Do exposure to Arsenic, occupation and diet have synergistic effects on prostate cancer risk?

Background: Diverse environmental exposures, as well as dietary and lifestyle factors, are associated with prostate cancer (PC) etiology; however little is known about joint interactive influences. The aim of this study was to analyse effects of diet combined with arsenic in drinking water and agricultural occupation on PC risk. Methods: A case-control study was conducted in Córdoba, Argentina (period 2008-2015) including 147 cases of PC and 300 controls. All subjects were interviewed about food consumption, socio-demographic and lifestyle characteristics. A sample of drinking water was taken to determine arsenic concentrations. Adherence scores to the Traditional Dietary Pattern were estimated, based on a principal component factor analysis. A two-level logistic regression model was fitted in order to assess effects of the Traditional Pattern, occupation and arsenic exposure on the occurrence of PC (outcome). Family history of PC was considered as a clustering variable. Results: PC risk was greatest in subjects with high adherence to the Traditional Pattern (OR 2.18; 95%IC 1.097-4.344). Subjects exposed to arsenic in drinking water above 0.01mg/l who simultaneously performed agricultural activities showed a markedly elevated PC risk (OR 5.07; 95%IC 2.074-12.404). Variance of the random effect of family history of PC was significant. conclusion: Diet, arsenic and occupation in agriculture exert significant effects on PC risk. Further efforts are necessary to analyse risk factors integrally, in order to achieve a better understanding of the complex causal network for PC in this multiple-exposure population.Fil: Román, María Dolores. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Niclis, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Aballay, Laura Rosana. Universidad Nacional de Cordoba. Facultad de Medicina. Escuela de Nutrición; ArgentinaFil: Lantieri, María Josefina. Universidad Nacional de Córdoba. Facultad de Medicina. Cátedra de Histología,embriología y Genética I; ArgentinaFil: Díaz, María del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; ArgentinaFil: Muñoz, Sonia Edith. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentin

Nutrition, obesity and hormones

Obesity is a chronic pathological condition with a multifactorial aetiology, characterised by an excessive body fat accumulation with multiple organ-specific consequences. Emerging evidence highlights that obesity appears to be associated with multiple alterations in the endocrine system. However, the mechanisms underlying the interactions between obesity and this system remain still controversial. This review discusses the impact of obesity on various endocrine systems and, in particular, would provide a general overview on the biochemical changes that may occur in each of these axes in association with obesity

Optimization of Ex Vivo Machine Perfusion and Transplantation of Vascularized Composite Allografts

Background: Machine perfusion is gaining interest as an efficient method of tissue preservation of Vascularized Composite Allografts (VCA). The aim of this study was to develop a protocol for ex vivo subnormothermic oxygenated machine perfusion (SNMP) on rodent hindlimbs and to validate our protocol in a heterotopic hindlimb transplant model. Methods: In this optimization study we compared three different solutions during 6 h of SNMP ( n = 4 per group). Ten control limbs were stored in a preservation solution on Static Cold Storage [SCS]). During SNMP we monitored arterial flowrate, lactate levels, and edema. After SNMP, muscle biopsies were taken for histology examination, and energy charge analysis. We validated the best perfusion protocol in a heterotopic limb transplantation model with 30-d follow up ( n = 13). As controls, we transplanted untreated limbs ( n = 5) and hindlimbs preserved with either 6 or 24 h of SCS ( n = 4 and n = 5). Results: During SNMP, arterial outflow increased, and lactate clearance decreased in all groups. Total edema was significantly lower in the HBOC-201 group compared to the BSA group ( P = 0.005), 4.9 (4.3-6.1) versus 48.8 (39.1-53.2) percentage, but not to the BSA + PEG group ( P = 0.19). Energy charge levels of SCS controls decreased 4-fold compared to limbs perfused with acellular oxygen carrier HBOC-201, 0.10 (0.07-0.17) versus 0.46 (0.42-0.49) respectively ( P = 0.002). Conclusions: Six hours ex vivo SNMP of rodent hindlimbs using an acellular oxygen carrier HBOC-201 results in superior tissue preservation compared to conventional SCS. (c) 2021 Elsevier Inc. All rights reserved

Exceeding the Limits of Static Cold Storage in Limb Transplantation Using Subnormothermic Machine Perfusion

Background For 50 years, static cold storage (SCS) has been the gold standard for solid organ preservation in transplantation. Although logistically convenient, this preservation method presents important constraints in terms of duration and cold ischemia-induced lesions. We aimed to develop a machine perfusion (MP) protocol for recovery of vascularized composite allografts (VCA) after static cold preservation and determine its effects in a rat limb transplantation model. Methods Partial hindlimbs were procured from Lewis rats and subjected to SCS in Histidine-Tryptophan-Ketoglutarate solution for 0, 12, 18, 24, and 48 hours. They were then either transplanted (Txp), subjected to subnormothermic machine perfusion (SNMP) for 3 hours with a modified Steen solution, or to SNMP + Txp. Perfusion parameters were assessed for blood gas and electrolytes measurement, and flow rate and arterial pressures were monitored continuously. Histology was assessed at the end of perfusion. For select SCS durations, graft survival and clinical outcomes after transplantation were compared between groups at 21 days. Results Transplantation of limbs preserved for 0, 12, 18, and 24-hour SCS resulted in similar survival rates at postoperative day 21. Grafts cold-stored for 48 hours presented delayed graft failure (p = 0.0032). SNMP of limbs after 12-hour SCS recovered the vascular resistance, potassium, and lactate levels to values similar to limbs that were not subjected to SCS. However, 18-hour SCS grafts developed significant edema during SNMP recovery. Transplantation of grafts that had undergone a mixed preservation method (12-hour SCS + SNMP + Txp) resulted in better clinical outcomes based on skin clinical scores at day 21 post-transplantation when compared to the SCS + Txp group (p = 0.01613). Conclusion To date, VCA MP is still limited to animal models and no protocols are yet developed for graft recovery. Our study suggests that ex vivo SNMP could help increase the preservation duration and limit cold ischemia-induced injury in VCA transplantation.</p

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Nutrition, obesity and hormones

Obesity is a chronic pathological condition with a multifactorial aetiology, characterised by an excessive body fat accumulation with multiple organ-specific consequences. Emerging evidence highlights that obesity appears to be associated with multiple alterations in the endocrine system. However, the mechanisms underlying the interactions between obesity and this system remain still controversial. This review discusses the impact of obesity on various endocrine systems and, in particular, would provide a general overview on the biochemical changes that may occur in each of these axes in association with obesity

Maternal exposure to Cochlospermum regium: a toxicological evaluation

Cochlospermum regium (Schrank) Pilg., Bixaceae, is a Brazilian plant widely used as a folk medicine in the southwestern of the Brazil to treat inflammation and infection diseases. However, the effects of C. regium hydroethanolic extract on pregnant rats have not been assessed. To evaluate the effects of the C. regium on pregnant rats during the organogenic period, the hydroethanolic extract was administered via gavage at a dose of 11.5 mg/kg/day to rats from 6th to 15th day of pregnancy. No clinical signs of maternal toxicity were observed. The placenta's and fetuses' weight were similar in control and treated animals. The term fetuses dis not present malformations or anomalies although the number of live fetuses and birth rate were significantly decreased. In conclusion, the C. regium hydroethanolic extract is nontoxicant to the pregnant rat although it would be likely to interfere in the progress of the embryofetal development

Measurement of sorafenib plasma concentration by high-performance liquid chromatography in patients with advanced hepatocellular carcinoma: is it useful the application in clinical practice? A pilot study

Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at alpha = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful