Glomerulonephritis and Septic Pulmonary Embolism: A Rare but Life-Threatening Complication of Permanent Pacemaker Implantation.

Infection-related glomerulonephritis (IRGN) is an immunologically mediated glomerular injury triggered by an extrarenal infection. Infective endocarditis-associated glomerular nephritis is an entity caused by infection of the cardiac valves. IRGN is most common in children, and post-streptococcal glomerulonephritis (PSGN) is commonest in the age group of 2-14 years. In contrast to childhood PSGN and epidemic PSGN, which usually resolve completely with antibiotics, IRGN in adults has a guarded prognosis. Cardiovascular implantable electronic device-associated infective endocarditis (CIED-IE) is a phenomenon for which the incidence is on the rise (0.1-5.1%). The most frequent CIED-IE pathogens were staphylococci or other Gram-positive bacteria. CIED-IE poses difficult management problems for the clinician. We present the case of a 50-year-old patient with a pacemaker who was found to have infective endocarditis and septic embolism.

Novel chitosan-based barrier materials for environmental containment: Synthesis, characterization, and contaminant removal capacities and mechanisms.

This study critically appraises employing chitosan as a composite with bentonite, biochar, or both materials as an alternative to conventional barrier materials. A comprehensive literature review was conducted to identify the studies reporting chitosan-bentonite composite (CBC), chitosan amended biochar (CAB), and chitosan-bentonite-biochar composite (CBBC) for effective removal of various contaminants. The study aims to review the synthesis of these composites, identify fundamental properties affecting their adsorption capacities, and examine how these properties affect or enhance the removal abilities of other materials within the composite. Notably, CBC composites have the advantage of adsorbing both cationic and anionic species, such as heavy metals and dyes, due to the cationic nature of chitosan and the anionic nature of montmorillonite, along with the increased accessible surface area due to the clay. CAB composites have the unique advantage of being low-cost sorbents with high specific surface area, affinity for a wide range of contaminants owing to the high surface area and microporosity of biochar, and abundant available functional groups from the chitosan. Limited studies have reported the utilization of CBBC composites to remove various contaminants. These composites can be prepared by combining the steps employed in preparing CBC and CAB composites. They can benefit from the favorable adsorption properties of all three materials while also satisfying the mechanical requirements of a barrier material. This study serves as a knowledge base for future research to develop novel composite barrier materials by incorporating chitosan and biochar as amendments to bentonite.

Review of current perspectives and future outlook on bacterial disease prevention through vaccination in Asian seabass (Lates calcarifer).

Asian seabass, Lates calcarifer, is an important aquatic species in mariculture. Intensive farming of this species has faced episodes of bacterial diseases, including those due to vibriosis, scale drop, and muscle necrosis disease, big belly disease, photobacteriosis, columnaris, streptococcosis, aeromoniasis, and tenacibaculosis. Vaccination is one of the most efficient, non-antibiotic, and eco-friendly strategies for protecting fish against bacterial diseases, contributing to aquaculture expansion and ensuring food security. As of now, although numerous vaccines have undergone laboratory research, only one commercially available inactivated vaccine, suitable for both immersion and injection administration, is accessible for preventing Streptococcus iniae. Several key challenges in developing vaccines for Asian seabass must be addressed, such as the current limited understanding of immunological responses to vaccines, the costs associated with vaccine production, forms, and routes of vaccine application, and how to increase the adoption of vaccines by farmers. The future of vaccine development for the Asian seabass industry, therefore, is discussed with these key critical issues in mind. The focus is on improving our understanding of Asian seabass immunity, including maternal immunity, immunocompetence, and immune responses post-vaccination, as well as developing tools to assess vaccine effectiveness. The need for an alignment of fish vaccines with state-of-the-art vaccine technologies employed in human and terrestrial animal healthcare is also discussed. This review also discusses the necessity of providing locally-produced autogenous vaccines, especially for immersion and oral vaccines, to benefit small-scale fish farmers, and the potential benefits that might be extended through changes to current husbandry practices such as the vaccination of broodstock and earlier life stages of their off-spring.

Flow and contaminant transport dynamics in clay-amended barriers through flushing experiments and multi-porosity-based modeling.

Clay-amended barriers are widely used to prevent hazardous leachate percolation from landfill to subsurface. The performance of these barriers is mostly evaluated through numerical simulations with limited experimental investigation through leachate flushing experiments. To bridge this gap, contaminant loading and its flushing experiments were carried out to assess the performance of clay-amended composite materials as landfill liners. River sand (Sa), loamy soil (Ns), and alternative waste materials like fly ash (Fa) and flushed silt (Si) were used to prepare the composites. Composites fulfilling the hydraulic conductivity (<10-7 cm/s) and compressive strength (200 kPa) criteria were selected for contaminant loading and its flushing experiments to understand the fate of fluoride ions. The experimentally determined hydraulic conductivity (Ks) values for all the composites were in the order of 10-8 cm/s. The experimental breakthrough curves exhibited skewed shape, long tailing, and dual peaks. Dual porosity and dual permeability with immobile water models were employed to simulate these curves, revealing that preferential flow pathways and random chemical sorption sites significantly affect solute transport in clay-amended barriers. Further, scanning electron microscopy and energy-dispersive X-ray spectroscopy were employed to trace the preferred path of fluoride ions through the barrier. The removal efficiency and temporal moments were used to determine the percentage mass retained, mean arrival time, and spreading within the barrier. The highest solute mass was retained by sand-clay barrier (SaB30) (91%), followed by loam-clay barrier (NsB30) (59%), fly ash-clay barrier (FaB30) (38%), and silt-clay barrier (SiB30) (4%) with the least mass. The lowest mean arrival time was calculated for NsB30 (269 h) and the highest for SaB30 (990 h), with FaB30 (384 h) and SiB30 (512 h) having values in between. This study concludes that validating the design hypothesis of clay-amended barriers through contaminant loading and its flushing studies leads to an effective and sustainable design.

Effect of docosahexaenoic acid and olive oil supplementation on pup weight in alcohol-exposed pregnant rats.

Background: Low birth weight has been observed in offspring of alcoholic mothers due likely to unresolved inflammation and oxidative injury. Dietary lipids play a role in inflammation and its resolution. The primary objective was to investigate the effect of DHA and olive oil on the birth weight of pups born to alcohol-exposed dams. Methods: Pregnant rats were randomized to the control or three treatment (alcohol) groups. From gestational days (GD) 8-19, the control group received daily olive oil and malto/dextrose, whereas groups 2 and 3 received olive oil and low-dose alcohol or high-dose alcohol, respectively. Group 4 received daily DHA and high-dose alcohol. The dam's blood was collected on GD 15 and 20 for cytokine analysis. Dams were sacrificed on GD 20. The mean birth weight of pups was compared by one-way ANOVA with post hoc Duncan's test. Results: There was a significant increase in the pups' mean birth weight in the high-dose alcohol/DHA and high-dose alcohol/olive oil. Higher pro-inflammatory cytokines (IL-1ß and IL-12p70) were noted in the alcohol-exposed dams. Conclusions: DHA and olive oil supplementation in alcohol-exposed pregnant rats significantly increased their pups' birth weight despite having high pro-inflammatory cytokines. The mechanism of this effect remains to be determined.

Temporal assessment of SARS-CoV-2 detection in wastewater and its epidemiological implications in COVID-19 case dynamics.

This research evaluated the relationship between daily new Coronavirus Disease 2019 (COVID-19) cases and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) concentrations in wastewater, followed by effects of differential SARS-CoV-2 shedding loads across various COVID-19 outbreaks. Linear regression analyses were utilized to examine the lead time of the SARS-CoV-2 signal in wastewater relative to new COVID-19 clinical cases. During the Delta wave, no lead time was evident, highlighting limited predictive capability of wastewater monitoring during this phase. However, significant lead times were observed during the Omicron wave, potentially attributed to testing capacity overload and subsequent case reporting delays or changes in shedding patterns. During the Post-Omicron wave (Febuary 23 to May 19, 2022), no lead time was discernible, whereas following the lifting of the COVID-19 state of emergency (May 30, 2022 to May 30, 2023), the correlation coefficient increased and demonstrated the potential of wastewater surveillance as an early warning system. Subsequently, we explored the virus shedding in wastewater through feces, operationalized as the ratio of SARS-CoV-2 concentrations to daily new COVID-19 cases. This ratio varied significantly across the Delta, Omicron, other variants and post-state-emergency phases, with the Kruskal-Wallis H test confirming a significant difference in medians across these stages (P < 0.0001). Despite its promise, wastewater surveillance of COVID-19 disease prevalence presents several challenges, including virus shedding variability, data interpretation complexity, the impact of environmental factors on viral degradation, and the lack of standardized testing procedures. Overall, our findings offer insights into the correlation between COVID-19 cases and wastewater viral concentrations, potential variation in SARS-CoV-2 shedding in wastewater across different pandemic phases, and underscore the promise and limitations of wastewater surveillance as an early warning system for disease prevalence trends.

Assessment of periodontal health status in patients with Parkinson's disease-A systematic review and meta-analysis of cross-sectional studies.

INTRODUCTION: Parkinson's disease (PKD) is neurodegenerative disorder marked by tremors, bradykinesia, muscle rigidity and reduction in precise hand movements which could lead to improper oral hygiene and Periodontal disease. Current systematic review aims to review existing literature and provide assessment of periodontal health in PKD patients through a meta-analysis METHODS: Review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and registered in PROSPERO-CRD42023451700. Databases were searched for studies having sufficient data on periodontal health in patients with PKD compared to healthy controls and reporting outcomes in terms of various periodontal parameters of probing depth (PD), plaque index (PI), clinical attachment level (CAL), presence of bleeding on probing and gingivitis. Quality assessment of included was evaluated using Newcastle Ottawa Scale (NOS). RESULTS: Eleven studies fulfilled the eligibility criteria, of which ten studies were suitable for meta-analysis. Pooled estimate through the SMD showed that all periodontal parameters were altered and significantly deteriorated in PKD compared to controls but this group differences were statistically insignificant (p > 0.05). Publication bias through the funnel plot showed symmetric distribution with absence of systematic heterogeneity. CONCLUSION: Parkinson's disease could be a possible factor in deterioration of periodontal health.

A mass balance approach for quantifying the role of natural decay and fate mechanisms on SARS-CoV-2 genetic marker removal during water reclamation.

The recent SARS-CoV-2 outbreak yielded substantial data regarding virus fate and prevalence at water reclamation facilities (WRFs), identifying influential factors as natural decay, adsorption, light, pH, salinity, and antagonistic microorganisms. However, no studies have quantified the impact of these factors in full scale WRFs. Utilizing a mass balance approach, we assessed the impact of natural decay and other fate mechanisms on genetic marker removal during water reclamation, through the use of sludge and wastewater genetic marker loading estimates. Results indicated negligible removal of genetic markers during P/PT (primary effluent (PE) p value: 0.267; preliminary and primary treatment (P/PT) accumulation p value: 0.904; and thickened primary sludge (TPS) p value: 0.076) indicating no contribution of natural decay and other fate mechanisms toward removal in P/PT. Comparably, adsorption and decomposition was found to be the dominant pathway for genetic marker removal (thickened waste activated sludge (TWAS) log loading 9.75 log10 GC/day); however, no estimation of log genetic marker accumulation could be carried out due to high detections in TWAS. PRACTITIONER POINTS: The mass balance approach suggested that the contribution of natural decay and other fate mechanisms to virus removal during wastewater treatment are negligible compared with adsorption and decomposition in P/PT (p value: 0.904). During (P/PT), a higher viral load remained in the (PE) (14.16 log10 GC/day) compared with TPS (13.83 log10 GC/day); however, no statistical difference was observed (p value: 0.280) indicting that adsorption/decomposition most probably did not occur. In secondary treatment (ST), viral genetic markers in TWAS were consistently detected (13.41 log10 GC/day) compared with secondary effluent (SE), indicating that longer HRT and the potential presence of extracellular polymeric substance-containing enriched biomass enabled adsorption/decomposition. Estimations of total solids and volatile solids for TPS and TWAS indicated that adsorption affinity was different between solids sampling locations (p value: <0.0001).

A novel vaccination strategy against Vibrio harveyi infection in Asian seabass (Lates calcarifer) with the aid of oxygen nanobubbles and chitosan.

Immersion vaccination, albeit easier to administer than immunization by injection, sometimes has challenges with antigen uptake, resulting in sub-optimal protection. In this research, a new strategy to enhance antigen uptake of a heat-inactivated Vibrio harveyi vaccine in Asian seabass (Lates calcarifer) using oxygen nanobubble-enriched water (ONB) and positively charged chitosan (CS) was explored. Antigen uptake in fish gills was assessed, as was the antibody response and vaccine efficacy of four different combinations of vaccine with ONB and CS, and two control groups. Pre-mixing of ONB and CS before introducing the vaccine, referred to as (ONB + CS) + Vac, resulted in superior antigen uptake and anti-V. harveyi antibody (IgM) production in both serum and mucus compared to other formulas. The integration of an oral booster (4.22 × 108 CFU/g, at day 21-25) within a vaccine trial experiment set out to further evaluate how survival rates post exposure to V. harveyi might be improved. Antibody responses were measured over 42 days, and vaccine efficacy was assessed through an experimental challenge with V. harveyi. The expression of immune-related genes IL1ß, TNFα, CD4, CD8, IgT and antibody levels were assessed at 1, 3, and 7-day(s) post challenge (dpc). The results revealed that antibody levels in the group (ONB + CS) + Vac were consistently higher than the other groups post immersion immunization and oral booster, along with elevated expression of immune-related genes after challenge with V. harveyi. Ultimately, this group demonstrated a significantly higher relative percent survival (RPS) of 63 % ± 10.5 %, showcasing the potential of the ONB-CS-Vac complex as a promising immersion vaccination strategy for enhancing antigen uptake, stimulating immunological responses, and improving survival of Asian seabass against vibriosis.

Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer.

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08-1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00-1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies.

Pericyte Control of Gene Expression in the Blood-Brain Barrier Endothelium: Implications for Alzheimer's Disease.

Background: A strong body of evidence suggests that cerebrovascular pathologies augment the onset and progression of Alzheimer's disease (AD). One distinctive aspect of this cerebrovascular dysfunction is the degeneration of brain pericytes-often overlooked supporting cells of blood-brain barrier endothelium. Objective: The current study investigates the influence of pericytes on gene and protein expressions in the blood-brain barrier endothelium, which is expected to facilitate the identification of pathophysiological pathways that are triggered by pericyte loss and lead to blood-brain barrier dysfunction in AD. Methods: Bioinformatics analysis was conducted on the RNA-Seq expression counts matrix (GSE144474), which compared solo-cultured human blood-brain barrier endothelial cells against endothelial cells co-cultured with human brain pericytes in a non-contact model. We constructed a similar cell culture model to verify protein expression using western blots. Results: The insulin resistance and ferroptosis pathways were found to be enriched. Western blots of the insulin receptor and heme oxygenase expressions were consistent with those observed in RNA-Seq data. Additionally, we observed more than 5-fold upregulation of several genes associated with neuroprotection, including insulin-like growth factor 2 and brain-derived neurotrophic factor. Conclusions: Results suggest that pericyte influence on blood-brain barrier endothelial gene expression confers protection from insulin resistance, iron accumulation, oxidative stress, and amyloid deposition. Since these are conditions associated with AD pathophysiology, they imply mechanisms by which pericyte degeneration could contribute to disease progression.

Is There a Change in Anxiety and Depression Following Total Knee Arthroplasty?

BACKGROUND: The primary purpose of this study was to investigate whether anxiety and depression change following total knee arthroplasty (TKA). A secondary objective was to explore the association between preoperative variables and changes in anxiety and depression. METHODS: This was a prospective, multicenter, cohort study. Participants (n = 1,852, age 64 ± 8.7 years, a body mass index of 31.3, a modified Comorbidity Index of 1.0 ± 1.3, and 61.7% were women) completed the EuroQol 5-dimension 5-level preoperatively and at 1- and 3-month postoperatively. Fulfillment of physical activity expectations and preparedness to resume activities was assessed at 3 months. The anxiety or depression dimension was analyzed using the Paretian classification profile changes and compared with the sign Fisher's exact test. Logistic regressions were used to analyze the relationship between patient characteristics, preoperative anxiety or depression, activity expectations, preparedness to resume activities, and changes in anxiety/depression. RESULTS: The percentage of patients reporting Level 1 (no anxious or depressed feelings) significantly (P < .0001) increased from preoperative (62.2%) to 3 months (77.1%) postoperative, while levels 2 to 5 (slightly through extremely anxious or depressed) all decreased. The percentage of worsening anxiety and depression was significantly (P < .0001) greater in patients who did not feel they were well prepared to resume activities of daily living (17.7 versus 4.4%) and physical recreation (12.9 versus 3.9%). Preoperative anxiety and depression (odds ratio [OR] 52.27, 95% confidence interval [CI]: 34.98, 80.67), EuroQol 5-dimension 5-level (OR: 2.55, 95% CI: 1.04, 6.34), activity of daily living (OR: 1.57, 95% CI: 1.19, 2.06), and body mass index (OR: 1.05, 95% CI: 1.02, 1.08) were significant (P < .05) predictors of an improving Paretian change profile at 3 months postoperative. CONCLUSIONS: Anxiety and depression decrease following TKA, and these changes appear heavily dependent on a patient's preoperative psychological well-being and postoperative preparedness to resume daily activities. Physicians' awareness of preoperative patient psychological well-being and management of patient preparedness and expectations to resume physical activity may modulate postoperative anxiety and depression.

Per- and poly-fluoroalkyl substances removal in multi-barrier advanced water purification system for indirect potable reuse.

The study evaluated the removal efficacy of per- and poly-fluoroalkyl substances (PFAS) across various advanced water treatment (AWT) processes in a field-scale AWT train using secondary effluent samples from a full-scale water reclamation facility (WRF). Samples collected from April to October 2020 revealed PFCAs as the dominant PFAS compounds in the WRF secondary effluent, with PFPeA having the highest average concentration and PFSAs in notably lower amounts. Temporal fluctuations in total PFAS concentrations peaked in September 2020, which may reflect the seasonality in PFAS discharges related to applications like AFFFs and pesticides. In assessing AWT processes, coagulation-flocculation-clarification-filtration system showed no notable PFAS reduction, while ozonation resulted in elevated PFBS and PFBA concentrations. Biological activated carbon (BAC) filtration effectively removed long-chain PFAS like PFOS and PFHxS but saw increased concentrations of short-chain PFAS post-treatment. Granular activated carbon (GAC) filtration was the most effective treatment, reducing all PFSAs below the detection limits and significantly decreasing most PFCAs, though short-chain PFCAs persisted. UV treatment did not remove short-chain PFCAs such as PFBA, PFPeA, and PFHxA. The findings highlight the efficacy of AWT processes like GAC in PFAS reduction for potable reuse, but also underscore the challenge presented by short-chain PFAS, emphasizing the need for tailored treatment strategies. PRACTITIONER POINTS: Secondary effluents showed higher concentrations of PFCAs compared to PFSAs. Advanced water treatment effectively removes long-chain PFAS but not short-chain. Ozonation may contribute to formation of short-chain PFAS. BAC is less effective on short-chain PFAS, requiring further GAC treatment.

Association Between Digitally Provided Education and 90-Day Return to Sexual Activity Following Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Contemporary total knee arthroplasty patients have increased expectations of returning to predisease function, including sexual activity (SA). The purpose of this study was to determine whether patients using a digital care management platform (DCMP) were more likely to have a higher rate and frequency of return to SA. METHODS: We conducted an exploratory analysis of a prospective, multicenter, randomized controlled trial that enrolled patients undergoing total knee arthroplasty. A total of 304 patients were randomized to a DCMP (n = 119) providing preoperative and postoperative education regarding return to SA or standard postoperative care (control group; n = 185). Return to SA, assessed via questionnaire, patient-reported outcome measures, Timed Up and Go test, single leg stance, active range of motion and need for manipulation under anesthesia were assessed at 90 days postoperatively. RESULTS: More patients in the DCMP group returned to SA compared to control at 90 days (58.4 versus 39.6%, P = .018); however, the control group resumed SA sooner (33.1 versus 42.0 days, P = .023). Patients who returned to SA were younger (61.6 versus 65.9 year), more often men (56 versus 35%) (P < .001), higher performing on the Timed Up and Go and single leg stance tests (P < .001), and had greater active range of motion (P = .007). There were no differences in patient-reported outcome measures or need for manipulation under anesthesia between patients that returned to SA and those who did not. CONCLUSIONS: More patients using a DCMP resumed SA at 90 days; however, patients in the control group returned to SA sooner. Those who returned to SA were younger, possessed greater physical function, and were more often men.

Contaminants of emerging concern reduction and microbial community characterization across a three-barrier advanced water treatment system.

This research investigated the removal of contaminants of emerging concern (CECs) and characterized the microbial community across an advanced water treatment (AWT) train consisting of Coagulation/Flocculation/Clarification/Granular Media Filtration (CFCGMF), Ozone-Biological Activated Carbon Filtration (O3/BAC), Granular Activated Carbon filtration, Ultraviolet Disinfection, and Cartridge Filtration (GAC/UV/CF). The AWT train successfully met the goals of CECs and bulk organics removal. The microbial community at each treatment step of the AWT train was characterized using 16S rRNA sequencing on the Illumina MiSeq platform generated from DNA extracted from liquid and solid (treatment media) samples taken along the treatment train. Differences in the microbial community structure were observed. The dominant operational taxonomic units (OTU) decreased along the treatment train, but the treatment steps did impact the microbial community composition downstream of each unit process. These results provide insights into microbial ecology in advanced water treatment systems, which are influenced and shaped by each treatment step, the microbial community interactions, and their potential metabolic contribution to CECs degradation.

Immersion prime and oral boost vaccination with an inactivated Vibrio harveyi vaccine confers a specific immune response and protection in Asian seabass (Lates calcarifer).

Asian seabass (Lates calcarifer) holds significant economic value in fish farming in the Asia-Pacific region. Vibriosis caused by Vibrio harveyi (Vh) is a severe infectious disease affecting intensive farming of this species, for which prevention strategies by vaccination have been developed. This study investigated an alternative approach to injectable vaccination to prevent vibriosis in Asian seabass juveniles. The strategy begins with an immersion prime vaccination with a heat-inactivated Vh vaccine, followed by two oral booster doses administered at 14- and 28-days post-vaccination (dpv). Expression of five immune genes TNFα, IL1ß, CD4, CD8, and IgM in the head kidney and spleen, along with investigation of anti-Vh antibody response (IgM) in both systemic and mucosal systems, was conducted on a weekly basis. The efficacy of the vaccines was assessed by a laboratory challenge test at 43 dpv. The results showed that the immunized fish displayed higher levels of mRNA transcripts of the immune genes after the immersion prime and the first oral booster dose compared to the control group. The expression levels peaked at 14 and 28 dpv and then declined to baseline at 35 and 42 dpv. Serum specific IgM antibodies were detected as early as 7 dpv (the first time point investigated) and exhibited a steady increase, reaching the first peak at 21 dpv, and a second peak at 35 dpv. Although the antibody levels gradually declined over subsequent weeks, they remained significantly higher than the control group throughout the experiment. A similar antibody response pattern was also observed in the mucosal compartment. The laboratory challenge test demonstrated high protection by injection with 1.65 × 104 CFU/fish, with a relative percent of survival (RPS) of 72.22 ± 7.86 %. In conclusion, our findings highlight the potential of an immersion prime-oral booster vaccination strategy as a promising approach for preventing vibriosis in Asian seabass.

Multiple sclerosis-associated uveitis - A series from South India.

PURPOSE: To report clinical profiles of multiple sclerosis (MS)-associated uveitis in seven cases from a single tertiary eye care center in South India. METHODS: Retrospective case series 2013-2023. RESULTS: Seven cases of MS-associated uveitis were retrieved from our databases. There were five females and two males. The diagnosis of MS was made by the neurologist in all cases. Bilaterality was seen in all cases. Intermediate uveitis was the most common presentation (five cases). It was associated with peripheral retinal vasculitis (two cases) and disc pallor (two cases). Fuchs heterochromic iridocyclitis (one case) and incomplete Vogt-Koyanagi-Harada (VKH)-like presentation with a peripapillary choroidal neovascular membrane (one case) were the other presentations. In the case with incomplete VKH-like presentation, whole genome sequencing revealed a heterozygous non-synonymous variation (c.1228C>T) in exon 10 of TNFRSF1A, suggestive of susceptibility to multiple sclerosis 5 due to mutation in the TNFRS1A gene on chromosome 12p13.31. All cases received systemic steroids. Azathioprine (three cases) and rituximab (three cases) were the commonly used immunomodulatory drugs. The visual outcome was good in all cases at the last follow-up. CONCLUSION: MS-associated uveitis is underreported in India. This series highlights the clinical profile of MS-associated uveitis in India.

Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis.

Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription-quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.

Endoxifen downregulates AKT phosphorylation through protein kinase C beta 1 inhibition in ERα+ breast cancer.

Endoxifen, a secondary tamoxifen metabolite, is a potent antiestrogen exhibiting estrogen receptor alpha (ERα) binding at nanomolar concentrations. Phase I/II clinical trials identified clinical activity of Z-endoxifen (ENDX), in endocrine-refractory metastatic breast cancer as well as ERα+ solid tumors, raising the possibility that ENDX may have a second, ERα-independent, mechanism of action. An unbiased mass spectrometry approach revealed that ENDX concentrations achieved clinically with direct ENDX administration (5 µM), but not low concentrations observed during tamoxifen treatment (<0.1 µM), profoundly altered the phosphoproteome of the aromatase expressing MCF7AC1 cells with limited impact on the total proteome. Computational analysis revealed protein kinase C beta (PKCß) and protein kinase B alpha or AKT1 as potential kinases responsible for mediating ENDX effects on protein phosphorylation. ENDX more potently inhibited PKCß1 kinase activity compared to other PKC isoforms, and ENDX binding to PKCß1 was confirmed using Surface Plasma Resonance. Under conditions that activated PKC/AKT signaling, ENDX induced PKCß1 degradation, attenuated PKCß1-activated AKTSer473 phosphorylation, diminished AKT substrate phosphorylation, and induced apoptosis. ENDX's effects on AKT were phenocopied by siRNA-mediated PKCß1 knockdown or treatment with the pan-AKT inhibitor, MK-2206, while overexpression of constitutively active AKT diminished ENDX-induced apoptosis. These findings, which identify PKCß1 as an ENDX target, indicate that PKCß1/ENDX interactions suppress AKT signaling and induce apoptosis in breast cancer.

Diversely functionalized isoquinolines and their core-embedded heterocyclic frameworks: a privileged scaffold for medicinal chemistry.

Isoquinoline-enrooted organic small-molecules represent a challenging molecular target in the organic synthesis arsenal attributed to their structural diversity and therapeutic importance. Into the bargain, isoquinolines are significant structural frameworks in modern medicinal chemistry and drug development. Consequently, synthetic organic and medicinal chemists have been intensely interested in efficient synthetic tactics for the sustainable construction of isoquinoline frameworks and their derivatives in enantiopure or racemic forms. This review accentuates an overview of the literature on the modern synthetic approaches exploited in synthesising isoquinolines and their core embedded heterocyclic skeletons from 2021 to 2022. In detail, the methodologies and inspected pharmacological studies for the array of diversely functionalized isoquinolines or their core-embedded heterocyclic/carbocyclic structures involving the introduction of substituents at C-1, C-3, and C-4 carbon and N-2 atom, bond constructions at the C1-N2 atom and C3-N2 atom, and structural scaffolding within isoquinoline compounds have been reviewed. This intensive study highlights the need for and relevance of relatively unexplored bioisosterism employing isoquinoline-based small-molecules in drug design.