Safety and Efficacy of Vinpocetine as a Neuroprotective Agent in Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Vinpocetine as a neuroprotective agent is effective in acute ischemic stroke in some randomized controlled trials (RCTs). Since the last systematic review has been published in 2008, which didn't find conclusive evidence favoring its use, two more RCTs have also been completed. METHODS: Relevant electronic databases were searched with a suitable combination of Medical Subject Headings terms to detect publications describing RCTs exploring the safety and efficacy of vinpocetine in patients with acute ischemic stroke. The risk of bias was determined by using the Cochrane Collaboration's tool for assessing the risk of bias in RCTs after full-text review and relevant data extraction. Higgins and Thompson's I2 method was used to assess heterogeneity in studies. The presence of publication bias was assessed by Egger's test. We used a random effect model when I2 was more than 50% and a fixed-effect model for other parameters. RESULTS: Four placebo-controlled RCTs enrolling a total of 601 and 236 patients in vinpocetine and placebo groups, respectively, were included. The number of patients with death or significant disability was lower in the vinpocetine group than that in the placebo group at both 1 and 3 months (relative risk 0.80, 95% confidence interval [CI] 0.65-0.99 and relative risk 0.67, CI 0.48-0.92, p = 0.04 and 0.02, respectively). The degree of disability in participants at 1 month and 3 months was also lower in vinpocetine group than that in the placebo group (standardized mean difference (SMD) 0.49, 95% CI 0.03-0.95 and SMD 1.22, CI 0.23-2.24, p = 0.001 and 0.04, respectively). Change in mini-mental state examination score compared with baseline at trial enrolment was also better in the vinpocetine group than in the placebo group (pooled weighted mean difference 0.92, 95% CI 0.02-1.82, p = 0.04). CONCLUSIONS: Vinpocetine has some promising efficacy in patients with ischemic stroke when used in the acute stage in reducing the disability, but presently there is not enough evidence to suggest that it also reduces case fatality. More double-blind, placebo-controlled RCTs of adequate sample size are needed before making recommendations for the routine administration of vinpocetine for all patients with acute ischemic stroke.

Efficacy and safety profile of selumetinib in symptomatic inoperable plexiform neurofibromas.

INTRODUCTION: Selumetinib is a MEK inhibitor, which is effective with an acceptable safety profile in reducing the volume of symptomatic inoperable plexiform neurofibromas in some clinical trials and also has been recently approved by FDA for use in children aged 2 years or older. However, no systematic review has yet been performed to provide a collective estimate of the results of all these trials. EVIDENCE ACQUISITION: Articles describing the use of selumetinib in patients with neurofibromatosis type-1 (NF1) with inoperable plexiform neurofibromas were searched from different electronic databases. The objectives were to provide a pooled estimate of efficacy evaluated by direct measurement and also by various functional measures, as well as the proportion of patients with adverse events. For determining pooled estimates, we included only studies with a minimum sample size of 15 with a prospective study design. EVIDENCE SYNTHESIS: A total of eight articles with 137 patients were found and 134 patients in six uncontrolled trials were included in the quantitative review. Out of these 26 were adults (69% male; 33.2±18.4 years, range 18-60 years) and 108 were in the pediatric age group (74% boys, 10.9±2.3 years, range-2-18 years,). Total 77.86% (95% CI: 55.91-99.81%) patients had a partial response, 71.24% (95% CI: 53.62-89.93%) had a confirmed partial response, and 56.25% (95% CI: 37.53-72.49%) had a durable partial response. The average time to initial response was 7.3±2.9 cycles (range, 4 to 20), and the median time to best response was 15.4±5.8 cycles (range, 4 to 36). The average change in neurofibroma volume at best response was -28.15% (95% CI: -17.95%, -38.34%, range, -55.1% to 2.2%). Progression-free survival was observed in 93.12% of patients at the time of data cut-off. Overall, 73.26% (95% CI: 54.07%, 92.45%) patients had improvement in at least one of the functional or patient-reported outcome assessments. The most common adverse effects were grade 1 and 2 gastrointestinal symptoms (65%), an asymptomatic increase in the creatine phosphokinase level (31%), paronychia (6%), and acneiform rash (17%). A total of 17% patients required dose reduction due to these toxic effects and 10.5% (95% CI: 4.0%, 17.0%) of patients discontinued due to toxic effects. CONCLUSIONS: Selumetinib can produce sustained shrinkage in the majority of patients with NF1 and symptomatic plexiform neurofibroma to provide clinically meaningful benefit in functional ability, with more robust evidence in children. The acceptable safety profile and absence of cumulative toxic effects permit long-term treatment with selumetinib.

Systematic Review and Meta-analysis of Efficacy and Safety of Melatonin and Triclofos for Inducing Adequate Sedation for Sleep Electroencephalogram in Children.

Introduction Triclofos and melatonin are commonly used oral sedatives in children for obtaining a sleep electroencephalogram (EEG) record. There has been no systematic review till now to compare the efficacy and safety of these two medications. Objectives The review intended to compare the efficacy of oral triclofos and melatonin in children <18 years of age for inducing adequate sedation for obtaining a sleep EEG record. We also attempted to compare the adverse effects, impact on EEG record, the yield of epileptiform abnormalities, and sleep onset latency in both groups. Methods A systematic search was conducted on "MEDLINE/PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, and Google Scholar" till November 30, 2020, with the following keywords/the Medical Subject Headings (MESH) terms while searching: "sleep EEG," "electroencephalogram," "triclofos," "melatonin" OR "ramelteon" AND "epilepsy," "seizure," OR "convulsion." ROB 2.0 and ROBINS-I tool was used to determine the risk of bias. To assess heterogeneity in studies, Higgins and Thompson's I 2 method was utilized. When I 2 was more than 50%, a random effects model was utilized and a fixed-effect model was used for other parameters. To assess the presence of publication bias, Egger's test was used. Results For describing the efficacy of triclofos in 1,284 and melatonin in 1,532 children, we selected 16 articles. The indirect comparison between the pooled estimate of all children receiving individual medications revealed comparable efficacy in obtaining successful sleep EEG record with a single dose (90 vs. 76%, p = 0.058) and repeat dose ( p = 0.054), detection of epileptiform abnormalities ( p = 0.06), and sleep onset latency ( p = 0.06), but more proportion of children receiving triclofos had adverse effects ( p = 0.001) and duration of sleep was also higher with triclofos ( p = 0.001). Conclusion Efficacy of triclofos and melatonin are comparable in inducing sleep for recording EEG in children, although triclofos is more likely to cause adverse effects. However, the level of evidence is low for this conclusion and the weak strength of recommendation for the results of this review is likely to change in the future after completion of controlled trials exploring these two medications.

Efficacy and Tolerability of Lacosamide in Lennox-Gastaut Syndrome: A Systematic Review and Meta-analysis.

Purpose Lennox-Gastaut syndrome (LGS) is one of the most difficult to treat childhood-onset epileptic encephalopathies. There is growing evidence that lacosamide is safe and efficacious in patients and adults with refractory epilepsy. However, the evidence regarding the efficacy of lacosamide in LGS is controversial so far. We aimed to evaluate the efficacy and tolerability of lacosamide in patients with LGS. Methods We conducted a systematic review on MEDLINE, EMBASE, COCHRANE CENTRAL, Google Scholar, and Web of Science, collating all available literature till July 31, 2020. The qualitative review included case reports, case series, and both controlled/uncontrolled trials as well as retrospective studies, but for determining pooled estimates, we only included studies with a sample size of 5 or more. The primary outcome was the efficacy of lacosamide in patients with LGS. Clinical variables related to efficacy and adverse events attributed to lacosamide were extracted from each publication. The pooled estimate of variables related to these parameters was performed using a random-effect model. Results Of the 68 items identified by the search, 14 were reviewed as full-text. Eleven articles including two prospective and six retrospective studies fulfilled eligibility criteria and described outcomes in 81 patients (42 adults, 39 children, 60% male, range-1.4-61 years). On average, 35.2%, 27.9%, 7.3%, and 29.4% patients had > 50% reduction, < 50% reduction, no change, and worsening of seizure frequency, respectively. Although 36% of patients had adverse events like somnolence, behavioral abnormalities including irritability, aggressiveness, nausea, tremor, memory problems, dizziness, gastrointestinal discomfort, vomiting, and weight loss, no serious adverse events were noted. Conclusion The evidence available in the current literature is not sufficient to support or refute the use of lacosamide in patients with LGS. Although it is one of the possible therapeutic options worth exploring in patients with LGS, caution is still necessary, as there are reports of worsening of seizure frequency in some patients.

COVID-19 treatment in children: A systematic review and meta-analysis.

BACKGROUND: Exact information about the efficacy of various medications proposed by regulatory bodies in children with COVID-19 is limited due to the lack of controlled trials in the existing literature. METHODS: Different electronic databases (MEDLINE, EMBASE, Web of Science, COCHRANE CENTRAL, LitCovid, medRxiv, and bioRxiv) were searched for articles describing the management of COVID-19 cases in children with 18 shortlisted medications. Prospective/retrospective studies/case series (with at least 20 cases) reporting COVID-19 in patients aged ≤14 years were searched to collect information regarding clinical details and severity of participants, medications used, and outcome. The pooled estimate of these parameters across studies was performed using a random-effect or fixed-effect meta-analysis depending on the degree of heterogeneity. RESULTS: From a total of 5794 records, 97 studies/case series (8243 patients) fulfilled the eligibility criteria and were included in this systematic review. A total of 21% children received at least one medication specifically used for COVID-19. While antivirals were used in 15.3% of children, remedesivir was the most commonly used antiviral drug in 6.2% of included children without many reports of serious adverse effects. There was a more prevalent use of anti-inflammatory medications including corticosteroids (27.8%, P = 0.01). Total 91% of severe cases described in literature in children received some anti-inflammatory medications. Among them, corticosteroids (17%) and Intravenous immune globulin (IVIG) (17.5%) were the most predominant followed by interferon (4.2%), tocilizumab (1.5%), and anakinra (0.8%). The most predominant therapy among multisystem inflammatory syndrome in children (MIS-C) cases were IVIG (81%), followed by aspirin (67%), corticosteroids (64%), inotropes (62%), and anticoagulation (56%, mostly low molecular weight heparin, LMWH). Overall mortality was only 1.3%, but when we analyzed separately including only cases with moderate and severe disease, the mortality rate was 4.6%. CONCLUSION: Among pharmacological modalities, anti-inflammatory agents like corticosteroids and antivirals like remdesivir have the most promising evidence for severe cases of pediatric COVID-19. Intravenous immunoglobulin and other anti-inflammatory/immunomodulatory agents like anakinra, aspirin, and anticoagulants have important therapeutic role in cases with MIS-C. Most of the mild cases recover with conservative treatment only.

Clinico-laboratory characteristics and outcome of patients with eucalyptus oil-induced/provoked seizures: A case series and systematic review of the published patients.

Seizures triggered by skin application, inhalation or ingestion of over-the-counter medications containing eucalyptus oil are known. We report five children who suffered likewise. We made a systematic search for all reported cases and performed a pooled analysis to provide a comprehensive estimate of the type of seizures, their management and outcome. In 110 cases (49 children), inhalational use was the most predominant, generalised tonic-clonic (the commonest semiology) and levetiracetam was the most common anti-convulsant treatment used. Most cases had an uneventful recovery. Adults were less likely to have prolonged and multiple seizures, requiring intensive care or mechanical ventilation.

Efficacy and safety of rufinamide as adjunctive therapy in patients with Lennox Gastaut syndrome: A systematic review and Meta-analysis.

INTRODUCTION: Rufinamide is an antiseizure medication that acts through sodium channels and is found to be efficacious in patients with Lennox Gastaut syndrome (LGS). However, no systematic review has been conducted in LGS patients to provide an estimate of the efficacy and safety of rufinamide. METHODS: Different electronic databases were searched for articles describing the use of rufinamide in patients with LGS. For determining primary efficacy outcomes as compared to placebo, we included only studies comparing the efficacy of rufinamide with placebo in LGS patients. We performed an additional analysis to include other uncontrolled studies with a minimum sample size of 20 to provide a more comprehensive estimate of efficacy. RESULTS: A total of ten studies included 557 patients. Out of them, five studies were placebo-controlled, enrolling a total of 265 patients in the rufinamide group and 203 patients in the placebo group. The average percentage reduction in total seizure frequency per 28 days during the double-blind phase was 29.3% in the rufinamide group compared with 8.3% in the placebo group (difference between the two groups was 20.9%, 95%CI-14.4%-27.3%, p <0.00001). Even for individual seizure types like tonic-clonic seizures, atypical absence seizures, atonic seizures, focal seizures, and myoclonic seizures, rufinamide was more efficacious than placebo(p<0.00001). The number of patients with at least one treatment-emergent adverse effects was significantly higher in rufinamide treated patients (60.2%vs50.7%, p=0.02, RR-1.24(1.03,1.51). CONCLUSION: Rufinamide is efficacious as adjunctive therapy in patients with LGS in terms of reduction in total seizure frequency and has mild adverse reaction.

Efficacy, tolerability, and safety of zonisamide in children with epileptic spasms: A systematic review and meta-analysis.

BACKGROUND: Valproate, levetiracetam, benzodiazepines, and topiramate are antiseizure medications (ASMs) considered to have definite efficacy in reducing the frequency of epileptic spasm frequency, apart from ketogenic dietary therapies. Although zonisamide has also been shown to have efficacy as second-line ASM for epileptic spasms, various studies have conflicting results in literature. This systematic review aims to summarize clinical studies regarding the efficacy of zonisamide for epileptic spasms. METHODS: We conducted a systematic literature search collating all available literature. The primary objective was to determine efficacy in terms of proportion with complete spasm resolution, we also intended to determine proportion with at least 50% spasm reduction, hypsarrhythmia resolution, and nature/frequency of adverse effects. All prospective/retrospective, controlled/uncontrolled studies describing the use of zonisamide with epileptic spasms were included in the qualitative review excluding case reports, but for metanalysis pertaining to key outcomes, we included studies with at least 10 participants. RESULTS: A total of nineteen publications were found eligible for inclusion in the qualitative review, out of 101 search items. A total of 401 children with epileptic spasms were tried up to a maximum of 9.9-35 mg/kg/day dose with only mild adverse effects in a few patients. Total 20.8% (95% CI-11.4%-29.2%) and 23.4% (95% CI-17.8%-29.1%) patients had complete cessation of spasms and at least a 50% reduction in total spasm frequency as compared to baseline after starting zonisamide. Similarly, 20.3% (95% CI-10.1%-30.5%) had resolution of hypsarrhythmia in EEG after starting zonisamide. CONCLUSION: Zonisamide can reduce spasms in 21% of children with epileptic spasms, without major adverse effects. But there are only limited studies on epileptic spasms of sufficient quality to give high confidence in meta-analysis. Large controlled trials are needed in this regard to provide high-quality evidence favoring/disfavoring its use in patients with epileptic spasms.

Efficacy and Safety of Thalidomide in Patients with Complicated Central Nervous System Tuberculosis: A Systematic Review and Meta-Analysis.

Thalidomide, an anti-inflammatory and immunomodulatory agent, has a potential role in cases with central nervous system tuberculosis (CNS-TB) with paradoxical reactions. Although several articles have described the use of thalidomide in CNS-TB, no systematic review has been performed in this regard. Different electronic databases were searched for articles describing the use of thalidomide in patients with CNS-TB. For determining pooled estimates in the quantitative review, studies with a minimum sample size of 5 were only considered, whereas for qualitative synthesis even single case reports were included. Fixed or random effect models were used suitably depending on the degree of heterogeneity. Fourteen articles describing a total of 107 patients (98 children and 9 adults) were selected from 156 records. A favorable clinical response was observed in 89% of patients with CNS-TB who had paradoxical reactions refractory to corticosteroids. Majority of the studies used a dose of 2-6 mg/kg/day and around 24% suffered from at least one adverse effect, with a mortality of 5%. Predominant adverse effects were rash (9.5%), neuropathy (6%), and elevated liver transaminases (9.5%). Only one placebo-controlled trial has been performed till now, which showed that high-dose thalidomide has numerous adverse effects, without any clinically significant improvement as compared with placebo. While in HIV-positive patients with TB-immune reconstitution inflammatory syndrome thalidomide was helpful in around 82% of cases. Low-dose thalidomide is helpful in patients with CNS-TB who had a paradoxical reaction and unresponsive to corticosteroids. Large, randomized trials are needed to provide more concrete information regarding the safety and efficacy of thalidomide.

Efficacy of lacosamide and phenytoin in status epilepticus: A systematic review.

OBJECTIVES: To compare the evidence on efficacy, safety, tolerability, and impact on short term/long functional outcome of lacosamide (LCM) and phenytoin (PHT) in patients with status epilepticus. MATERIALS & METHODS: We conducted a systematic literature search of relevant electronic databases using a suitable search strategy to identify studies directly comparing PHT and LCM, irrespective of dose and duration in patients with convulsive and/or nonconvulsive status epilepticus (SE). We used a standardized assessment form to extract information on the study design, data sources, methodologic framework, efficacy, and adverse events attributed to PHT and LCM from included studies and compared the efficacy and safety outcomes, using a fixed/random effect model. RESULTS: Five studies were found to be eligible for inclusion out of 192 search items, enrolling a total of 115 and 166 participants (predominantly with SE) in LCM and PHT arm, respectively. Baseline characteristics were comparable between both arms. The proportion with seizure control was comparable between both arms (57.3% in LCM vs. 45.7% in PHT arm, p = 0.28) and even in the subgroup analysis separately for convulsive and non-convulsive SE. Proportion with treatment-emergent adverse events (TEAE) were comparable in both (17.6% vs. 12.2%, p = 0.20), but serious adverse events (SAE) were higher in PHT arm (5.1% vs. 0.8%, p = 0.049). The proportion with all-cause mortality and survival with moderate-severe disability were comparable between both arms (p = 0.23 and 0.37, respectively). CONCLUSION: LCM has comparable efficacy with fewer SAEs as compared to PHT for achieving seizure control in patients with SE.

Efficacy and safety of corpus callosotomy and ketogenic diet in children with Lennox Gastaut syndrome: a systematic review and meta-analysis.

BACKGROUND: Both corpus callosotomy (CC) and the ketogenic diet (KD) are commonly used in patients with Lennox Gastaut syndrome (LGS), as a significant proportion of these patients develop pharmacoresistant epilepsy. But no systematic review has yet compared the efficacy and safety of these two measures. METHODS: We conducted a systematic search on various databases to collating all available literature until 30th November 2020 with a primary objective to compare the efficacy of KD and CC in terms of the proportion of patients with complete seizure freedom, at least 75% and 50% reduction in seizure frequency at various time points after the institution of these modalities. We also attempted to compare the proportion and nature of adverse effects, impact on EEG, cognition, and behavior with these modalities. We only included original articles enrolling at least 10 patients with CC or KD for quantitative synthesis to determine a pooled estimate. We used a fixed or random effects model, depending on the degree of heterogeneity. RESULTS: We selected 23 and 7 articles describing the efficacy of CC and KD in 436 and 185 LGS patients out of 217 search items, but none of the studies compared directly these two entities. The indirect comparison between the pooled estimate of all patients with individual modalities revealed more patients with CC had seizure freedom, at least 75% and 50% reduction in seizure frequency (p=0.0001, 0.01, and 0.04 respectively). The proportion of patients with adverse effects was also higher for CC patients (p=0.01), although the proportion with serious adverse effects was not significantly different between the two modalities. Patients selected for CC were older, had higher seizure burden, more lag time after the onset of seizures, and received more number of antiseizure medications previously. Due to the availability of limited data, a firm conclusion could not be determined regarding the effect on EEG, cognition, and behavior with CC and KD. CONCLUSION: CC is more efficacious than KD in reducing seizure frequency in patients with LGS, although it has relatively more adverse effects during the immediate perioperative period.

Efficacy and tolerability of fenfluramine in patients with Dravet syndrome: A systematic review and meta-analysis.

BACKGROUND: Dravet syndrome (DS) is an infantile-onset developmental and epileptic encephalopathy syndrome with limited treatment options. We aimed to evaluate the efficacy and tolerability of fenfluramine in patients with Dravet syndrome using meta-analytical techniques. METHODS: We searched for relevant randomized controlled trials and non-randomized studies involving children with Dravet syndrome on fenfluramine therapy in MEDLINE, CENTRAL, EMBASE, Google Scholar and Web of Science database (31 July 2020). The primary outcome for the efficacy of fenfluramine was reduction in monthly convulsive seizure frequency. We carried out a random effect meta-analysis focusing on efficacy and safety variables. Only Randomized Controlled Trials (RCT) were included in the meta-analysis. The risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Of 61 publications initially screened, 12 were reviewed as full-text. Seven articles including 2 RCTs, 4 uncontrolled studies (3 prospective and one retrospective study), and one case report described responses to fenfluramine in 144 DS patients (54 % male, mean age of 8.8 years, median dose of 0.4 mg/kg/day). Fenfluramine was found to be more efficacious than placebo, in terms of mean convulsive and total seizure frequency reduction (mean difference: -45.3 % (95 % CI: -48.1 %, -42.4 %, p < 0.00001) and -39.7 % (-46.7 %, -32.7 %, p < 0.00001)). A greater proportion of patients in the fenfluramine arm achieved >25 %, >50 %, >75 % and 100 % seizure reductions (odds ratios: 6.5 (3.7, 11.5, p < 0.00001), 10.6 (5.3, 21.3, p < 0.00001), 22.7(6.9, 75.3, p < 0.00001) and 9.3(1.7, 51.4, p = 0.01) respectively). The incidence of serious adverse events was not greater in the fenfluramine groups (OR: 1.02 (0.5, 2.19, p = 0.96)). CONCLUSION: Fenfluramine appears to be a safe and efficacious antiseizure medication in patients with Dravet syndrome.

Neurological Complications of SARS-CoV-2 Infection in Children: A Systematic Review and Meta-Analysis.

BACKGROUND: Knowledge about neurological complications of COVID-19 in children is limited due to the paucity of data in the existing literature. Some systematic reviews are available describing overall clinical features of COVID-19 in children and neurological complications of COVID-19 in adults. But to the best of our knowledge, no systematic review has been performed to determine neurological manifestations of COVID-19. METHODS: Six different electronic databases (MEDLINE, EMBASE, Web of Science, CENTRAL, medRxiv and bioRxiv) were searched for articles related to COVID-19 and neurological complications in children. Studies/case series reporting neurological manifestations of COVID-19 in patients aged ≤18 years, as well as case reports, as neurological complications appear to be rare. The pooled estimate of various non-specific and specific neurological manifestations was performed using a random effect meta-analysis. RESULTS: Twenty-one studies/case series and five case reports (3707 patients) fulfilled the eligibility criteria and were included in this systematic review, from a total of 460 records. Headache, myalgia and fatigue were predominant non-specific neurological manifestations, presenting altogether in 16.7% cases. Total of 42 children (1%) were found to have been reported with definite neurological complications, more in those suffering from a severe illness (encephalopathy-25, seizure-12, meningeal signs-17). Rare neurological complications were intracranial hemorrhage, cranial nerve palsy, Guillain-Barré syndrome and vision problems. All children with acute symptomatic seizures survived suggesting a favorable short-term prognosis. CONCLUSION: Neurological complications are rare in children suffering from COVID-19. Still, these children are at risk of developing seizures and encephalopathy, more in those suffering from severe illness.

Feasibility and effectiveness of teleconsultation in children with epilepsy amidst the ongoing COVID-19 pandemic in a resource-limited country.

INTRODUCTION: The ongoing COVID-19 pandemic and the lockdown measures employed by the government have forced neurologists across the world to look upon telemedicine as the only feasible and practical option to continue providing health care towards children with epilepsy in home isolation. Children with epilepsy are challenging for teleconsultation as direct information from the patient is missing, regarding seizures and adverse effects, especially behavioral and psychological side effects. METHODS: Clinical and epilepsy-related details of telephonic consultations for children 1 month-18 years, performed between 26th March and 17th May 2020 in a tertiary care teaching hospital in Uttarakhand (a state of India known for hilly terrains with low per capita income) were recorded. Suitable changes in the dose/commercial brand of antiepileptic drug (AED) regimen were performed, along with the addition of new AED and referral to local practitioners for immediate hospitalization, when urgent health care issues were detected. Voice call, text message, picture/video message, and all other possible measures were employed to accumulate maximum clinical information in real-time. RESULTS: A total of 153 children(95 males [62 %], 9.45 ±â€¯3.24 years, 140 lower/middle socioeconomic status) were enrolled after screening 237 children with various neurological disorders, whose caregivers contacted for teleconsultation. A total of 278 telephone consultations performed for these 153 children (1-5 telephone calls per patient). Hundred-thirteen children were identified to have a total of 152 significant clinical events (breakthrough seizure/uncontrolled epilepsy (108), AED related (13), and unrelated systemic adverse effects (24), worsening of associated co-morbidities (7). In rest of the patients, the query of the caregiver included unavailability of AED/prescribed commercial brand in the locality, query related to the dose of drugs, proxy for a scheduled routine visit (no active issues), and concern regarding COVID-19 related symptoms and effect of COVID-19 and lockdown in children with epilepsy. Ninety-three (60 %) patients required hiking up of AED dose, whereas 29 (17 %) patients required the addition of a new AED/commercial brand. Five children were advised immediate admission to a nearby hospital. Overall, 147 (96 %) caregivers were satisfied with the quality of medical advice. CONCLUSION: Teleconsultation is one of the few feasible options with good effectiveness for providing medical advice to children with epilepsy during pandemic times.

Pancytopenia without Hepatosplenomegaly: A Rare Manifestation of Extrapulmonary Tuberculosis in an Adolescent Boy.

Extrapulmonary tuberculosis (TB) is a well-recognized cause of pyrexia of unknown origin. However, clinical presentation of TB in children with isolated hematological abnormalities is extremely rare. Anemia, usually normocytic, normochromic, leukopenia, leukocytosis, thrombocytopenia, thrombocytosis, and monocytosis are more common complications of TB rather than pancytopenia. Only anecdotal case reports and small case series are available in this regard. We are reporting an 18-year-old boy who presented with on and off low-grade fever for 3 months and anorexia and progressive pallor for 1 month. After extensive workup, pancytopenia remained unexplained. Bone marrow (BM) examination revealed caseating granulomas, along with Mantoux positivity and contact with sputum-positive pulmonary TB. He responded favorably to antitubercular therapy (ATT) within 2 months. This report alerts clinicians to be vigilant regarding the rare possibility of BM TB while investigating unexplained pancytopenia, as it is completely reversible with ATT.

Immunocytochemistry using Liquid-based Cytology: A Tool in Hormone Receptor Analysis of Breast Cancer.

CONTEXT: Efficacy of immunocytochemistry (ICC) in determining molecular biomarkers like estrogen receptor (ER), progesterone receptors (PRs), and human epidermal growth factor receptor-2 (HER2). AIMS: To evaluate biomarkers using ICC in breast cancer as per American Society of Clinical Oncology/College of American Pathology (ASCO/CAP) guidelines. SETTINGS AND DESIGN: The study was conducted over a period of 2 years from September 2012 to August 2014 and is the first such study in eastern India. MATERIALS AND METHODS: Fine needle aspiration cytology (FNAC) was done for suspected cases of breast cancers and slides were prepared using ThinPrep (TP) technology of liquid-based cytology (LBC) for ICC and corresponding biopsy specimens were processed as formalin fixed paraffin embedded (FFPE) sections for comparison. Both the LBC slides and tissue sections were subjected to immunostaining for ER, PR, and HER2. ICC was evaluated by Allred Scoring and IHC by Quick Scoring. STATISTICAL ANALYSIS USED: Statistical analysis done by Wilconxon Signed rank test on the SPSS program, Chicago, Illinois, USA. The results of ICC and IHC were compared by evaluation of sensitivity, specificity, kappa-value (k-value), positive predictive value (PPV), and negative predictive value (NPV). RESULTS: The comparison of ICC with immunohistochemistry (IHC), ER, and PR showed very good correspondence rate, sensitivity, specificity, NPV, PPV, and agreement with k-value; whereas for HER2 the results were only good. CONCLUSION: ICC using LBC can be a useful tool in assessing biomarkers in advanced cases of breast cancer where surgery is not possible or cases where ASCO/CAP guidelines for management are not followed.

Studies of protein-protein interactions in Fanconi anemia pathway to unravel the DNA interstrand crosslink repair mechanism.

Fanconi anemia (FA), a cancer predisposition syndrome exhibits hallmark feature of radial chromosome formation, and hypersensitivity to DNA crosslinking agents. A set of FA pathway proteins mainly FANCI, FANCD2 and BRCA2 are expressed to repair the covalent crosslink between the dsDNA. However, FA, BRCA pathways play an important role in DNA ICL repair as well as in homologous recombination repair, but the presumptive role of FA-BRCA proteins has not clearly explored particularly in context to function associated protein-protein interactions (PPIs). Here, in-vivo, in-vitro and in-silico studies have been performed for functionally relevant domains of FANCI, FANCD2 and BRCA2. To our conclusion, FANCI ARM repeat interacts with FANCD2 CUE domain and BRCA2 C-terminal region. Interestingly, FANCD2 CUE domain also interacts strongly with BRCA2 C-terminal region. Interactions between BRCA2 CTR and functionally relevant mutations Ser222Ala (cell cycle checkpoint mutant) and Leu231Arg (DNA ICL repair mutant) present in FANCD2 CUE domain have been analysed. To our finding, these mutations abrogate the binding between FANCD2 CUE domain and BRCA2 CTR. Furthermore, (1) different domain of FANCI, FANCD2 and BRCA2 are playing important role in PPIs, (2) mutations cause the impairment in the PPIs which in turn may disrupt the DNA ICL repair mechanism.

Doxorubicin inhibits E. coli division by interacting at a novel site in FtsZ.

The increase in antibiotic resistance has become a major health concern in recent times. It is therefore essential to identify novel antibacterial targets as well as discover and develop new antibacterial agents. FtsZ, a highly conserved bacterial protein, is responsible for the initiation of cell division in bacteria. The functions of FtsZ inside cells are tightly regulated and any perturbation in its functions leads to inhibition of bacterial division. Recent reports indicate that small molecules targeting the functions of FtsZ may be used as leads to develop new antibacterial agents. To identify small molecules targeting FtsZ and inhibiting bacterial division, we screened a U.S. FDA (Food and Drug Administration)-approved drug library of 800 molecules using an independent computational, biochemical and microbial approach. From this screen, we identified doxorubicin, an anthracycline molecule that inhibits Escherichia coli division and forms filamentous cells. A fluorescence-binding assay shows that doxorubicin interacts strongly with FtsZ. A detailed biochemical analysis demonstrated that doxorubicin inhibits FtsZ assembly and its GTPase activity through binding to a site other than the GTP-binding site. Furthermore, using molecular docking, we identified a probable doxorubicin-binding site in FtsZ. A number of single amino acid mutations at the identified binding site in FtsZ resulted in a severalfold decrease in the affinity of FtsZ for doxorubicin, indicating the importance of this site for doxorubicin interaction. The present study suggests the presence of a novel binding site in FtsZ that interacts with the small molecules and can be targeted for the screening and development of new antibacterial agents.

Optimization of the sublethal dose of silver nanoparticle through evaluating its effect on intestinal physiology of Nile tilapia (Oreochromis niloticus L.).

Silver nanoparticles (SNPs) are widely used in a variety of biomedical and consumer products as an antimicrobial additive. The present study was conducted to evaluate the impacts of low-dose SNPs on intestinal physiology of tilapia (Oreochromis niloticus L.) for assessing its apparent environmental risk due to extensive commercial use. SNPs were synthesized by a chemical reduction method yielding 1-27 nm oval shaped particles. Early fingerlings of tilapia were exposed with two sublethal concentrations (0.8 and 0.4 mg L(-1)) of SNPs for twenty one days period and its impact on the intestinal physiology was evaluated by histochemistry, catalase expression, glutamate dehydrogenase activity, SDS-PAGE and gut micro flora count. Histological analysis showed thinning of intestinal wall, swelling on mucosal layer and immunohistochemical assay exhibited an enhanced catalase expression in SNPs treated fishes. Gut microflora count elicited a dose-dependent depletion and a variable SDS-PAGE profile followed by significant (P < 0.05) elevations in glutamate dehydrogenase activity in SNPs-treated fishes. This study was designed to provide a better understanding of environmentally acceptable, dose-dependent SNPs delivery in fishes and to formulate guidelines in aquatic toxicology.

Evaluation of sub-cellular distribution of glutamate dehydrogenase (GDH) in Drosophila melanogaster larvae.

Glutamate dehydrogenase (GDH) enzyme was conventionally known as a mitochondrial marker. However, subsequently it was reported to be present in the nuclei as well. So far, the nuclear distribution of GDH has been reported in a number of organisms including yeast, rat, cow, chicken. However, the sub-cellular distribution of GDH, illustrated by in situ methods still remains elusive. Here, by assaying the GDH activity and by immuno-blotting using anti-GDH antibody in the fractionated nuclear and cytoplasmic fractions of Drosophila larvae, we demonstrate the cytoplasmic distribution of GDH. This observation was further supported by in situ immunostaining of salivary gland, Malpighian tubules and eye imaginal discs of Drosophila larvae. Collectively, our results demonstrate that in Drosophila larvae, GDH is not found in the nucleus, but is localized exclusively in the cytoplasm.