Sleep and Epilepsy: A Complex Interplay.

In this review we look to provide an overview of the complex interactions between sleep and epilepsy, and how knowledge of the interplay between the two can help in guiding management of disorders in both areas.

Transgenic analysis of GFAP promoter elements.

Transcriptional regulation of the glial fibrillary acidic protein gene (GFAP) is of interest because of its astrocyte specificity and its upregulation in response to CNS injuries. We have used a transgenic approach instead of cell transfection to identify promoter elements of the human GFAP gene, since previous observations show that GFAP transcription is regulated differently in transfected cultured cells from in the mouse. We previously showed that block mutation of enhancer regions spanning from bp -1488 to -1434 (the C1.1 segment) and -1443 to -1399 (C1.2) resulted in altered patterns of expression and loss of astrocyte specificity, respectively. This analysis has now been extended upstream to bp -1612 to -1489 (the B region), which previously has been shown especially important for expression. Block mutation of each of four contiguous sequences, which together span the B region, each decreased the level of transgene activity by at least 50%, indicating that multiple sites contribute to the transcriptional activity in a cooperative manner. Several of the block mutations also altered the brain region pattern of expression, astrocyte specificity and/or the developmental time course. Transgenes were then analyzed in which mutations were limited to specific transcription factor binding sites in each of the 4 B block segments as well as in C1.1 and C1.2. Whereas mutation of the conserved consensus AP-1 site unexpectedly had little effect on transgene expression; NFI, SP1, STAT3, and NF-κB were identified as having important roles in regulating the strength of GFAP promoter activity and/or its astrocyte specificity.

NR2B antagonists restrict spatiotemporal spread of activity in a rat model of cortical dysplasia.

Freeze-lesion-induced focal cortical dysplasia in rats closely resembles human microgyria, a neuronal migration disorder associated with drug-resistant epilepsy. Alterations in expression of N-methyl-D-aspartate receptors (NMDARs) containing NR2B subunits have been suggested to play a role in the hyperexcitability seen in this model. We examined the effect of NMDAR antagonists selective for NR2B subunits (Ro 25-6981 and ifenprodil) on activity evoked by intracortical stimulation in brain slices from freeze-lesioned rat neocortex. Whole-cell voltage-clamp recordings showed that Ro 25-6981 (1 microM) significantly reduced the response area of evoked postsynaptic currents in pyramidal cells from the paramicrogyral area whereas responses were unaffected in slices from control (sham operated) animals. Voltage-sensitive dye imaging was used to examine spatiotemporal spread of evoked activity in lesioned and control cortices. The imaging experiments revealed that peak amplitude, duration, and lateral spread of evoked activity in the paramicrogyral area was reduced by bath application of Ro 25-6981 (1 microM) and ifenprodil (10 microM). Ro 25-6981 had no effect on evoked activity in neocortical slices from control animals. The non-selective NMDAR antagonist d-2-amino-5-phosphonvaleric acid (APV, 20 microM) reduced activity evoked in presence of 50 microM 4-aminopyridine (known to increase excitability by enhancing neurotransmitter release) in neocortical slices from control animals whereas Ro 25-6981 (1 microM) did not. These results suggest that NR2B subunit-containing NMDARs contribute significantly to the enhanced spatiotemporal spread of paroxysmal activity observed in vitro in the rat freeze-lesion model of focal cortical dysplasia.

Health & Demographic Surveillance System Profile: The Birbhum population project (Birbhum HDSS).

The Birbhum HDSS was established in 2008 and covers 351 villages in four administrative blocks in rural areas of Birbhum district of West Bengal, India. The project currently follows 54 585 individuals living in 12557 households. The population being followed up is economically underprivileged and socially marginalized. The HDSS, a prospective longitudinal cohort study, has been designed to study changes in population demographic, health and healthcare utilization. In addition to collecting data on vital statistics and antenatal and postnatal tracking, verbal autopsies are being performed. Moreover, periodic surveys capturing socio-demographic and economic conditions have been conducted twice. Data on nutritional status (children as well as adults), non-communicable diseases, smoking etc. have also been collected in special surveys. Currently, intervention studies on anaemia, undernutrition and common preschool childhood morbidities through behavioural changes are under way. For access to the data, a researcher needs to send a request to the Data Manager [suri.shds@gmail.com]. Data are shared in common formats like comma-separated files (csv) or Microsoft Excel (xlsx) or Microsoft Access Database (mdb).The HDSS will soon upgrade its data management system to a more integrated platform, coordinated and guided by INDEPTH data sharing policy.

Cough syncope in a 43-year-old woman with glomus jugulare tumor.

We present an unusual case of recurrent cough syncope in a 43-year-old woman, which was initially thought to be seizures. Syncopal episodes were triggered by paroxysms of cough and were characterized by unresponsiveness and myoclonic jerks in her extremities. She had a left-sided glomus jugulare tumor that extended into the posterior cranial fossa with evidence of worsening communicating hydrocephalus on brain imaging. We postulate that bouts of cough produced increased intracranial pressure both by raising intrathoracic and intraabdominal pressures as well as by transient obstruction to cerebrospinal fluid flow secondary to intermittent tonsillar herniation during cough. This resulted in diffuse decrease in cerebral blood flow causing syncope. The patient's syncopal episodes decreased in frequency once an external ventricular drain was placed followed by a ventriculoperitoneal shunt. Search for factors that can increase intracranial pressure seems warranted in patients with recurrent cough syncope.

Efficacy of alternate-day versus everyday dosing of atorvastatin.

BACKGROUND: Atorvastatin has a longer duration of action than other hydroxymethylglutaryl coenzyme A reductase inhibitors. OBJECTIVES: The objective was to evaluate the efficacy of alternate day vs. daily dosing of atorvastatin for the treatment of hyperlipidemia. MATERIALS AND METHODS: In this prospective, open label, crossover study, 40 patients with plasma low-density cholesterol (LDL-C) of more than 130 mg/dl and total cholesterol (TC) more than 200 mg/dl were recruited. After baseline tests, they were randomly allocated to two groups. Group A received 20 mg atorvastatin on alternate days and group B received 20 mg atorvastatin daily for 12 weeks. After 4 weeks of washout period, the groups were crossed over to the other treatment regimen for another 12 weeks. Fasting plasma lipid profile and serum alanine transaminase (ALT) and aspartate transaminase (AST) were measured for both groups at 6(th), 12(th), 16(th), 22(nd), and 28(th) weeks. Results were pooled across the periods and data between the two groups were compared using unpaired t-test. RESULTS: Among the 40 enrolled subjects, 38 completed the study. Both treatment regimens significantly reduced LDL-C and TC compared to baseline. There was no statistically significant difference between the two groups in terms of reduction of plasma LDL-C and TC at 6 and 12 weeks of treatment. Both the regimens were well tolerated. CONCLUSION: Alternate-day treatment with atorvastatin is comparable in efficacy and safety to the established daily treatment regimen, thus being a cost effective alternative.

Micro-albuminuria: a predictor of short-term mortality in acute ischaemic stroke.

We studied 89 non-diabetic patients of acute ischaemic stroke, confirmed by imaging, admitted within 24 hours of onset, to investigate the prevalence and significance of micro-albuminuria (MA) as a predictor of in-hospital mortality. Two control groups consisted of 70 patients with non-stroke chronic neurological diseases and 60 age- and sex- matched healthy individuals. Spot urinary albumin-to-creatinine ratio was measured in first morning sample on days 1, 4 and/or 7. Functional status was assessed daily for 7 days by National Institute of Health Stroke Scale (NIHSS). Outcome data were recorded for 14 days. MA was found in 61.79% of acute ischaemic stroke patients on day 1 compared to 13% in non-stroke neurological patients and 7% of healthy controls. Patients with MA were older and had a higher systolic blood pressure. The 14-day disease-specific mortality was higher in patients with MA (25.45%) compared to patients without it (5.88%). High day 1 MA (>100 microg/mg) and rising or static value from day 1 to day 4 or day 7 correlated with statistically more chance of death. Increasing MA had a positive correlation with higher NIHSS score. Thus, MA was found to be a reliable predictor of shortterm in-hospital mortality in acute ischaemic stroke.

Dopaminergic modulation of local network activity in rat prefrontal cortex.

Dopamine modulates prefrontal cortex excitability in complex ways. Dopamine's net effect on local neuronal networks is therefore difficult to predict based on studies on pharmacologically isolated excitatory or inhibitory connections. In the present work, we have studied the effects of dopamine on evoked activity in acute rat brain slices when both excitation and inhibition are intact. Whole cell recordings from layer II/III pyramidal cells under conditions of normal synaptic transmission showed that bath-applied dopamine (30 microM) increased the outward inhibitory component of composite postsynaptic currents, whereas inward excitatory currents were not significantly affected. Optical imaging with the voltage-sensitive dye N-(3-(triethylammonium)propyl)-4-(4-(p-diethylaminophenyl)buta-dienyl)pyridinium dibromide revealed that bath application of dopamine significantly decreased the amplitude, duration, and lateral spread of activity in local cortical networks. This effect of dopamine was observed both with single and train (5 at 20 Hz) stimuli. The effect was mimicked by the D1-like receptor agonistR(+)-6-chloro-7,8-dihydroxy-1-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (1 microM) and was blocked by R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (10 microM), a selective antagonist for D1-like receptors. The D2-like receptor agonist quinpirole (10 microM) had no significant effect on evoked dye signals. Our results suggest that dopamine's effect on inhibition dominates over that on excitation under conditions of normal synaptic transmission. Such neuromodulation by dopamine may be important for maintenance of stability in local neuronal networks in the prefrontal cortex.

Endogenous acetylcholine enhances synchronized interneuron activity in rat neocortex.

Application of 4-aminopyridine (4-AP) along with EAA) receptor antagonists produces gamma-aminobutyric acid (GABAA) receptor-dependent synchronized activity in interneurons. This results in waves of activity propagating through upper cortical layers. Because interneurons in the neocortex are excited by nicotinic acetylcholine receptor (nAChR) agonists, ACh may influence synchronization of these local neocortical interneuronal networks. To study this possibility, we have used voltage-sensitive dye imaging using the fluorescent dye RH 414 (30 microM) in rat neocortical slices. Recordings were obtained in the presence of 4-AP (100 microM) and the EAA receptor antagonists D-2-amino-5-phosphonvaleric acid (20 microM) and 6-cyano-7-nitro-quinoxaline-2,3-dione (10 microM). In response to intracortical stimulation, localized or propagated activity restricted to upper cortical layers was seen. Bath application of the ACh esterase inhibitor neostigmine (10 microM) and the nAChR agonist 1,1-dimethyl-4-phenyl-piperazinium iodide (DMPP; 10 microM) increased the response amplitude, the extent of spread, and the duration of this activity. These changes were seen in 13 of 16 slices tested with neostigmine (10 microM) and 4 of 7 slices tested with DMPP (10 microM). Application of the muscarinic AChR antagonist atropine (1 microM) did not block the enhancement of activity by neostigmine (n = 7). Application of dihydro-beta-erythroidine (10 microM), known, at this concentration, to selectively antagonize alpha4beta2-like nAChRs, blocked the effect of neostigmine (n = 5). The selective alpha7-like nAChR antagonist methyllycaconitine (50 nM) was ineffective (n = 5). These results suggest that activation of alpha4beta2-like nAChRs by endogenously released ACh can enhance synchronized activity in local neocortical inhibitory networks.

Dopamine enhances spatiotemporal spread of activity in rat prefrontal cortex.

Dopaminergic modulation of prefrontal cortex (PFC) is important for neuronal integration in this brain region known to be involved in cognition and working memory. Because of the complexity and heterogeneity of the effect of dopamine on synaptic transmission across layers of the neocortex, dopamine's net effect on local circuits in PFC is difficult to predict. We have combined whole cell patch-clamp recording and voltage-sensitive dye imaging to examine the effect of dopamine on the excitability of local excitatory circuits in rat PFC in vitro. Whole cell voltage-clamp recording from visually identified layer II/III pyramidal neurons in rat brain slices revealed that, in the presence of bicuculline (10 microM), bath-applied dopamine (30-60 microM) increased the amplitude of excitatory postsynaptic currents (EPSCs) evoked by weak intracortical stimulus. The effect was mimicked by the selective D1 receptor agonist SKF 81297 (1 microM). Increasing stimulation resulted in epileptiform discharges. SKF 81297 (1 microM) significantly lowered the threshold stimulus required for generating epileptiform discharges to 83% of control. In the imaging experiments, bath application of dopamine or SKF 81297 enhanced the spatiotemporal spread of activity in response to weak stimulation and previously subthreshold stimulation resulted in epileptiform activity that spread across the whole cortex. These effects could be blocked by the selective D1 receptor antagonist SCH 23390 (10 microM) but not by the D2 receptor antagonist eticlopride (5 microM). These results indicate that dopamine, by a D1 receptor-mediated mechanism, enhances spatiotemporal spread of synaptic activity and lowers the threshold for epileptiform activity in local excitatory circuits within PFC.

Effect of Sonachandi Chyawanprash and Chyawanprash Plus--two herbal formulations on immunomodulation.

The immunomodulatory effects of Sonachandi Chyawanprash and Chyawanprash Plus--two herbal formulations have been evaluated. Both the drugs increased the macrophage activity and their number indicating enhancement of non-specific immune response and reduction of chances of infection. Besides that both Sonachandi Chyawanprash and Chyawanprash Plus efficiently protected Cyclosporine A induced immunosuppression suggesting the immunoprotective role of the aforesaid herbal formulations.