ER-resident STIM1/2 couples Ca2+ entry by NMDA receptors to pannexin-1 activation.

Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca2+ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus-recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca2+ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.

Use of secukinumab in erythrodermic psoriasis: A single center experience.

Background: Erythrodermic psoriasis is an acute inflammatory condition presenting as erythema and scaling involving more than 90% of body surface area in patients with a history of psoriasis vulgaris. If not treated promptly, metabolic complications and infections due to acute skin failure can cause significant morbidity and mortality in this condition. Interleukin-17 (IL-17) is considered to be the key player in initiating the inflammatory cascade in psoriasis. IL-17 blockers have been successfully used in the management of psoriasis vulgaris. However, its use in unstable erythrodermic psoriasis is limited to isolated case reports. Methods: We hereby report an observational study of nine patients of unstable psoriatic erythroderma successfully managed with injection secukinumab and followed up over the next 24 months. Results: Nine patients were managed during the study period, and a successful outcome was noted in all the patients. The Psoriasis Area and Severity Index response rate improved by at least 75% from baseline in 33.3% (3/9) at week 4 and improved to 88.9% (8/9) at week 12. None of the patients had a recurrence of erythroderma till 24 months of followup. Conclusion: The study concluded that secukinumab is quick, safe, and efficient in psoriatic erythroderma, and there was no relapse of erythroderma in any of the patients in the 24 months of followup.

Cardiometabolic effects of DOCA-salt in male C57BL/6J mice are variably dependent on sodium and nonsodium components of diet.

Hypertension characterized by low circulating renin activity accounts for roughly 25%-30% of primary hypertension in humans and can be modeled experimentally via deoxycorticosterone acetate (DOCA)-salt treatment. In this model, phenotypes develop in progressive phases, although the timelines and relative contributions of various mechanisms to phenotype development can be distinct between laboratories. To explore interactions among environmental influences such as diet formulation and dietary sodium (Na) content on phenotype development in the DOCA-salt paradigm, we examined an array of cardiometabolic endpoints in young adult male C57BL/6J mice during sham or DOCA-salt treatments when mice were maintained on several common, commercially available laboratory rodent "chow" diets including PicoLab 5L0D (0.39% Na), Envigo 7913 (0.31% Na), Envigo 2920x (0.15% Na), or a customized version of Envigo 2920x (0.4% Na). Energy balance (weight gain, food intake, digestive efficiency, and energy efficiency), fluid and electrolyte homeostasis (fluid intake, Na intake, fecal Na content, hydration, and fluid compartmentalization), renal functions (urine production rate, glomerular filtration rate, urine Na excretion, renal expression of renin, vasopressin receptors, aquaporin-2 and relationships among markers of vasopressin release, aquaporin-2 shedding, and urine osmolality), and blood pressure, all exhibited changes that were subject to interactions between diet and DOCA-salt. Interestingly, some of these phenotypes, including blood pressure and hydration, were dependent on nonsodium dietary components, as Na-matched diets resulted in distinct phenotype development. These findings provide a broad and robust illustration of an environment × treatment interaction that impacts the use and interpretation of a common rodent model of low-renin hypertension.

Understanding the dynamics of IgM & IgG antibodies in COVID-19-positive patients.

Background & objectives: The pandemic caused by the SARS-CoV-2 has been a threat to humankind due to the rapid spread of infection and appearance of multiple new variants. In the present study, we report the dynamics and persistence of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in asymptomatic and symptomatic COVID-19 patients by chemiluminescent assay. Methods: A total of 463 serum samples from 218 SARS-CoV-2 PCR-positive patients were collected over a period of 124 days post-onset of disease (POD). Antibody levels were measured by chemiluminescence bioanalyzer. Neutralizing antibody titres were assessed by plaque reduction neutralization test (PRNT) for SARS-CoV-2. Results: Both IgM and IgG started appearing from day five post-infection in symptomatic and asymptomatic patients. IgM antibody response peaked around day 35 POD and rapidly diminished thereafter, with the last IgM-positive sample observed at 90 days POD. IgG antibody response peaked around 45 days POD and persisted till 124 days. The chemiluminescence immunoassay (CLIA) results showed a moderate correlation (R=0.5846, P<0.001) compared with PRNT. Additional analysis indicated a neutralizing titre of 250 corresponded to 12.948 AU/ml of YHLO iFlash SARS-CoV-2 IgG units. Interpretation & conclusions: Both symptomatic and asymptomatic COVID-19 patients seem to initiate production of antibody responses from day five of onset of disease. Although the CLIA gives high sensitivity and specificity and also its binding IgG antibody titres may correlate moderately with protective immunity, our results indicate that the values of binding antibody alone may not be a perfect guide to represent virus neutralization titre during donor selection for plasma therapy. However, IgM and IgG antibody detection may help in monitoring the status of disease progression and burden in the community.

Leukocytoclastic vasculitis as a cutaneous manifestation of ChAdOx1 nCoV-19 corona virus vaccine (recombinant).

With the present COVID-19 vaccination drive across the world, adverse skin reactions post COVID-19 vaccine is expected. Majority of these reactions seen were transient or local injection site reactions. However, as the larger population is being vaccinated, certain uncommon dermatological presentations including leukocytoclastic vasculitis, pityriasis rosea, and exacerbation of pre-existing autoimmune diseases are now being reported. Among all the COVID-19 vaccines, most of these reactions are seen with messenger ribonucleic acid-based Pfizer/BioNTech (BNT162b2) and Moderna (mRNA-1273) vaccine. We report two cases of leukocytoclastic vasculitis following ChAdOx1 nCoV-19 corona virus vaccine (recombinant) that bring out potential new dermatological manifestations of recombinant corona virus vaccine being administered across the European, South American, and Asian countries. It is important for all health care workers and patients to be aware of the corona virus vaccine associated adverse cutaneous reactions.

Copper-impregnated socks: A novel therapeutic option for combating occupational dermatophytosis.

BACKGROUND: Operational and training requirements of soldiers necessitate prolonged use of occlusive footwear which makes them susceptible to Tinea pedis and affects their performance. This study assesses copper oxide-impregnated socks as a treatment modality in soldiers with Tinea pedis. METHODS: Three hundred serving soldiers with Tinea pedis were randomly divided in two groups of 150 cases each. One group was supplied with 02 pairs of polyester copper oxide-impregnated socks and the second group was treated with oral terbinafine 250mg /day for two weeks and topical terbinafine twice a day for three weeks. Five end points viz. scaling, erythema, fissuring, vesicular eruptions and itching were monitored using the visual analogue score (VAS) weekly for 03 weeks. RESULTS: Copper oxide socks helped in reducing all the end points as assessed by VAS. The group treated with terbinafine showed better response; however test socks were as efficacious as oral and topical terbinafine in controlling fissuring and vesiculation. Safety profile of the copper impregnated socks was comparable with the conventional treatment. CONCLUSION: Copper-impregnated socks are effective and safe in treating Tinea pedis. They may also have prophylactic role in tinea pedis in susceptible serving soldiers deployed at remote locations in different terrain and weather conditions.

Pannexin-1 in the CNS: Emerging concepts in health and disease.

Pannexin-1 (Panx1) is a large pore membrane channel with unique conduction properties ranging from non-selective ion permeability to the extracellular release of signalling molecules. The release of ATP by Panx1 has been particularly well-characterized with implications in purine signalling across a variety of biological contexts. Panx1 activity is also important in inflammasome formation and the secretion of pro-inflammatory molecules such as interleukin-1ß. Within the central nervous system (CNS), Panx1 is expressed on both neurons and glia, and is thought to mediate crosstalk between these cells. A growing body of literature now supports the pathological activity of Panx1 in contributing to disease processes including seizure, stroke, migraine headache and chronic pain. Emerging evidence also reveals a physiological function of Panx1 in regulating neural stem cell survival, neuronal maturation and synaptic plasticity, with possible relevance to normal cognitive functioning. The aim of this review is to summarize the current evidence regarding the roles of Panx1 in the CNS, with emphasis on how putative signalling properties and activation mechanisms of this channel contribute to various physiological and pathophysiological processes.

Exploration of cardiometabolic and developmental significance of angiotensinogen expression by cells expressing the leptin receptor or agouti-related peptide.

Angiotensin II (ANG II) Agtr1a receptor (AT1A) is expressed in cells of the arcuate nucleus of the hypothalamus that express the leptin receptor (Lepr) and agouti-related peptide (Agrp). Agtr1a expression in these cells is required to stimulate resting energy expenditure in response to leptin and high-fat diets (HFDs), but the mechanism activating AT1A signaling by leptin remains unclear. To probe the role of local paracrine/autocrine ANG II generation and signaling in this mechanism, we bred mice harboring a conditional allele for angiotensinogen (Agt, encoding AGT) with mice expressing Cre-recombinase via the Lepr or Agrp promoters to cause cell-specific deletions of Agt (AgtLepr-KO and AgtAgrp-KO mice, respectively). AgtLepr-KO mice were phenotypically normal, arguing against a paracrine/autocrine AGT signaling mechanism for metabolic control. In contrast, AgtAgrp-KO mice exhibited reduced preweaning survival, and surviving adults exhibited altered renal structure and steroid flux, paralleling previous reports of animals with whole body Agt deficiency or Agt disruption in albumin (Alb)-expressing cells (thought to cause liver-specific disruption). Surprisingly, adult AgtAgrp-KO mice exhibited normal circulating AGT protein and hepatic Agt mRNA expression but reduced Agt mRNA expression in adrenal glands. Reanalysis of RNA-sequencing data sets describing transcriptomes of normal adrenal glands suggests that Agrp and Alb are both expressed in this tissue, and fluorescent reporter gene expression confirms Cre activity in adrenal gland of both Agrp-Cre and Alb-Cre mice. These findings lead to the iconoclastic conclusion that extrahepatic (i.e., adrenal) expression of Agt is critically required for normal renal development and survival.

Evaluation of Push-out Bond Strength of a Resin Sealer to Dentin after a Final Flush of Three Irrigants.

AIM: To evaluate the push-out bond strength of resin-based sealer to root dentin after a final flush of three different irrigants. MATERIALS AND METHODS: Thirty extracted human mandibular premolars were sectioned 4 mm below the cement-enamel junction and 60 horizontal disks of 2 mm from middle one-third of the root were prepared. The disks were immersed in 3% sodium hypochlorite for 1 minute, and after drying the disks, they were finally flushed with the following irrigants: group I-Chitosan solution, group II-Morinda citrifolia juice (MCJ), and group III-ethylenediaminetetraacetic acid (EDTA). The disks were filled with AH Plus sealer, and after 7 days, the disks were subjected to push-out bond strength using a universal testing machine. RESULTS: EDTA had the highest push-out bond strength followed by MCJ and then chitosan. CONCLUSION: Chitosan and MCJ can be used as alternative irrigants as a final flush during the cleaning and shaping of the root canals. CLINICAL SIGNIFICANCE: EDTA, chitosan solution, and MCJ are efficient in smear layer removal which thereby increases better sealer penetration and prevents the dislocation of obturating materials.

A comparative study for plaque removing efficacy between commonly used denture cleansers in India.

AIM: A comparative study for plaque removing efficacy between toothpaste, liquid handwashing soap, and two chemical-soak denture cleansers (clinsodent denture cleansing powder and fittydent denture cleansing tablet). MATERIALS AND METHODS: A total of 140 healthy complete denture patients were selected and checked for denture cleansing using toothpaste, liquid handwashing soap, and two chemical denture cleansers: Clinsodent powder and fittydent tablets. Cleansing with plain water was kept as control for twenty patients. RESULTS: The data were analyzed using Wilcoxon signed ranks test for checking the efficacy. The Kruskal-Wallis test was used for comparing the plaque removing efficacies of each denture cleanser used in the study. All four denture cleansers were significantly effective in removing plaque when compared with plain water, but there was no significant difference among them. CONCLUSIONS: There was no significant difference among action of four denture cleansers used in this study. Thus we can infer that patients can use liquid handwashing soap or commercial products to overcome disadvantages of toothpastes. Recommendation from the results of this study is the use of liquid handwashing soap for cleansing after every meal and soaking of the denture in commercial denture cleanser during the night.

20-HETE and CYP4A2 ω-hydroxylase contribute to the elevated blood pressure in hyperandrogenemic female rats.

In male rats, androgen supplements increase 20-hydroxyeicosatetraenoic acid (20-HETE) via cytochrome P-450 (CYP)4A ω-hydroxylase and cause an increase in blood pressure (BP). In the present study, we determined the roles of 20-HETE and CYP4A2 on the elevated BP in hyperandrogenemic female rats. Chronic dihydrotestosterone (DHT) increased mean arterial pressure (MAP) in female Sprague-Dawley rats (96 ± 2 vs. 108 ± 2 mmHg, P < 0.05) and was associated with increased renal microvascular CYP4A2 mRNA expression (15-fold), endogenous renal 20-HETE (5-fold), and ω-hydroxylase activity (3-fold). Chronic DHT also increased MAP in low salt-fed Dahl salt-resistant female rats (81 ± 4 vs. 95 ± 1 mmHg, P < 0.05) but had no effect on MAP in Dahl salt-sensitive female rats (154 ± 3 vs. 153 ± 3 mmHg), which are known to be 20-HETE deficient. To test the role of CYP4A2, female CYP4A2(-/-) and SS.5(Bn) (wild type) rats were treated with DHT. DHT increased MAP in SS.5(Bn) female rats (104 ± 1 vs. 128 ± 1 mmHg, P < 0.05) but had no effect in CYP4A2(-/-) female rats (118 ± 1 vs. 120 ± 1 mmHg). Renal microvascular 20-HETE was reduced in control CYP4A2(-/-) female rats and was increased with DHT in SS.5(Bn) female rats (6-fold) but not CYP4A2(-/-) female rats. ω-Hydroxylase activity was 40% lower in control CYP4A2(-/-) female rats than in SS.5(Bn) female rats, and DHT decreased ω-hydroxylase activity in SS.5(Bn) female rats (by 50%) but significantly increased ω-hydroxylase activity in CYP4A2(-/-) female rats (3-fold). These data suggest that 20-HETE via CYP4A2 contributes to the elevation in BP in hyperandrogenemic female rats. The data also suggest that 20-HETE synthesis inhibition may be effective in treating the elevated BP in women with hyperandrogenemia, such as women with polycystic ovary syndrome.

Low-dose testosterone protects against renal ischemia-reperfusion injury by increasing renal IL-10-to-TNF-α ratio and attenuating T-cell infiltration.

Renal ischemia-reperfusion (I/R) in male rats causes reductions in plasma testosterone, and infusion of testosterone 3 h postreperfusion is protective. We tested the hypotheses that acute high doses of testosterone promote renal injury after I/R, and that acute low-dose testosterone is protective by the following: 1) increasing renal IL-10 and reducing TNF-α; 2) its effects on nitric oxide; and 3) reducing intrarenal T-cell infiltration. Rats were subjected to renal I/R, followed by intravenous infusion of vehicle or testosterone (20, 50, or 100 µg/kg) 3 h postreperfusion. Low-dose testosterone (20 µg/kg) reduced plasma creatinine, increased nitrate/nitrite excretion, increased intrarenal IL-10, and reduced intrarenal TNF-α, whereas 50 µg/kg testosterone failed to reduce plasma creatinine, increased IL-10, but failed to reduce TNF-α. A higher dose of testosterone (100 mg/kg) not only failed to reduce plasma creatinine, but significantly increased both IL-10 and TNF-α compared with other groups. Low-dose nitro-l-arginine methyl ester (1 mg·kg(-1)·day(-1)), given 2 days before I/R, prevented low-dose testosterone (20 µg/kg) from protecting against I/R injury, and was associated with lack of increase in intrarenal IL-10. Intrarenal CD4(+) and CD8(+) T cells were significantly increased with I/R, but were attenuated with low-dose testosterone, as were effector T helper 17 cells. The present studies suggest that acute, low-dose testosterone is protective against I/R AKI in males due to its effects on inflammation by reducing renal T-cell infiltration and by shifting the balance to favor anti-inflammatory cytokine production rather than proinflammatory cytokines.

1064 nm dispersive Raman spectroscopy of tissues with strong near-infrared autofluorescence.

Raman spectroscopy is an established technique for molecularly specific characterization of tissues. However, even with near-infrared (NIR) excitation, some tissues possess background autofluorescence, which can overwhelm Raman scattering. Here, we report collection of spectra from tissues with strong autofluorescence using a 1064 nm system with a high-throughput dispersive spectrometer and deep-cooled InGaAs array. Spectra collected at 1064 nm were compared with those collected at 785 nm in specimens from human breast, liver, and kidney. The results demonstrate superior performance at 1064 nm in the liver and kidney, where NIR autofluorescence is intense. The results indicate the feasibility of new biomedical applications for Raman spectroscopy at 1064 nm in tissues with strong autofluorescence.

Comparing Laser-Assisted and Conventional Excision in the Management of Oral Soft Lesions: A Prospective Clinical Study.

Introduction: Oral soft lesions represent a diverse array of pathological conditions that necessitate precise and effective treatment. Laser-assisted excision has gained prominence due to its purported benefits in terms of reduced procedural time, decreased bleeding, and improved aesthetic outcomes. However, conventional excision remains a common practice. Materials and Methods: A total of 100 patients with clinically diagnosed oral soft lesions were enrolled in this prospective study. The patients were randomly divided into two groups: the laser-assisted excision group and the conventional excision group. Demographics, lesion characteristics, and medical histories were recorded for each patient. Procedural parameters such as operative time and intraoperative bleeding were meticulously documented. Results: The laser-assisted excision group exhibited a statistically significant reduction in procedural duration compared to the conventional excision group (P < 0.05), with mean operative times of 15.2 and 20.8 min, respectively. Intraoperative bleeding was significantly reduced in the laser-assisted group (P < 0.01), with an average blood loss of 15.7 ml, while the conventional excision group reported an average blood loss of 28.6 ml. Postoperative complications analysis demonstrated that the laser-assisted group had a lower incidence of wound infections (P < 0.05) compared to the conventional excision group (5% vs. 15%). Additionally, the laser-assisted group exhibited significantly reduced scarring (P < 0.01) as reported by both patients and clinicians. Patient satisfaction scores were consistently higher in the laser-assisted excision group, with 85% of patients reporting contentment with the procedure, in contrast to 65% in the conventional excision group. Conclusion: In light of the results obtained from this study, laser-assisted excision emerges as a favorable approach for the management of oral soft lesions.

Practical Aspects of Acne Scar Management: ASAP 2024.

Acne scars are one of the most common complications of acne. They can significantly affect the patient's quality of life. Often, several types of atrophic acne scars are observed simultaneously; therefore, consideration must be given to the type of scar while choosing the treatment modality. Effective treatment is not only important to prevent and improve acne scars but also crucial in preventing psychosocial effects. Treatment of acne scars requires an algorithmic approach that targets each component of the scars, and combination therapy on a patient-specific basis may offer the best chance for significant improvement. The goal of the current article is to discuss the practical aspects of management of atrophic acne scars using the vast modalities of treatment available. The panel of dermatologists and plastic surgeons, each one with at least 20 years of experience in acne scar treatment, participated in a series of 'Practical Aspects of Acne Scar Management' (ASAP) meetings: ASAP 2024. ASAP meetings were organized by "Scar Forum India" from March 2023 to July 2023 in four Indian cities (Mumbai, Delhi, Bengaluru, and Kolkata), each one for a duration of at least three hours. During these meetings and discussions, panelists reviewed and discussed the acne scar-related literature, their clinical experience in its management, available treatment options, along with recent advances. Consequently, a summary of the discussion and practical approach for the management of acne scars is developed. It was concluded that, though there is no specific guideline available to optimize acne scar management despite the multitude of treatment options, the best results can be achieved through the synergy of multiple treatment modalities and using the algorithmic approach.

Real-World Study of Definisse Threads for Facial Reshaping in Indian Patients: REDEFINE FACE Study.

INTRODUCTION: In recent years, thread lifting has gained popularity as a less invasive cosmetic surgery. It helps raise and realign sagging tissue. The newest thread type for thread lifting procedure is poly-lactic acid-polycaprolactone (PLCL) Definisse threads (RELIFE S.r.l., Florence, Italy). These are fourth-generation absorbable suspended barbed threads. Their double action involves an immediate elevating impact through mechanical action and, over time, the promotion of histological rejuvenating activity through inducing fibroblasts and the synthesis of elastin, hyaluronic acid, and collagen. OBJECTIVES: The REDEFINE FACE study assessed the effectiveness and tolerance of Definisse threads in a real-world setting for facial reshaping in patients in India. METHODS: This multicenter, retrospective observational research included patients treated with Definisse threads for face contouring. RESULTS: Three hundred seventeen patients with a mean follow-up of 4.9 months and an average age of 48.6 years participated in the study. All patients underwent thread lifts using either a single or a combination of Definisse thread reshaping techniques. The Global Aesthetic Improvement Scale for Physicians and Subjects (PGAIS and SGAIS) reported improvement instantly following the treatment (mean score- 3.23 and 3.18, respectively). Improvements continued to enhance during the follow-up visits (mean score- 4.09 and 4.03, respectively). Following the procedure, 96% of patients on the PGAIS and SGAIS exhibited enhancement. Most procedure-related side effects were minor and went away on their own in a few days without the need for proactive care. CONCLUSION: The results of this real-world analysis showed that the latest Definisse threads effectively achieve facial reshaping on patients in India and have both immediate and long-term effects. Treatment was generally well tolerated, and no patient experienced serious adverse events.