Bispectral index-guided comparison of dexmedetomidine and fentanyl as an adjuvant with propofol to achieve an adequate depth for endotracheal intubation - A double-blind randomised controlled trial.

Background and Aims: Laryngoscopy and tracheal intubation require an adequate depth of anaesthesia. The study's primary objective was to compare the time needed to achieve the bispectral index (BIS)-guided adequate depth of anaesthesia for endotracheal intubation using fentanyl and dexmedetomidine. Methods: After institutional ethics committee clearance and written informed consent, this randomised study was conducted on 140 patients of either gender between 18 and 60 years who were scheduled for elective surgeries under general anaesthesia. Patients were randomised to intravenous dexmedetomidine 1 µg/kg (Group D) or fentanyl 2 µg/kg (Group F). The drugs were given as an intravenous infusion over 10 min before induction of anaesthesia. The primary outcome was the time required to achieve BIS 50. Normally distributed variables were compared using Student's t-test, and non-normally distributed variables were compared using the Mann-Whitney U test. Qualitative data were analysed using Chi-square/Fisher's exact test. A P value <0.05 was considered significant. Results: The time to achieve BIS 50 was lesser in Group F, 1546 (27) as compared to Group D, 1558 (11) s [mean difference (95% confidence interval (CI) 12[5.11, 18.89]), P < 0.001]. Haemodynamic parameters were comparable at all time points between both the groups, except heart rate, which was significantly lower. Propofol consumption was significantly less in group D than in group F [125.9 (25.36) versus 157.3 (42.80) mg, respectively, mean difference (95% CI) 31.4 (-44.16 to -20.63) P < 0.001)]. Conclusion: Dexmedetomidine achieves BIS 50 faster and has a propofol-sparing effect as compared to fentanyl.

Tear Film Dynamics in Visual Display Terminal Users: A Review of Impact on Goblet Cells, Lacrimal and Meibomian Gland Function.

PURPOSE: The prevalence of dry eye disease (DED) is rising among visual display terminal (VDT) users, a trend that correlates with the growing use of digital devices. The prevalence of VDT-associated DED is reported based on dry eye questionnaires; however, VDT's impact on tear film parameters is less understood. METHODS: A review of published literature on both the alterations in tear film observed in VDT users and the impact of various interventions on their tear film. RESULTS: Most studies show reduction in tear stability as well as reduction in the blink rate. The role of lacrimal gland hypofunction in visual display terminal (VDT) users is a subject of ongoing debate. Schirmer test values typically exceed the 10 mm threshold, suggesting normal tear production, and tear osmolarity remains within normal ranges but VDT users consistently present with lower Schirmer values compared to non-VDT users. The effects on Meibomian glands and mucin levels need more research as the numbers studied are small. Very few studies have analysed mucin levels in VDT users with reports of normal or reduced values. Even asymptomatic users can have tear film instability; hence, the diagnostic criteria need to be formulated and validated. Different interventions such as neurostimulation, blink improving apps, eyelid warming devices, moist goggles, and lubricants have been explored in VDT users but without a control arm and in asymptomatic VDT users in most studies. CONCLUSION: The alterations have been observed on aqueous, lipid and mucin components of the tear film, although the extent of the impact is variable across studies. There is urgent need of well-designed studies for studying the tear film changes and management options for the upcoming lifestyle epidemic in VDT users.

Body composition parameters as predictors of low back pain in rural homemakers of North India.

Background: Homemakers are the backbones of families, but in rural India, females suffer from many musculoskeletal problems due to excessive workload in their houses. The objective of the present study is to compare body composition parameters as predictors of low back pain (LBP) in nonworking rural homemakers of North India. Materials and Methods: The study was conducted among 296 homemakers from rural areas of Lucknow district in Uttar Pradesh. Details of LBP and body composition parameters (body mass index, body fat, visceral fat) were taken. Results: The prevalence of LBP among homemakers was found to be 15.54%. BMI was found to be a better predictor of LBP than body fat and visceral fat. The risk of LBP is 7.24 times higher in BMI ≥23 than in women with BMI <23. The risk of LBP is 3.67 times more in visceral fat % ≥10% than in women with visceral fat % <10%. Conclusion: Age, type of family, socioeconomic status income was identified as risk factors in this population. Maintaining an adequate BMI is essential for the prevention of LBP.

A New Immortalized Human Lacrimal Gland Cell Line.

The lacrimal gland is crucial for maintaining ocular health by producing the aqueous component of the tear film, which hydrates and nourishes the ocular surface. Decreased production of this component results in dry eye disease, a condition affecting over 250 million people worldwide. However, the scarcity of primary human material for studying its underlying mechanisms and the absence of a cell model for human lacrimal gland epithelial cells present significant challenges. Here, we describe the generation of immortalized human lacrimal gland cell lines through the introduction of an SV40 antigen. We successfully isolated and characterized three cell clones from a female lacrimal gland donor, confirming their epithelial identity through genomic and protein analyses, including PCR, RNAseq, immunofluorescence and cultivation in a 3D spheroid model. Our findings represent a significant advancement, providing improved accessibility to investigate the molecular pathogenesis mechanisms of dry eye disease and potential therapeutic interventions. We identified the expression of typical epithelial cell marker genes and demonstrated the cells' capability to form 2D cell sheets and 3D spheroids. This establishment of immortalized human lacrimal gland cells with epithelial characteristics holds promise for future comprehensive studies, contributing to a deeper understanding of dry eye disease and its cellular mechanisms.

Two sisters with RSPRY1-related spondyloepimetaphyseal dysplasia.

Biallelic variants in RSPRY1 have been found to result in spondyloepimetaphyseal dysplasia. Two siblings presenting with short stature, facial dysmorphism, progressive vertebral defects, small epiphysis, cupping and fraying of metaphyses, brachydactyly, and short metatarsals harbored a homozygous missense variant c.1652G>A;p.(Cys551Tyr) in the RSPRY1 gene. The phenotype in our patients resembles spondyloepimetaphyseal dysplasia, Faden-Alkuraya type. Thus, our study provides further evidence to support the association of RSPRY1 variants with spondyloepimetaphyseal dysplasia. We observed joint dislocation as a novel clinical feature of this condition.

Congenital cardiac anomalies in non-syndromic cleft lip and cleft palate patients: A systematic review and meta-analysis.

The aim was to establish a specific and definite connection between non-syndromic orofacial cleft patients and associated congenital heart disease (CHD). Following PRISMA guidelines, selective databases were searched for data collection. Studies showing a definite association of CHD with orofacial cleft were included, and studies non-specific of the association of orofacial cleft with CHD were excluded. Data extraction criteria were study design, frequency of CHD in overall non-syndromic orofacial cleft and in specific cleft type, and most prevalent congenital cardiac anomaly. DerSimonian Laird random effects model was used to estimate the pooled proportion of CHD, along with corresponding 95% confidence intervals (CIs) for each measure. Publication bias was assessed using Fail-Safe N analysis and the Rosenthel approach. Of a total of 182 articles searched, only 30 studies were assessed. The overall pooled estimate of the proportion of CHD in total cleft lips/palates was 16% (95% CI: 13-19). The odds of developing CHD in cleft palates was 4.08 times more as compared to cleft lips with 95% CIs of 3.86-4.33, and 1.65 more as compared to cleft lips and palates both with 95% CI of 1.52-1.68. We affirm the upsurging prevalence of CHD in non-syndromic cleft children and vehemently propose that it is of utmost importance to inculcate it in practice and policy-making to screen all non-syndromic orofacial cleft children for congenital cardiac anomaly. This study was registered on PROSPERO (ID no. CRD42023391597) on February 24, 2023.

Erratum: Antibacterial Efficacy of ZnO/Bentonite (Clay) Nanocomposites against Multidrug-Resistant Escherichia coli.

[This corrects the article DOI: 10.1021/acsomega.3c07950.].

Alzheimer's disease and clinical trials.

Alzheimer's disease (AD) is spreading its root disproportionately among the worldwide population. Many genes have been identified as the hallmarks of AD. Based upon the knowledge, many clinical trials have been designed and conducted. Attempts have been made to alleviate the pathology associated with AD by targeting the molecular products of these genes. Irrespective of the understanding on the genetic component of AD, many clinical trials have failed and imposed greater challenges on the path of drug discovery. Therefore, this review aims to identify research and review articles to pinpoint the limitations of drug candidates (thiethylperazine, CT1812, crenezumab, CNP520, and lecanemab), which are under or withdrawn from clinical trials. Thorough analysis of the cross-talk pathways led to the identification of many confounding factors, which could interfere with the success of clinical trials with drug candidates such as thiethylperazine, CT1812, crenezumab, and CNP520. Though these drug candidates were enrolled in clinical trials, yet literature review shows many limitations. These limitations raise many questions on the rationale behind the enrollments of these drug candidates in clinical trials. A meticulous prior assessment of the outcome of clinical studies may stop risky clinical trials at their inceptions. This may save time, money, and resources.

A gain of function mutation in AKT1 increases hexokinase 2 and diminishes oxidative stress in meningioma.

Increasing evidence suggests the oncogenic role of missense mutation (AKT1-E17K) of AKT1 gene in meningiomas. Upon investigating the connection between the pro-tumorigenic role of AKT1-E17K and cellular metabolic adaptations, elevated levels of glycolytic enzyme hexokinase 2 (HK2) was observed in meningioma patients with AKT1-E17K compared to patients harboring wild-type AKT1. In vitro experiments also suggested higher HK2 levels and its activity in AKT1-E17K cells. Treatment with the conventional drug of choice AZD5363 (a pan AKT inhibitor) enhanced cell death and diminished HK2 levels in AKT1 mutants. Given the role of AKT phosphorylation in eliciting inflammatory responses, we observed increased levels of inflammatory mediators (IL-1ß, IL6, IL8, and TLR4) in AKT1-E17K cells compared to AKT1-WT cells. Treatment with AKT or HK2 inhibitors dampened the heightened levels of inflammatory markers in AKT1-E17K cells. As AKT and HK2 regulates redox homeostasis, diminished ROS generation concomitant with increased levels of NF-E2- related factor 2 (Nrf2) and superoxide dismutase 1 (SOD1) were observed in AKT1-E17K cells. Increased sensitivity of AKT1-E17K cells to AZD5363 in the presence of HK2 inhibitor Lonidamine was reversed upon treatment with ROS inhibitor NAC. By affecting metabolism, inflammation, and redox homeostasis AKT1-E17K confers a survival advantage in meningioma cells. Our findings suggest that targeting AKT-HK2 cross-talk to induce ROS-dependent cell death could be exploited as novel therapeutic approach in meningiomas.

Metal nanoparticles to improve the heat resilience in wheat (Triticum aestivumL.).

This study evaluated the efficacy of phytogenic silver and zinc nanoparticles in improving heat resilience in various wheat varieties. The silver and zinc nanoparticles were synthesized using plant leaf extract and characterized using various techniques. Four wheat varieties (DBW187, Black Wheat, DBW 50, and PBW 621) were subjected to field trials. The random block design was used, and nanoparticles in different concentrations were applied at various growth stages and morphologically, and yield parameters were recorded. UV-vis spectroscopy spectral analysis showed peaks for Ag nanoparticles at 420 nm wavelength and Zn nanoparticles at 240 and 350 nm wavelength, depicting the preliminary confirmation of nanoparticle synthesis. Electron microscopic analysis (TEM and SEM) provided morphological insights and confirmed synthesis of fine-sized particle mostly in a range between 10 and 60 nm. Energy dispersive x-ray analysis confirmed the elemental composition of the synthesized nanoparticles, with Ag and Zn elements detected in their respective samples. It also confirmed the oxide nature of synthesized ZnNPs. Dynamic light scattering analysis provided size distribution profiles, indicating average sizes of approximately 61.8 nm for Ag nanoparticles and 46.5 nm for Zn nanoparticles. The concentrations of Ag and Zn nanoparticles in the samples were found to be 196.3 ppm and 115.14 ppm, respectively, through atomic absorption spectroscopic analysis. Fourier transform infrared spectroscopy analysis revealed characteristic functional groups present in the nanoparticles. The results of field experiments established that Ag nanoparticles at 75 ppm concentration exhibited the most significant enhancements in plant growth. Conversely, Zn nanoparticles at a 100 ppm concentration demonstrated the most substantial improvements in the growth and yield of heat-stressed wheat varieties. The study concludes that optimized concentrations of silver and zinc nanoparticles can effectively improve heat stress resilience in wheat. These findings are promising to enhance abiotic stress resilience in crops.

The Synthesis, Characterization, and Assessment of Antibacterial Properties of an Orthodontic Adhesive Containing Cerium-Substituted Hydroxyapatite Nanoparticles: An In Vitro Study.

Introduction White spot lesions (WSLs) are early enamel caries lesions often seen in individuals receiving fixed orthodontic treatment. These lesions occur due to the buildup of plaque and the colonization of bacteria. WSL formation can be prevented by adequate oral hygiene measures and by the incorporation of antimicrobial nanoparticles (NPs) in orthodontic appliances and bonding systems. The aim of this research was to synthesize cerium-substituted hydroxyapatite nanoparticles (Ce-HAp NPs), characterize them, and assess their antimicrobial activity. Materials and methods This in vitro investigation involved the preparation of Ce-HAp NPs using the co-precipitation method, followed by their characterization using scanning electron microscope (SEM), energy-dispersive X-ray (EDAX), and Fourier transform infrared (FTIR). The NPs were prepared and subsequently added to an orthodontic adhesive. Antibacterial testing was conducted using the disc diffusion method against common oral pathogens (Staphylococcus aureus, Lactobacillus acidophilus, and Streptococcus mutans). The zones of inhibition were measured for two different concentrations of the adhesive. Results  The Ce-HAp NPs were successfully prepared and had an irregular agglomerated shape, measuring 63 nm in size. The major characteristic chemical groups of Ce-HAp were PO43-, OH-, and CO32-, and it was confirmed by the FTIR spectrum. The EDAX results of the synthesized NPs showed theoretical weight percentages (Wt%) of O, 52.6%; Ca, 20.9%; P, 11.8%; C, 10.3%; and Ce, 4.3%. A higher concentration of 40 µg/mL (30 mm for S. aureus and L. acidophilus and 25 mm for S. mutans) showed good antibacterial activity against the tested bacterial strains, compared to control antibiotics. Conclusion Cerium oxide (CeO2)-HAp NPs were prepared and incorporated into an orthodontic adhesive. The prepared adhesive exhibited effective antibacterial activity against prevalent oral pathogens.

Mitochondrial atp1 mRNA knockdown by a custom-designed pentatricopeptide repeat protein alters ATP synthase.

Spontaneous mutations are rare in mitochondria and the lack of mitochondrial transformation methods has hindered genetic analyses. We show that a custom-designed RNA-binding pentatricopeptide repeat (PPR) protein binds and specifically induces cleavage of ATP synthase subunit1 (atp1) mRNA in mitochondria, significantly decreasing the abundance of the Atp1 protein and the assembled F1Fo ATP synthase in Arabidopsis (Arabidopsis thaliana). The transformed plants are characterized by delayed vegetative growth and reduced fertility. Five-fold depletion of Atp1 level was accompanied by a decrease in abundance of other ATP synthase subunits and lowered ATP synthesis rate of isolated mitochondria, but no change to mitochondrial electron transport chain complexes, adenylates, or energy charge in planta. Transcripts for amino acid transport and a variety of stress response processes were differentially expressed in lines containing the PPR protein, indicating changes to achieve cellular homeostasis when ATP synthase was highly depleted. Leaves of ATP synthase-depleted lines showed higher respiratory rates and elevated steady-state levels of numerous amino acids, most notably of the serine family. The results show the value of using custom-designed PPR proteins to influence the expression of specific mitochondrial transcripts to carry out reverse genetic studies on mitochondrial gene functions and the consequences of ATP synthase depletion on cellular functions in Arabidopsis.

Antibacterial Efficacy of ZnO/Bentonite (Clay) Nanocomposites against Multidrug-Resistant Escherichia coli.

The emergence of multidrug-resistant (MDR) bacteria has spurred the exploration of therapeutic nanomaterials such as ZnO nanoparticles. However, the inherent nonspecific toxicity of ZnO has posed a significant obstacle to their clinical utilization. In this research, we propose a novel approach to improve the selectivity of the toxicity of ZnO nanoparticles by impregnating them onto a less toxic clay mineral, Bentonite, resulting in ZB nanocomposites (ZB NCs). We hypothesize that these ZB NCs not only reduce toxicity toward both normal and carcinogenic cell lines but also retain the antibacterial properties of pure ZnO nanoparticles. To test this hypothesis, we synthesized ZB NCs by using a precipitation technique and confirmed their structural characteristics through X-ray diffraction and Raman spectroscopy. Electron microscopy revealed composite particles in the size range of 20-50 nm. The BET surface area of ZB NCs, within a relative pressure (P/P0) range of 0.407-0.985, was estimated to be 31.182 m2/g. Notably, 50 mg/mL ZB NCs demonstrated biocompatibility with HCT 116 and HEK 293 cell lines, supported by flow cytometry and fluorescence microscopy analysis. In vitro experiments further confirmed a remarkable five-log reduction in the population of MDR Escherichia coli in the presence of 50 mg/mL of ZB NCs. Antibacterial activity of the nanocomposites was also validated in the HEK293 and HCT 116 cell lines. These findings substantiate our hypothesis and underscore the effectiveness of ZB NCs against MDR E. coli while minimizing nonspecific toxicity toward healthy cells.

Neuroinflammation and Acetylcholinesterase Inhibitory Potentials of a Spiroketal-Enol Ether Polyyne Isolated from Artemisia pallens Wall. ex DC.

Artemisia pallens Wall. ex DC (Asteraceae) is cultivated for the production of high-value essential oil from its aerial biomass. In this study, the chemical composition of the root (crop-residue) essential oil was investigated for the first time, using column-chromatography, GC-FID, GC-MS, LC-QTOF, and NMR techniques, which led to the identification of twenty constituents, with isolation of (E)-2-(2',4'-hexadiynylidene)-1,6-dioxaspiro [4.5]dec-3-ene (D6). The D6 was evaluated in vitro for neuroinflammation and acetylcholinesterase inhibitory potential. It showed inhibition of neuroinflammation in a concentration-dependent manner with significant inhibition of pro-inflammatory cytokines (TNF-α and IL-6) in LPS-stimulated BV2 microglial cells. D6 did not have any significant effect on the viability of the cells at the therapeutic concentrations. D6 also has shown acetylcholinesterase inhibitory potential (51.90±1.19 %) at the concentration of log 106  nM. The results showed that D6 has a potential role in the resolution of neuroinflammation, and its acetylcholinesterase inhibitory potential directs further investigation of its role in the management of Alzheimer's disease-related pathogenesis.

Comprehensive Study on the Age-Strengthened Mg-Zn-Mn-Ca/ZnO Composites for Fracture Fixation: Microstructure, Mechanical, and In Vitro Biocompatibility Evaluation.

The present work investigates the use of age-strengthened Mg-Zn-Mn-Ca/xZnO as resorbable materials in temporary orthopedic implants. Quaternary Mg-Zn-Mn-Ca alloy, reinforced with zinc oxide particles, was stir-cast, followed by solution treatment and a range of aging treatments. Optical and electron microscopy, mechanical, electrochemical, immersion, and dynamic mechanical testing, with biocompatibility assessment were carried out. The observed 2θ shift in the (101) peaks of ZMX611/ZnO-ST and ZMX611/ZnO-H indicated lattice shrinkage. The formation of Mg7Zn3 and Ca2Mg6Zn3 in the grain boundary compositions was observed. ZMX611/ZnO-ST had a smaller ß-phase fraction, indicating a finer microstructure. ZMX611/ZnO-H had the highest tensile yield strength (102.97 ± 3.92 MPa), and ZMX611/ZnO-ST showed the highest ultimate tensile strength (127.21 ± 7.48 MPa), indicating precipitation hardening of Zn enrichment. The uniformly dispersed secondary phases played a dual role in corrosion behavior. ZMX611/ZnO-ST showed a better cytocompatibility response among all samples. Composite materials exhibited satisfactory biocompatibility and mechanical compatibility as indicated by in silico results of deviatoric strain-based mechanical stimuli at the fracture interface.

Unveiling the cytotoxic and anti-proliferative potential of green-synthesized silver nanoparticles mediated by Colletotrichum gloeosporioides.

Fungal endophytes are a putative source of bioactive metabolites that have found significant applications in nanomedicine due to their metabolic versatility. In the present study, an aqueous extract of the fungal endophyte, Colletotrichum gloeosporioides associated with a medicinal plant Oroxylum indicum, has been used for the fabrication of green silver nanoparticles (CgAgNPs) and further evaluated their cytotoxic and anti-proliferative activity. Bioanalytical techniques including UV-Vis spectral analysis revealed a sharp band at 435 nm and functional molecules from the aqueous extract involved in the synthesis of CgAgNPs were evidenced through FTIR. Further, the crystalline nature of CgAgNPs was determined through XRD analysis and microscopy techniques including AFM, TEM and FESEM demonstrated the spherical shape of CgAgNPs exhibiting a crystalline hexagonal lattice and the size was found to be in the range of 9-29 nm. The significant cytotoxic potential of CgAgNPs was observed against breast cancer cells, MDA-MB-231 and MCF-7 with IC50 values of 18.398 ± 0.376 and 38.587 ± 1.828 µg mL-1, respectively. The biochemical study revealed that the treatment of MDA-MB-231 and MCF-7 cells with CgAgNPs reduces glucose uptake, suppresses cell proliferation, and enhances LDH release, indicating reduced cell viability and progression. Moreover, our research revealed differential expression of genes associated with apoptosis, cell cycle inhibition and metastasis suppression, evidencing anti-proliferative activity of CgAgNPs. The main objective of the present study is to harness anti-breast cancer activity of novel biogenic nanoparticles synthesized using the aqueous extract of O. indicum associated C. gloeosporioides and study the underlying mechanistic pathway exerted by these mycogenic nanoparticles.

Efficient and sustained FOXP3 locus editing in hematopoietic stem cells as a therapeutic approach for IPEX syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder caused by mutations in the FOXP3 gene, required for generation of regulatory T (Treg) cells. Loss of Treg cells leads to immune dysregulation characterized by multi-organ autoimmunity and early mortality. Hematopoietic stem cell (HSC) transplantation can be curative, but success is limited by autoimmune complications, donor availability and/or graft-vs.-host disease. Correction of FOXP3 in autologous HSC utilizing a homology-directed repair (HDR)-based platform may provide a safer alternative therapy. Here, we demonstrate efficient editing of FOXP3 utilizing co-delivery of Cas9 ribonucleoprotein complexes and adeno-associated viral vectors to achieve HDR rates of >40% in vitro using mobilized CD34+ cells from multiple donors. Using this approach to deliver either a GFP or a FOXP3 cDNA donor cassette, we demonstrate sustained bone marrow engraftment of approximately 10% of HDR-edited cells in immune-deficient recipient mice at 16 weeks post-transplant. Further, we show targeted integration of FOXP3 cDNA in CD34+ cells from an IPEX patient and expression of the introduced FOXP3 transcript in gene-edited primary T cells from both healthy individuals and IPEX patients. Our combined findings suggest that refinement of this approach is likely to provide future clinical benefit in IPEX.