Markers Of Function Research Articles

CD74 is a functional MIF receptor on activated CD4+ T cells

Next to its classical role in MHC II-mediated antigen presentation, CD74 was identified as a high-affinity receptor for macrophage migration inhibitory factor (MIF), a pleiotropic cytokine and major determinant of various acute and chronic inflammatory conditions, cardiovascular diseases and cancer. Recent evidence suggests that CD74 is expressed in T cells, but the functional relevance of this observation is poorly understood. Here, we characterized the regulation of CD74 expression and that of the MIF chemokine receptors during activation of human CD4+ T cells and studied links to MIF-induced T-cell migration, function, and COVID-19 disease stage. MIF receptor profiling of resting primary human CD4+ T cells via flow cytometry revealed high surface expression of CXCR4, while CD74, CXCR2 and ACKR3/CXCR7 were not measurably expressed. However, CD4+ T cells constitutively expressed CD74 intracellularly, which upon T-cell activation was significantly upregulated, post-translationally modified by chondroitin sulfate and could be detected on the cell surface, as determined by flow cytometry, Western blot, immunohistochemistry, and re-analysis of available RNA-sequencing and proteomic data sets. Applying 3D-matrix-based live cell-imaging and receptor pathway-specific inhibitors, we determined a causal involvement of CD74 and CXCR4 in MIF-induced CD4+ T-cell migration. Mechanistically, proximity ligation assay visualized CD74/CXCR4 heterocomplexes on activated CD4+ T cells, which were significantly diminished after MIF treatment, pointing towards a MIF-mediated internalization process. Lastly, in a cohort of 30 COVID-19 patients, CD74 surface expression was found to be significantly upregulated on CD4+ and CD8+ T cells in patients with severe compared to patients with only mild disease course. Together, our study characterizes the MIF receptor network in the course of T-cell activation and reveals CD74 as a novel functional MIF receptor and MHC II-independent activation marker of primary human CD4+ T cells.

Multikingdom and functional gut microbiota markers for autism spectrum disorder.

Associations between the gut microbiome and autism spectrum disorder (ASD) have been investigated although most studies have focused on the bacterial component of the microbiome. Whether gut archaea, fungi and viruses, or function of the gut microbiome, is altered in ASD is unclear. Here we performed metagenomic sequencing on faecal samples from 1,627 children (aged 1-13 years, 24.4% female) with or without ASD, with extensive phenotype data. Integrated analyses revealed that 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes and 12 metabolic pathways were altered in children with ASD. Machine learning using single-kingdom panels showed area under the curve (AUC) of 0.68 to 0.87 in differentiating children with ASD from those that are neurotypical. A panel of 31 multikingdom and functional markers showed a superior diagnostic accuracy with an AUC of 0.91, with comparable performance for males and females. Accuracy of the model was predominantly driven by the biosynthesis pathways of ubiquinol-7 or thiamine diphosphate, which were less abundant in children with ASD. Collectively, our findings highlight the potential application of multikingdom and functional gut microbiota markers as non-invasive diagnostic tools in ASD.

Multikingdom and functional gut microbiota markers for autism spectrum disorder.

Associations between the gut microbiome and autism spectrum disorder (ASD) have been investigated although most studies have focused on the bacterial component of the microbiome. Whether gut archaea, fungi and viruses, or function of the gut microbiome, is altered in ASD is unclear. Here we performed metagenomic sequencing on faecal samples from 1,627 children (aged 1-13 years, 24.4% female) with or without ASD, with extensive phenotype data. Integrated analyses revealed that 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes and 12 metabolic pathways were altered in children with ASD. Machine learning using single-kingdom panels showed area under the curve (AUC) of 0.68 to 0.87 in differentiating children with ASD from those that are neurotypical. A panel of 31 multikingdom and functional markers showed a superior diagnostic accuracy with an AUC of 0.91, with comparable performance for males and females. Accuracy of the model was predominantly driven by the biosynthesis pathways of ubiquinol-7 or thiamine diphosphate, which were less abundant in children with ASD. Collectively, our findings highlight the potential application of multikingdom and functional gut microbiota markers as non-invasive diagnostic tools in ASD.

A low testosterone level impairs erectile function by increasing endocan expression in rat penile corpus cavernosum.

The mechanism by which a state of low testosterone leads to erectile dysfunction (ED) has not been determined. Endocan is a novel marker of endothelial function. However, whether endocan is involved in the regulation of erectile function under low testosterone levels remains unclear. In this study we sought to determine whether a low-testosterone state inhibits erectile function by regulating endocan expression in the endothelial cells of the rat penile corpus cavernosum. Thirty-six male Sprague-Dawley rats aged 8 weeks were randomly assigned to 6 groups (n = 6 per group) as follows: (1) control, (2) castration, (3) castration + testosterone treatment (treated with 3mg/kg testosterone propionate per 2days), (4) control + transfection (4weeks after castration, injected with lentiviral vector (1 × 108 transduction units/mL, 10μL), (5) castration + transfection, or (6) castration + empty transfection. One week after the injection, we measured the maximal intracavernous pressure/mean arterial pressure (ICPmax/MAP), serum testosterone and nitric oxide (NO) levels, and the expression of endocan, phospho-endothelial NO synthase (p-eNOS), eNOS, phospho-protein kinase B (p-AKT), and AKT in the rat penile corpus cavernosum. Under a low-androgen state, the expression of endocan in the rat penile corpus cavernosum was significantly increased, which inhibited the AKT/eNOS/NO signaling pathway and resulted in ED. In the castration group, the expression of endocan in the rat penile corpus cavernosum was significantly higher than that in the control group (P < .05). Additionally, the levels of p-AKT/AKT, p-eNOS/eNOS, and NO in the rat penile corpus cavernosum and ICPmax/MAP were significantly lower in the castration group than in the control group (P < .05). In the castration + transfection group compared with the castration group there was a significant decrease in the expression of endocan (P < .05) and an increase in the ratios of p-AKT/AKT, p-eNOS/eNOS, and ICPmax/MAP (P < .05) in the rat penile corpus cavernosum. Downregulating the expression of endocan in the penile corpus cavernosum may be a feasible approach for treating ED caused by hypoandrogenism. The results of this study indicte that endocan may affect NO levels and erectile function through multiple signaling pathways, but further experiments are needed to clarify the relationship between endocan and androgens. A low-testosterone state inhibits the AKT/eNOS/NO signaling pathway by increasing the expression of endocan in the rat penile corpus cavernosum and impairing erectile function in rats. Decreasing the expression of endocan in the penile corpus cavernosum can improve erectile function in rats with low testosterone levels.

Integrating multiple kidney function markers to predict all-cause and cardiovascular disease mortality: prospective analysis of 366,758 UK Biobank participants

Integrating multiple kidney function markers to predict all-cause and cardiovascular disease mortality: prospective analysis of 366,758 UK Biobank participants

Simultaneous Biogas Upgrading and Valuable Chemical Production Using Homoacetogens in a Membrane Biofilm Reactor.

Biogas produced from anaerobic digestion usually contains impurities, particularly with a high content of CO2 (15-60%), thus decreasing its caloric value and limiting its application as an energy source. H2-driven biogas upgrading using homoacetogens is a promising approach for upgrading biogas to biomethane and converting CO2 to acetate simultaneously. Herein, we developed a novel membrane biofilm reactor (MBfR) with H2 and biogas separately supplied via bubbleless hollow fiber membranes. The gas-permeable hollow fibers of the MBfR enabled high H2 and CO2 utilization efficiencies (∼98% and ∼97%, respectively) and achieved concurrent biomethane (∼94%) and acetate (∼450 mg/L/d) production. High-throughput 16S rRNA gene amplicon sequencing suggested that enriched microbial communities were dominated by Acetobacterium (38-48% relative abundance). In addition, reverse transcription quantitative PCR of the functional marker gene formyltetrahydrofolate synthetase showed that its expression level increased with increasing H2 and CO2 utilization efficiencies. These results indicate that Acetobacterium plays a key role in CO2 to acetate conversion. These findings are expected to facilitate energy-positive wastewater treatment and contribute to the development of a new solution to biogas upgrading.

Effects of Anthocyanins on Cognition and Vascular Function: A Systematic Review.

Good vascular function is crucial for cerebral blood flow and cognitive performance. Diets high in anthocyanins have been shown to improve vascular function and are associated with improvements in cognition. This systematic review investigates randomized controlled trials examining the impact of anthocyanin intake on both cognition and vascular function. Of the 1486 studies identified through searching Ovid Medline and AMED, PsychInfo, Web of Science, and Scopus, 20 studies are selected which measured cognitive and vascular function. Overall, positive effects on verbal and working memory are observed, which are supported by studies using functional magnetic resonance imagingto demonstrate increased blood flow in brain regions related to these cognitive domains. However, effects of anthocyanins on blood pressure and markers of endothelial function are inconsistent. This systematic review provides evidence for a positive effect of anthocyanins on cognition and insight into the relevance of endothelial function. Anthocyanins are widely available and can be easily consumed in a range of different fruits, vegetables, and other products. Further studies should establish the optimal daily intake of anthocyanins for cardiovascular and cognitive health.

O-013 Population pharmacokinetics of follitropin delta during ovarian stimulation

Abstract Study question Which patient characteristics affect serum follicle stimulating hormone (FSH) concentrations in women undergoing ovarian stimulation (OS) with follitropin delta, a human cell line derived FSH? Summary answer Body weight is the main determinant of serum FSH concentrations during OS. Renal function, race, ethnicity, hepatic function and age have at most small influence. What is known already The pharmacokinetics of FSH have been studied in dedicated studies with serial blood sampling, typically conducted in healthy subjects. Such studies are designed to provide detailed pharmacokinetic profile information but lack the statistical power for identifying individual patient characteristics affecting FSH exposure. Population pharmacokinetic modelling enables evaluating the influence of patient characteristics based on few FSH measurements per patient if data from many patients are available. Study design, size, duration Serum FSH concentrations were assessed by immunoassay in seven randomized, controlled, blinded, multicentre trials of follitropin delta in women undergoing an assisted reproductive technology program. The trials were conducted in the United States, Canada, Europe, Brazil, and Asia. In all, 2,721 women treated with follitropin delta contributed to the evaluation with 6,952 FSH measurements. Participants/materials, setting, methods FSH concentrations were described with a pre-specified one-compartment population pharmacokinetic model. The key model parameters were the apparent total clearance (CL/F) of follitropin delta, the interindividual variability in CL/F and the effects of baseline values of body weight, age, race, ethnicity, renal and hepatic function on CL/F. Renal function was assessed using the estimated glomerular filtration rate (eGFR) and hepatic function by alanine transaminase (ALT) and bilirubin levels. Main results and the role of chance Area under the FSH concentration-time curve during a dosing interval (AUC) was derived from dose and CL/F. Body weight had the most pronounced effect on AUC, both in terms of effect magnitude and statistical significance. AUC was 1.28-fold higher (90% confidence limits: 1.25; 1.30) in women with a body weight of 47 kg (5th percentile) compared to women with a median body weight of 62 kg. The effect estimates of eGFR, Asian race and Black race on CL/F were within the bioequivalence limits of 0.80 and 1.25, but with 90% confidence limits not including a value of 1. The effect of Black race was estimated to be a 1.19 fold (90% confidence limits: 1.12; 1.26) higher AUC, as compared to White race. Despite this, the individual estimates of AUC were close to identical comparing these patient populations (mean (SD) relative to a typical study participant: 1.00 (0.25) and 0.97 (0.23), respectively). This is likely due to the mean body weight being higher in Black trial participants compared to White trial participants (78.3 kg compared to 68.2 kg). The effects of age, ethnicity and the hepatic function markers ALT and bilirubin were well within the bioequivalence range of 0.80 – 1.25. Limitations, reasons for caution Potential effects of subject characteristics on PK parameters such as subcutaneous absorption rate or volume of distribution could not be evaluated due to the number of serum FSH concentration measurements available per patient. Wider implications of the findings After follitropin delta administration, serum FSH concentrations are inversely related to body weight; this may be helpful for determining whether there is a need to consider body weight when selecting dose. Trial registration number NCT01426386, NCT02309671, NCT01956110, NCT03228680, NCT03296527, NCT03740737, NCT03738618, NCT03809429

P-351 Reproductive outcomes in a cohort of lymphoma patients

Abstract Study question What are the reproductive outcomes in women with malignant lymphoma Hodgkins (HD) and non-Hodgkins (NH) from a single, experienced center? Summary answer 74 children were born to 43 women (28 with HD, 15 with NH) giving a live birth rate (LBR) of 81% and 72%, respectively. What is known already The risk of premature ovarian insufficiency (POI) after HD and NH is related to female age, type and dose of gonadotoxic treatment. Where ABVD regimens in HD patients and CHOEP regimens in most young NH patients, rarely results in POI and reduced fertility, treatment with BEACOPP or BEAM and stem cell transplantation seems to be associated with a much higher risk of ovarian failure. However, studies are heterogeneous and there is still a need for studies with structural follow up on repeated measurements of ovarian function markers in relation to clinical outcomes. Study design, size, duration This cohort study was conducted as a single center study at the fertility clinic in a large public Danish university hospital. Data was collected retrospectively from medical records from 1999 to 2020 and prospectively from 2020 to 2023. We included all female patients with HD (n = 63) and NH (n = 32), who were referred to our clinic for fertility preservation between 1999 and 2022. End of follow up was December 31st, 2023. Participants/materials, setting, methods Age at referral ranged from 14 to 33 years. Information about diagnoses, gonadotoxic treatment, gynecologic (including endocrine parameters) and obstetric history was retrieved from medical records. Permission to obtain retrospective data from 1999 to 2020 was given by the Danish Patient Safety Authorities (jrn 3-3013-2790/1) and prospective data collection was given by informed consent from the patients from 2020 and onwards. Main results and the role of chance 33% of patients with HD had ABVD only, and the remaining BEACOPP or other high-dose alkylating regimens. 72% of patients with NH had CHOEP, and the rest other high-dose alkylating regimens. 78/95 women had fertility preservation. Of these, 95% had ovarian tissue cryopreservation (OTC), 5% had IVF with vitrification of oocytes or embryos. Following chemotherapy 33 women (52%) with HD and 18 (56%) with NH became pregnant. Of these, 28 women with HD had 51 deliveries, and 15 with NH had 23 deliveries. The LBR was 0,81 for HD and 0,72 for NH. For HD patients, 54% of the deliveries were achieved by women who had ABVD compared to about 40% after other high-dose alkylating regimens. For NH patients, 73% of deliveries were achieved by women who had CHOEP compared to 13% after other high-dose alkylating regimens. Most pregnancies were conceived spontaneously. A total of 15/74 women had ovarian tissue transplantation (OTT). Of these, 7 women with HD became pregnant resulting in 4 deliveries, and 4 women with NH became pregnant resulting in 2 deliveries giving an overall pregnancy rate of 73% in this group of women and a LBR of 40%. Limitations, reasons for caution This study is based on information from medical records in public Danish hospitals, containing information on all deliveries. Pregnancies and deliveries outside of Denmark might therefore not be included. Furthermore, for some women the follow-up period was only one year, which could underestimate the fertility in this group of patients. Wider implications of the findings This study shows a reassuringly high rate of spontaneous pregnancies in female survivors of malignant lymphomas. Only 20% of the women have so far used their tissue stored before chemotherapy. Current results might question whether we overtreat our lymphoma patients by offering OTC to the majority Trial registration number not applicable

Role of Apigenin in Rats with Type 1 Diabetic Complications

Abstract Background and Aim The main factor contributing to diabetes morbidity and mortality is cardiovascular problems. Apigenin, a naturally occurring flavonoid with anti-inflammatory and anti-diabetic characteristics, was investigated for its cardioprotective potential. Methods Type 1 diabetes model was induced using single injection of streptozotocin and diabetic rats were injected with apigenin. ECG recording and measurement of blood pressure were performed. Biochemical analyses of serum glucose, lipid profile, and creatine kinase were done. Histological examination of cardiac tissues was also performed. Results Diabetic rats had higher levels of glucose and creatine kinase, and impaired lipid profile as compared to the control group. Apigenin improved glycemic control, dyslipidemia, and cardiac function markers. Diabetic group had significantly higher blood pressure values as compared to the control group. The mean systolic and diastolic blood pressure levels dropped after apigenin treatment. ECG showed decrease in heart rate and increase in R-voltage after apigenin-injection as compared to diabetic rats. Moreover, apigenin-injection resulted in reduced histological changes of cardiac tissues compared to diabetic rats. Conclusion Apigenin could serve as potential therapeutic agent to reverse effects of hyperglycemia and its cardiovascular complications in diabetes.

Boiling histotripsy exhibits anti-fibrotic effects in animal models of liver fibrosis

Liver fibrosis is a hallmark of chronic liver disease which could lead to liver cirrhosis or liver cancer. However, there is currently lack of a direct treatment for liver fibrosis. Boiling histotripsy (BH) is an emerging non-invasive high-intensity focused ultrasound technique that can be employed to mechanically destruct solid tumour at the focus via acoustic cavitation without significant adverse effect on surrounding tissue. Here, we investigated whether BH can mechanically fractionate liver fibrotic tissue thereby exhibiting an anti-fibrotic effect in an animal model of liver fibrosis. BH-treated penumbra and its identical lobe showed reduced liver fibrosis, accompanied by increased hepatocyte specific marker expression, compared to the BH-untreated lobe. Furthermore, BH treatment improved serological liver function markers without notable adverse effects. The ability of BH to reduce fibrosis and promote liver regeneration in liver fibrotic tissue suggests that BH could potentially be an effective and reliable therapeutic approach against liver fibrosis.

Metabolic effects of very-low calorie diet, Semaglutide, or combination of the two, in individuals with type 2 diabetes mellitus

Background & AimsVery-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. MethodsThirty individuals with T2D (age 18-75 years, BMI 27-50kg.m-2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. ResultsSignificantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p<0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p<0.01). ConclusionVLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management.

Exercise mitigates reductive stress-induced cardiac remodeling in mice

The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG). RNA sequencing showed notable alterations in the ER transcriptome of TG hearts at 4, 12, and 24 weeks (16, 28, and 35 genes, respectively). Notably, the downregulation of ER genes was significant at 12 weeks, and further pronounced at 24 weeks, at which the cardiac pathology is evident. We also observed increased levels of ubiquitinated proteins in CaNrf2-TG hearts across all ages, along with VCP, a marker of ERAD function, at 24 weeks. These findings indicate that constitutive Nrf2 activation and RS impair protein-folding activity and augments ERAD function over time. Exercise intervention for 20 weeks (beginning at 6 weeks of age), reduced cardiomyocyte hypertrophy (from 448μm2 to 280μm2) in TG mice, through adaptive remodeling, and preserved the cardiac function. However, while exercise did not influence antioxidants or ER stress protein levels, it significantly improved ERAD function and autophagy flux (LC-I to LC-II) in the TG-EXE hearts. Collectively, our findings underscore the prophylactic potential of exercise in mitigating RS-associated pathology, highlighting its essential role in maintaining cellular proteostasis through ER-independent mechanisms.

Enhanced thorium decorporation and mitigation of toxicity through combined use of Liv52® and diethylenetriamine pentaacetate

Thorium-232 (Th-232) is a promising fuel for advanced nuclear reactors. However, in case of internal human exposure to Th, there is currently no effective modality for its removal from liver and skeleton or for mitigating its effect. The FDA-approved agent, diethylenetriaminepentaacetate (DTPA), can remove Th and other actinides from blood circulation only. For the first time, a rationally-selected polyherbal hepatoprotective i.e. Liv52® (L52S), was evaluated in-combination with DTPA for its Th decorporation ability in Swiss mice. Inductively-coupled plasma mass spectroscopic analysis showed that oral administration of L52S in conjunction with DTPA significantly decreased Th burden from liver (20 %) and skeleton (33 %) as well as enhanced Th excretion (∼2.5 folds) through urine in comparison to DTPA or L52S alone. The combinatorial therapy was found to be complementary in-action, ameliorating Th-induced tissue damage in liver, spleen, and bone more effectively than monotherapy. Furthermore, markers of liver function (alanine transaminase) and liver inflammation and fibrosis (NF-κB & keratin) further validated the beneficial effect of L52S. The human consumption of L52S for various liver disorders further supports its clinical application for Th decorporation and mitigation of its health effects.

Genetic variants in the TNF pathway impact TNFi response in a mixed population with rheumatoid arthritis

Rheumatoid arthritis (RA) is a multifactorial autoimmune inflammatory disease that mainly affects the joints, on reducing functional capacity and impacting quality of life. Cytokines such as tumor necrosis factor (TNF) and interleukin 6 (IL-6) are crucial in the pathogenesis and treatment of this disease. Some patients using TNF inhibitors (TNFi) do not respond or lose their response to these medications. Clinical, sociodemographic, and genetic data were used to evaluate the associations of single nucleotide polymorphisms (SNP) in TNF, TNFRSF1A, and TNFRSF1B genes with the diagnosis of RA, standardized score results, laboratory tests, and response to TNFi. In one subsample, TNF and IL-6 serum levels cytokines were performed. A total of 654 subjects (360 healthy controls and 294 diagnosed with RA) were included in the analysis. Higher levels of TNF have been found in individuals diagnosed with RA. IL-6 levels were higher in individuals who did not respond to TNFi treatment, while responders had levels comparable to those without the disease. No associations were found between the SNPs studied and the diagnosis of RA; however, rs767455-C seems to play a role in the response to golimumab treatment, being related to better therapeutic response and lower mean serum leukocyte levels. In addition, rs1061622-G was associated with poorer functional capacity and rs1800629-A was associated with higher leukocyte values and serum transaminase levels. The rs1061622-G and rs767455-C may play a role in the response to TNFi treatment, especially for patients using golimumab, although they do not seem to be associated with the diagnosis of RA. Polymosphisms in the TNF pathway may impact baseline levels of immune cells and markers of renal and hepatic function in RA patients. Our results highlight the importance of evaluating the impact of these polymorphisms on TNFi response and safety, particularly in larger-scale studies.

Acute effects of atrazine on the immunoexpressions of sertoli and germ cells molecular markers, cytokines, chemokines, and sex hormones levels in mice testes and epididymides

Atrazine is currently one of the most commonly used agrochemicals in the United States and elsewhere. Here, we studied the immunoexpression of molecular markers of mammalian testicular functions: androgen receptor (AR), promyelocytic leukemia zinc finger (PLZF), GDNF family receptor alpha-1 (GFRA1), VASA/DDX4 (DEAD-Box Helicase 4) as well as the levels of intratesticular and intra-epididymal estradiol (E2) and dihydrotestosterone (DHT), tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), interleukins (IL-1β and IL-6, IL-10) and testicular chemokines (CXCL-1, CCL-2 and CCL3) in BalB/c mice after a sub-acute gavage treatment with a gonado-toxin, atrazine (50 mg/kg body wt.) for three days. We found high numbers of AR immunopositive Sertoli cells and low numbers of GFRA1, PLZF and VASA/DDX4-positive germ cells in the seminiferous tubule regions of the testes. While TNF-α level in the testes fell and remained unchanged in the epididymides, IFN-γ levels in the testes remained constant but increased in the epididymides. E2 and DHT concentrations remained unaltered in the testes but were changed in the epididymides. There were no significant changes in the levels of interleukins in the testis and epididymis. Intratesticular chemokines were also not significantly altered, except for CCL-4, which was increased in the testis. Light microscopy of the epididymis showed detached epithelium and some detached cells in the lumen. It is concluded that atrazine changed the inflammatory status of the gonads and highlighted Sertoli and undifferentiated spermatogonia as important targets for atrazine's toxic effects in the testis of mice. Concerning the epididymis, atrazine altered the epididymal hormonal concentrations and promoted histopathological modifications in its parenchyma.

Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and post-pubertal males with FA, DC/TBD or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median 7.31 ng/mL, range: 3.46-18.82, P=0.03) or healthy male volunteers (median 7.66 ng/mL, range: 3.3-14.67, P=0.008). Males with DC/TBD had lower levels of AMH (median 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median 5.31 ng/mL, range: 1.2-17.77, P=0.01) or healthy volunteers (median 5.995 ng/mL, range: 1.57-14.67, P<0.001). Males with DBA had similar levels of AMH (median 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median 4.66 ng/mL, range: 0.09-13.51, P=0.56) and healthy volunteers (median 5.81 ng/mL, range: 1.57-14.67, P=0.10). Our findings suggest a defect in the production of AMH in post-pubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Accuracy of glomerular filtration rate estimation using creatinine and cystatin C for identifying and monitoring moderate chronic kidney disease: the eGFR-C study.

Estimation of glomerular filtration rate using equations based on creatinine is widely used to manage chronic kidney disease. In the UK, the Chronic Kidney Disease Epidemiology Collaboration creatinine equation is recommended. Other published equations using cystatin C, an alternative marker of kidney function, have not gained widespread clinical acceptance. Given higher cost of cystatin C, its clinical utility should be validated before widespread introduction into the NHS. Primary objectives were to: (1) compare accuracy of glomerular filtration rate equations at baseline and longitudinally in people with stage 3 chronic kidney disease, and test whether accuracy is affected by ethnicity, diabetes, albuminuria and other characteristics; (2) establish the reference change value for significant glomerular filtration rate changes; (3) model disease progression; and (4) explore comparative cost-effectiveness of kidney disease monitoring strategies. A longitudinal, prospective study was designed to: (1) assess accuracy of glomerular filtration rate equations at baseline (n = 1167) and their ability to detect change over 3 years (n = 875); (2) model disease progression predictors in 278 individuals who received additional measurements; (3) quantify glomerular filtration rate variability components (n = 20); and (4) develop a measurement model analysis to compare different monitoring strategy costs (n = 875). Primary, secondary and tertiary care. Adults (≥ 18 years) with stage 3 chronic kidney disease. Estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Measured glomerular filtration rate was the reference against which estimating equations were compared with accuracy being expressed as P30 (percentage of values within 30% of reference) and progression (variously defined) studied as sensitivity/specificity. A regression model of disease progression was developed and differences for risk factors estimated. Biological variation components were measured and the reference change value calculated. Comparative costs of monitoring with different estimating equations modelled over 10 years were calculated. Accuracy (P30) of all equations was ≥ 89.5%: the combined creatinine-cystatin equation (94.9%) was superior (p < 0.001) to other equations. Within each equation, no differences in P30 were seen across categories of age, gender, diabetes, albuminuria, body mass index, kidney function level and ethnicity. All equations showed poor (< 63%) sensitivity for detecting patients showing kidney function decline crossing clinically significant thresholds (e.g. a 25% decline in function). Consequently, the additional cost of monitoring kidney function annually using a cystatin C-based equation could not be justified (incremental cost per patient over 10 years = £43.32). Modelling data showed association between higher albuminuria and faster decline in measured and creatinine-estimated glomerular filtration rate. Reference change values for measured glomerular filtration rate (%, positive/negative) were 21.5/-17.7, with lower reference change values for estimated glomerular filtration rate. Recruitment of people from South Asian and African-Caribbean backgrounds was below the study target. Prospective studies of the value of cystatin C as a risk marker in chronic kidney disease should be undertaken. Inclusion of cystatin C in glomerular filtration rate-estimating equations marginally improved accuracy but not detection of disease progression. Our data do not support cystatin C use for monitoring of glomerular filtration rate in stage 3 chronic kidney disease. This trial is registered as ISRCTN42955626. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/103/01) and is published in full in Health Technology Assessment; Vol. 28, No. 35. See the NIHR Funding and Awards website for further award information.

Comparison of Cycling and Cross Trainer on Rate Pressure Product in Hypertensive Patients: A Cross-Sectional Study

Introduction: The Rate pressure product is the valuable marker of cardiac function. It is the product of heart rate and systolic blood pressure. It plays a pivotal role in understanding the relationship between exercise and the cardiovascular system, particularly in hypertensive individuals. Hypertension is a primary risk factor for coronary heart disease, stroke, congestive heart failure, renal failure and peripheral vascular disease. The aim of the study is to determine the effect of cycling and cross trainer on rate pressure product in hypertensive patients. Methodology: A cross-sectional study includes 30 hypertensive patients with age group of 25-65 years and those who have any recent surgery or any neurological or psychological issues are excluded. Patients vitals were monitored pre exercise. Every patient does exercise on both cross trainer and cycling for 15 min each on alternate day to avoid superimpose effect of each other. Rate pressure product was calculated and compared between cross trainer and cycling exercise. Result: Result has been obtained from SPSS 20. Mean age of patients is 45.9+10.2. Comparison between cycling and cross trainer found using independent t-test (t=-2.534). There was significant difference of RPP between patients performing cycling and cross trainer. RPP of cross trainer (mean=19.09) is more than RPP of cycling (mean=18.14) having significant difference p&lt;0.05. Conclusion: This study concluded that there is greater rate pressure product during cross trainer exercise than in cycling. This shows that more myocardial oxygen consumption is greater in cross trainer as it involves both upper and lower extremity. So, cross trainer and cycling can be used effectively for exercise prescription and preventing cardiovascular risk in hypertensive patients, but the cycling was more effective as the mean difference was low compared to cross trainer. Keywords: Static cycling, rate pressure product, cross trainer, hypertension

Luteal phase sertraline treatment of premenstrual dysphoric disorder (PMDD): Effects on markers of hypothalamic pituitary adrenal (HPA) axis activation and inflammation

RationalePremenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AimsThe goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. MethodsParticipants were females age 18–50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. ResultsThe sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p’s>0.05). ConclusionSerum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.