Preventing development of post-stroke hyperexcitability by optogenetic or pharmacological stimulation of cortical excitatory activity.

Stroke is the most common cause of acquired epilepsy, but treatment for preventing the development of post-stroke epilepsy is still unavailable. Since stroke results in neuronal damage and death as well as initial loss of activity in the affected brain region, homeostatic plasticity may be trigged and contribute to an increase in network hyperexcitability that underlies epileptogenesis. Correspondingly, enhancing brain activity may inhibit hyperexcitability from enhanced homeostatic plasticity and prevent post-stroke epileptogenesis. To test these hypotheses, we first used in vivo two-photon and mesoscopic imaging of activity of cortical pyramidal neurons in Thy1-GCaMP6 transgenic mice to determine longitudinal changes in excitatory activity after a photothrombotic ischemic stroke. At 3-days post-stroke, there was a significant loss of neuronal activity in the peri-injury area as indicated by reductions in the frequency of calcium spikes and percentage of active neurons, which recovered to baseline level at day 7, supporting a homeostatic activity regulation of the surviving neurons in the peri-injury area. We further used optogenetic stimulation to specifically stimulate activity of pyramidal neurons in the peri-injury area of Thy-1 channelrhodopsin transgenic mice from day 5 to day 15 after stroke. Using pentylenetetrazole test to evaluate seizure susceptibility, we showed that stroke mice are more susceptible to Racine stage V seizures (time latency 54.3 ± 12.9 min) compared to sham mice (107.1 ± 13.6 min), but optogenetic stimulation reversed the increase in seizure susceptibility (114.0 ± 9.2 min) in mice with stroke. Similarly, administration of D-cycloserine, a partial N-methyl-d-aspartate (NMDA) receptor agonist that can mildly enhance neuronal activity without causing post-stroke seizure, from day 5 to day 15 after a stroke significantly reversed the increase in seizure susceptibility. The treatment also resulted in an increased survival of glutamic acid decarboxylase 67 (GAD67) positive interneurons and a reduced activation of glial fibrillary acidic protein (GFAP) positive reactive astrocytes. Thus, this study supports the involvement of homeostatic activity regulation in the development of post-stroke hyperexcitability and potential application of activity enhancement as a novel strategy to prevent post-stroke late-onset seizure and epilepsy through regulating cortical homeostatic plasticity.

Effectiveness of Clinical Presentation (CP) Curriculum in teaching clinical medicine to undergraduate medical students: A cross-sectional study.

Introduction: The Clinical Presentation (CP) curriculum was first formulated in 1990 at the University of Calgary, Canada. Since then, it has been adopted at various medical schools, including Patan Academy of Health Sciences (PAHS), a state-funded medical school in a low-income country (LIC), Nepal. This study aims to evaluate the perceived effectiveness of the CP curriculum by students and faculty at PAHS, and test knowledge retention through a surprise non-routine exam administered to students.  Method: This is a cross-sectional study to evaluate the efficacy of the CP curriculum in teaching clinical medicine to the first batch of MBBS students of PAHS School of Medicine. Ethical approval was obtained from the Institutional Review Committee (IRC)-PAHS (Ref no std1505911069). Perceived effectiveness was evaluated using a set of questionnaires for faculty and students. A total of 33 students and 34 faculty filled the perception questionnaires. Subsequently, a questionnaire consisting of 50 Multiple Choice Questions (MCQs) from different clinical medicine disciplines was administered to test students' knowledge retention. Out of 49 students, 38 participated in the surprise non-routine exam.   Result: A significantly higher number of faculty preferred the CP curriculum compared to the traditional system of teaching clinical medicine (16 vs 11, Kruskal Wallis: 0.023, ie. P-value < 0.05). A significantly higher number of the students liked and recommended CP curriculum in the clinical year of medical education (20 vs. 13 with p-value < 0.05). In the non-routine surprise exam, two thirds of the students scored 60% or above.  Conclusion: Both faculty and students perceive that the CP curriculum system is an effective teaching and learning method in medical education, irrespective of their different demographic and positional characteristics. The students' overall performance was good in surprise, non-routine exams taken without scheduling or reminders.

Effectiveness of low-dose radiation therapy in COVID-19 patients globally: A systematic review.

Background: Novel Corona Virus Disease 2019 (COVID-19) can affect multiple organs, including the lungs, resulting in pneumonia. Apart from steroids, other anti-COVID drugs that have been studied appear to have little or no effect on COVID-19 pneumonia. There is a well-known history of inflammatory disease, including pneumonia, treated with low-dose radiation therapy (LDRT). It reduces the production of proinflammatory cytokines, Interleukin-1a (IL-1a), and leukocyte recruitment.   Methods: A comprehensive literature search was conducted using PubMed, Scopus, Embase, CINAHL, and Google Scholar, with keywords such as "radiotherapy," "low-dose radiation therapy," "low-dose irradiation," "covid-19 pneumonia," "SARS-CoV-2 pneumonia," and "covid pneumonia." with additional filters for human studies and customized articles in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. We reviewed randomized controlled trials, quasi-experimental studies, cohort, case-control, and cross-sectional studies with a clearly defined intervention, including low-dose radiotherapy alone or in combination with any therapy to treat COVID-19 pneumonia from December 2019 to May 2021. Patients receiving standard or high-dose radiotherapy, including for other diseases, were excluded. Zotero software was used to collect and organize research from various databases, remove duplicates, extract relevant data, and record decisions. Participants' demographics and baseline status were obtained from the full-text articles along with the intervention's outcome/effect on patient status.  Results: Four studies with 61 participants that met the inclusion criteria were included. One was a double-blind randomized controlled trial, one a non-randomized trial, while the other two were single-arm clinical trials. Low-dose radiation therapy did not show any significant improvement in COVID-19 patients.  Conclusion: Only two studies included in this review demonstrated an improvement in inflammatory markers; however, patients were also given steroids or other drugs. Therefore, the confounding effects must be considered before drawing conclusions. This systematic review does not support mortality benefit, clinical course improvement, or imaging changes with LDRT.

Performance and preference of problem-based learning (PBL) and lecture-based classes among medical students of Nepal.

Background: PBL (problem based learning) is new active learning educational strategy that has been extensively tested and used in recent years. Patan Academy of Health Sciences (PAHS) is one of medical schools from Nepal, a Low Income Country (LIC) implementing PBL for undergraduate medical education. This study aims to compare PAHS students' understanding and knowledge retention when taught through PBL and lecture-based classes and compare students' perceptions of PBL and lectures in medical education. Methods: This is a cross-sectional study of medical students of a PBL based medical school in Nepal, a non-Western low-income country. Ethical approval was given by the institutional research committee of the Patan Academy of Health Sciences. Understanding and knowledge retention was assessed with 50 vignette-based multiple-choice questions, half of which were taught through PBL sessions, and the remaining half were taught in didactic lectures during basic science years of medical school. A separate pre-validated perception questionnaire was used to assess students' preferences regarding PBL and lectures. Results: Out of 107 students, 99 participated in the understanding and knowledge retention questionnaires and 107 completed perception questionnaires. Understanding and knowledge retention of students was found to be the same for topics taught by PBL and lectures, with median scores of 17 and s16, respectively. PBL were mostly preferred for the physiology (59.81%), pathology (51.40%) and pharmacology (53.27%) concepts, and lectures were mostly preferred for the anatomy (78.50%), biochemistry (45.79%), and microbiology (42.99%) topics. Students wanted the same concepts to be taught through both PBL and lectures, especially for anatomy. Conclusions: Understanding and knowledge retention is the same for topics taught by either PBL or lectures during the basic science years of undergraduate medical education. Students prefer PBL for physiology, pathology, and pharmacology-related concepts, conventional didactic lecture for physiology and microbiology, and a combination of lecture and PBL sessions for anatomy.

Unilateral Facial Palsy at High Altitude: A Case Report.

Poudel Sangeeta, Bibechan Thapa, Saroj Adhikari Yadav, and Brenton Systermans. Unilateral facial palsy at high altitude: a case report. High Alt Med Biol. 22:426-428, 2021.-The facial nerve has a long and tortuous route predisposing it to palsy or paresis. Bell's palsy is the most common cause of facial nerve palsy. Most often Bell's palsy is self-limited but it is very crucial to rule out other causes and provide prompt treatment accordingly. Some causes of facial palsy that are specific to high altitude include hypoxia, cold weather, vitamin D deficiency, and high-altitude cerebral edema. Health facilities and diagnostic tools are compromised in resource-limited settings such as at high altitudes. This leads to a diagnostic dilemma, possibly delaying targeted treatment, and resulting in poorer outcomes. Clinical diagnosis plays an important role in such settings. The immediate descent and initiation of steroids improve the condition in many cases. In this article, we discuss the case of a Sherpa who presented to the Everest emergency clinic during the 2021 climbing season with unilateral facial palsy.

Hereditary Vitamin-D Dependent Rickets Type II: A Case Report.

Hereditary vitamin D dependent rickets type II is a rare genetic disorder in children characterized by early onset of rickets and deranged biochemical parameters. Low serum calcium level, high alkaline phosphatase, high parathyroid hormone, and high values of 1,25-dihydroxy vitamin D are characteristic biochemical findings. We are reporting a rare case of Vitamin D Dependent Rickets and subsequent improvement after addition of cinacalcet. This is a case report of a 2.5-year-child with Hereditary Vitamin D Dependent Rickets type II receiving cinacalcet as adjunct to oral calcium and calcitriol. Oral cinacalcet (0.25mg/kg/day) was added to the regimen as an adjunct after treatment failure with high dose of oral calcium and calcitriol. A significant improvement in radiological findings and normal homeostasis of calcium, phosphate and parathyroid hormone was achieved after initiation of cinacalcet.

Intraperitoneal injection of lipopolysaccharide prevents seizure-induced respiratory arrest in a DBA/1 mouse model of SUDEP.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the cause of premature death of 50% patients with chronic refractory epilepsy. Respiratory failure during seizures is regarded as an important mechanism of SUDEP. Previous studies have shown that abnormal serotonergic neurotransmission is involved in the pathogenesis of seizure-induced respiratory failure, while enhancing serotonergic neurotransmission in the brainstem suppresses it. Because peripheral inflammation is known to enhance serotonergic neuron activation and 5-HT synthesis and release, we investigated the effect of intraperitoneal lipopolysaccharide (LPS)-induced inflammation on the S-IRA susceptibility during audiogenic seizures in DBA/1 mice. METHODS: After DBA/1 mice were primed by exposing to sound stimulation for three consecutive days, they were tested for seizure severity and seizure-induced respiratory arrest (S-IRA) induced by sound stimulation under different conditions. We determined the dose and time course of the effects of intraperitoneal administration of LPS on audiogenic seizures and S-IRA. The effects of blocking TLR4 or RAGE receptors and blocking 5-HT receptors on the LPS-induced effect on S-IRA were investigated. Statistical significance was evaluated using the Kruskal-Wallis test. RESULTS: Intraperitoneal injection of LPS significantly had dose-dependent effects in reducing the incidence of S-IRA as well as seizure severity in DBA/1 mice. The protective effect of LPS on S-IRA peaked at 8-12 hours after LPS injection and was related to both reducing seizure severity and enhancing autoresuscitation. Blocking TLR4 or RAGE receptor with TAK-242 or FPS-ZM1, respectively, prior to LPS injection attenuated its effects on S-IRA and seizure severity. Injection of a nonselective 5-HT receptor antagonist, cyproheptadine, or a 5-HT3 receptor antagonist, ondansetron, was effective in blocking LPS-induced effect on S-IRA. Immunostaining results showed a significant increase in c-Fos-positive serotonergic neurons in the dorsal raphe. SIGNIFICANCE: This is the first study that demonstrates the effect of intraperitoneal LPS injection-induced inflammation on reducing S-IRA susceptibility and provides additional evidence supporting the serotonin hypothesis on SUDEP. Our study suggests that inflammation may enhance brainstem 5-HT neurotransmission to promote autoresuscitation during seizure and prevent SUDEP.

Isolated Gall Bladder Perforation in a Tertiary Care Hospital in Eastern Nepal: A Descriptive Cross-sectional Study.

INTRODUCTION: Cholelithiasisis is a common surgical problem worldwide. Gall bladder perforation is a rare life-threatening complication with considerable mortality. This study aims to find the etiology, demography, type of perforation, and outcome of gall bladder perforation. METHODS: This descriptive cross-sectional study was done on patients above 18 years of age visiting the department of surgery of B. P. Koirala Institute of Health Sciences (BPKIHS) who were diagnosed with isolated gall bladder perforation. The study was done from 1st January 2006 till 30 December 2016. Ethical approval was obtained from the Institutional Review Committee (reference number. 34/074/075). The convenient sampling method was used. Data were entered in excel sheets and analyzed. RESULTS: Out of 49 patients included in the study, 28 (57.14%) were females and the commonest age group was 36 to 50 years 22 (44.9%) followed by 51 to 65 years 16 (32.6%). Most of the patients presented in emergency with pain in their abdomen. Diabetes mellitus was the commonest co-morbidity present in 10 (20.41%) patients. Operative management was done in 45 (91.84%) of the patient and conservative management in 4 (8.16%). After surgery of 45 patients, 43 (95.56%) improved and 2 (4.44%) expired. The most common type of perforation was Niemeier Type I in 21 (46.67%) followed by Type III 14 (31.11%). The most common histopathological diagnosis was acute cholecystitis 20 (44.44%). CONCLUSIONS: Isolated gall bladder perforation is not an uncommon complication. The most common etiological factor was acute cholecystitis with a slight female predominance. Most of the patients needed surgical intervention and they had good outcomes when diagnosed and managed on time.