Structured and disordered regions of Ataxin-2 contribute differently to the specificity and efficiency of mRNP granule formation.

Ataxin-2 (ATXN2) is a gene implicated in spinocerebellar ataxia type II (SCA2), amyotrophic lateral sclerosis (ALS) and Parkinsonism. The encoded protein is a therapeutic target for ALS and related conditions. ATXN2 (or Atx2 in insects) can function in translational activation, translational repression, mRNA stability and in the assembly of mRNP-granules, a process mediated by intrinsically disordered regions (IDRs). Previous work has shown that the LSm (Like-Sm) domain of Atx2, which can help stimulate mRNA translation, antagonizes mRNP-granule assembly. Here we advance these findings through a series of experiments on Drosophila and human Ataxin-2 proteins. Results of Targets of RNA Binding Proteins Identified by Editing (TRIBE), co-localization and immunoprecipitation experiments indicate that a polyA-binding protein (PABP) interacting, PAM2 motif of Ataxin-2 may be a major determinant of the mRNA and protein content of Ataxin-2 mRNP granules. Experiments with transgenic Drosophila indicate that while the Atx2-LSm domain may protect against neurodegeneration, structured PAM2- and unstructured IDR- interactions both support Atx2-induced cytotoxicity. Taken together, the data lead to a proposal for how Ataxin-2 interactions are remodelled during translational control and how structured and non-structured interactions contribute differently to the specificity and efficiency of RNP granule condensation as well as to neurodegeneration.

Airway management of postburn neck contracture in pediatric patient - A challenge for anesthesiologist!

Pediatric difficult airway management is more challenging for an anesthesiologist due to anatomical and physiological differences as compared to adults. Moreover, the familiarity with the use of difficult airway equipment in adults does not equate to proficiency for the same in children. So, here we are presenting the management of a unique case of a difficult airway due to postburn neck contracture in a 4-year-old child, which was managed successfully with the help of a video laryngoscope after the failure attempt with a flexible fiberoptic bronchoscope.

Postoperative Seizure Control in Adult Diffuse Insular Gliomas Presenting with Seizures: A Retrospective Single-Center Experience and Proposal of a Novel Risk Scoring System.

Background: Studies on insular gliomas (IGs) generally focus on the oncological endpoints with a relative scarcity of literature focusing on the seizure outcomes. Objectives: To study the predictors of long-term postoperative seizure control in IG and propose a novel risk scoring system. Methods: Histopathologically proven, newly diagnosed adult IGs (>18 years) operated over a 10-year period were studied for postoperative seizure control as per International League Against Epilepsy (ILAE) grades at 6 weeks and at last follow-up (minimum of 6 months, median 27 months). Logistic regression analysis was performed and regression coefficients with nearest integers were used to build a risk prediction model. Receiver operator curve (ROC) analysis determined the predictive accuracy of this model. Results: The 6-week postoperative seizure freedom dropped to 41% at the last follow-up. The seizure-free group lived longer (100.69 months, 95% CI = 84.3-116.99 (60%)) than those with persistent postoperative seizures (27.92 months, 95% CI = 14.99-40.86). Statistically significant predictors (preoperative seizure control status, extent of resection, tumor extension to temporal lobe, and lack of postoperative adjuvant therapy) were used to compute a risk score, the score ranging from 0 to 9. A score of four most optimally distinguished the risk of postoperative seizures with an area under the ROC of 91.4% (95% CI: 84.1%, 98.7%, P < 0.001). Conclusion: In our experience, around 60% of patients obtained seizure freedom after surgery, which reduces over time. Control of seizures paralleled survival outcomes. Our proposed scoring system may help tailor management strategies for these patients.

Compliance Assessment of Tobacco Products to Cigarettes and Other Tobacco Products Act in India with Reference to Third Amendment Rules, 2020.

OBJECTIVE: Tobacco use is associated with mortality in low- and middle-income countries including India with dual burden of smoking and smokeless tobacco (SLT). Aligning with the FCTC, India has made substantial amendments in strengthening graphic warning under Cigarettes and Other Tobacco Products Act (COTPA) for sections 7,8 9 and "Specified warning". Compliance assessment studies are necessary to understand current status of implementation for packaging laws. This study aimed to assess the compliance of COTPA sections 7,8 9 and Cigarettes and other Tobacco Products (Packaging and Labelling) Third Amendment Rules, 2020 in Delhi. METHODS: Cross-sectional study was conducted in two districts of Delhi selected by simple random sampling. Fifteen points of sales were selected from each district through purposive sampling and 57 smoking and smokeless tobacco products were collected with Indian and foreign origin. An observation checklist for product analysis was prepared and pack analysis done based on COTPA sections 7,8 and 9 along with Third Amendment,2020 which included pictures and warnings to be circulated in 2021. RESULT: Total 57 samples has smoking (49.1%), smokeless (50.9%) with no SLT product of foreign origin. SLT and foreign products had low compliance of Section 7 and third amendment 2020 rules which includes manufacturing date and origin. Indian smoking products were highly compliant to section 8 and 9 whereas foreign and SLT products showed low compliance to section 8. COTPA Third Amendment Rules (2020) compliance was seen in Indian products with regards to SW (68.4%), PW (61.4%) and quit line (78.9%) with no compliance at all for foreign products. CONCLUSION: Foreign brands and SLT products had low compliance with sections 7 and 8 of COTPA and its amendments (2020). Compliance with illicit trade and SW needs regulation and strict implementation of law for SLT products.

Insular glioblastoma: surgical challenges, survival outcomes and prognostic factors.

BACKGROUND: Insular gliomas are unique, challenging and evoke a lot of interest amongst neurosurgeons. Publications on insular glioma generally focus on the surgical intricacies and extent of resection pertaining to the low-grade gliomas. Insular glioblastomas (iGBM) have not been analysed separately before. METHODS: Histologically proven WHO grade IV gliomas involving the insula over a 9-year period were studied. Their clinical presentation, radiological features, surgical findings and survival outcomes were assessed. Statistical methods were used to determine the favourable predictors of survival. RESULTS: Out of 27 patients (M:F = 2.9:1), 18 (66%) patients had a tumour extension beyond the insula, 10 (37%) of whom had basal ganglia involvement. Total, near total and subtotal excisions were performed in 7 (26%), 9 (33%) and 11 (40.7%) patients, respectively. Twenty-three patients had glioblastoma, while four had gliosarcoma. IDH mutation was negative in six of the seven patients where it was done. Median overall survival was 5 months. Multivariate analysis showed that a female gender (p = 0.013), seizures in the preoperative period (p = 0.048) and completion of adjuvant therapy (p = 0.003) were associated with a longer survival. CONCLUSION: Insular glioblastomas have a poor prognosis. Insular location and certain tumour characteristics often limit the extent of resection of iGBMs. Moreover, postoperative complications sometimes negate the advantages of a radical resection. A female gender, presentation with seizures and completion of adjuvant chemoradiotherapy appear to be good prognostic factors.

A Review on Polymeric Nanostructured Micelles for the Ocular Inflammation-Main Emphasis on Uveitis.

BACKGROUND: Various types of nano-formulations are being developed and tested for the delivery of the ocular drug. They also have anatomical and physiological limitations, such as tear turnover, nasal lachrymal waste, reflex squinting, and visual static and dynamic hindrances, which pose challenges and delay ocular drug permeation. As a result of these limitations, less than 5% of the dose can reach the ocular tissues. OBJECTIVE: The basic purpose of designing these formulations is that they provide prolonged retention for a longer period and can also increase the course time. METHODS: To address the aforementioned issues, many forms of polymeric micelles were developed. Direct dissolving, dialysis, oil-in-water emulsion, solvent evaporation, co-solvent evaporation, and freeze-drying are some of the methods used to make polymeric nano micelles. RESULTS: Their stability is also very good and also possesses reversible drug loading capacity. When the drug is given through the topical route, then it has very low ocular bioavailability. CONCLUSION: The definition and preparation process of polymeric micelles and anti-inflammatory drugs used in uveitis and the relation between uveitis and micelles are illustrated in detail.

Comparative Evaluation of the Intravenous Dexmedetomidine and Nalbuphine for Treatment of Post Spinal Shivering-A Randomized Prospective Trial.

BACKGROUND: Shivering is one of the most common complications of spinal anesthesia because of inhibition of the thermoregulatory control. Dexmedetomidine and nalbuphine are the two commonly used drugs for treatment of perioperative shivering, but owing to paucity of their comparative data, we planned this study to compare the efficacy of these two drugs for treatment of post spinal shivering. METHODS: This study was conducted on 80 American Society of Anesthesiologists physical status I or II patients aged from 18 to 60 years who developed post-spinal shivering of grade III or IV during elective surgeries. These patients were randomly allocated into two groups (40 each). In group D, dexmedetomidine 0.50 µg/kg, and in group N, nalbuphine 0.08 mg/kg was given intravenously for treatment of shivering. Data regarding response time, recurrence rate and success rate along with their adverse effects were noted, and statistical analysis was performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL, USA). RESULTS: The mean response time was significantly shorter in group D as compared to Group N (1.9 ± 0.6 min and 4.7 ± 1.1 min, respectively; P ＜ 0.001), but the success rate in both groups was 100%. Recurrence of shivering was greater in group N as compared to group D, but this difference was statistically insignificant. Although hypotension and bradycardia were observed more in group D and nausea was observed more in group N, the difference among both the groups was statistically insignificant. CONCLUSIONS: Dexmedetomidine is a better alternative than nalbuphine for treatment of post spinal shivering with quicker response time and comparable side effects.

Comparative evaluation of propofol versus dexmedetomidine infusion for hypotensive anesthesia during functional endoscopic sinus surgery: a prospective randomized trial.

BACKGROUND: During functional endoscopic sinus surgery (FESS), intranasal bleeding affects operative field visibility and increases the frequency of complications. Therefore, hypotensive anesthesia is a widely used technique to improve surgical outcomes. This study aimed to compare the efficacy of propofol and dexmedetomidine infusion for hypotensive anesthesia in patients undergoing FESS. METHODS: This prospective randomized trial was conducted in 80 adult patients who were scheduled for FESS under general anesthesia. Patients were randomly divided into two groups: group P (n = 40) received propofol infusion of 100-200 µg/kg/min and group D (n = 40) received dexmedetomidine infusion with a loading dose of 1 µg/kg over 10 min after induction, followed by maintenance infusion of 0.4-0.8 µg/kg/h. Intraoperative blood loss, quality of the surgical field (Fromme- Boezaart scale), hemodynamic control, and patient recovery were recorded. Statistical analysis was performed using Student's t-test, chi-square test, and Mann-Whitney U test. RESULTS: The mean arterial pressure and heart rate were significantly lower in group D throughout the surgery than in group P. Blood loss was significantly higher in group P (100.73 ± 18.12 ml) than in group D (85.70 ± 18.56 ml). The average number of patients with Fromme's score 1/2/3 was comparable between the groups. Intraoperatively, only one incidence of bradycardia and hypotension was observed in group D (2.5%) compared to group P. CONCLUSIONS: Both dexmedetomidine and propofol are efficacious and safe drugs for facilitating controlled hypotension during FESS; however, dexmedetomidine provides better hemodynamic control and is associated with lesser blood loss without any significant adverse effects.

Balancing the Extent of Resection and Ischemic Complications in Insular Glioma Surgery: Technical Nuances and Proposal of a Novel Composite Postoperative Outcome Index.

Background: Maximal safe resection remains the most desired goal of insular glioma surgery. Intraoperative surgical adjuncts provide better tumor visualization and real-time "safety" data but remain limited due to a high cost and limited availability. Objective: To highlight the importance of anatomical landmarks in insular glioma resection and avoidance of vascular complications. We also propose to objectify the onco-functional balance in insular glioma surgery. Methods: Forty-six insular gliomas operated upon by a single surgeon between January 2015 and February 2020 were reviewed, focusing on the operative technique and clinical outcomes. A novel composite postoperative outcome index (CPOI) was designed, comprising the extent of resection and permanent postoperative deficits, and utilized to assess the surgical outcomes. Results: Gross-total, near-total, and subtotal resections were achieved in 10.9%, 52.1% (n = 24), and 36.9% (n = 17) patients, respectively. The median overall survival (OS) was 20 months (95% CI = 9.56-30.43). CPOI was optimal in 38 patients (82.6%). A well-defined tumor margin (P = 0.01) and surgeon's experience (P = 0.04) were significantly associated with an optimal CPOI. Out of seven (15.2%) patients who developed permanent neurological deficits, three (6.5%) patients had severe disability. Favorable prognostic factors of survival included younger age (<40 years) (P = 0.002), tumors with only frontal lobe extension (P = 0.011), tumors with caudate head involvement (P = 0.04), and non-glioblastoma histology (P = 0.006). Conclusion: Tumor margin and increasing surgeon experience are critical to an optimal postoperative outcome. Respecting the basi-sulcal plane is key to lenticulostriate artery preservation. Caudate head involvement is a new favorable prognostic factor in insular gliomas.

Evaluation of Dexmedetomidine as an Adjuvant to Ropivacaine in Transversus Abdominis Plane Block for Postoperative Analgesia in Unilateral Infraumbilical Surgeries-A Randomized Prospective Trial.

BACKGROUND: Transversus abdominis plane (TAP) block has been demonstrated to be an effective module of multimodal analgesic treatments for infra-umbilical surgeries with limited duration of action. Various adjuvants have been studied to increase the efficacy of this technique. Herein, we evaluated the analgesic efficacy of dexmedetomidine with ropivacaine in TAP block for unilateral infra-umbilical surgeries under spinal anesthesia. METHODS: The study was conducted on 60 adult patients with the age of 18-65 years, who were planned for unilateral infra-umbilical surgeries under spinal anesthesia. These patients are randomly divided into 2 groups (30 each). In group A, 20 mL of 0.25% ropivacaine with 1 mL of normal saline, and in group B, 20 mL of 0.25% ropivacaine with 0.5 µg/kg (1 mL) dexmedetomidine was given in ultrasound-guided TAP block. Duration, quality of analgesia, and total analgesic consumption were noted. Statistical analysis was performed with SPSS software version 21.0 (IBM Corp., Armonk, NY, USA) by using Student's t-test and chi-square test. RESULTS: The mean duration of analgesia was significantly longer in group B than group A (842.50 ± 38.74 min and 435.17 ± 25.75 min, respectively). Verbal numerical rating scale was persistently low in both groups, except at the 7th hour and 20th hour in group A and the 12th hour in group B. Total analgesic consumption and number of analgesics doses during 24 hours after surgery were also lower in group B. CONCLUSIONS: The addition of dexmedetomidine as adjuvant to 0.25% ropivacaine for TAP block significantly increases the duration and quality of analgesia without any significant adverse effects.

The transcriptional response to oxidative stress is independent of stress-granule formation.

Cells respond to stress with translational arrest, robust transcriptional changes, and transcription-independent formation of mRNP assemblies termed stress granules (SGs). Despite considerable interest in the role of SGs in oxidative, unfolded protein and viral stress responses, whether and how SGs contribute to stress-induced transcription have not been rigorously examined. To address this, we characterized transcriptional changes in Drosophila S2 cells induced by acute oxidative-stress and assessed how these were altered under conditions that disrupted SG assembly. Oxidative stress for 3 h predominantly resulted in induction or up-regulation of stress-responsive mRNAs whose levels peaked during recovery after stress cessation. The stress transcriptome is enriched in mRNAs coding for chaperones including HSP70s, small heat shock proteins, glutathione transferases, and several noncoding RNAs. Oxidative stress also induced cytoplasmic SGs that disassembled 3 h after stress cessation. As expected, RNAi-mediated knockdown of the conserved G3BP1/Rasputin protein inhibited SG assembly. However, this disruption had no significant effect on the stress-induced transcriptional response or stress-induced translational arrest. Thus SG assembly and stress-induced gene expression alterations appear to be driven by distinctive signaling processes. We suggest that while SG assembly represents a fast, transient mechanism, the transcriptional response enables a slower, longer-lasting mechanism for adaptation to and recovery from cell stress.

Endoscopic Keyhole Approach for Intracranial Epidermoid.

Objective In contemporary neurosurgical practice, keyhole endoscopic approach has established its role in various neurosurgical pathologies. Intracranial epidermoid is an ideal pathology for endoscopic keyhole approach as epidermoid is well encapsulated, extra-axial, avascular, and easily suckable. The objective of this study is to share our experience of endoscopic keyhole approach for intracranial epidermoids at various locations as a new minimally invasive neurosurgical approach to deal with these lesions. Materials and Methods We conducted a retrospective study on 26 patients who underwent keyhole pure endoscopic excision of intracranial epidermoid between July 2015 and December 2019. Patient's demographics, clinical features, radiological imaging, and postoperative complications were noted. Follow-up outcome of preoperative symptoms and postoperative complications were also analyzed. Results The mean age of the study population was 30.5 years with a mean follow-up of 30 months. The common presenting features were headache, hearing loss, and trigeminal neuralgic pain. Gross total resection was achieved in 73.1% cases, while near total resection and subtotal resection were achieved in 19.2 and 7.7% cases, respectively. In the follow-up, maximal improvement was seen in trigeminal neuralgic pain (83%) and headache (66.7%). Major postoperative complications were facial nerve paresis, lower cranial nerve paresis, and transient facial hypoesthesia, most of which improved over time. None of the patients required resurgery till date. Statistical Analysis Patients' data were analyzed using SPSS software version 23 (Statistical Package for Social Sciences, IBM, Chicago, United States). Conclusion This study demonstrates that with careful patient selection, endoscopic keyhole excision of epidermoid is a good alternative to conventional microsurgical excision with comparable surgical and functional outcomes.

The Dilemma of Multifocality in Insular Tumors: Multicentricity versus Metastasis.

BACKGROUND AND PURPOSE: Multifocality and metastasis from insular glioma are extremely rare. Pathological insights and elaboration of the clinical course of this condition will contribute to their better understanding. MATERIALS AND METHODS: Among 123 consecutively operated insular gliomas, 5 patients (4.2%) presented with a multifocal tumor. The clinico-radiological, histo-molecular, and treatment outcomes were noted and compared with the unifocal insular glioma cohort. RESULTS: Among the five patients, all were males and involved the right insular lobe. Three patients presented with synchronous tumors, while two patients developed metachronous multifocal tumors. The histology of the insular tumor was Grade I glioma in 1, Grade II astrocytoma with p53 mutation in 2, and anaplastic astrocytoma and glioblastoma in one patient each. Histological confirmation of the second lesion was performed in two patients, showing the same histology of the insular tumor. Interconnection between the tumors was apparent through cerebrospinal fluid pathways in four patients, while no such connection could be established in one patient. Barring the patient of Grade I glioma, the rest of the patients died within months of the diagnosis. CONCLUSION: Multifocal insular glioma is rare and probably represents a biologically more aggressive tumor. Insular glioma that touches the ventricle appears a common denominator for multifocality. True multicentricity is rare. The prognosis in insular glioma with multifocality is poor in non-Grade I gliomas.

Antagonistic roles for Ataxin-2 structured and disordered domains in RNP condensation.

Ataxin-2 (Atx2) is a translational control molecule mutated in spinocerebellar ataxia type II and amyotrophic lateral sclerosis. While intrinsically disordered domains (IDRs) of Atx2 facilitate mRNP condensation into granules, how IDRs work with structured domains to enable positive and negative regulation of target mRNAs remains unclear. Using the Targets of RNA-Binding Proteins Identified by Editing technology, we identified an extensive data set of Atx2-target mRNAs in the Drosophila brain and S2 cells. Atx2 interactions with AU-rich elements in 3'UTRs appear to modulate stability/turnover of a large fraction of these target mRNAs. Further genomic and cell biological analyses of Atx2 domain deletions demonstrate that Atx2 (1) interacts closely with target mRNAs within mRNP granules, (2) contains distinct protein domains that drive or oppose RNP-granule assembly, and (3) has additional essential roles outside of mRNP granules. These findings increase the understanding of neuronal translational control mechanisms and inform strategies for Atx2-based interventions under development for neurodegenerative disease.

Surgery in High-Grade Insular Tumors: Oncological and Seizure Outcomes from 41 Consecutive Patients.

BACKGROUND: Insular high-grade gliomas are uncommon and constitute approximately 10% of all intracranial high-grade gliomas. Several publications in the recent years have thrown substantial light in the understanding of insular low-grade gliomas. However, there is a paucity of information concerning the spectrum of high-grade lesions affecting the insula, the mode of presentation vis-à-vis low-grade gliomas, and the survival rates to modern therapy. AIMS AND OBJECTIVES: We aim to highlight various clinical patterns, histo-pathological spectrum and the survival rates in patients with high-grade insular lesions. Also, we explore the factors that govern favourable outcomes. MATERIALS AND METHODS: A retrospective study of 41 patients operated for high-grade insular tumors at our institute between March 2010 to December 2018 was done to evaluate the clinico-radiological features, surgical nuances, survival rates and seizure outcomes. RESULTS: Raised intracranial pressure was the most frequent clinical presentation (n=28/41, 68.3%). Nearly 60% of the patients (n=25) had involvement of all four Berger-Sanai zones. The high-grade tumors encountered in our series were: glioblastoma (n=15), gliosarcoma (n=3), and embryonal tumor, not otherwise specified in 3 patients, while 21 patients had grade 3 astrocytoma. 33 out of 41 patients (80.5%) in our study showed excellent seizure control (ILAE grade 1A) at follow-up. Clinical presentation with seizures (P = 0.01, HR=0.3), WHO grade IV histopathology (P = 0.04, HR=3.7) and development of recurrence (P = 0.05, HR=5.5) were found to be independent predictors of OS. CONCLUSION: Insular high-grade gliomas are commoner than thought and nearly half of these are grade IV tumors (51%). A presentation with seizures may indicate precursor low-grade gliomas and portend a better survival. A maximum "safe" surgical resection, keeping the postoperative quality of life in mind, should be the goal.

Direct involvement of Hsp70 ATP hydrolysis in Ubr1-dependent quality control.

Chaperones can mediate both protein folding and degradation. This process is referred to as protein triage, which demands study to reveal mechanisms of quality control for both basic scientific and translational purposes. In yeast, many misfolded proteins undergo chaperone-dependent ubiquitination by the action of the E3 ligases Ubr1 and San1, allowing detailed study of protein triage. In cells, both HSP70 and HSP90 mediated substrate ubiquitination, and the canonical ATP cycle was required for HSP70's role: we have found that ATP hydrolysis by HSP70, the nucleotide exchange activity of Sse1, and the action of J-proteins are all needed for Ubr1-mediated quality control. To discern whether chaperones were directly involved in Ubr1-mediated ubiquitination, we developed a bead-based assay with covalently immobilized but releasable misfolded protein to obviate possible chaperone effects on substrate physical state or transport. In this in vitro assay, only HSP70 was required, along with its ATPase cycle and relevant cochaperones, for Ubr1-mediated ubiquitination. The requirement for the HSP70 ATP cycle in ubiquitination suggests a possible model of triage in which efficiently folded proteins are spared, while slow-folding or nonfolding proteins are iteratively tagged with ubiquitin for subsequent degradation.

COVID-19 and safer investment bets.

I examine the spillover effects across the three different long-short portfolio indices during the COVID-19 pandemic. The relative outperformance of the ESG portfolio, reported by Nofsinger and Varma (2014) and Lins et al. (2017), comes from the fact that the probability of its returns getting affected by the other safer investment strategies increases during an economic slowdown. It implies that investors become more attentive to corporate fundamentals - causing capital flowing away from the defensive and EAFE portfolios to the ESG portfolio during crisis periods. Investors find refuge in the ESG approach as it focuses on the long-run sustainability of firms.

Genetic underpinnings of lung function and COPD.

Spirometry based measurement of lung function is a global initiative for chronic obstructive lung disease (GOLD) standard to diagnose chronic obstructive pulmonary disease (COPD), one of the leading causes of mortality worldwide. The environmental and behavioural risk factors for COPD includes tobacco smoking, air pollutants and biomass fuel exposure, which can induce one or more abnormal lung function patterns. While smoking remains the primary risk factor, only 15-20% smokers develop COPD, indicating that the genetic factors are also likely to play a role. According to the study of Global Burden of Disease 2015, ∼174 million people across the world have COPD. From a comprehensive literature search conducted using the 'PubMed' and 'GWAS Catalogue' databases, and reviewing the literature available, only a limited number of studies were identified which had attempted to investigate the genetics of COPD and lung volumes, implying a huge research gap. With the advent of genomewide association studies several genetic variants linked to lung function and COPD, like HHIP, HTR4, ADAM19 and GSTCD etc., have been found and validated in different population groups, suggesting their potential role in determining lung volume and risk for COPD. This article aims at reviewing the present knowledge of the genetics of lung function and COPD.