Serious psychiatric disorders such as schizophrenia, bipolar disorder, and major depression are important causes of mortality and morbidity worldwide. While these are primarily diseases involving ...altered brain functioning, numerous studies have documented increased rates of gastrointestinal inflammation and dysfunction in many individuals with these disorders. Toxoplasma gondii is an apicomplexan protozoan intracellular parasite with a widespread distribution in both developed and developing countries. Toxoplasma organisms enter the ecosystem through the shedding of oocysts by Toxoplasma-infected felines. In almost all cases of postnatal human infection, Toxoplasma enters its hosts through the intestinal tract either by the ingestion of oocysts or by the consumption of meat from food animals which themselves were infected by Toxoplasma oocysts. It had previously been thought that most cases of Toxoplasma infection in immune competent children and adults were inapparent and asymptomatic. However, recent studies cast doubt on this concept as exposure to Toxoplasma has been associated with a range of acute and chronic symptoms. Of particular note has been the finding of an increased rate of a range of neurological and psychiatric disorders associated with serological evidence of Toxoplasma exposure. A role of Toxoplasma infection in brain diseases is also supported by the consistent finding of altered cognition and behavior in animal models of infections. Much of the attention relating to the role of Toxoplasma infection in neuropsychiatric disorders has focused on the brain, where Toxoplasma tissue cysts can persist for extended periods of time. However, recent discoveries relating to the role of the gastrointestinal tract in cognition and behavior suggest that Toxoplasma may also increase susceptibility to human brain diseases through immune activation, particularly involving the gastrointestinal mucosa. The study of the pathways relating to the pathobiology and immunology of Toxoplasma infection may provide insights into the pathogenesis of a range of human neuropsychiatric disorders as well as into cognitive functioning in otherwise healthy individuals.
Cyanide-a fast-acting poison-is easy to obtain given its widespread use in manufacturing industries. It is a high-threat chemical agent that poses a risk of occupational exposure in addition to being ...a terrorist agent. FDA-approved cyanide antidotes must be given intravenously, which is not practical in a mass casualty setting due to the time and skill required to obtain intravenous access. Glyoxylate is an endogenous metabolite that binds cyanide and reverses cyanide-induced redox imbalances independent of chelation. Efficacy and biochemical mechanistic studies in an FDA-approved preclinical animal model have not been reported. Therefore, in a swine model of cyanide poisoning, we evaluated the efficacy of intramuscular glyoxylate on clinical, metabolic, and biochemical endpoints. Animals were instrumented for continuous hemodynamic monitoring and infused with potassium cyanide. Following cyanide-induced apnea, saline control or glyoxylate was administered intramuscularly. Throughout the study, serial blood samples were collected for pharmacokinetic, metabolite, and biochemical studies, in addition, vital signs, hemodynamic parameters, and laboratory values were measured. Survival in glyoxylate-treated animals was 83% compared with 12% in saline-treated control animals (p < .01). Glyoxylate treatment improved physiological parameters including pulse oximetry, arterial oxygenation, respiration, and pH. In addition, levels of citric acid cycle metabolites returned to baseline levels by the end of the study. Moreover, glyoxylate exerted distinct effects on redox balance as compared with a cyanide-chelating countermeasure. In our preclinical swine model of lethal cyanide poisoning, intramuscular administration of the endogenous metabolite glyoxylate improved survival and clinical outcomes, and ameliorated the biochemical effects of cyanide.
While individuals diagnosed with autism spectrum disorders (ASD) have higher levels of antibodies directed towards gliadin, a component of wheat gluten, no study has examined anti‐gliadin antibodies ...(AGA) in etiologically relevant periods before diagnosis. The objective of this study was to investigate if maternal levels of AGA, during pregnancy and at the time of birth, are associated with ASD in offspring. We analyzed AGA in archived neonatal dried blood spots (NDBS) for 921 ASD cases and 1090 controls, and in paired maternal sera collected earlier in pregnancy for a subset of 547 cases and 428 controls. We examined associations with ASD diagnoses as a group and considering common comorbidities (intellectual disability ID and attention‐deficit/hyperactivity disorder). We compared 206 cases to their unaffected siblings to examine the potential for confounding by shared familial factors. Odds of ASD tended to be lower among those with the highest levels (≥90th percentile) of AGA compared to those with low levels (<80th percentile; OR 0.78, 95% CI 0.56–1.09, measured in NDBS). This pattern was more apparent for ASD with comorbid ID when measured in NDBS (0.51, 0.30–0.87), with a similar trend in maternal sera (0.55, 0.24–1.29). High levels of AGA were similarly associated with lower odds of ASD in the sibling comparison. In summary, we found little association between maternal antibodies raised against components of gluten and risk of ASD in general. Exposure to high levels of AGA in the pre‐ and perinatal periods may be protective in terms of risk for ASD with ID.
Lay Summary
There is a debate among both scientists and community members as to whether an immune reaction to gluten exposure could be considered a cause of autism. We examined antibodies that are directed against gliadin, a part of gluten, in samples collected from pregnant mothers and their newborn babies. We did not see any major differences in the antibody level among those children diagnosed with ASD or their mothers compared to children who were not diagnosed with ASD. High levels of the antibodies were in fact associated with a somewhat lower risk of ASD with co‐occurring intellectual disabilities, though we cannot tell from this study why that might be the case.
Lay Summary
There is a debate among both scientists and community members as to whether an immune reaction to gluten exposure could be considered a cause of autism. We examined antibodies that are directed against gliadin, a part of gluten, in samples collected from pregnant mothers and their newborn babies. We did not see any major differences in the antibody level among those children diagnosed with ASD or their mothers compared to children who were not diagnosed with ASD. High levels of the antibodies were in fact associated with a somewhat lower risk of ASD with co‐occurring intellectual disabilities, though we cannot tell from this study why that might be the case.
Modern advances in sequencing technology have enabled the census of microbial members of many natural ecosystems. Recently, attention is increasingly being paid to the microbial residents of ...human-made, built ecosystems, both private (homes) and public (subways, office buildings, and hospitals). Here, we report results of the characterization of the microbial ecology of a singular built environment, the International Space Station (ISS). This ISS sampling involved the collection and microbial analysis (via 16S rDNA PCR) of 15 surfaces sampled by swabs onboard the ISS. This sampling was a component of Project MERCCURI (Microbial Ecology Research Combining Citizen and University Researchers on ISS). Learning more about the microbial inhabitants of the "buildings" in which we travel through space will take on increasing importance, as plans for human exploration continue, with the possibility of colonization of other planets and moons.
Sterile swabs were used to sample 15 surfaces onboard the ISS. The sites sampled were designed to be analogous to samples collected for (1) the Wildlife of Our Homes project and (2) a study of cell phones and shoes that were concurrently being collected for another component of Project MERCCURI. Sequencing of the 16S rDNA genes amplified from DNA extracted from each swab was used to produce a census of the microbes present on each surface sampled. We compared the microbes found on the ISS swabs to those from both homes on Earth and data from the Human Microbiome Project.
While significantly different from homes on Earth and the Human Microbiome Project samples analyzed here, the microbial community composition on the ISS was more similar to home surfaces than to the human microbiome samples. The ISS surfaces are species-rich with 1,036-4,294 operational taxonomic units (OTUs per sample). There was no discernible biogeography of microbes on the 15 ISS surfaces, although this may be a reflection of the small sample size we were able to obtain.
Aim: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate glycaemic control haemoglobin A1c (HbA1c) ≥ 6.5 and ≤10% on metformin ...monotherapy.
Methods: After a metformin dose titration/stabilization period (≥1500 mg/day), 1172 patients were randomized to the addition of sitagliptin 100 mg q.d. (N = 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N = 584) for 52 weeks. The primary analysis assessed whether sitagliptin was non‐inferior to glipizide regarding HbA1c changes from baseline at Week 52 using a per‐protocol approach.
Results: From a mean baseline of 7.5%, HbA1c changes from baseline were −0.67% at Week 52 in both groups, confirming non‐inferiority. The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide). Fasting plasma glucose changes from baseline were −0.56 mmol/l (−10.0 mg/dl) and −0.42 mmol/l (−7.5 mg/dl) for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide‐treated patients compared with 50 events in sitagliptin‐treated patients. Sitagliptin led to weight loss (change from baseline =−1.5 kg) compared with weight gain (+1.1 kg) with glipizide between‐treatment difference (95% confidence interval) =−2.5 kg (−3.1, −2.0); p < 0.001.
Conclusions: In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c‐lowering efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.
Nutritional programming in Nile tilapia Deck, Courtney A; Salger, Scott A; Reynolds, Hannah M ...
PloS one,
10/2023, Letnik:
18, Številka:
10
Journal Article
Recenzirano
Nutritional programming is the idea that early nutrient contributions can influence organismal structure or function and is documented in a variety of vertebrates, yet studies in fish are largely ...lacking. Tilapia are an important foodfish, with global production having increased rapidly since the 1990s. They exhibit high disease-resistance and grow well on formulated feeds which makes them an ideal aquaculture species, however incorporating high quality proteins into feeds can be costly. As feed constitutes 50-70% of total production costs in aquaculture, reducing protein content could curb these costs and increase revenue. Thus, we examined the effects of feeding Nile tilapia (O. niloticus) fry a restricted protein diet for the first 7-21 days on growth, gut microbial flora, and the intestinal transcriptome. Fish were fed either a 25% restricted or 48% control crude protein starter (ST) diet for up to 21 days and then switched to a 25% or 38% control crude protein growout (GO) diet. Fish fed a 25% ST diet for 14 days followed by a 38% GO diet had significantly higher lengths and weights and better feed efficiency than fish fed the control 48% ST and 38% GO diet after 56 days of culture. Growth of fry on the 25% ST, 7-day/38% GO and the 25% ST,7-day/25% GO diets did not differ from the those fed the control protein diets, while fish fed the 25% ST diet for 21 days had significantly lower growth and survival rates. We observed no significant differences in either alpha or beta diversity of the gut microbial flora between diets, however species richness (Shannon Index) was higher in fry fed the 25% protein ST diet regardless of the GO diet. Similarly, fish fed the 25% ST diet for 14 days followed by the 38% GO diet had minimal changes to the intestinal transcriptome relative to fish fed the control 48% ST and 38% GO diet. However, those fed 25% ST and GO diets for the entire 56 days exhibited substantial differences in the gut transcriptome from other groups showing gene expression profiles characteristic of detrimental changes to gut physiology, protein metabolism and immune function. Results suggest protein restriction for up to 14 days early in development leads to enhanced growth and feed efficiency with minimal effects on gut microbes or intestinal function. Protein restriction beyond this period appears detrimental to fish growth and health as underscored by expression of disease related genes and higher mortality rates.
Background. While significant attention has been paid to the potential risk of pathogenic microbes aboard crewed spacecraft, the non-pathogenic microbes in these habitats have received less ...consideration. Preliminary work has demonstrated that the interior of the International Space Station (ISS) has a microbial community resembling those of built environments on Earth. Here we report the results of sending 48 bacterial strains, collected from built environments on Earth, for a growth experiment on the ISS. This project was a component of Project MERCCURI (Microbial Ecology Research Combining Citizen and University Researchers on ISS). Results. Of the 48 strains sent to the ISS, 45 of them showed similar growth in space and on Earth using a relative growth measurement adapted for microgravity. The vast majority of species tested in this experiment have also been found in culture-independent surveys of the ISS. Only one bacterial strain showed significantly different growth in space. Bacillus safensis JPL-MERTA-8-2 grew 60% better in space than on Earth. Conclusions. The majority of bacteria tested were not affected by conditions aboard the ISS in this experiment (e.g., microgravity, cosmic radiation). Further work on Bacillus safensis could lead to interesting insights on why this strain grew so much better in space.
To enhance cancer prevention and survivorship care by local health care providers, a school of public health introduced an innovative telelearning continuing education program using the Extension for ...Community Healthcare Outcomes (ECHO) model. In ECHO's hub and spoke structure, synchronous videoconferencing connects frontline health professionals at various locations ("spokes") with experts at the facilitation center ("hub"). Sessions include experts' didactic presentations and case discussions led by spoke site participants. The objective of this study was to gain a better understanding of the reasons individuals choose or decline to participate in the Cancer ECHO program and to identify incentives and barriers to doing so.
Study participants were recruited from the hub team, spoke site participants, and providers who attended another ECHO program but not this one. Participants chose to take a survey or be interviewed. The Consolidated Framework for Implementation Research guided qualitative data coding and analysis.
We conducted 22 semistructured interviews and collected 30 surveys. Incentives identified included the program's high-quality design, supportive learning climate, and access to information. Barriers included a lack of external incentives to participate and limited time available. Participants wanted more adaptability in program timing to fit providers' busy schedules.
Although the merits of the Cancer ECHO program were widely acknowledged, adaptations to facilitate participation and emphasize the program's benefits may help overcome barriers to attending. As the number of telelearning programs grows, the results of this study point to ways to expand participation and spread health benefits more widely.
Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist ...development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.
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