The effect of insulin and glucagon on splanchnic oxygen consumption

The purpose of these experiments was to measure the influence of insulin and glucagon on the splanchnic oxygen consumption. Two experiments were performed. METHODS: In one experiment, the influence of hyperinsulinaemia was investigated in six healthy subjects, who were studied during a euglycaemic hyperinsulinaemic clamp. In another experiment, the influence of glucagon was investigated in seven healthy subjects, who were studied twice during a pancreatic islet clamp with either supplementation of insulin and glucagon, or of insulin alone. In both situations the measurements were performed during euglycaemia. Splanchnic oxygen consumption and net substrate balances were studied by the arterio-hepatic venous catheterisation technique and measurement of splanchnic blood flow in all experiments. RESULTS: During the euglycaemic hyperinsulinaemic clamp, the splanchnic blood flow increased significantly and the splanchnic oxygen consumption decreased by about 20%, while the net splanchnic glucose output reversed to a net uptake. In the pancreatic islet clamp experiments there was a significant difference between the net splanchnic glucose outputs whether glucagon and insulin or only insulin was supplemented. In spite of this, the splanchnic oxygen consumption decreased by about 20% in both situations, i.e. independent of glucagon supplementation. In both experiments there was a pronounced inhibition of lipolysis, which led to decreased fatty acids availability to the liver. This resulted in a concomitant decrease in hepatic ketone body formation. This decrease could account for about 30% of the decrease in splanchnic oxygen consumption. CONCLUSION: The reduction in splanchnic oxygen consumption can be explained by decreased ketogenesis, decreased protein synthesis and changes in splanchnic fuel selection, while changes in the rate of gluconeogenesis does not seem to play a significant role.     

Cyclin-dependent kinase inhibitors p21 and p27 function as critical regulators of liver regeneration following 90% hepatectomy in the rat

BACKGROUNDLiver reduction is the main curative treatment for primary liver cancer, but its use remains limited as liver regeneration requires a minimum of 30% functional parenchyma. AIMTo study the dynamics of the liver regeneration process and consequent behavior of cell cycle regulators in rats after extended hepatectomy (90%) and postoperative glucose infusions.METHODSPost-hepatectomy liver failure was triggered in 84 Wistar rats by reducing their liver mass by 90%. The animals received a post-operative glucose infusion and were randomly assigned to two groups: One to investigate the survival rate and the other for biochemical analyses. Animals that underwent laparotomy or 70% hepatectomy were used as controls. Blood and liver samples were collected on postoperative days 1 to 7. Liver morphology, function, and regeneration were studied with histology, immunohistochemistry, and western blotting. RESULTSPostoperative mortality after major resection reached 20% and 55% in the first 24 h and 48 h, respectively, with an overall total of 70% 7 d after surgery. No apparent signs of apoptotic cell death were detected in the extended hepatectomy rat livers, but hepatocytes displaying a clear cytoplasm and an accumulation of hyaline material testified to changes affecting their functional activities. Liver regeneration started properly, as early events initiating cell proliferation occurred within the first 3 h, and the G1 to S transition was detected in less than 12 h. However, a rise in p27 (Kip1) followed by p21 (Waf1/Cip1) cell cycle inhibitor levels led to a delayed S phase progression and mitosis. Overall, liver regeneration in rats with a 90% hepatectomy was delayed by 24 h and associated with a delayed onset and lower peak magnitude of hepatocellular deoxyribonucleic acid synthesis. CONCLUSIONThis work highlights the critical importance of the cyclin/cyclin-dependent kinase inhibitors of the Cip/Kip family in regulating the liver regeneration timeline following extended hepatectomy.     

Influence of antithymocyte globulin treatment of brain‐dead organ donor on inflammatory response in cardiac grafts: an experimental study in mice

The expression of proinflammatory cytokines in donor hearts after antithymocyte globulin (ATG) treatment given prior to organ removal was evaluated to analyze changes in inflammatory response. Adult female OF‐1 mice were randomized into brain death (BD) groups (BD Control, BD ATG) with or without treatment, and Controls (Control, ATG). BD induction was performed through gradual inflation of an intracranial positioned balloon catheter. At the end of a 6‐h observation period, ATG (1 mg/kg BW) was given intravenously. After 45 min, the donor hearts were removed. Proinflammatory markers IL‐2 and IL‐6 were examined using ELISA and immunohistochemistry staining. After single administration of ATG, the inflammatory reaction in the myocardium showed a significant reduction in IL‐2 expression (BD Control vs. BD ATG, P = 0.033). Our investigation showed expected increase in proinflammatory mediators after BD. This increase was abolished by single infusion of ATG, indicated by significant reduction in IL‐2 levels in the myocardium. We observed a reduction of IL‐6 deposition in media cells in ATG‐treated specimens. Further research is necessary to evaluate the role of ATG in donor management considering a potentially positive effect of ATG on IL‐2‐directed inflammatory response and possible reduction of IL‐6‐mediated vascular changes.     

Simultaneous Pharmacokinetic Modeling of Gentamicin,Tobramycin and Vancomycin Clearance from Neonates to Adults: Towards a Semi-physiological Function for Maturation in Glomerular Filtration

Purpose

Since glomerular filtration rate (GFR) is responsible for the elimination of a large number of water-soluble drugs, the aim of this study was to develop a semi-physiological function for GFR maturation from neonates to adults.

Methods

In the pharmacokinetic analysis (NONMEM VI) based on data of gentamicin, tobramycin and vancomycin collected in 1,760 patients (age 1 day–18 years, bodyweight 415 g–85 kg), a distinction was made between drug-specific and system-specific information. Since the maturational model for clearance is considered to contain system-specific information on the developmental changes in GFR, one GFR maturational function was derived for all three drugs.

Results

Simultaneous analysis of these three drugs showed that maturation of GFR mediated clearance from preterm neonates to adults was best described by a bodyweight-dependent exponent (BDE) function with an exponent varying from 1.4 in neonates to 1.0 in adults (Cl_GFR?=?Cl_drug*(BW/4 kg)^BDE with BDE?=?2.23*BW^?0.065). Population clearance values (Cl_drug) for gentamicin, tobramycin and vancomycin were 0.21, 0.28 and 0.39 L/h for a full term neonate of 4 kg, respectively.

Discussion

Based on an integrated analysis of gentamicin, tobramycin and vancomycin, a semi-physiological function for GFR mediated clearance was derived that can potentially be used to establish evidence based dosing regimens of renally excreted drugs in children.     

Women's Perspectives on Female-Initiated Barrier Methods for the Prevention of HIV in the Context of Methamphetamine Use and Partner Violence

BackgroundFemale-initiated barrier methods for the prevention of HIV may be an effective alternative for drug-using women who are unable to negotiate safe sex, often as a result of physical and/or sexual partner violence.MethodsUtilizing a SAVA (substance abuse, violence, and AIDS) syndemic framework, we qualitatively examined perspectives on female condoms and vaginal microbicides among 18 women with histories of methamphetamine abuse and partner violence in San Diego, California.FindingsMost women were not interested in female condoms owing to perceived discomfort, difficulty of insertion, time-intensive effort, and unappealing appearance. Alternatively, most women viewed vaginal microbicides as a useful method. Positive aspects included convenience, ability to disguise as a lubricant, and a sense of control and empowerment. Concerns included possible side effects, timing of application, and unfavorable characteristics of the gel. Acceptability of female-initiated barrier methods was context dependent (i.e., partner type, level of drug use and violence that characterized the sexual relationship).ConclusionsFindings indicate that efforts are needed to address barriers identified for vaginal microbicides to increase its uptake in future HIV prevention trials and marketing of future Food and Drug Administration-approved products. Strategies should address gender-based inequalities (e.g., partner violence) experienced by drug-using women and promote female empowerment. Education on female-initiated barrier methods is also needed for women who use drugs, as well as health care providers and other professionals providing sexual health care and contraception to women with histories of drug use and partner violence.     

IL-9 exerts biological function on antigen-experienced murine T cells and exacerbates colitis induced by adoptive transfer

IL-9 is involved in various T cell-dependent inflammatory models including colitis, encepahlitis, and asthma. However, the regulation and specificity of IL-9 responsiveness by T cells during immune responses remains poorly understood. Here, we addressed this question using two different models: experimental colitis induced by transfer of naive CD4⁺CD45RB^high T cells into immunodeficient mice, and OVA-specific T cell activation. In the colitis model, constitutive IL-9 expression exacerbated inflammation upon transfer of CD4⁺CD45RB^high T cells from WT but not from Il9r^−/− mice, indicating that IL-9 acts directly on T cells. Suprisingly, such naïve CD4⁺CD45RB^high T cells failed to express the Il9r or respond to IL-9 in vitro, in contrast with CD4⁺CD45RB^low T cells. By using OVA-specific T cells, we observed that T cells acquired the capacity to respond to IL-9 along with CD44 upregulation, after long-lasting (5 to 12 days) in vivo antigenic stimulation. Il9r expression was associated with Th2 and Th17 phenotypes. Interestingly, in contrast to the IL-2 response, antigen restimulation downregulated IL-9 responsiveness. Taken together, our results demonstrate that IL-9 does not act on naïve T cells but that IL-9 responsiveness is acquired by CD4⁺ T cells after in vivo activation and acquisition of memory markers such as CD44.     

Dietary Quality of Women of Reproductive Age in Low-Income Settings: A Cross-Sectional Study in Kyrgyzstan

Dietary diversity and adequate nutrient intake are essential for conducting a healthy life. However, women in low-income settings often face difficulties in ensuring dietary quality. This research assessed relationships between the dietary diversity, nutrient adequacy, and socio-economic factors among women of reproductive age (WRA) in Kyrgyzstan. A cross-sectional study was undertaken in four locations, including two rural and two urban areas in the north and south of Kyrgyzstan. A survey with pre-coded and open-ended questions was employed during the interviews of 423 WRAs aged 18–49. Data collection was conducted in March–May 2021. The average value body mass index (BMI) of WRA was 24.2 ± 4.6 kg/m². The dietary diversity score (DDS) was higher among rural women (common language effect size) cles = 0.67, adjusted p < 0.001) in the northern region (cles = 0.61, p < 0.05) who have cropland (cles = 0.60, p < 0.001) and a farm animal (cles = 0.60, p < 0.05). Mean nutrient adequacy ratio (NAR) was below 1 in most micronutrients, whereas thiamine, riboflavin, vitamins B6 and C, folic acid, calcium, and magnesium were even lower than 0.5. Women with a kitchen garden or a cropland had better NAR energy (cles = 0.57), NAR carbohydrate (cles = 0.60), NAR fiber (cles = 0.60), NAR vitamin B1 (cles = 0.53), and NAR folic acid (cles = 0.54). Respondents who receive remittances and a farm animal have better NARs for energy, carbohydrates, fiber, vitamin B1, folic acid, iron, zinc, and mean adequacy ratio for 16 nutrients (MAR 16) than those who do not. Education and income have a negative correlation with dietary quality. This study contributes to the limited literature on the quality of diets in Kyrgyzstan. Hidden hunger and undernutrition are a severe problem among WRA in low-income settings. Recommendations are including study programs in nutrition, teaching households farming practices, and raising awareness on adequate nutrition.