Empowering women and health care

Women health workers have made great contributions to the health of their community for many years. In India, women physicians have established some hospitals, e.g., Christian Medical Colleges in Ludhiana and Vellore. Some such hospitals operate in remote areas to serve the poor and the suffering. Women health workers of Jamkhed, Deen Bandhu of Pachod, have proved that village women can improve the health status of their community, particularly that of women and children, if they receive encouragement to learn health care skills In India, community health care lies mainly with women (e.g., nursing personnel and in rural areas). Yet, despite their competence and experience, few become physicians, health project directors, and administrators because the society continues to be patriarchal and discriminates against females. Women need to become empowered to ensure equal opportunities for training and promotion and equal wages for equal work. In Bangladesh, use of bicycles to visit houses allows women paramedical workers from Gonasasthya Kendra, Sawar, freedom and imparts confidence. People must identify customs, practices, laws, attitudes, religious misrepresentations, and policies that discriminate against women and then oppose them. They should set these changes in motion at home, in villages, and from district to national, and even global levels. In India, society blames the mother for having a girl, but the man donates the chromosome determining sex. In Gandhigram, a woman physician and her peers have effected an apparent change in attitude toward the birth of a girl. Now the people confer equal happiness to her birth as they do to a boy's birth. Yet, female infanticides still occur in some villages of Salem District of Tamil Nadu. Sex determination tests often lead to abortion of female fetuses. Once a woman marries she has no right to her maternal home and often suffers from domestic violence. Many people resist legislation to grant women more rights, e.g., property rights. Various media promote women's empowerment.     

Diagnosing "dayans" and "demons"

The new ?Witch Craft Prevention Bill? prohibiting witch hunting was passed in Bihar, India, in reaction to the branding and subsequent killing of more than 500 helpless women as "dayans" (witches) in the past 7 years. Most of them were single, widows, or deserted women victimized by the pathological greed of some of the male members of their families or by some powerful persons in the village community interested in claiming their property. Even with the passage of the bill, though, most of these crimes will remain unpunished because the community is an accomplice in them, and they tend not to be reported. What is needed overall is socioeconomic and political development that will lead to the empowerment of women to ensure that there will be an end to the cruel and inhuman activities (such as witch hunting) instigated by traditional healers or "Ojhas".     

Voltage-sensor movements in the Eag Kv channel under an applied electric field

Voltage-dependent ion channels regulate the opening of their pores by sensing the membrane voltage. This process underlies the propagation of action potentials and other forms of electrical activity in cells. The voltage dependence of these channels is governed by the transmembrane displacement of the positive charged S4 helix within their voltage-sensor domains. We use cryo-electron microscopy to visualize this movement in the mammalian Eag voltage-dependent potassium channel in lipid membrane vesicles with a voltage difference across the membrane. Multiple structural configurations show that the applied electric field displaces S4 toward the cytoplasm by two helical turns, resulting in an extended interfacial helix near the inner membrane leaflet. The position of S4 in this down conformation is sterically incompatible with an open pore, thus explaining how movement of the voltage sensor at hyperpolarizing membrane voltages locks the pore shut in this kind of voltage-dependent K⁺ (K_v) channel. The structures solved in lipid bilayer vesicles detail the intricate interplay between K_v channels and membranes, from showing how arginines are stabilized deep within the membrane and near phospholipid headgroups, to demonstrating how the channel reshapes the inner leaflet of the membrane itself.

In voltage-dependent ion channels, the transmembrane voltage determines whether the pore opens. At the same time, the flow of ions through the open pore alters the membrane voltage by charging the membrane capacitance. This recursive regulation of ion channel activity by membrane voltage is the fundamental process at the heart of cellular electricity. As described by Hodgkin and Huxley (1), voltage-dependent membrane permeability to Na⁺ and K⁺ (ion channels as molecular entities had not yet been discovered) generates the action potential, which is by far the most rapid form of information transfer across long distances in cells. Voltage-dependent ion channels underlie many other aspects of cell signaling as well, including the initiation of muscle contraction by voltage-dependent Ca²⁺ channels (2, 3) and the control of cardiac and neuronal pacemaker frequency by the hyperpolarization-activated cyclic nucleotide–gated (HCN) channel (4, 5).Voltage-dependent ion channels contain structural domains called voltage sensors that control pore opening by membrane voltage. Whether in K⁺, Na⁺, Ca²⁺, or cation channels like HCN channels or transient receptor potential (TRP) channels, voltage sensors have a conserved structure comprising four transmembrane helices, named S1, S2, S3, and S4 (3, 6, 7). The fourth helix, S4, contains repeats of the amino acid triplet (RXX)_n, where R stands for arginine, sometimes substituted by lysine, X for hydrophobic amino acid, and n varies widely among different channels. At the center of voltage sensors, inside the membrane’s interior, a constellation of negative charged amino acids, aspartate or glutamate, and a phenylalanine residue forms a gating-charge transfer center that stabilizes the positive charged side chains of arginine and lysine as they cross the membrane (8, 9). In some voltage sensors, S4 undergoes a transition from an α to a 3₁₀ helix to direct the arginine and lysine side chains of S4 into the gating-charge transfer center (8–11). The displacement of S4 across the membrane is detectable as a nonlinear capacitive current, called gating current in electrophysiology experiments (9, 12), and is ultimately responsible for voltage control of a voltage-dependent ion channel’s pore.So far, voltage-dependent ion channel structures have been determined in crystals, detergent micelles, or nanodiscs without a voltage difference across them (8, 13–19). Under such conditions, most voltage sensors adopt a depolarized conformation, which is expected in a membrane at 0 mV. Chemical cross links, metal affinity bridges, mutations, and toxins have been used to capture or stabilize voltage sensors in conformations thought to mimic the hyperpolarized (i.e., negative voltage inside) condition (10, 11, 20–23). Here, we present a cryo-electron microscopy (cryo-EM) analysis of the mammalian Eag voltage-dependent K⁺ (K_v) channel in lipid membrane vesicles with a voltage generated across the membrane using K⁺ ion gradients in the presence of valinomycin. Doing so allows us to not only visualize how the voltage sensors respond to the applied electric field but also to see how the lipid membrane near the channel, which is intimately tied to the function of voltage-dependent ion channels, is reshaped by these conformational changes.     

Mutant p53 gain of function mediates cancer immune escape that is counteracted by APR-246

Background p53 mutants contribute to the chronic inflammatory tumour microenvironment (TME). In this study, we address the mechanism of how p53 mutants lead to chronic inflammation in tumours and how to transform it to restore cancer immune surveillance.Methods Our analysis of RNA-seq data from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) project revealed that mutant p53 (mtp53) cancers correlated with chronic inflammation. We used cell-based assays and a mouse model to discover a novel gain of function of mtp53 and the effect of the mtp53 reactivating compound APR-246 on the anti-tumour immune response.Results We found that tumour samples from patients with breast carcinoma carrying mtp53 showed elevated Interferon (IFN) signalling, Tumour Inflammation Signature (TIS) score and infiltration of CD8+ T cells compared to wild type p53 (wtp53) tumours. We showed that the expression of IFN and immune checkpoints were elevated in tumour cells in a mtp53-dependent manner, suggesting a novel gain of function. Restoration of wt function to mtp53 by APR-246 induced the expression of endogenous retroviruses, IFN signalling and repressed immune checkpoints. Moreover, APR-246 promoted CD4+ T cells infiltration and IFN signalling and prevented CD8+ T cells exhaustion within the TME in vivo.Conclusions Breast carcinomas with mtp53 displayed enhanced inflammation. APR-246 boosted the interferon response or represses immune checkpoints in p53 mutant tumour cells, and restores cancer immune surveillance in vivo. Subject terms: Immunosurveillance, Targeted therapies     

Effects of Turmeric Powder on Aflatoxin M1 and Aflatoxicol Excretion in Milk from Dairy Cows Exposed to Aflatoxin B1 at the EU Maximum Tolerable Levels

Due to the climatic change, an increase in aflatoxin B1 (AFB1) maize contamination has been reported in Europe. As an alternative to mineral binders, natural phytogenic compounds are increasingly used to counteract the negative effects of AFB1 in farm animals. In cows, even low dietary AFB1 concentrations may result in the milk excretion of the genotoxic carcinogen metabolite aflatoxin M1 (AFM1). In this study, we tested the ability of dietary turmeric powder (TP), an extract from Curcuma longa (CL) rich in curcumin and curcuminoids, in reducing AFM1 mammary excretion in Holstein–Friesian cows. Both active principles are reported to inhibit AFM1 hepatic synthesis and interact with drug transporters involved in AFB1 absorption and excretion. A crossover design was applied to two groups of cows (n = 4 each) with a 4-day washout. Animals received a diet contaminated with low AFB1 levels (5 ± 1 µg/kg) for 10 days ± TP supplementation (20 g/head/day). TP treatment had no impact on milk yield, milk composition or somatic cell count. Despite a tendency toward a lower average AFM1 milk content in the last four days of the treatment (below EU limits), no statistically significant differences with the AFB1 group occurred. Since the bioavailability of TP active principles may be a major issue, further investigations with different CL preparations are warranted.     

Relative efficacy of lasmiditan versus rimegepant and ubrogepant as acute treatments for migraine: network meta-analysis findings

BackgroundIn the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA).MethodsData included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II–IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings.ResultsAcross 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9–45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant.ConclusionsThe efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting.350/350 wordsSupplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01440-w.     

Orbital dermoid cyst

Background:Dermoid cyst, a developmental benign choristoma, is the most common orbital tumor of childhood, arising from ectodermal sequestration along the lines of embryonic fusion of mesodermal processes, lined by keratinized stratified squamous epithelium and expanding slowly due to constant desquamation and dermal glandular elements. Approximately 80% are found in the head and neck region and comprise 3-9% all orbital masses.Purpose:It is mandatory to know about the variable presentations of orbital dermoids and the surgical techniques that can be adopted based on the site, extent, age and aesthetic needs, presence of inflammation and possibility of intraoperative rupture.Synopsis:Orbital dermoids can be classified as juxta-sutural, sutural or soft tissue cysts; superficial or deep; intraosseous or extraosseous, and intraorbital or extraorbital. These smooth, painless, mobile or partially mobile lesions mostly present at the fronto-zygomatic suture with proptosis, displacement, ptosis or diplopia, depending on depth and extent. Therefore, it is important to understand the various presentations and the appropriate surgical techniques.Highlights:We describe the embryological origin, types and clinical features of dermoids in this video and demonstrate the surgical and minimally invasive techniques for their management.Video link: https://youtu.be/-q3xD2igjcQ