Insulin sensitizes neural and vascular TRPV1 receptors in the trigeminovascular system

Background Clinical observations suggest that hyperinsulinemia and insulin resistance can be associated with migraine headache. In the present study we examined the effect of insulin on transient receptor potential vanilloid 1 (TRPV1) receptor-dependent meningeal nociceptor functions in rats. Methods The effects of insulin on the TRPV1 receptor stimulation-induced release of calcitonin gene related peptide (CGRP) from trigeminal afferents and changes in meningeal blood flow were studied. Colocalization of the insulin receptor, the TRPV1 receptor and CGRP was also analyzed in trigeminal ganglion neurons. Results Insulin induced release of CGRP from meningeal afferents and consequent increases in dural blood flow through the activation of TRPV1 receptors of trigeminal afferents. Insulin sensitized both neural and vascular TRPV1 receptors making them more susceptible to the receptor agonist capsaicin. Immunohistochemistry revealed colocalization of the insulin receptor with the TRPV1 receptor and CGRP in a significant proportion of trigeminal ganglion neurons. Conclusions Insulin may activate or sensitize meningeal nociceptors that may lead to enhanced headache susceptibility in persons with increased plasma insulin concentration.

AVAILABILITY OF ESSENTIAL MEDICINES IN PUBLIC HEALTH FACILITIES OF JIMMA ZONE, SOUTHWEST ETHIOPIA

Background: Availability is the relationship between the type and quantity of product or services needed and the type and quantity of product or services provided. Availability of essential medicines at facility level is an important factor to address patients' satisfaction and increase their health seeking behavior. The objective of this study is to determine the availability and associated factors of essential medicines in public health facilities of Jimma zone, South West Ethiopia. Methods: Facility-based cross-sectional study design was employed. Based on WHO recommendation, thirty health facilities were selected from five districts and six health facilities were chosen from each district of the zone. Availability of 29 key essential medicines that were selected from 2014 Ethiopian national essential medicine list were checked in stores and dispensaries as well as the store keepers, head of health facilities and dispensaries were selected for interview. The data were checked for completeness, edited, and coded then entered and analyzed using excels 2016 and SPSS version 23. Descriptive statistics were computed and tables, graphs and numerical summary presented results. Result: Average availability of selected core essential medicines (n=29) was 78.6% in surveyed health facilities. With regard to stock level, 8% of the surveyed medicines were in critical level, 55.2% were in safe level and 36.8% were in over stock level. Six hundred six patients were participated in the study with a response rate of 97%. Among total respondents, 77.7% left the facility with all of their prescribed medicines while 22.3% received only part of their prescribed medicines. Conclusion: The availability of essential medicines was fairly high in surveyed health facilities during the study period. In this study, many patients seeking treatment in public health facilities failed to obtain significant proportion of prescribed medicines. Peer Review History: Received: 4 November 2021; Revised: 10 December; Accepted: 22 December, Available online: 15 January 2022 Academic Editor: Dr. A.A. Mgbahurike, University of Port Harcourt, Nigeria, [email protected] UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. Received file: Reviewer's Comments: Average Peer review marks at initial stage: 5.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Dr. A.A. Mgbahurike, University of Port Harcourt, Nigeria, [email protected] Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, [email protected] Similar Articles: ACCESS TO MEDICINES STRATEGIES OF THE NATIONAL CANCER CONTROL PROGRAMME IN CAMEROON THE EFFICIENCY OF INEFFICIENCY: MEDICINE DISTRIBUTION IN SUDAN

Effect of Adjuvant Chemotherapy in Stage III Cervical Cancer Patients Treated With Concurrent Chemoradiation: A Multicenter Study

Introduction: A significant proportion of cervical cancer (CC) patients are diagnosed at a locally advanced stage. Concurrent chemoradiotherapy (CCRT) is the cornerstone of treatment for patients with locally advanced CC. However, the role of adjuvant chemotherapy (AC) after CCRT is controversial. In this study, we analyzed the efficacy of AC after CCRT in stage III CC patients. Methods: We performed a multicenter, retrospective analysis of 139 FIGO stage III CC patients treated with CCRT of whom 45.3% received AC. Our goal was to determine the impact of AC on survival in these patients. Results: Five-year progression-free survival was 37.5% and 16% in patients receiving CCRT with and without AC, respectively (p=0.008). Median PFS was 30.9 months (CI 95 %14.8-46.9) and 16.6 months (CI 95% 9.3-23.9) in patients receiving CCRT with and without AC, respectively. Five-year overall survival was 78.2% and 28.4% in patients receiving CCRT with and without AC, respectively (p<0.001). Median OS was 132.2 months (CI 95, %66.5-197.8) and 34.9 months (CI 95% 23.1-46.7) in patients receiving CCRT with and in without AC, respectively. Conclusion: Our study suggests that AC provides OS and PFS benefit in stage III CC patients. Larger studies are needed to identify subgroups of patients who would benefit from AC.

Glaucoma Diagnostic Performance of Macular Ganglion Cell Complex Thickness Using Regular and Long Axial Length Normative Databases

The risks of misdiagnosing a healthy individual as glaucomatous or vice versa may be high in a population with a large majority of highly myopic individuals, due to considerable morphologic variability in high myopic fundus. This study aims to compare the diagnostic ability of the regular and long axial length databases in the RS-3000 Advance SD-OCT (Nidek) device to correctly diagnose glaucoma with high myopia. Patients with high myopia (axial length ≥ 26.0 mm) in Chang Gung Memorial Hospital, Taiwan between 2015 and 2020 were included. Glaucoma was diagnosed based on glaucomatous discs, visual field defects and corresponding retinal nerve fiber layer defects. The sensitivity, specificity, diagnostic accuracy and likelihood ratios of diagnosing glaucoma via mGCC thickness in both superior/inferior and GChart mapping using the regular and long axial length normative databases. The specificity and diagnostic accuracy of mGCC thickness for distinguishing glaucomatous eyes from nonglaucomatous eyes among highly myopic eyes were significantly improved using the long axial length database (p=0.046). There were also significant proportion changes in S/I mapping as well as GChart mapping (37.3% and 48.0%, respectively; p<0.01) from abnormal to normal in the myopic normal eye group when using the long axial length normative database. The study revealed that clinicians could utilize a long axial length database to effectively decrease the number of false-positive diagnoses or to correctly identify highly myopic normal eyes misdiagnosed as glaucomatous eyes.

Current status of calcitonin gene-related peptide-based therapies in migraine: a scoping review

A significant proportion of patients exhibit sub-optimal response to the standard treatment of acute migraine such as triptans and NSAIDs. Even the conventional preventive therapies (e.g. beta-blockers) indicated for patients with frequent migraine attacks have varying responses. Moreover, evidence from animal studies elucidated the role of calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine. Currently two classes are drug, the small molecule CGRP receptor antagonist or the ‘gepants’ (Ubrogepant, Rimegepant, Atogepant, Zavegepant) and CGRP monoclonal antibodies (Erenumab, Galcanezumab, Fremanezumab, Eptinezumab) have been found efficacious and safe in various clinical trials for the treatment and prevention of migraine. While the small molecule CGRP receptor antagonists are given orally, the monoclonal antibodies are injectable drugs. Ubrogepant and Rimegepant are the second-generation gepants approved for treatment of migraine. Zavegepant is a third generation gepant which has proven efficacy for acute treatment of migraine in a phase III trial. Atogepant has been approved for prevention of migraine. Rimegepant has also proven to be efficacious for preventing migraine attacks but has not yet been approved for this indication. Erenumab is the only monoclonal antibody which neutralizes the CGRP receptor. The latter three monoclonal antibodies target the CGRP peptide. The monoclonal antibodies have been approved for the prevention of migraine as a subcutaneously or intravenous infusion (Eptinezumab) given once a month or quarterly. Both the classes of drugs were well-tolerated in the clinical trials. Nausea was the most common adverse effect with gepants while injection-site pain was commonly reported with the antibodies.

Large crop production losses induced by global ozone stress based on interval evaluation

Global crop yield loss due to ground-level ozone (O3) concentrations is a major challenge to food security, but a dose-response association is not easy to quantify. Here, we propose using a new metric, O3 sensitivity of crop yield (Yo), to estimate yield loss under different O3 time intervals using four observational databases. The Yo metric shows a non-linear parabola with elevated atmospheric O3 for wheat, maize, rice, soybean, and assorted vegetables. Spatial heterogeneity of yield loss varies as a function of crop type and O3 intervals. Estimates of yield loss from ozone suggest recent losses (2017-2019) may reach as high as 537 million tonnes, with a significant proportion coming with lower (30-40 ppb) exposure (325 million tonnes). Our results suggest that previous research, which only included higher (>40 ppb ozone), may have had grossly underestimated the negative effect of atmospheric O3 on crop production. Suppose these results are endemic to global crop production. In that case, additional research will be necessary to reassess ozone sensitivity and dose-responses, both spatially and temporally, to determine future air pollution impacts.

A convergent malignant phenotype in B-cell acute lymphoblastic leukemia involving the splicing factor SRRM1

A significant proportion of B-cell acute lymphoblastic leukemia (B-ALL) patients remains with a dismal prognosis due to yet undetermined mechanisms. We performed a comprehensive multicohort analysis of gene fusions, gene expression, and RNA splicing alterations to uncover molecular signatures potentially linked to the observed poor outcome. We identified 84 fusions with significant allele frequency across patients. We identified an expression signature that predicts high risk independently of the gene fusion background. This signature includes the upregulation of the splicing factor SRRM1, which potentially impacts splicing events associated with poor outcomes through protein-protein interactions with other splicing factors. Experiments in B-ALL cell lines provided further evidence for the role of SRRM1 on cell survival, proliferation, and invasion. Our findings reveal a convergent mechanism of aberrant RNA processing that sustains a malignant phenotype independently of gene fusions and could complement current clinical strategies in B-ALL.

SARS-CoV-2 infection induces a pro-inflammatory cytokine response through cGAS-STING and NF-κB

SARS-CoV-2 is a novel virus that has rapidly spread, causing a global pandemic. In the majority of infected patients, SARS-CoV-2 leads to mild disease; however, in a significant proportion of infections, individuals develop severe symptoms that can lead to long-lasting lung damage or death. These severe cases are often associated with high levels of pro-inflammatory cytokines and low antiviral responses, which can cause systemic complications. Here, we have evaluated transcriptional and cytokine secretion profiles and detected a distinct upregulation of inflammatory cytokines in infected cell cultures and samples taken from infected patients. Building on these observations, we found a specific activation of NF-κB and a block of IRF3 nuclear translocation in SARS-CoV-2 infected cells. This NF-κB response was mediated by cGAS-STING activation and could be attenuated through several STING-targeting drugs. Our results show that SARS-CoV-2 directs a cGAS-STING mediated, NF-κB-driven inflammatory immune response in human epithelial cells that likely contributes to inflammatory responses seen in patients and could be therapeutically targeted to suppress severe disease symptoms.

From heart to muscle: Pathophysiological mechanisms underlying long-term physical sequelae from SARS-CoV-2 infection

The long-term sequelae of the coronavirus disease 2019 (COVID-19) are multifaceted and, besides the lungs, impact other organs and tissues, even in cases of mild infection. Along with commonly reported symptoms such as fatigue and dyspnea, a significant proportion of those with prior COVID-19 infection also exhibit signs of cardiac damage, muscle weakness, and ultimately, poor exercise tolerance. This review provides an overview of evidence indicating cardiac impairments and persistent endothelial dysfunction in the peripheral vasculature of those previously infected with COVID-19, irrespective of the severity of the acute phase of illness. Additionally, VO2peak appears to be lower in convalescent patients, which may stem, in part, from alterations in O2 transport such as impaired diffusional O2conductance. Together, the persistent multi-organ dysfunction induced by COVID-19 may set previously healthy individuals on a trajectory towards frailty and disease. Given the large proportion of individuals recovering from COVID-19, it is critically important to better understand the physical sequelae of COVID-19, the underlying biological mechanisms contributing to these outcomes, and the long-term effects on future disease risk. This review highlights relevant literature on the pathophysiology post-COVID-19 infection, gaps in the literature, and emphasizes the need for the development of evidence-based rehabilitation guidelines.

Ibrutinib in Refractory or Relapsing Primary Central Nervous System Lymphoma: A Systematic Review

Primary Central Nervous System Lymphoma (PCNSL) is a rare variant of Non-Hodgkin Lymphoma (NHL) representing 1–2% of all NHL cases. PCNSL is defined as a lymphoma that occurs in the brain, spinal cord, leptomeninges, or eyes. Efforts to treat PCNSL by traditional chemotherapy and radiotherapy have generally been unsuccessful as a significant proportion of patients have frequent relapses or are refractory to treatment. The prognosis of patients with Refractory or Relapsed (R/R) PCNSL is abysmal. The optimal treatment for R/R PCNSL is poorly defined as there are only a limited number of studies in this setting. Several studies have recently shown that ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has promising results in the treatment of R/R PCNSL. However, these are preliminary studies with a limited sample size. In this systematic review, we explored and critically appraised the evidence about the efficacy of the novel agent ibrutinib in treating R/R PCNSL.