Sodium-glucose co-transporter-2 inhibitors are associated with kidney benefits at all degrees of albuminuria: A retrospective cohort study of adults with diabetes.

AIM: To estimate the real-world effectiveness of sodium-glucose co-transporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) at reducing loss of kidney function and adverse kidney events in adults with varying levels of albuminuria. MATERIALS AND METHODS: In this retrospective cohort study using administrative data, we matched new SGLT2i users 1:2 to DPP4i users on diabetes therapy, chronic kidney disease (CKD) stage, albuminuria and time-conditional propensity score. Albuminuria was defined by spot urine albumin or equivalent as mild, moderate or severe. Linear regression was used to model the estimated glomerular filtration rate (eGFR), and Poisson regression for a composite kidney outcome (> 40% loss of eGFR, kidney replacement therapy or death from kidney causes) and all-cause mortality. RESULTS: SGLT2i users (n = 19 238, median age 57.9 years, female 40.9%) had mostly nil/mild albuminuria (70.7%). SGLT2is were associated with a 1.36 (95% CI 0.98-1.74) mL/min/1.73m2 (P < .001) acute (≤ 60 days) decline in eGFR, relative to DPP4is. Thereafter, SGLT2is were associated with 1.04 (95% CI 0.93-1.15) mL/min/1.73m2 (P < .001) less annual eGFR loss. SGLT2i users had fewer adverse kidney outcomes (incidence rate ratio [IRR] 0.58 [0.47-0.71]; P < .001), but not all-cause mortality (IRR 0.82 [0.66-1.01]; P = .06). Outcomes were similar considering only those with nil/mild albuminuria. CONCLUSIONS: SGLT2is may prevent eGFR decline and reduce the risk of adverse kidney events in adults with diabetes and nil or non-severe albuminuria.

Effects of dietary 2-(2H-benzotriazol-2-yl)-4-methylphenol (UV-P) exposure on Japanese medaka (Oryzias latipes) in a short-term reproduction assay.

Benzotriazole ultraviolet stabilizers (BZT-UVs) are added to various products to prevent damage caused by UV light and have emerged as contaminants of concern. Although BZT-UVs are detected in aquatic biota globally, few studies have assessed their potential toxic effects. The objective of the present study was to assess effects of 2-(2H-Benzotriazol-2-yl)-4-methylphenol (UV-P) on reproductive success of Japanese medaka (Oryzias latipes) in a standard 21-day reproduction assay. Japanese medaka were exposed to dietary UV-P at concentrations of 0, 36, 158, and 634 ng UV-P/g food, for a total of 28 days which included 7 days of exposure prior to the start of the 21-day reproduction assay. No significant effect on egg production or fertilization success was observed. Abundances of transcripts of erα, vtgI, cyp1a, or cyp3a4 were not significantly different in livers from male or female fish exposed to UV-P. However, abundances of transcripts of cyp11a and cyp19a were significantly lower in gonads from female fish. There was a trend of increasing concentrations of E2 and a non-significant increase of T in the 634 ng/g treatment in plasma from female fish exposed to UV-P. Concentrations of 11-KT were unchanged in plasma from males exposed to UV-P. These responses suggest weak perturbation of steroidogenesis, consistent with an antiandrogenic mode of action. However, this perturbation was insufficient to impair reproductive performance. Metabolomics analysis of female livers suggests altered concentrations of various metabolites and biological pathways, including glutathione metabolism, suggesting that UV-P might cause responses related to oxidative stress or phase II metabolism. However, metabolomics revealed no obvious mechanism of toxicity. Overall, results of this study indicate that dietary exposure to UV-P up to 634 ng/g food does not significantly impact reproductive performance of Japanese medaka but impacts on steroidogenesis could indicate a potential mechanism of toxicity which might lead to reproductive impairment in more sensitive species.

Inhibition of Oocyte Maturation by Malathion and Structurally Related Chemicals in Zebrafish (Danio rerio) After In Vitro and In Vivo Exposure.

Oogenesis is the process by which a primary oocyte develops into a fertilizable oocyte, making it critical to successful reproduction in fish. In zebrafish (Danio rerio), there are five stages of oogenesis. During the final step (oocyte maturation), the maturation-inducing hormone 17α,20ß-dihydroxy-4-pregnen-3-one (MIH) activates the membrane progestin receptor, inducing germinal vesicle breakdown. Using in vitro assays, it has been shown that anthropogenic stressors can dysregulate MIH-induced oocyte maturation. However, it is unknown whether the in vitro assay is predictive of reproductive performance after in vivo exposure. We demonstrate that a known inhibitor of oocyte maturation, malathion, and a structurally related chemical, dimethoate, inhibit oocyte maturation. However, malaoxon and omethoate, which are metabolites of malathion and dimethoate, did not inhibit oocyte maturation. Malathion and dimethoate inhibited maturation to a similar magnitude when oocytes were exposed for 4 h in vitro or 10 days in vivo, suggesting that the in vitro zebrafish oocyte maturation assay might be predictive of alterations to reproductive performance. However, when adult zebrafish were exposed to malathion for 21 days, there was no alteration in fecundity or fertility in comparison with control fish. Our study supports the oocyte maturation assay as being predictive of the success of in vitro oocyte maturation after in vivo exposure, but it remains unclear whether inhibition of MIH-induced oocyte maturation in vitro correlates to decreases in reproductive performance. Environ Toxicol Chem 2022;41:1381-1389. © 2022 SETAC.

1H NMR based metabolomic profiling of early life stage zebrafish (Danio rerio) exposed to a water-soluble fraction of weathered sediment-bound diluted bitumen.

Spills of diluted bitumen (dilbit) from pipelines pose a risk to the health of aquatic organisms, including fish, and with expected increases in production and transportation of dilbit, these risks could increase. To date, the majority of studies have investigated effects of fresh dilbit on aquatic organisms, but little is known about effects of weathered sediment-bound dilbit, including mechanisms of toxicity. The goal of this study was to use 1H NMR based metabolomics to identify altered metabolites and pathways in early life-stages of zebrafish (Danio rerio) exposed to a sediment derived water-soluble fraction of dilbit (SDWSF) to better understand mechanisms of adverse effects. Zebrafish embryos exposed to the SDWSF until 120 h post-fertilization exhibited increased prevalence of pericardial edema, yolk sac edema, and swim bladder malformations that are typical of exposure to fresh dilbit. Concentrations of nine metabolites (alanine, glutamine, lysine, threonine, tyrosine, betaine, taurine, inosine, and glycerol) were significantly altered in embryos exposed to SDWSF. Pathway topology analysis revealed four potentially impacted pathways: 1) phenylalanine, tyrosine, and tryptophan biosynthesis, 2) taurine and hypotaurine metabolism, 3) alanine, aspartate, and glutamate metabolism, and 4) glycine, serine, and threonine metabolism. Altered metabolites were linked to several biological process, that when perturbed could be key events in mechanisms of developmental effects observed in embryos. Future studies should further investigate the role of perturbations to these metabolites and pathways to determine the specific role they might play in adverse effects of exposure to dilbit.

Toxicity of Weathered Sediment-Bound Dilbit to Early Life Stages of Zebrafish (Danio rerio).

Due to high viscosity, bitumen extracted from the Alberta oil sands is diluted with natural gas condensates to form diluted bitumen (dilbit) to facilitate transport through pipelines. Dilbit that is spilled into or near a waterbody is subject to environmental weathering processes such as evaporation and interaction with sediments. This is the first study that assessed the toxicity of weathered sediment-bound dilbit (WSD) to fish early life stages. Exposure of zebrafish (Danio rerio) embryos to water-soluble fractions (WSFs) or water-accommodated fractions (WAFs) of WSD from 30 min to 120 h postfertilization resulted in pericardial edema, yolk sac edema, and incidences of uninflated swim bladder. The presence of oil-mineral aggregates (OMAs) in the WAFs greatly increased toxicity, despite all fractions having similar concentrations of dissolved polycyclic aromatic hydrocarbons (PAHs). There were greater cyp1a mRNA abundances in larvae exposed to WAFs, suggesting that there were differences in bioavailability of PAHs between fractions. However, there was little evidence that embryotoxicity was caused by oxidative stress. Results suggest that evaporation and sediment interaction do not completely attenuate toxicity of dilbit to zebrafish early life stages, and OMAs in exposures exacerbate toxicity.

Aerobic Fitness Markers Associated with Post-Paddling Breath-hold Capacity in Competitive Surfers.

Competitive surfing is a growing sport with evolving performance and safety demands. One particular challenge surfers face is the need to endure long breath-holds following bouts of surf paddling. The purpose of this study was to examine the association between aerobic fitness markers, such as VO2peak and ventilatory thresholds, and post-paddling breath-hold capacity in competitive surfers. Eleven male collegiate level competitive surfers completed both a maximal graded exercise test and a simulated post-paddling breath-hold challenge on a modified paddling ergometer. Associations between markers of aerobic fitness and post-paddling breath-hold capacity were tested using linear regression modeling. The overall regression model indicated a positive linear association between the assessed markers of aerobic fitness and post-paddling breath-hold capacity (r = .828, r 2 = 0.686, p = 0.035). This association was explained by differences in VO2peak (ß = 0.975, p = .034). These findings suggest that VO2peak may be an important training target for programs aimed at improving breath-hold capacity in surfers.

Epstein-Barr virus infection after kidney transplantation.

Besides the well-known association of Epstein-Barr virus (EBV) and lymphomas developing posttransplantation, there are only a few data concerning the prevalence of EBV antibodies (abs) in organ donors and recipients, the posttransplant development of antibody titer in the recipient population, the extent of EBV-IgM seroconversion, and the clinical and laboratory signs associated with infection. Therefore, in a retrospective analysis, we evaluated the data of 119 organ donors and 215 kidney graft recipients who received their kidney allografts between 1993 and 1995. A total of 665 sera were quantitatively tested by means of immunofluorescence assay for EBV abs against capsid (CA; IgM, IgG), early (IgG), and nuclear (IgG) antigens. Recipient sera were obtained for testing before kidney transplantation (KTx) and at post-KTx days 32, 67, and 649 (mean values). Pre-KTx all organ donors and 98.65% of the recipients wre EBV-CA-IgG positive, only in two cases was there a D+/R- (donor/recipient) combination leading to primary EBV infection. In comparison with the organ donors, in kidney graft recipients the pre-KTx IgG antibody titers (geometric mean) against EBV-CA were significantly elevated (1:428 vs 1:574; U-test). Post-KTx, EBV-CA-IgM seroconversion was observed in 29.5% (52 out of 176) of first graft recipients and in 47.8% (11 out of 23) of regrafted patients up to the last follow-up day 649. In 219 out of these 52 recipients, IgM abs again cytomegalovirus (CMV) could also be detected; the other 23 did not develop CMV-IgM abs. The most frequently associated clinical signs were fever (74%), elevated aminotransferases (57%), and deterioration of graft function (26%). In the EBV-IgM+/CMV-IgM+ group there were significantly more rejection therapies than in the EBV-IgM+/CMV-IgM- group. With respect to the severity of EBV infections, 68% were asymptomatic or mild, 27% moderate, and 4% (only 1) severe. Thus, besides the post-KTx CMV monitoring, EBV monitoring should also belong to the follow-up checks.

Thyroid lid surgery.

A retrospective study of 58 thyroid patients undergoing eyelid surgery for thyroid related lid malposition is reported. A treatment strategy is suggested, based on the results of this experience. The following points are stressed: (1) The importance of recognising and relieving the inferior rectus tethering component of upper lid retraction when present. (2) The usefulness of a scleral graft in lower lid retractor recession. (3) The inadequacy of lateral tarsorrhaphy in relieving lid retraction but its value in camouflage.

[Longitudinal studies in children with pyelonephritis and glomerulonephritis with special reference to selected immune parameters]. / Längsschnittuntersuchungen an Kindern mit Pyelonephritis und Glomerulonephritis unter besonderer Berücksichtigung ausgewählter Immunparameter.

In children with a glomerulonephritis the immune laboratory parameters used by us showed deviations from the norm which are necessary to be pursued. This particularly concerns the differentiation of B- and T-cells, the determination of the subpopulations of the T-cells, furthermore also the control of the serum-IgM as well as the investigation of complement and C-factors 3 and 4, respectively. The laboratory methods mentioned deserve to be compared with and related to clinical, paraclinical and renal bioptic data of the GN-patients. Such correlations promise deeper insights into the pathogenic connections of certain forms of glomerulonephritis and possibly also as statement concerning the control of therapy.

[In vitro sensitivity of T lymphocytes to theophylline in healthy adults and patients following cadaver kidney allotransplantation]. / T-Lymphozyten mit unterschiedlicher In-vitro-Sensitivität gegenüber Theophyllin bei gesunden Erwachsenen und Patienten nach Leichennierenallotransplantation.

In the peripheral blood of healthy adults the number of theophylline-resistant T-lymphocytes (T-res) is 51 +/- 4% and 1,161 +/- 326/microliter, respectively, and the number of theophyllins-sensitive 11 +/- 2% and 252 +/- 95/microliters. The membrane markers show a heterogeneous distribution. The quotient from T-res/T-sens is 4.9 +/- 1.3. Within the T-sens 14% are CD4+ and 30% CD8+, 29% carry Fc-IgC and 34% Fc-IgM-receptors. Thus the T-res in their netto-function were helper cells and the T-sens suppressor/cytotox cells. Before the transplantation the preoperative ratio of the two subpopulation is significantly diminished (Q = 3.66 +/- 1.53), however, prognostic statements cannot be deduced from this. Activations of the immune system (rejection crises, cytomegalovirus infections) are accompanied by significant diminutions of the T-sens, whereby the T-res/T-sens-Quotient increases. Thus they are unequivocally included into immunoregulatory processes.

Normal values and membrane markers of theophylline-sensitive and theophylline-resistant human T-lymphocytes.

In 32 healthy adults between 20 and 50 years, the number of theophylline-resistant T-lymphocytes (T-res) was determined to be 51 +/- 4% or 1,161 +/- 326 per microliter, and that of theophylline-sensitive T-lymphocytes (T-sens), 11 +/- 2% or 252 +/- 95.--The decrease in number of rosette-forming cells after incubation with 1 mM theophylline was not caused by reduced vitality (51Cr-release test). The testing of various theophylline concentrations (1, 3, 5, and 10 mM) did not result in a changed count of T-sens. By a variation of the lymphocyte: sheep erythrocyte ratio and of incubation temperature it was found that T-sens possess high-affine and T-res low-affine receptors for sheep erythrocytes. While about 30% of the cells of both subpopulations proved to have Fc-IgM-receptors, among T-sens a significantly higher number of cells carried Fc-IgG-receptors than among T-res (29% vs. 10%).

[Effect of plasmapheresis treatment on immunoglobulin and immune complex levels in patients following kidney transplantation]. / Zum Einfluss der Plasmapheresebehandlung auf Immunglobulin- und Immunkomplexkonzentration bei Patienten nach Nierentransplantation.

Five patients who received cadaver kidneys between May 1982 and January 1983 in the Kidney Transplant Centre in Berlin were subjected to two plasmapheresis (= pph.) treatments in addition to basic immunosuppression with Prednisolone and Azathioprine. The decision to use pph. was due to the presence of donor-specific, complement-dependent lymphocytotoxic antibodies (51Cr release test) in the recipient's serum taken immediately before transplantation. The 1st pph. was carried out on the 1st or 2nd day after operation and the 2nd pph. between the 2nd and 4th day. The quantity of plasma exchanged was between 1.6 and 3.1 1 per pph. Four of the five transplants commenced functioning after 12 to 47 days, and one transplant had to be removed. Frequent measurement of the immunoglobulin and immune-complex levels in the serum revealed drastic reduction due to pph. The concentration of immunoglobulin (G, A, M) was reduced by 42-55% after the 1st pph. and by 20-35% after the 2nd. Whereas the IgM level was normalized after a few days, the levels of IgG and IgA only rose again 2-4 weeks later. The immunodeficiency induced by means of pph. and immunosuppression is accompanied by an increased risk of infection. It is therefore considered important that an adequate anti-infectious treatment including i. v. human gammaglobulin be administered parallel to pph. The final evaluation of the efficacy of pph. in protecting transplants will depend on further studies.