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This work deals with the groundwater hydro-geochemistry, intake and irrigation water quality, and noncarcinogenic human healthiness concerns in a dry environment. Water quality characteristics were measured in samples which were gathered from the countryside and city. The findings showed that the composition of groundwater is acidic and stony. There was a wide range of nitrate and fluoride concentrations, with a mean concentration of 1.4 mg/ltr, 65.7 mg/ltr, and 0 to 13.3 mg/ltr. Only 14% of the samples were rated excellent by the water quality index, while 38% were rated good, 28% were rated bad, and 12% were classified unfit/unsuitable for eating. The quantities of nitrate and fluoride in groundwater are estimated to be 68% higher than the permitted range for noncarcinogenic ingestion, posing a major health risk to the local people. A range of indicators and graphical approaches were used to assess the appropriateness of groundwater. The geogenic origin of fluoride was demonstrated to be followed by the anthropogenic source of NO−3, K+, Na+, Cl−, and HCO-3, and the predominant hydro-chemical facies Ca−2+ and HCO-3 are done.

Peter Dogterom,1 Robert Riesenberg,2 Rik de Greef,1 Justin Dennie,3 Martin Johnson,1 Venkatesh Pilla Reddy,1 André MM Miltenburg,1 Robert L Findling,4 Abhijeet Jakate,5 Timothy J Carrothers,5 Matthew D Troyer3 1Early Stage Development, Merck Sharp and Dohme, Oss, the Netherlands; 2Atlanta Center for Medical Research, Atlanta, GA, 3Merck, Kenilworth, NJ, 4Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, 5Allergan, Madison, NJ, USA Purpose: This study aimed to characterize the pharmacokinetic (PK) properties, safety, and tolerability of asenapine, and to develop a population PK model in pediatric patients with schizophrenia, bipolar disorder, or other psychiatric disorders. Methods: Two Phase I multiple ascending-dose studies were conducted to evaluate the PK, safety, and tolerability of sublingual asenapine in pediatric patients (age 10–17 years) with schizophrenia or bipolar I disorder. Patients received asenapine 1–10 mg twice daily for up to 12 days. PK parameters (maximum concentration [Cmax], area under the curve from 0 to 12 hours [AUC0–12], time to Cmax [Tmax], and half-life) were summarized for asenapine with descriptive statistics, and safety parameters were collected. A population PK model, which included the two Phase I studies and two additional Phase III efficacy studies (asenapine 2.5–10 mg twice daily for up to 8 weeks, age 10–17 years), was developed using nonlinear mixed-effect modeling based on a previously developed adult PK model. The final model was used in simulations to obtain asenapine-exposure estimates across pediatric subgroups and to determine if intrinsic covariates warrant dose adjustments. Results: The PK of asenapine showed rapid absorption (Tmax ~1 hour) with an apparent terminal half-life between 16 and 32 hours. Increases in mean Cmax and AUC0–12 appeared to be dose-proportional in one study and near dose-proportional in the second study. Steady state was attained within 8 days. The most frequently occurring treatment-emergent adverse events were dysgeusia, sedation, and oral hypoesthesia. Simulation-based estimates of Cmax and AUC0–12 were similar for pediatric and adult patients; age, body-mass index, race, and sex were not associated with changes in asenapine exposure. Conclusion: Asenapine was generally safe and well tolerated in pediatric patients aged 10–17 years. PK and safety data were similar to that observed in the adult population. Intrinsic factors had no significant impact on asenapine exposure, indicating there is no need for dose adjustments in the pediatric population. Keywords: asenapine, pharmacokinetics, schizophrenia, bipolar disorder, child and adolescent, atypical antipsychotic

Abstract: SH-SY5Y neuroblastoma cells, a model for studying neuronal differentiation, are able to differentiate into either cholinergic or dopaminergic/adrenergic phenotypes depending on media conditions. Using this system, we asked whether guanosine (Guo) or guanosine-5′-triphosphate (GTP) are able to drive differentiation towards one particular phenotype. Differentiation was determined by evaluating the frequency of cells bearing neurites and assessing neurite length after exposure to different concentrations of Guo or GTP for different durations. After 6 days, 0.3mM Guo or GTP induced a significant increase in the number of cells bearing neurites and increased neurite length. Western blot analyses confirmed that purines induced differentiation; cells exposed to purines showed increases in the levels of GAP43, MAP2, and tyrosine hydroxylase. Proliferation assays and cytofluorimetric analyses indicated a significant anti-proliferative effect of purines, and a concentration-dependent accumulation of cells in S-phase, starting after 24h of purine exposure and extending for up to 6 days. A transcriptional profile analysis using gene arrays showed that an up-regulation of cyclin E2/cdk2 evident after 24h was responsible for S-phase entry, and a concurrent down-regulation of cell-cycle progression-promoting cyclin B1/B2 prevented S-phase exit. In addition, patch-clamp recordings revealed that 0.3mM Guo or GTP, after 6 day incubation, significantly decreased Na+ currents. In conclusion, we showed Guo- and GTP-induced cell-cycle arrest in neuroblastoma cells and suggest that this makes these cells more responsive to differentiation processes that favor the dopaminergic/adrenergic phenotype. [Copyright &y& Elsevier]

Context: Although violence among US youth is a current major concern, bullying is infrequently addressed and no national data on the prevalence of bullying are available.Objectives: To measure the prevalence of bullying behaviors among US youth and to determine the association of bullying and being bullied with indicators of psychosocial adjustment, including problem behavior, school adjustment, social/emotional adjustment, and parenting.Design, Setting, and Participants: Analysis of data from a representative sample of 15 686 students in grades 6 through 10 in public and private schools throughout the United States who completed the World Health Organization's Health Behaviour in School-aged Children survey during the spring of 1998.Main Outcome Measure: Self-report of involvement in bullying and being bullied by others.Results: A total of 29.9% of the sample reported moderate or frequent involvement in bullying, as a bully (13.0%), one who was bullied (10.6%), or both (6.3%). Males were more likely than females to be both perpetrators and targets of bullying. The frequency of bullying was higher among 6th- through 8th-grade students than among 9th- and 10th-grade students. Perpetrating and experiencing bullying were associated with poorer psychosocial adjustment (P<.001); however, different patterns of association occurred among bullies, those bullied, and those who both bullied others and were bullied themselves.Conclusions: The prevalence of bullying among US youth is substantial. Given the concurrent behavioral and emotional difficulties associated with bullying, as well as the potential long-term negative outcomes for these youth, the issue of bullying merits serious attention, both for future research and preventive intervention. [ABSTRACT FROM AUTHOR]

Stroke results in immediate sensory or motor disability and increases the risk for long term cognitive-affective impairments. Thus, therapies are urgently needed to improve quality of life for stroke survivors, especially women who are at a greater risk for severe stroke after menopause. Most current research on stroke therapies target the central nervous system; however, stroke also impacts peripheral organ systems. Our studies using acyclic (estrogen-deficient) middle aged female Sprague Dawley rats show that this group not only displays worse outcomes after stroke as compared to adult females, but also has lower levels of the neuroprotective peptide Insulin-like Growth Factor (IGF1) in circulation. Intracerebroventricular (ICV) administration of IGF1 to this group decreases infarct volume and improves sensory motor performance in the acute phase. In this study, we show that, despite this neuroprotection, ICV-IGF1 did not reduce peripheral inflammation or improve post stroke cognitive impairment in the chronic phase. In view of the evidence that stroke induces rapid gut dysfunction, we tested whether systemic delivery of IGF1 (intraperitoneal, IP) would promote gut health and consequently improve long-term behavioral outcomes. Surprisingly, while IP-IGF1, delivered 4 h and 24 h after ischemic stroke, did not reduce infarct volume or acute sensory motor impairment, it significantly attenuated circulating levels of pro-inflammatory cytokines, and attenuated stroke-induced cognitive impairment. In addition, IP-IGF1 treatment reduced gut dysmorphology and gut dysbiosis. Our data support the conclusion that therapeutics targeting peripheral targets are critical for long-term stroke recovery, and that gut repair is a novel therapeutic target to improve brain health in aging females., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Dogs with acute hemorrhagic diarrhea syndrome (AHDS) present with similar clinical signs and histopathological findings as dogs with parvovirosis, in which fecal microbiota transplantation (FMT) has led to a significantly faster resolution of diarrhea and shorter hospitalization times. We investigated whether FMT results in faster clinical improvement and normalization of the intestinal microbiome compared to standard treatment., Animals: 32 client-owned dogs with AHDS., Methods: A prospective, double-anonymized clinical trial included 3 groups: symptomatic treatment (n = 12), FMT treatment (FMTT; 12), and antibiotic treatment (AT; 8). Clinical improvement was determined on the basis of AHDS index, changes in the microbiome based on the dysbiosis index, and PCR results for clostridial strains., Results: Overall, no significant differences in clinical scores between the treatment groups over time were detected except on day 2 (higher AHDS index in the AT group compared to FMTT group; P = .046). The dysbiosis index increased and P hiranonis decreased on day 1 in some dogs, but these changes were transient in the symptomatic treatment and FMTT groups. In the AT group, the dysbiosis index was persistently elevated and 4 of 8 dogs showed a reduced abundance of P hiranonis on day 42. In 67% of the dogs on day 1, NetF-encoding Clostridium perfringens was detected and enterotoxin-encoding strains increased, but these changes were transient in all dogs, regardless of therapy., Clinical Relevance: Overall, in dogs with AHDS, neither FMT nor AT resulted in faster clinical improvement. In addition, C perfringens strains are self-limiting and do not require antibiotic therapy.

Introduction: Anxiety and cognitive dysfunction are frequent, difficult to treat and burdensome comorbidities in human and canine epilepsy. Fecal microbiota transplantation (FMT) has been shown to modulate behavior in rodent models by altering the gastrointestinal microbiota (GIM). This study aims to investigate the beneficial effects of FMT on behavioral comorbidities in a canine translational model of epilepsy., Methods: Nine dogs with drug-resistant epilepsy (DRE) and behavioral comorbidities were recruited. The fecal donor had epilepsy with unremarkable behavior, which exhibited a complete response to phenobarbital, resulting in it being seizure-free long term. FMTs were performed three times, two weeks apart, and the dogs had follow-up visits at three and six months after FMTs. Comprehensive behavioral analysis, including formerly validated questionnaires and behavioral tests for attention deficit hyperactivity disorder (ADHD)- and fear- and anxiety-like behavior, as well as cognitive dysfunction, were conducted, followed by objective computational analysis. Blood samples were taken for the analysis of antiseizure drug (ASD) concentrations, hematology, and biochemistry. Urine neurotransmitter concentrations were measured. Fecal samples were subjected to analysis using shallow DNA shotgun sequencing, real-time polymerase chain reaction (qPCR)-based Dysbiosis Index (DI) assessment, and short-chain fatty acid (SCFA) quantification., Results: Following FMT, the patients showed improvement in ADHD-like behavior, fear- and anxiety-like behavior, and quality of life. The excitatory neurotransmitters aspartate and glutamate were decreased, while the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and GABA/glutamate ratio were increased compared to baseline. Only minor taxonomic changes were observed, with a decrease in Firmicutes and a Blautia&#95;A species, while a Ruminococcus species increased. Functional gene analysis, SCFA concentration, blood parameters, and ASD concentrations remained unchanged., Discussion: Behavioral comorbidities in canine IE could be alleviated by FMT. This study highlights FMT's potential as a novel approach to improving behavioral comorbidities and enhancing the quality of life in canine patients with epilepsy., Competing Interests: HV has served as a paid consultant in the field of epilepsy for Boehringer Ingelheim, CEVA Animal Health, Nestle Purina and served as contract researcher for: Nestle Purina, Desitin Pharma and Boehringer Ingelheim. JS and RP were employees of the Gastrointestinal Laboratory at Texas A&M University which offers microbiome assessment on a fee-for-service basis. JS was the Purina PetCare Endowed Chair for Microbiome Research and receives support for microbiome research through the Purina PetCare Research Excellence Funds. JS has also received consulting or speaking fees from Nestle Purina, IDEXX Laboratories, Royal Canin and Hill’s Pet Nutrition, Inc. AF participates in academia-industry partnerships with Nestle Purina and Vetoquinol. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AW declared a past collaboration with the authors HV to the handling editor., (Copyright © 2024 Watanangura, Meller, Farhat, Suchodolski, Pilla, Khattab, Lopes, Bathen-Nöthen, Fischer, Busch-Hahn, Flieshardt, Gramer, Richter, Zamansky and Volk.)

Introduction: Alterations in the composition and function of the gut microbiome have been reported in idiopathic epilepsy (IE), however, interactions of gut microbes with the enteric nervous system (ENS) in this context require further study. This pilot study examined how gastrointestinal microbiota (GIM), their metabolites, and nutrients contained in intestinal contents communicate with the ENS., Methods: Fecal supernatants (FS) from healthy dogs and dogs with IE, including drug-naïve, phenobarbital (PB) responsive, and PB non-responsive dogs, were applied to cultured myenteric neurons to test their activation using voltage-sensitive dye neuroimaging. Additionally, the concentrations of short-chain fatty acids (SCFAs) in the FS were quantified., Results: Our findings indicate that FS from all examined groups elicited neuronal activation. Notably, FS from PB non-responsive dogs with IE induced action potential discharge in a higher proportion of enteric neurons compared to healthy controls, which exhibited the lowest burst frequency overall. Furthermore, the highest burst frequency in enteric neurons was observed upon exposure to FS from drug-naïve dogs with IE. This frequency was significantly higher compared to that observed in PB non-responsive dogs with IE and showed a tendency to surpass that of healthy controls., Discussion: Although observed disparities in SCFA concentrations across the various FS samples might be associated with the induced neuronal activity, a direct correlation remains elusive at this point. The obtained results hint at an involvement of the ENS in canine IE and set the basis for future studies., Competing Interests: HV served as paid consultant in the field of epilepsy for Boehringer Ingelheim, CEVA animal health, Nestle Purina, and served as contract researcher for Nestle Purina and Boehringer Ingelheim. JS is an employee of the Gastrointestinal Laboratory at Texas A&M University that provides microbiome testing on a fee-for-service basis and is on the Scientific Advisory Board of Nestle Purina and received speaker honoraria from Royal Canin, Nutramax Laboratories, ExeGi Pharma, LLC, and Hill’s Pet Nutrition, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elfers, Watanangura, Hoffmann, Suchodolski, Khattab, Pilla, Meller, Volk and Mazzuoli-Weber.)

While shifts in gut microbiota have been studied in diseased states, the temporal variability of the microbiome in cats has not been widely studied. This study investigated the temporal variability of the feline dysbiosis index (DI) and the abundance of core bacterial groups in healthy adult cats. The secondary aim was to evaluate the relationship between the fecal abundance of Clostridium hiranonis and the fecal concentrations of unconjugated bile acids. A total of 142 fecal samples collected from 17 healthy cats were prospectively included: nine cats with weekly collection over 3 weeks (at least four time points), five cats with monthly collection over 2 months (three time points), and three cats with additional collections for up to 10 months. The DI remained stable within the reference intervals over two months for all cats (Friedman test, p > 0.2), and 100% of the DI values ( n = 142) collected throughout the study period remained within the RI. While some temporal individual variation was observed for individual taxa, the magnitude was minimal compared to cats with chronic enteropathy and antibiotic exposure. Additionally, the abundance of Clostridium hiranonis was significantly correlated with the percentage of fecal primary bile acids, supporting its role as a bile acid converter in cats.

Bile acid metabolism is a key pathway modulated by intestinal microbiota. Peptacetobacter ( Clostridium ) hiranonis has been described as the main species responsible for the conversion of primary into secondary fecal unconjugated bile acids (fUBA) in dogs. This multi-step biochemical pathway is encoded by the bile acid-inducible ( bai ) operon. We aimed to assess the correlation between P. hiranonis abundance, the abundance of one specific gene of the bai operon ( baiCD ), and secondary fUBA concentrations. In this retrospective study, 133 fecal samples were analyzed from 24 dogs. The abundances of P. hiranonis and baiCD were determined using qPCR. The concentration of fUBA was measured by gas chromatography-mass spectrometry. The baiCD abundance exhibited a strong positive correlation with secondary fUBA (ρ = 0.7377, 95% CI (0.6461, 0.8084), p < 0.0001). Similarly, there was a strong correlation between P. hiranonis and secondary fUBA (ρ = 0.6658, 95% CI (0.5555, 0.7532), p < 0.0001). Animals displaying conversion of fUBA and lacking P. hiranonis were not observed. These results suggest P. hiranonis is the main converter of primary to secondary bile acids in dogs.

The aim of this study was to further describe the oral microbiota of healthy dogs by DNA shotgun sequencing and compare those to dogs with oral tumors. Oral swabs (representative of all niches of the oral cavity) were collected from healthy dogs (n = 24) and from dogs with different oral tumors (n = 7). DNA was extracted from the swabs and shotgun metagenomic sequencing was performed. Only minor differences in microbiota composition were observed between the two groups. At the phylum level, the Bacteroidota, Proteobacteria, Actinobacteriota, Desulfobacterota and Firmicutes were most abundant in both groups. Observed Operational Taxonomic Units-OTUs (species richness) was significantly higher in the healthy patients, but there was no significant difference in the Shannon diversity index between the groups. No significant difference was found in beta diversity between the groups. The core oral microbiota consisted of 67 bacterial species that were identified in all 24 healthy dogs. Our study provides further insight into the composition of the oral microbiota of healthy dogs and in dogs with oral tumors.

Next generation sequencing (NGS) studies in healthy equine eyes have shown a more diverse ocular surface microbiota compared to culture-based techniques. This study aimed to compare the bacterial ocular surface microbiota in both eyes of horses with unilateral ulcerative keratitis (UK) with controls free of ocular disease. Conjunctival swabs were obtained from both ulcerated eyes and unaffected eyes of 15 client-owned horses with unilateral UK following informed consent, as well as from one eye of 15 healthy horses. Genomic DNA was extracted from the swabs and sequenced on an Illumina platform using primers that target the V4 region of bacterial 16S rRNA. Data were analyzed using Quantitative Insights Into Molecular Ecology (QIIME2). The ocular surface of ulcerated eyes had significantly decreased species richness compared with unaffected fellow eyes (Chao1 q = 0.045, Observed ASVs p = 0.045) with no differences in evenness of species (Shannon q = 0.135). Bacterial community structure was significantly different between either eye of horses with UK and controls (unweighted UniFrac: control vs. unaffected, p = 0.03; control vs. ulcerated, p = 0.003; unaffected vs. ulcerated, p = 0.016). Relative abundance of the gram-positive taxonomic class, Bacilli, was significantly increased in ulcerated eyes compared with controls (q = 0.004). Relative abundance of the taxonomic family Staphylococcaceae was significantly increased in ulcerated and unaffected eyes compared with controls (q = 0.030). The results suggest the occurrence of dysbiosis in infected eyes and reveal alterations in beta diversity and taxa of unaffected fellow eyes. Further investigations are necessary to better understand the role of the microbiome in the pathophysiology of ocular surface disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Julien et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Chronic enteropathy (CE) in cats encompasses food-responsive enteropathy, chronic inflammatory enteropathy (or inflammatory bowel disease), and low-grade intestinal T-cell lymphoma. While alterations in the gut metabolome have been extensively studied in humans and dogs with gastrointestinal disorders, little is known about the specific metabolic profile of cats with CE. As lipids take part in energy storage, inflammation, and cellular structure, investigating the lipid profile in cats with CE is crucial. This study aimed to measure fecal concentrations of various fatty acids, sterols, and bile acids. Fecal samples from 56 cats with CE and 77 healthy control cats were analyzed using gas chromatography-mass spectrometry, targeting 12 fatty acids, 10 sterols, and 5 unconjugated bile acids. Fecal concentrations of nine targeted fatty acids and animal-derived sterols were significantly increased in cats with CE. However, fecal concentrations of plant-derived sterols were significantly decreased in cats with CE. Additionally, an increased percentage of primary bile acids was observed in a subset of cats with CE. These findings suggest the presence of lipid maldigestion, malabsorption, and inflammation in the gastrointestinal tract of cats with CE. Understanding the lipid alterations in cats with CE can provide insights into the disease mechanisms and potential future therapeutic strategies.