Presynaptic Cell Dependent Modulation of Inhibition in Cortical Regions

Several lines of evidence suggest that the modulation of presynaptic GABA release is mediated by a variety of receptors including; presynaptic AMPA, cannabinoid, GABAB, kainate, metabotropic glutamate, NMDA, and opioid receptors. The evidence supporting presynaptic modulation of inhibition is predominantly obtained from studying stimulus elicited, spontaneous or miniature synaptic events, where the information regarding the identity of the presynaptic cell is lost. This article summarises these findings then focuses on another approach to study the presynaptic modulation of GABA release by comparing the modulation of GABA release at unitary synapses identified morphologically, immunocytochemically and electrophysiologically. To date, evidence for cell-type specific regulation of presynaptic inhibition at identified synapses involving most of the above presynaptic receptors does not exist. Therefore, the key presynaptic modulators that will be focused on here are kainate and cannabinoid receptors and their intracellular signalling cascades that orchestrate GABA release. There will be some discussion on presynaptic modulation via opioid receptors at identified synapses. This review provides evidence to suggest a cell-type specific modulation of presynaptic inhibition in cortical regions

Endocannabinoid Release Modulates Electrical Coupling between CCK Cells Connected via Chemical and Electrical Synapses in CA1

Electrical coupling between some subclasses of interneurons is thought to promote coordinated firing that generates rhythmic synchronous activity in cortical regions. Synaptic activity of cholecystokinin (CCK) interneurons which co-express cannabinoid type-1 (CB1) receptors are powerful modulators of network activity via the actions of endocannabinoids. We investigated the modulatory actions of endocannabinoids between chemically and electrically connected synapses of CCK cells using paired whole-cell recordings combined with biocytin and double immunofluorescence labeling in acute slices of rat hippocampus at P18–20 days. CA1 stratum radiatum CCK Schaffer collateral-associated cells were coupled electrically with each other as well as CCK basket cells and CCK cells with axonal projections expanding to dentate gyrus. Approximately 50% of electrically coupled cells received facilitating, asynchronously released inhibitory postsynaptic potential (IPSPs) that curtailed the steady-state coupling coefficient by 57%. Tonic CB1 receptor activity which reduces inhibition enhanced electrical coupling between cells that were connected via chemical and electrical synapses. Blocking CB1 receptors with antagonist, AM-251 (5 μM) resulted in the synchronized release of larger IPSPs and this enhanced inhibition further reduced the steady-state coupling coefficient by 85%. Depolarization induced suppression of inhibition (DSI), maintained the asynchronicity of IPSP latency, but reduced IPSP amplitudes by 95% and enhanced the steady-state coupling coefficient by 104% and IPSP duration by 200%. However, DSI did not did not enhance electrical coupling at purely electrical synapses. These data suggest that different morphological subclasses of CCK interneurons are interconnected via gap junctions. The synergy between the chemical and electrical coupling between CCK cells probably plays a role in activity-dependent endocannabinoid modulation of rhythmic synchronization

Etiology and outcome of severe community acquired pneumonia in immunocompetent adults.

BACKGROUND: Community Acquired Pneumonia (CAP) is a commonly encountered disease, one third of which is Severe Community Acquired Pneumonia (SCAP) that can be potentially fatal. There is a paucity of data on etiology and outcome of patients with SCAP in South Asian Population. METHODS: A retrospective cross-sectional study was conducted from March 2002 till December 2008 on patients of 16 years and above who were admitted with the diagnosis of SCAP in accordance to the criteria of American Thoracic Society Guidelines (2001). The patients underwent clinical and diagnostic evaluations to detect the severity of illness as well as the etiology and other risk factors influencing the eventual outcome of SCAP. RESULTS: A total of 189 patients were included in the study. The mean age was 60 ± 18.0 years and 110 (58%) patients were males. The most common isolated pathogens were Staphylococcus aureus (15 patients), Streptococcus pneumoniae (14 patients) and Pseudomonas aeruginosa (9 patients). The highest mortality was seen in patients with Pseudomonas aeruginosa (89%) and Staphylococcus aureus (53%). Overall mortality rate was 51%. On univariate analysis, septic shock (p \u3c0.001), prior antibiotic use (p = 0.04), blood urea nitrogen \u3e 30 mg/dl (p = 0.03), hematocrit \u3c 30% (p = 0.03) and Acute Physiology and Chronic Health Evaluation (APACHE) II score \u3e 20 (p \u3c 0.001) were significantly different between the patients who survived as compared to those who did not. On multivariate analysis, septic shock (p \u3c0.001, OR: 4.70; 95% CI= 2.49-8.87) was found to be independently associated with mortality. CONCLUSION: The microbes causing SCAP in our study are different from the usual spectrum. Staphylococcus aureus and Pseudomonas aeruginosa were the common causative pathogens and associated with high mortality. It is important to establish clinical guidelines for managing SCAP according to the etiologic organisms in our setting

Clinical outcomes of pneumocystis pneumonia from a tertiary care centre in Pakistan.

Objective: To assess the predisposing immunocompromised states, administration of pneumocystis jirovecii pneumonia prophylaxis, the disease course and outcomes of patients with pneumocystis jirovecii pneumonia. Methods: The retrospective study was conducted at the Aga Khan University Hospital in Karachi. The medical records of patients diagnosed with pneumocystis jirovecii pneumonia from January 1995 to October 2015 were retrieved. Baseline characteristics, clinical course, treatment, and mortality rates were noted. SPSS 19 was used for data analysis. Results: Of the 37 patients, 24(64.9%) were men and 13(35.1%) were women. The overall mean presenting age was 47.08±16.21 years(range: 19-83 years). Ten (27%) patients were positive for human immunodeficiency virus; 12(32.4%) had an underlying autoimmune disease; 3(8.1%) were transplant recipients; 10(27%) had an underlying malignancy, and 19(51.3%) were on long-term corticosteroid therapy. Only 2(5.4%) patients had received pneumocystis jirovecii pneumonia prophylaxis with trimethoprim-sulfamethoxazole. Moreover, 8(21.6%) patientsrequired intensive care unit admission with a mean stay of 2.03±4.91 days (range: 1-22 days).The overall mortality rate was 7(18.9%). Conclusion: Pneumonia due to pneumocystis jirovecii was found to be a life-threatening disease in the immunocompromised population. The high mortality burden and resource intensive management of the disease emphasizes the need for PCP prophylaxis in immunosuppressed individuals

Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD

Age-Dependent Sex Differences in Perineuronal Nets in an APP Mouse Model of Alzheimer’s Disease Are Brain Region-Specific

Alzheimer’s disease (AD) is the most common form of dementia, which disproportionately affects women. AD symptoms include progressive memory loss associated with amyloid-β (Aβ) plaques and dismantled synaptic mechanisms. Perineuronal nets (PNNs) are important components of the extracellular matrix with a critical role in synaptic stabilisation and have been shown to be influenced by microglia, which enter an activated state during AD. This study aimed to investigate whether sex differences affected the density of PNNs alongside the labelling of microglia and Aβ plaques density.We performed neurochemistry experiments using acute brain slices from both sexes of the APPNL-F/NL-F mouse model of AD, aged-matched (2–5 and 12–16 months) to wild-type mice, combined with a weighted gene co-expression network analysis (WGCNA). The lateral entorhinal cortex (LEC) and hippocampal CA1, which are vulnerable during early AD pathology, were investigated and compared to the presubiculum (PRS), a region unscathed by AD pathology. The highest density of PNNs was found in the LEC and PRS regions of aged APPNL-F/NL-F mice with a region-specific sex differences. Analysis of the CA1 region using multiplex-fluorescent images from aged APPNL-F/NL-F mice showed regions of dense Aβ plaques near clusters of CD68, indicative of activated microglia and PNNs. This was consistent with the results of WGCNA performed on normalised data on microglial cells isolated from age-matched, late-stage male and female wild-type and APP knock-in mice, which revealed one microglial module that showed differential expression associated with tissue, age, genotype, and sex, which showed enrichment for fc-receptor-mediated phagocytosis. Our data are consistent with the hypothesis that sex-related differences contribute to a disrupted interaction between PNNs and microglia in specific brain regions associated with AD pathogenesis

A systematic review of psychosocial interventions for people with intellectual disabilities and dementia

OBJECTIVES: As the life expectancy of individuals with intellectual disabilities (ID) continues to increase, there is an increased risk of developing dementia. While psychosocial interventions are gaining prominence, evidence is limited for people with both dementia and ID. This review discusses the effectiveness of direct psychosocial interventions and adaptations to facilitate delivery within this population. METHODS: The review followed the PRISMA guidelines. Five electronic databases, grey literature, and reference lists of included articles were searched for relevant studies. 10 eligible studies were appraised and analysed by narrative synthesis. RESULTS: Ten distinct interventions were identified and categorised based on their purpose and delivery. All interventions were beneficial in improving a range of outcomes, though some studies were of low quality and most had small samples. Common adaptations included simplification of tasks and material, higher staff-to-client ratio, and alternative communication methods. CONCLUSION: There is emerging evidence for several psychosocial interventions for people with ID and dementia, though further research is required on effectiveness and generalisability. The adaptations discussed may guide implementation into routine care and contribute to current policies and guidelines on improving ID and dementia care

Alzheimer’s Disease Enhanced Tonic Inhibition is Correlated With Upregulated Astrocyte GABA Transporter-3/4 in a Knock-In APP Mouse Model

Cognitive decline is a major symptom in Alzheimer’s disease (AD), which is strongly associated with synaptic excitatory-inhibitory imbalance. Here, we investigated whether astrocyte-specific GABA transporter 3/4 (GAT3/4) is altered in APP knock-in mouse model of AD and whether this is correlated with changes in principal cell excitability. Using the APPNL-F/NL-F knock-in mouse model of AD, aged-matched to wild-type mice, we performed in vitro electrophysiological whole-cell recordings combined with immunohistochemistry in the CA1 and dentate gyrus (DG) regions of the hippocampus. We observed a higher expression of GAD67, an enzyme that catalyses GABA production, and GAT3/4 in reactive astrocytes labelled with GFAP, which correlated with an enhanced tonic inhibition in the CA1 and DG of 12–16 month-old APPNL-F/NL-F mice compared to the age-matched wild-type animals. Comparative neuroanatomy experiments performed using post-mortem brain tissue from human AD patients, age-matched to healthy controls, mirrored the results obtained using mice tissue. Blocking GAT3/4 associated tonic inhibition recorded in CA1 and DG principal cells resulted in an increased membrane input resistance, enhanced firing frequency and synaptic excitation in both wild-type and APPNL-F/NL-F mice. These effects exacerbated synaptic hyperactivity reported previously in the APPNL-F/NL-F mice model. Our data suggest that an alteration in astrocyte GABA homeostasis is correlated with increased tonic inhibition in the hippocampus, which probably plays an important compensatory role in restoring AD-associated synaptic hyperactivity. Therefore, reducing tonic inhibition through GAT3/4 may not be a good therapeutic strategy for A

Coinfection with Lichtheimia corymbifera and Aspergillus flavus in an Immune-Competent Patient Mimicking as Pulmonary-Renal Syndrome

Lichtheimia corymbifera and Aspergillus flavus pulmonary coinfection has been rarely reported in immune-competent patients. We report case of a young male who presented with clinical features of pulmonary-renal syndrome and was later diagnosed to have bilateral polymicrobial fungal lung infection

Association of airborne Aspergillus with asthma exacerbation in Southern Pakistan.

Background: Exposure to airborne fungi has been related with exacerbation of asthma in adults and children leading to increased outpatient, emergency room visits, and hospitalizations. Hypersensitivity to these airborne fungi may be an important initial predisposing factor in the development and exacerbation of asthma. Objective: This study was conducted to determine an association between fungal types and spore concentrations with the risk of asthma exacerbation in adults. Methods: This cross-sectional study was conducted from May 2008 to August 2009 at the Aga Khan University Hospital Karachi, Pakistan. All adult (age≥16 years) patients presenting to the hospital with acute asthma exacerbation were enrolled after informed consent. A home survey was conducted for each patient to assess their environmental characteristics. Indoor air samples were also obtained from the patient’s home to determine the type and spore concentration of fungi within the week of their enrollment in the study. Results: Three hundred and ninety-one patients with an acute asthma exacerbation were enrolled during the study period. The mean age of participants was 46 years (standard deviation, ±18 years) and 247 (63.2%) were females. A trend of higher asthma enrollment associated with higher Aspergillus concentrations was found in two consecutive summers. A total of nineteen types of fungi were found in air samples. Aspergillus spp. was the most frequently isolated fungus with acute asthma exacerbation. Conclusion: An association of higher concentration of indoor Aspergillus spp. with asthma exacerbation in adults was observed in this study