Development of Indian Council of Medical Research (ICMR) Standard Treatment Workflows for Skin Diseases: A Step Toward Universal Health Coverage.

Background: Skin conditions form a major bulk of diseases in the community. With a disproportionately low number of dermatologists in the country, and a greatly unequal distribution between urban versus rural areas, ineffective treatment and mismanagement of skin conditions are, however, commonplace. Objective: To develop standard treatment workflows (STWs) for certain skin diseases for use by clinicians at primary, secondary, and tertiary care centers. Methodology: Seven members, from various academic institutes across the country, were selected for formulation of the STWs. They were provided logistic and technical support by the ICMR, Department of Health Research (DHR), and WHO India office. Multiple rounds of online and physical discussions were performed to identify topics that would be most useful in the management of skin diseases for the health care personnel (HCP) and subsequently to frame the STW content. Results: The selected diseases included acne and rosacea, alopecia, bacterial skin infections, cutaneous adverse drug reactions, dermatophytosis, eczema/dermatitis, immunobullous dermatoses, psoriasis, scabies, varicella and herpes, vitiligo, and urticaria. There was one separate module on rational use of topical corticosteroids. The STWs for these conditions have been finalised and are available as physical posters in health centers and can also be accessed online and through mobile applications. Conclusion: Thirteen STW modules have been prepared with a view to optimize management of skin diseases at various levels of health care system of the country.

The Anti-Leukemic Activities of Campesterol and Α-Tocopherol Against BCL-2 Target through Computational Drug Design Approaches.

INTRODUCTION: Heterogeneous Acute Myeloid Leukemia (AML) causes substantial worldwide morbidity and death. AML is characterized by excessive proliferation of immature myeloid cells in the bone marrow and impaired apoptotic regulator expression. METHOD: B-Cell Lymphoma 2 (BCL-2), an anti-apoptotic protein overexpressed in AML, promotes leukemic cell survival and chemoresistance. Thus, reducing BCL-2 may treat AML. Anticancer activities are found in Aloe barbadensis Miller (Aloe vera). Thus, this work used molecular modeling to assess Aloe vera bioactive chemicals as BCL-2 inhibitors. Molecular docking simulation showed that all identified Aloe vera phytocompounds have strong BCL-2 binding affinities (-6.7 to -8.7 kcal/mol). RESULT: Campesterol and α-tocopherol were identified as promising compounds for BCL-2 inhibitor research based on their drug-likeness, pharmacokinetics, and toxicity profiles. The stability and conformational of the BCL-2-compound complexes showed that the compounds were stable in BCL-2's binding pocket. CONCLUSION: Campesterol and α-tocopherol are promising BCL-2 inhibitors that might become effective anti-leukemic therapies with additional in vitro and in vivo research.

Distalization of Ectopically Erupted Molars Using a Modified Humphrey's Appliance.

Ectopic eruption of molars occurs more frequently in developing permanent dentition, and requires immediate intervention. Herein, two cases are discussed with ectopic eruption of permanent maxillary first molars which were diagnosed and managed conservatively using a modified Humphrey's appliance, named the NR's appliance. The appliance was fabricated by band adaptation and using wire components of a 21-gauge stainless-steel wire. Also, the Nance palatal arch was used as the anchorage unit. The molars were uprighted and distalized within 3 months. Early diagnosis and prompt treatment could result in prevention of malocclusion in the early mixed dentition period.

Identification of Potential Inhibitors of TGFßR1 for the treatment of Cancer through Structure-based virtual screening and Molecular dynamics simulations.

Globally, cancer is one of the leading causes of death. Resistance to conventional medications, such as chemotherapy and radiation, continues to be a significant challenge in the treatment of cancer despite the availability of numerous medicines. Therefore, the highest priority is to hunt for new therapeutic agents. Transforming growth factor-beta is a pivotal regulatory cytokine that exerts significant influence over cellular processes, particularly emphasizing its role in facilitating and modulating cell proliferation. TGFß1, identified as most promising active site of the TGF-ß signaling, is a potent drug target site that has garnered wide attention for developing new anticancer agents. The present investigation investigates the potential phytochemicals as TGFßR1 inhibitors. The SB431542 complexed TGFßR1 protein model was used to screen the natural product database to obtain a compound with high binding potential. NPC247629 has emerged as the best-scored compound among all the screened compounds, demonstrating the highest affinity towards the TGFßR1 regarding docking score -17.54 kcal/mol. The MD simulation study indicated that all proposed hits are retained inside the receptor in dynamic states. The best-screened hits, NPC247629 and NPC60735, have excellent binding affinity and hold a massive potential for TGFßR1 inhibition, paving the way for promising future investigations in cancer treatment.

Magical role of iron nanoparticles for enhancement of thermal efficiency and gene regulation of fish in response to multiple stresses.

The present study addresses the challenges of uncontrolled temperature and pollution in aquatic environments, with a focus on fish ability to tolerate high temperature. The investigation aimed to determine the role of iron nanoparticles (Fe-NPs) in enhancing the thermal tolerance of Pangasianodon hypophthalmus exposed to high-temperature stress, arsenic (As), and ammonia (NH3) toxicity. Fe-NPs were synthesized using green approaches, specifically from fish gill. The dietary Fe-NPs were formulated and supplemented at 10, 15, and 20 mg kg⁻1 of feed. Notably, Fe-NPs at 15 mg kg⁻1 diet significantly reduced the critical thermal minimum (CTmin) (14.44 ± 0.21 °C) and the lethal thermal minimum (LTmin) (13.46 ± 0.15 °C), compared to the control and other treatment groups. Conversely, when Fe-NPs at 15 mg kg⁻1 were supplemented with or without exposure to stressors (As + NH3+T), the critical thermal maximum (CTmax) increased to 47.59 ± 0.16 °C, and the lethal thermal maximum (LTmax) increased to 48.60 ± 0.37 °C, both significantly higher than the control and other groups. A strong correlation was observed between LTmin and CTmin (R2 = 0.90) and between CTmax and LTmax (R2 = 0.98). Furthermore, dietary Fe-NPs at 15 mg kg⁻1 significantly upregulated the expression of stress-related genes, including HSP70, iNOS, Caspase-3a, CYP450, MT, cat, sod, gpx, TNFα, IL, TLR, and Ig. The enhanced thermal tolerance (LTmin and LTmax) can be attributed to these gene regulations, suggesting the mechanistic involvement of Fe-NPs in improving thermal resilience. Overall, the findings demonstrate that dietary supplementation with Fe-NPs, particularly at 15 mg kg⁻1, improves thermal tolerance and stress response in P. hypophthalmus by enhancing gene expression and overall thermal efficiency under stressor conditions.

Cranial nerve palsies in leprosy: a systematic review of published case reports and case series.

BACKGROUND: In leprosy, peripheral nerve involvement is well-documented, cranial nerve impairment in leprosy is less frequently reported, often through isolated case reports. This review aims to elucidate the pattern and spectrum of cranial nerve involvement in leprosy patients, enhancing understanding about pathogenesis and management. METHODS: Adhering to PRISMA guidelines, we conducted a systematic review of case reports and series documenting cranial nerve involvement in leprosy. Searches were performed across PubMed, Scopus, Embase, and Google Scholar up to February 2, 2024, without language restrictions. RESULTS: We identified 40 documents reporting on 49 patients, with a mean age of 41.3 years and a predominance of male patients (87.6%). Cranial nerve involvement included the trigeminal nerve (28.6%), facial nerve (38.8%), and instances of multiple cranial nerve palsies (10.2%). Magnetic resonance imaging findings indicated nerve T2/FLAIR hyperintensity/enhancements. Neuroimaging abnormalities extended up to brain stem. Approximately 30% of patients experienced lepra reactions, with 51% showing improvement following treatment. Following mutidrug therapy (MDT), neuroimaging abnormalities were vanished. CONCLUSION: Cranial nerve involvement in leprosy primarily affects the trigeminal and facial nerves, with multiple cranial nerves also being implicated. Exaggerated inflammation during lepra reaction involve nerve trunks and/or brainstem nuclei.

Forecasting the Pharmacological Mechanisms of Plumbago zeylanica and Solanum xanthocarpum in Diabetic Retinopathy Treatment: A Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation Study.

(1) Background: Diabetic retinopathy (DR) is a major complication of diabetes, marked by abnormal angiogenesis, microaneurysms, and retinal hemorrhages. Traditional Ayurvedic medicine advocates multi-target strategies for DR management. However, the mechanisms by which Solanum xanthocarpum (SX) and Plumbago zeylanica (PZ) exert therapeutic effects are not well understood; (2) Methods: To investigate these mechanisms, we employed network pharmacology and molecular docking techniques. Phytochemicals from SX and PZ were identified using the IMPPAT database and Swiss Target Prediction tool. DR-related protein targets were sourced from the GeneCards database, and common targets were identified through Venn diagram analysis. STRING and Cytoscape were used to construct and analyze protein-protein interaction networks. Pathway enrichment was performed with Gene Ontology and KEGG databases; (3) Results: We identified 28 active phytoconstituents, targeting proteins such as EGFR, SRC, STAT3, AKT1, and HSP90AA1. Molecular docking and dynamics simulations confirmed the strong binding affinities of these compounds to their targets; (4) Conclusions: The study highlights the multi-target activity of SX and PZ, particularly in pathways related to EGFR tyrosine kinase inhibitor resistance and PI3K-AKT signaling. These findings provide valuable insights into their therapeutic potential for DR, suggesting the effective modulation of key molecular pathways involved in the disease.

Profiling sorghum-microbe interactions with a specialized photoaffinity probe identifies key sorgoleone binders in Acinetobacter pittii.

Interactions between plants and soil microbial communities that benefit plant growth and enhance nutrient acquisition are driven by the selective release of metabolites from plant roots, or root exudation. To investigate these plant-microbe interactions, we developed a photoaffinity probe based on sorgoleone (sorgoleone diazirine alkyne for photoaffinity labeling, SoDA-PAL), a hydrophobic secondary metabolite and allelochemical produced in Sorghum bicolor root exudates. We applied SoDA-PAL to the identification of sorgoleone-binding proteins in Acinetobacter pittii SO1, a potential plant growth-promoting microbe isolated from sorghum rhizosphere soil. Competitive photoaffinity labeling of A. pittii whole cell lysates with SoDA-PAL identified 137 statistically enriched proteins, including putative transporters, transcriptional regulators, and a subset of proteins with predicted enzymatic functions. We performed computational protein modeling and docking with sorgoleone to prioritize candidates for experimental validation and then confirmed binding of sorgoleone to four of these proteins in vitro: the α/ß fold hydrolase SrgB (OH685_09420), a fumarylacetoacetase (OH685_02300), a lysophospholipase (OH685_14215), and an unannotated hypothetical protein (OH685_18625). Our application of this specialized sorgoleone-based probe coupled with structural bioinformatics streamlines the identification of microbial proteins involved in metabolite recognition, metabolism, and toxicity, widening our understanding of the range of cellular pathways that can be affected by a plant secondary metabolite.IMPORTANCEHere, we demonstrate that a photoaffinity-based chemical probe modeled after sorgoleone, an important secondary metabolite released by sorghum roots, can be used to identify microbial proteins that directly interact with sorgoleone. We applied this probe to the sorghum-associated bacterium Acinetobacter pittii and showed that probe labeling is dose-dependent and sensitive to competition with purified sorgoleone. Coupling the probe with proteomics and computational analysis facilitated the identification of putative sorgoleone binders, including a protein implicated in a conserved pathway essential for sorgoleone catabolism. We anticipate that discoveries seeded by this workflow will expand our understanding of the molecular mechanisms by which specific metabolites in root exudates shape the sorghum rhizosphere microbiome.

A Thorough Review on Ethnomedicinal Value of Bioactive Compounds of Pteridophytes against Cancer: Clinical Applications and Future Prospects.

Most cancers have become immune to normal cancer therapy, like chemotherapy and radiation. Therefore, exploring more effective and economical treatment options is important. Plants and herbs contain substances called phytochemicals, which have biological effects. Many phytochemicals having antioxidant and anticancer properties have been studied previously. There is increasing evidence that phytochemicals' anti-carcinogenic benefits originate from their ability to inhibit oxidation, inflammation, cell proliferation, and angiogenesis. These phytochemicals inhibit the spread of cancer by controlling the cell cycle and other molecular processes, such as metastasis. Along with therapeutic potential, other advantages, like their abundance, greater tolerability, and economic use, increase their utility in cancer therapeutics. In recent years, a number of scientists have examined lycophytes and ferns for their potential medicinal and phytochemical properties. This analysis emphasizes the significance of chemicals obtained from ferns and their derivatives in therapeutics. The authors discuss the pteridophyte's anti-cancer properties and other medical uses in this article. This information may help researchers in further research related to the most promising anticancer phytochemicals and their possibility as alternative drugs against cancer.

Multiple Effects of L-Leucine in Escherichia coli Lead to L-Leucine-Sensitive Growth in the Absence of Unphosphorylated PtsN.

In E. coli K-12, the absence of unphosphorylated PtsN (unphospho-PtsN) has been proposed to cause an L-leucine-sensitive growth phenotype (LeuS) by hyperactivated K+ uptake mediated impairment of the expression of the ilvBN operon, encoding subunits of the L-valine (Val)-sensitive acetohydroxyacid synthase I (AHAS I) that renders residual AHAS activity susceptible to inhibition by Leu and K+. This leads to AHAS insufficiency and a requirement for L-isoleucine (Ile). Herein, we provide an alternate mechanism for the LeuS of the ∆ptsN mutant. Genetic and physiological studies with suppressors of the LeuS indicate that impaired expression of the ilvBN operon jointly caused by the absence of unphospho-PtsN and the presence of Leu coupled to Leu-mediated repression of expression of AHAS III leads to AHAS insufficiency rendering residual AHAS activity susceptible to chronic Val stress that may be generated by exogenous Leu. Hyperactivated K+ uptake and an elevated α-ketobutyrate level mediate elevation of ilvBN expression and alleviate the LeuS. The requirement of unphospho-PtsN as a positive regulator of ilvBN expression may buffer Ile biosynthesis against Leu-mediated AHAS insufficiency and protect AHAS I function from chronic endogenous Val generated by Leu and could be realized in certain environments that impair AHAS function.

Modified nasopharyngeal airway for pressure support ventilation in airway management of a case of Robin sequence with bilateral temporomandibular joint ankylosis.

The association of Robin sequence (RS) with temporomandibular joint (TMJ) ankylosis is not a common occurrence. Due to restricted mouth opening, difficult bag valve mask ventilation and difficult intubation, such cases are always challenging for anaesthesiologists.A male patient in early childhood with RS and bilateral TMJ ankylosis was scheduled for bilateral gap arthroplasty. Airway management was planned with fibreoptic intubation under sedation to preserve spontaneous ventilation. After sedating the patient, a nasopharyngeal airway modified by using an endotracheal tube connector was inserted in the left nostril and connected to the ventilator circuit with a 15 mm universal connector. Pressure support ventilation was given with continuous end-tidal CO2 monitoring. Fibreoptic intubation was done through the right nostril with maintenance of spontaneous ventilation.Nasal pressure support ventilation assembly can be made with available equipment in the operation theatre. It can be a substitute for a high-flow nasal cannula in particular cases.

Exploring novel Apalutamide analogues as potential therapeutics for prostate cancer: design, molecular docking investigations and molecular dynamics simulation.

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100 nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Emergence of Interfacial Magnetism in Strongly-Correlated Nickelate-Titanate Superlattices.

Strongly-correlated transition-metal oxides are widely known for their various exotic phenomena. This is exemplified by rare-earth nickelates such as LaNiO3, which possess intimate interconnections between their electronic, spin, and lattice degrees of freedom. Their properties can be further enhanced by pairing them in hybrid heterostructures, which can lead to hidden phases and emergent phenomena. An important example is the LaNiO3/LaTiO3 superlattice, where an interlayer electron transfer has been observed from LaTiO3 into LaNiO3 leading to a high-spin state. However, macroscopic emergence of magnetic order associated with this high-spin state has so far not been observed. Here, by using muon spin rotation, x-ray absorption, and resonant inelastic x-ray scattering, direct evidence of an emergent antiferromagnetic order with high magnon energy and exchange interactions at the LaNiO3/LaTiO3 interface is presented. As the magnetism is purely interfacial, a single LaNiO3/LaTiO3 interface can essentially behave as an atomically thin strongly-correlated quasi-2D antiferromagnet, potentially allowing its technological utilization in advanced spintronic devices. Furthermore, its strong quasi-2D magnetic correlations, orbitally-polarized planar ligand holes, and layered superlattice design make its electronic, magnetic, and lattice configurations resemble the precursor states of superconducting cuprates and nickelates, but with an S→1 spin state instead.

CSF-venous fistulas associated with traumatic spinal pseudomeningoceles.

CSF-venous fistulas (CVFs) are a common cause of spontaneous intracranial hypotension. These fistulas usually occur without any preceding major trauma, surgery, or other iatrogenic cause. Occasionally, patients have a history of minor trauma, though such cases are usually still considered spontaneous. Little is known about predisposing factors that cause patients to develop spontaneous CVFs. Most patients with CVFs have multiple meningeal diverticula on spine imaging, and fistulas usually arise in association with a diverticulum. In the vast majority of cases, the culprit diverticulum from which the CVF arises is atraumatic in origin, presumably on the spectrum of normal variation in spinal anatomy. Here, we present two cases of CVFs that arose in association with posttraumatic pseudomeningoceles. To our knowledge, this phenomenon has not yet been reported, and it potentially represents a novel etiology for CVFs that furthers understanding of their pathogenesis.

Prolactinoma: Navigating the Dual Challenge of Side Effects and Treatment Strategies - A Comprehensive Review.

This narrative review provides a succinct exploration of prolactinoma, the most common pituitary adenoma, focusing on its epidemiology, clinical manifestations, and therapeutic interventions. Beginning with an overview of its prevalence and aetiology, the review delves into the gender distribution and familial associations of prolactinoma. Clinical presentations, including endocrine disruptions, reproductive health issues, and metabolic disturbances, are examined, emphasizing their impact on hormonal regulation and cardiovascular health. The narrative then navigates through pharmacological treatments, surgical interventions, and radiation therapy, highlighting their efficacy, side effects, and long-term management challenges. Strategies to mitigate side effects and optimize treatment outcomes are discussed, emphasizing the importance of multidisciplinary collaboration in prolactinoma management. This review is a concise yet comprehensive resource for healthcare professionals and researchers, providing insights into prolactinoma's clinical complexities and therapeutic nuances to guide optimal patient care strategies.

Predictive identification and design of potent inhibitors targeting resistance-inducing candidate genes from E. coli whole-genome sequences.

Introduction: This work utilizes predictive modeling in drug discovery to unravel potential candidate genes from Escherichia coli that are implicated in antimicrobial resistance; we subsequently target the gidB, MacB, and KatG genes with some compounds from plants with reported antibacterial potentials. Method: The resistance genes and plasmids were identified from 10 whole-genome sequence datasets of E. coli; forty two plant compounds were selected, and their 3D structures were retrieved and optimized for docking. The 3D crystal structures of KatG, MacB, and gidB were retrieved and prepared for molecular docking, molecular dynamics simulations, and ADMET profiling. Result: Hesperidin showed the least binding energy (kcal/mol) against KatG (-9.3), MacB (-10.7), and gidB (-6.7); additionally, good pharmacokinetic profiles and structure-dynamics integrity with their respective protein complexes were observed. Conclusion: Although these findings suggest hesperidin as a potential inhibitor against MacB, gidB, and KatG in E. coli, further validations through in vitro and in vivo experiments are needed. This research is expected to provide an alternative avenue for addressing existing antimicrobial resistances associated with E. coli's MacB, gidB, and KatG.

Estimation of the injection criteria for magnetic hyperthermia therapy based on tumor morphology.

Intratumoral multi-injection strategy enhances the efficacy of magnetic nanoparticle hyperthermia therapy (MNPH). In this study, criteria for the selection of injections and their location depending on the tumor shape/geometry are developed. The developed strategy is based on the thermal dosimetry results of different invasive 3D tumor models during MNPH simulation. MNPH simulations are conducted on physical tumor tissue models encased within healthy tissue. The tumor shapes are geometrically divided into a central tumor region containing maximum tumor volume and a peripheral tumor portion protruding in any random direction. The concepts of core and invasive radius are used to geometrically divide the tumor volume. Primary & secondary injections are used to inject MNP fluid into these respective tumor regions based on the invasiveness of the tumor. The optimization strategy is devised based on the zone of influence of primary & secondary injection. Results indicate that the zone of influence of secondary injection lies between 0.7 and 0.8 times the radial distance between the center of the tumor core and branch node point (extreme far endpoint on the invasive tumor surface). Additionally, the multi-injection strategy is more effective when the protrusion volume exceeds10%of the total volume. The proposed algorithm is used to devise multi-injection strategies for arbitrarily shaped tumors and will assist in pre-planning magnetic nanoparticle hyperthermia therapy.