Offspring of diabetic pregnancies are at risk of cardiovascular disease at birth and throughout life, purportedly through fuel-mediated influences on the developing heart. Preventative measures focus on glycemic control, but the contribution of additional offenders, including lipids, is not understood. Cellular bioenergetics can be influenced by both diabetes and hyperlipidemia and play a pivotal role in the pathophysiology of adult cardiovascular disease. This study investigated whether a maternal high-fat diet, independently or additively with diabetes, could impair fuel metabolism, mitochondrial function, and cardiac physiology in the developing offspring's heart. Sprague-Dawley rats fed a control or high-fat diet were administered placebo or streptozotocin to induce diabetes during pregnancy and then delivered offspring from four groups: control, diabetes exposed, diet exposed, and combination exposed. Cardiac function, cellular bioenergetics (mitochondrial stress test, glycolytic stress test, and palmitate oxidation assay), lipid peroxidation, mitochondrial histology, and copy number were determined. Diabetes-exposed offspring had impaired glycolytic and respiratory capacity and a reduced proton leak. High-fat diet-exposed offspring had increased mitochondrial copy number, increased lipid peroxidation, and evidence of mitochondrial dysfunction. Combination-exposed pups were most severely affected and demonstrated cardiac lipid droplet accumulation and diastolic/systolic cardiac dysfunction that mimics that of adult diabetic cardiomyopathy. This study is the first to demonstrate that a maternal high-fat diet impairs cardiac function in offspring of diabetic pregnancies through metabolic stress and serves as a critical step in understanding the role of cellular bioenergetics in developmentally programmed cardiac disease.
Mitochondrial dysfunction is increasingly recognized and studied as a mediator of heart disease. Extracellular flux analysis (XF) has emerged as a powerful tool to investigate cellular bioenergetics in the context of cardiac health and disease, however its use and interpretation requires improved understanding of the normal metabolic differences in cardiomyocytes (CM) at various stages of maturation. This study standardized XF analyses methods (mitochondrial stress test, glycolytic stress test and palmitate oxidation test) and established age related differences in bioenergetics profiles of healthy CMs at newborn (NB1), weaning (3WK), adult (10WK) and aged (12–18MO) time points. Findings show that immature CMs demonstrate a more robust and sustained glycolytic capacity and a relative inability to oxidize fatty acids when compared to older CMs. The study also highlights the need to recognize the contribution of CO2 from the Krebs cycle as well as lactate from anaerobic glycolysis to the proton production rate before interpreting glycolytic capacity in CMs. Overall, this study demonstrates that caution should be taken to assure that translatable developmental time points are used to investigate mitochondrial dysfunction as a cause of cardiac disease. Specifically, XF analysis of newborn CMs should be reserved to study fetal/neonatal disease and older CMs (≥10 weeks) should be used to investigate adult disease pathogenesis. Knowledge gained will aid in improved investigation of developmentally programmed heart disease and stress the importance of discerning maturational differences in bioenergetics when developing mitochondrial targeted preventative and therapeutic strategies for cardiac disease.
Minimum inhibitory concentrations were determined with 1494 microorganisms isolated from the mammary glands of dairy heifers. The antimicrobial agents tested were penicillin, cloxacillin, cephapirin, ceftiofur, novobiocin, enrofloxacin, erythromycin, and pirlimycin. All minimum inhibitory concentrations were expressed as micrograms per milliliter. The isolates tested included 135 Staphylococcus aureus, 1222 Staphylococcus sp., 42 Streptococcus sp., 15 Enterococcus sp., 60 enteric species, and 20 miscellaneous organisms. The minimum inhibitory concentrations for 90% of isolates for the various antimicrobial agents with Staph. aureus were as follows: penicillin, .13; cloxacillin, .5; cephapirin, .5; ceftiofur, 1; novobiocin, .5; enrofloxacin, .5; erythromycin, .5, and pirlimycin, .5. In comparison, the minimum inhibitory concentrations for 90% of isolates for the Staphylococcus sp. were 1, 1, .5, 1, .5, .5, 1, and .5 for penicillin, cloxacillin, cephapirin, ceftiofur, novobiocin, enrofloxacin, erythromycin, and pirlimycin, respectively. The minimum inhibitory concentrations for 90% of isolates for the Streptococcus sp. were 2, 32, 2, 2, 8, 1, 64, and 32 for the respective antimicrobial agents; the minimum inhibitory concentrations for 90% of isolates were 4, 64, 32, 64, 4, 1, 4, and 4 for the enterococci. Against the Gram-negative enteric bacilli, only ceftiofur and enrofloxacin were active; minimum inhibitory concentrations for 90% of isolates were 1 microgram/ml for ceftiofur and .25 microgram/ml for enrofloxacin. Results indicated that the majority of staphylococcal strains were susceptible to the antimicrobial agents tested but that antimicrobial susceptibility varied for Streptococcus sp. Compounds currently available in intramammary infusion products demonstrated poor activity against the enteric organisms.
Several studies have implicated the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in inhibition of normal platelet function, suggesting a role for platelets in EPA- and DHA-mediated cardioprotection. However, it is unclear whether the cardioprotective mechanisms arise from alterations to platelet-platelet, platelet-matrix, or platelet-coagulation factor interactions. Our previous results led us to hypothesize that EPA and DHA alter the ability of platelets to catalyze the generation of thrombin. We tested this hypothesis by exogenously modifying platelet membranes with EPA and DHA, which resulted in compositional changes analogous to increased dietary EPA and DHA intake. Platelets treated with EPA and DHA showed reductions in the rate of thrombin generation and exposure of platelet phosphatidylserine. In addition, treatment of platelets with EPA and DHA decreased thrombus formation and altered the processing of thrombin precursor proteins. Furthermore, treatment of whole blood with EPA and DHA resulted in increased occlusion time and a sharply reduced accumulation of fibrin under flow conditions. These results demonstrate that EPA and DHA inhibit, but do not eliminate, the ability of platelets to catalyze thrombin generation in vitro. The ability of EPA and DHA to reduce the procoagulant function of platelets provides a possible mechanism behind the cardioprotective phenotype in individuals consuming high levels of EPA and DHA.
Mammary secretions, obtained before and after calving, were examined for visual appearance, SCC, and bacteriology as part of a larger study determining the prevalence of IMI in 1588 primigravid heifers. Appearance of secretions was categorized into five groups: thin and watery, honey-like, serumy, milky, or thickened colostrum. Precalving secretions were further characterized as low viscosity (thin and watery, serumy, or milky) or high viscosity (honey-like and thickened colostrum). Postcalving secretions were further characterized as normal (milky, thickened colostrum) or abnormal (thin and watery, serumy, or honey-like). Infected precalving quarters (81%) had low viscosity secretions. Quarters that were uninfected precalving (75%) had high viscosity secretions. Greater than 90% of all postcalving milk samples appeared to be normal, regardless of geographic location, season, or bacterial infection status. Only 77% of the samples from quarters infected with contagious and noncontagious mastitis pathogens had normal appearance. Precalving SCC from bacteriologically negative quarters were lower than SCC from infected quarters. Similarly, postcalving SCC were lower from the bacteriologically negative quarters than from the infected quarters. Infected quarters had higher mean SCC than the uninfected quarters during both pre- and postcalving periods.
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