Cell-specific extracellular vesicle-encapsulated exogenous GABA controls seizures in epilepsy.

BACKGROUND: Epilepsy affects ∼60 million people worldwide. Most antiseizure medications in the market act on voltage-gated sodium or calcium channels, indirectly modulating neurotransmitter GABA or glutamate levels or multiple targets. Earlier studies made significant efforts to directly deliver GABA into the brain with varied success. Herein, we have hypothesized to directly deliver exogenous GABA to the brain with epilepsy through extracellular vesicles (EVs) from human GABA-producing cells and their progenitors as EVs largely mimic their parent cell composition. METHODS: Human neural stem cells (NSCs), medial ganglionic eminence (MGE) cells, and GABAergic interneurons (INs) were generated from induced pluripotent stem cells (iPSCs) and characterized. EVs were isolated from NSCs, MGE cells, and INs and characterized for size and distribution, morphological features, and molecular markers. Exogenous GABA was passively loaded to the isolated EVs as a zwitterion at physiological pH, and the encapsulated dose of GABA was quantified. Epilepsy was developed through status epilepticus induction in Fisher rats by administration of repeated low doses of kainic acid. The extent of the seizures was measured for 10 h/ day for 3-6 months by video recording and its evaluation for stage III, IV and V seizures as per Racine scale. EVs from INs, MGE cells, and NSCs encapsulated with exogenous GABA were sequentially tested in the 4th, 5th, and 6th months by intranasal administration in the rats with epilepsy for detailed seizure, behavioral and synapse analysis. In separate experiments, several controls including exogenic GABA alone and EVs from INs and MGE cells were evaluated for seizure-controlling ability. RESULTS: Exogenic GABA could enter the brain through EVs. Treatment with EVs from INs and MGE cells encapsulated with GABA significantly reduced total seizures, stage V seizures, and total time spent in seizure activity. EVs from NSCs encapsulated with GABA demonstrated limited seizure control. Exogenic GABA alone and EVs from INs and MGE cells individually failed to control seizures. Further, exogenic GABA with EVs from MGE cells improved depressive behavior while partially improving memory functions. Co-localization studies confirmed exogenous GABA with presynaptic vesicles in the hippocampus, indicating the interaction of exogenous GABA in the brain with epilepsy. CONCLUSION: For the first time, the study demonstrated that exogenous GABA could be delivered to the brain through brain cell-derived EVs, which could regulate seizures in temporal lobe epilepsy. It is identified that the cellular origin of EVs plays a vital role in seizure control with exogenous GABA.

Small extracellular vesicle-loaded bevacizumab reduces the frequency of intravitreal injection required for diabetic retinopathy.

Diabetic retinopathy (DR) is associated with retinal neovascularization, hard exudates, inflammation, oxidative stress and cell death, leading to vision loss. Anti-vascular endothelial growth factor (Anti-VEGF) therapy through repeated intravitreal injections is an established treatment for reducing VEGF levels in the retina for inhibiting neovascularization and leakage of hard exudates to prevent vision loss. Although anti-VEGF therapy has several clinical benefits, its monthly injection potentially causes devastating ocular complications, including trauma, intraocular hemorrhage, retinal detachment, endophthalmitis, etc. Methods: As mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) demonstrated safety in clinical studies, we have tested the efficacy of MSC-derived small EVs (MSC-sEVs) loaded anti-VEGF drug bevacizumab in a rat model of DR. Results: The study identified a clinically significant finding that sEV loaded with bevacizumab reduces the frequency of intravitreal injection required for treating diabetic retinopathy. The sustained effect is observed from the reduced levels of VEGF, exudates and leukostasis for more than two months following intravitreal injection of sEV loaded with bevacizumab, while bevacizumab alone could maintain reduced levels for about one month. Furthermore, retinal cell death was consistently lower in this period than only bevacizumab. Conclusion: This study provided significant evidence for the prolonged benefits of sEVs as a drug delivery system. Also, EV-mediated drug delivery systems could be considered for clinical application of retinal diseases as they maintain vitreous clarity in the light path due to their composition being similar to cells.

Indian Traditional Treatments for Psoriasis: A Critical Appraisal of Available Evidence Supporting Efficacy.

OBJECTIVE: To examine data from studies supporting the clinical efficacy of medical approaches from India traditional systems of medicines like Ayurveda, Unani, Siddha, and Homeopathy for psoriasis using outcome indicators employed in clinical practice and research. METHODS: Searches were conducted between December 2019 and September 2020 in databases PubMed, Scopus, Web of Science and Ovid Medline using search terms including traditional, complementary, psoriasis, Kushtha, Ayurveda, Siddha, Unani, Homeopathy and clinical. Controlled trials, case series and case reports published from India were included. RESULTS: Data of 17 selected studies were extracted. Treatment efficacy in terms of improvement in Psoriasis Area and Severity Index (PASI) score or/and percentage reduction in score (PASI 50, PASI 75 and PASI 90) or/and patient-reported outcomes using instruments like Dermatology Life Quality Index and Psoriasis Disability Index were noted. All studies reported good improvement as per the study specific outcome. However, study characteristics, including study design, sample size, follow-up period, inclusion and exclusion criteria were heterogeneous, and the choice of outcome measures was not adequate to conclude the effectiveness of intervention. The use of some herbs as common ingredients in several formulations across different systems of medicines were noted in analyzing individual formulation. CONCLUSIONS: Future studies must incorporate a comprehensive study design with specific outcome measures like PASI, PASI 75, PASI 90, quality of life parameters, compliance to medications, adverse reactions, remission period, relapse rate and cost-effectiveness with long term follow-up. The currently available evidence on the roles of these herbs at molecular level in psoriasis is preliminary.

Deregulated miRNA clusters in ovarian cancer: Imperative implications in personalized medicine.

Ovarian cancer (OC) is one of the most common and fatal types of gynecological cancer. OC is usually detected at the advanced stages of the disease, making it highly lethal. miRNAs are single-stranded, small non-coding RNAs with an approximate size ranging around 22 nt. Interestingly, a considerable proportion of miRNAs are organized in clusters with miRNA genes placed adjacent to one another, getting transcribed together to result in miRNA clusters (MCs). MCs comprise two or more miRNAs that follow the same orientation during transcription. Abnormal expression of the miRNA cluster has been identified as one of the key drivers in OC. MC exists both as tumor-suppressive and oncogenic clusters and has a significant role in OC pathogenesis by facilitating cancer cells to acquire various hallmarks. The present review summarizes the regulation and biological function of MCs in OC. The review also highlights the utility of abnormally expressed MCs in the clinical management of OC.

Establishing links between assessments and expected learning outcomes through curriculum mapping in a dental physiology curriculum.

Background: . The relevance of curriculum mapping to determine the links between expected learning outcomes and assessment is well stated in the literature. Nevertheless, studies confirming the usage of such maps are minimal. Methods: . We assessed links through curriculum mapping, between assessments and expected learning outcomes of dental physiology curriculum of three batches of students (2012-14) at Melaka-Manipal Medical College (MMMC), Manipal. The questions asked under each assessment method were mapped to the respective expected learning outcomes, and students' scores in different assessments in physiology were gathered. Students' (n = 220) and teachers' (n=15) perspectives were collected through focus group discussion sessions and questionnaire surveys. Results: . More than 75% of students were successful (≥50% scores) in majority of the assessments. There was moderate (r=0.4-0.6) to strong positive correlation (r=0.7-0.9) between majority of the assessments. However, students' scores in viva voce had a weak positive correlation with the practical examination score (r=0.230). The score in the assessments of problem-based learning had either weak (r=0.1-0.3) or no correlation with other assessment scores. Conclusions: . Through curriculum mapping, we were able to establish links between assessments and expected learning outcomes. We observed that, in the assessment system followed at MMMC, all expected learning outcomes were not given equal weightage in the examinations. Moreover, there was no direct assessment of self-directed learning skills. Our study also showed that assessment has supported students in achieving the expected learning outcomes as evidenced by the qualitative and quantitative data.

Vernonia cinerea regenerates tubular epithelial cells in cisplatin induced nephrotoxicity in cancer bearing mice without affecting antitumor activity.

BACKGROUND: Traditional Siddha Medicine advises using metal-based formulations to treat cancers. In the case of any toxicities during the therapy, Siddha physicians use Vernonia cinerea (VC) whole plant kashayam (crude aqueous extract-CAE) to reverse the toxic effects. AIM: To evaluate the nephroprotective activity of CAE and its fractions in cisplatin-induced nephrotoxicity and to assess whether they compromise the anticancer efficacy of cisplatin. MATERIALS AND METHODS: Cisplatin-induced renal damage was induced in Ehrlich Ascites Carcinoma (EAC) bearing mice during mild phase of tumor growth. CAE and its butanol (BF) and aqueous (AF) fractions were administered orally from the 5th day for five days. Nephroprotective potential (serum urea, creatinine, renal histology) and effect of VC on cisplatin anticancer efficacy (tumor volume, viable tumor cells, percentage increase in life span (% ILS)) were calculated. RESULT: CAE and its fractions significantly reversed the cisplatin-induced renal damage. CAE and BF treated animals showed regeneration of 50%-75% of proximal tubular cells. Compared to EAC control mice, the % ILS of the cisplatin-treated group was 244% and it was further extended to 379% after CAE administration. The % ILS in the CAE treated group was 1.6 times higher than the cisplatin alone treated group. GC-MS study showed the presence of astaxanthin and betulin. CONCLUSION: CAE of VC reverses cisplatin-induced kidney damage as well as regenerates proximal tubular epithelial cells, without compromising the anticancer effect of cisplatin. When CAE was further fractionated, the nephroprotective activity was retained, but the beneficial anticancer effect of cisplatin was compromised.

Curriculum mapping of dental physiology curriculum: The path towards outcome-based education.

INTRODUCTION: Curriculum mapping provides a clear picture of curriculum content, learning opportunities and assessment methods employed to measure the achievement of learning outcomes with their interrelationships. It facilitates educators and teachers to examine the extent to which the curricular components are linked and hence to find out gaps in the curriculum. The objective of the study was, therefore, to evaluate the physiology curriculum of Bachelor of Dental Surgery (BDS) programme through curriculum mapping. MATERIALS AND METHODS: In this study, mapping of the physiology curriculum of three batches of BDS programme was conducted retrospectively. The components of the curriculum used for mapping were expected learning outcomes, curriculum content, learning opportunities, assessments and learning resources. The data were gathered by reviewing office records. RESULTS: Descriptive analysis of the data revealed reasonable alignment between the curriculum content and questions asked in examinations for all three batches. It was found that all the expected learning outcomes were addressed in the curriculum and assessed in different assessments. Moreover, the study revealed that the physiology curriculum was contributing to majority of the programme outcomes. Nevertheless, the study could identify some gaps in the curriculum, as well. CONCLUSION: This study revealed that majority of the components of the curriculum were linked and contributed to attaining the expected learning outcomes. It also showed that curriculum mapping was feasible and could be used as a tool to evaluate the curriculum.

Evaluation of a mentored student project programme using reflective summaries.

Background: . Undergraduate research experience has become increasingly relevant for today's medical students, considering the professional requirements of their challenging future. Methods: . In the mentored student project (MSP) programme at Melaka Manipal Medical College, students undertake a short-term group research project under the guidance of their mentor. After data collection and analysis, students are required to write an abstract, present a poster and also write individual reflective summaries of their research experience. We evaluated the MSP programme using reflective summaries of a batch of undergraduate medical students. Data from 41 reflective summaries were analysed using the thematic analysis approach. The learning outcomes at the third and fourth levels of the Kirkpatrick evaluation model were determined from the summaries. Results: . Students' reflective summaries indicated that they were satisfied with the MSP experience. In all the summaries, there was a mention of an improvement in teamwork skills through MSP. Improved relations with mentors were another relevant outcome. Improvement in communication skills and a positive change related to research attitude were also reported by students. Conclusions: . Reflective summaries as a means to evaluate the MSP programme was found to be an easy, feasible and cost-effective method. The qualitative approach adopted for data analysis enabled the programme coordinators to assess the strengths and barriers of the programme.

Using an integrated teaching approach to facilitate student achievement of the learning outcomes in a preclinical medical curriculum in India.

Today most education institutions around the world have adopted the philosophy of outcome-based education. The emphasis in outcome-based education is achievement of outcomes; hence the curriculum should be designed in a way that it includes the components targeted specifically at achieving these outcomes. A discipline-based approach results in fragmentation of learning and lack of clinical applicability. Integrated teaching could be a solution to achieve required outcomes in a holistic way. Hence, the aim of this study was to develop, implement, and evaluate an integrated teaching module. Temporal coordination of the basic sciences, along with correlation of learned topics to clinical settings, was done in the first year of the undergraduate medical program. The module was evaluated by obtaining qualitative and quantitative feedback from students. Student assessment was conducted with a test that had case vignettes and multiple-choice questions. In addition, students' change in learning approaches and self-directed learning readiness were collected. Students' perception regarding the educational environment was also obtained. Analysis of the data showed positive feedback from the students regarding the integrated teaching. Students' average score in the test was 86%. There was a significant increase in the scores for the deep approach and self-directed learning readiness in the posttest compared with the pretest. Moreover, students were found to be satisfied with the educational environment. Evaluation of integrated teaching revealed that it was well accepted by the students. Moreover, it facilitated the achievement of the students' outcomes.

Assessment for learning: a needs analysis study using formative assessment to evaluate the need for curriculum reform in basic sciences.

A needs analysis study for curriculum reform in basic sciences was conducted at Melaka Manipal Medical College, India, by means of a formative assessment method, namely Basic Science Retention Examination (BSRE). Students participated in a BSRE, which comprised recall and clinical multiple-choice questions in six discipline areas. They also rated the clinical relevance of each question and provided responses to three open-text questions about the exam. Pass rates were determined; clinical relevance ratings and performance scores were compared between recall type and clinical questions to test students' level of clinical application of basic science knowledge. Text comments were thematically analyzed to identify recurring themes. Only one-third of students passed the BSRE (32.2%). Students performed better in recall questions compared with clinical questions in anatomy (51.0 vs. 40.2%), pathology (45.1 vs. 38.1%), pharmacology (41.8 vs. 31.7%), and biochemistry (43.5 vs. 26.9%). In physiology, students performed better in clinical questions compared with the recall type (56.2 vs. 45.8%). Students' response to BSRE was positive. The findings imply that transfer of basic science knowledge was poor, and that assessment methods should emphasize clinical application of basic science knowledge.

Teaching and Assessing Reflecting Skills among Undergraduate Medical Students Experiencing Research.

INTRODUCTION: Reflection is the integral component of lifelong learning. Hence, there is a need for incorporating opportunities for students in the curriculum, to develop these skills. AIM: To evaluate the feasibility of incorporating teaching-learning activity on reflection early in the undergraduate medical curriculum using research experience as a context, and, to determine whether the reflective skills of students improve upon training. MATERIALS AND METHODS: The study was experimental with test and control groups and was conducted at Melaka Manipal Medical College, India. Senior batch of medical students in the second year of the course, about to complete their research project were considered as the test group and subsequent junior batch which was in middle of the research activity was the control. The test group was provided with a teaching-learning activity on reflection. Following this, students were asked to write reflective summary on experience of doing research. The control group who did not receive any training on reflection were also requested to write reflective summaries. Reflective summaries were graded by two authors independently using a newly developed rubric. Later, the grades were designated with scores. Perspective regarding this teaching-learning activity was collected from the test group. Feasibility was examined during teaching-learning activity and assessment. Mean reflective summary scores of control and test groups were expressed as mean±standard deviation and compared using independent samples t-test. A p-value of <0.05 was considered as statistically significant. Inter-rater reliability of the rubric was analyzed using Kappa statistics. RESULTS: The teaching-learning activity lasted for two hours. It took an average of five minutes for researchers to assess each reflective summary. There was a statistically significant (p<0.001) difference in the mean reflective summary scores between control (26.45±9.43) and test (51.66±6.56) groups. Kappa for inter-rater reliability was 0.784 denoting substantial agreement between two raters. Perceptions revealed acceptability of module (median 4, scale 1-5). CONCLUSION: Teaching and assessing reflecting skills among students using research experience as context was feasible. This study demonstrated that students acquire better reflecting skills after undergoing training.

Undergraduate pharmacology curriculum at an international medical college in India.

Pharmacology is an important aspect of rational therapeutics. There has been a long-standing need for a change in the undergraduate medical curriculum of pharmacology. A review of literature throws up different approaches to improve the curriculum and to provide more importance to conceptualization and relevance to clinical practice. This article describes the undergraduate pharmacology curriculum which is revised to meet the needs of our unique status as an international medical college in India. We highlight how our curriculum prepares the students for future clinical practice by inculcating higher cognitive skills and soft skills. This article also provides a model for program evaluation and also challenges faced by our department while executing the planned curriculum.

Development of a teaching module for parenteral drug administration and objective structured practical examination stations in pharmacology.

OBJECTIVES: Safe parenteral drug administration includes preparation of safe medication for administration. Training medical students is crucial to minimize medication administration errors. The study aims to develop a module to teach drug preparation skills and to develop objective structured practical examination (OSPE) stations to assess these skills. Students' perceptions regarding the module were also assessed. MATERIALS AND METHODS: A module was developed to teach following skills to 2(nd) year medical students: Aspiration of a drug from the ampule, aspiration of the drug from the vial, aspiration of the drug in powdered form from vial (reconstitution), and setting up an intravenous (IV) infusion. A randomized case control study design was used to establish the validity of OSPE stations. Student volunteers were grouped into case (n = 20) and control groups (n = 20) by simple randomization. The test group watched videos of skills and received demonstration of skills and a practice session before OSPE, whereas the control group watched videos before the OSPE and received demonstration and a practice session only after the OSPE. Each student was assessed by two faculty members during OSPE using a validated checklist. Mean OSPE scores of control and test groups were compared using independent samples t-test. Interrater reliability and concurrent validity of stations were analyzed using interclass correlation coefficient (ICC) and Pearson correlation, respectively. Students' responses were expressed as median and interquartile range. RESULTS: The response rate in the questionnaire was 100%. Significant difference between mean scores (P < 0.05) of test and control groups revealed fulfillment of construct validity of OSPE stations. Interrater reliability (ICC > 0.7) and concurrent validity (r value > 7) of all the stations was high. Perceptions revealed acceptability of module and OSPE stations by students (median 4, scale 1-5). CONCLUSIONS: A module to teach drug preparation skills was developed and along with valid and reliable OSPE stations that were acceptable to students. The study demonstrated that students acquire better skills through teaching than merely watching these skills in videos.

A rare case of myocardial infarction due to parathion poisoning.

Organophosphorus poisoning occurs very commonly in southern India where farmers form a significant proportion of the population who commonly use organophosphorus compounds like parathion as insecticides. Awareness of the complications caused by parathion poisoning is essential for proper monitoring and treatment. We report a case of suicidal parathion poisoning in a farmer who was treated with atropine and oximes. He subsequently developed myocardial infarction, to the treatment of which, he showed no response and succumbed. In conclusion, myocardial infarction is a rare complication of parathion poisoning. Awareness of this complication of parathion poisoning, proper monitoring and treatment could prevent fatalities.