two tablets of Caffergot containing 200 mg of caffeine and 2 mg of ergotamine 72 hours after lumbar puncture. The symptoms recurred 48 hours later, and a repeat dose of Caffergot was required. Magnetic resonance imaging (MRI) done 96 hours after lumbar puncture revealed the entire dura overlying the brain, including the posterior fossa, showing intense enhancement on contrast injection with leak at the lumbar puncture site. Oral caffeine (coffee, three times a day) was advised over 1 week. The patient remained asymptomatic, and a repeat MRI scan after 10 days showed complete clearing of the cerebrospinal fluid leak with no dural enhancement. The syndrome of cerebrospinal fluid hypovolemia following lumbar puncture is reported in a girl with idiopathic intracranial hypertension.