1,3-Butadiene has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to 1,3-butadiene primarily through ambient air. Inhaled 1,3-butadiene is carcinogenic in both mice and rats, inducing tumors at multiple sites at all concentrations tested in all identified studies. In addition, 1,3-butadiene is genotoxic in both somatic and germ cells of rodents. It also induces adverse effects in the reproductive organs of female mice at relatively low concentrations. The greater sensitivity in mice than in rats to induction of these effects by 1,3-butadiene is likely related to species differences in metabolism to active epoxide metabolites. Exposure to 1,3-butadiene in the occupational environment has been associated with the induction of leukemia; there is also some limited evidence that 1,3-butadiene is genotoxic in exposed workers. Therefore, in view of the weight of evidence of available epidemiological and toxicological data, 1,3-butadiene is considered highly likely to be carcinogenic, and likely to be genotoxic, in humans. Estimates of the potency of butadiene to induce cancer have been derived on the basis of both epidemiological investigation and bioassays in mice and rats. Potencies to induce ovarian effects have been estimated on the basis of studies in mice. Uncertainties have been delineated, and, while there are clear species differences in metabolism, estimates of potency to induce effects are considered justifiably conservative in view of the likely variability in metabolism across the population related to genetic polymorphism for enzymes for the critical metabolic pathway.
Calcium urolithiasis is often associated with increased intestinal absorption and urine excretion of calcium, and has been suggested to result from increased vitamin D production. The role of the enzyme 1 alpha-hydroxylase, the rate-limiting step in active vitamin D production, was evaluated in 36 families, including 28 sibships with at least a pair of affected sibs, using qualitative and quantitative trait linkage analyses. Sibs with a verified calcium urolithiasis passage (n = 117) had higher 24-h calciuria (P = 0.03), oxaluria (P = 0.02), fasting and postcalcium loading urine calcium/creatinine (Ca/cr) ratios (P = 0.008 and P = 0.002, respectively), and serum 1,25(OH)2 vitamin D levels (P = 0.02) compared with nonstone-forming sibs (n = 120). Markers from a 9-centiMorgan interval encompassing the VDD1 locus on chromosome 12q13-14 (putative 1 alpha-hydroxylase) were analyzed in 28 sibships (146 sib pairs) of single and recurrent stone formers and in 14 sibships (65 sib pairs) with recurrent-only (> or = 3 episodes) stone-forming sibs. Two-point and multipoint analyses did not reveal excess in alleles shared among affected sibs at the VDD1 locus. Linkage of stone formation to the VDD1 locus could be excluded, respectively, with a lambda d of 2.0 (single and recurrent stone formers) and 3.25 (recurrent stone formers). Quantitative trait analyses revealed no evidence for linkage to 24-h calciuria and oxaluria, serum 1,25(OH)2 vitamin D levels, and Ca/cr ratios. This study shows absence of linkage of the putative 1 alpha-hydroxylase locus to calcium stone formation or to quantitative traits associated with idiopathic hypercalciuria. In addition, there is coaggregation of calciuric and oxaluric phenotypes with stone formation.
This cross sectional study aims to investigate the associations between ectopic lipid accumulation in liver and skeletal muscle and biochemical measures, estimates of insulin resistance, anthropometry, and blood pressure in lean and overweight/obese children.
Fasting plasma glucose, serum lipids, serum insulin, and expressions of insulin resistance, anthropometry, blood pressure, and magnetic resonance spectroscopy of liver and muscle fat were obtained in 327 Danish children and adolescents aged 8-18 years.
In 287 overweight/obese children, the prevalences of hepatic and muscular steatosis were 31% and 68%, respectively, whereas the prevalences in 40 lean children were 3% and 10%, respectively. A multiple regression analysis adjusted for age, sex, body mass index z-score (BMI SDS), and pubertal development showed that the OR of exhibiting dyslipidemia was 4.2 (95%CI: [1.8; 10.2], p = 0.0009) when hepatic steatosis was present. Comparing the simultaneous presence of hepatic and muscular steatosis with no presence of steatosis, the OR of exhibiting dyslipidemia was 5.8 (95%CI: [2.0; 18.6], p = 0.002). No significant associations between muscle fat and dyslipidemia, impaired fasting glucose, or blood pressure were observed. Liver and muscle fat, adjusted for age, sex, BMI SDS, and pubertal development, associated to BMI SDS and glycosylated hemoglobin, while only liver fat associated to visceral and subcutaneous adipose tissue and intramyocellular lipid associated inversely to high density lipoprotein cholesterol.
Hepatic steatosis is associated with dyslipidemia and liver and muscle fat depositions are linked to obesity-related metabolic dysfunctions, especially glycosylated hemoglobin, in children and adolescents, which suggest an increased cardiovascular disease risk.
Cites: Child Obes. 2012 Dec;8(6):533-4123181919
Cites: Int J Pediatr Obes. 2011 Aug;6(3-4):188-9621529264
Cites: Int J Obes (Lond). 2014 Jan;38(1):40-523828099
To evaluate the impact on lipid and carbohydrate variables of a combined one-third ethinyl estradiol (EE)/levonorgestrel (LNG) dose reduction in oral contraceptives.
In an open-label, randomized study, a dose-reduced oral contraceptive containing 20 microg EE and 100 microg LNG (20 EE/100 LNG) was compared with a reference preparation containing 30 microg EE and 150 microg LNG (30 EE/150 LNG). One-year data from 48 volunteers were obtained.
We found a decrease of HDL2 cholesterol and increases of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol and total triglycerides in both treatment groups from baseline to the 13th treatment cycle. Although for four of six variables, the changes in the 20 EE group were lower compared with the 30 EE group, none of the differences between the two treatments were statistically significant. The median values for the fasting levels of insulin, C-peptide and free fatty acids slightly increased or remained unchanged while the fasting glucose levels slightly decreased after 13 treatment cycles. While the glucose area under the curve (AUC) (0-3 h) was similar in both groups during the OGTT, the insulin AUC(0-3 h) was less increased in the 20 EE/100 LNG group compared with the 30 EE/150 LNG group. None of the differences between the treatment groups for any of the carbohydrate metabolism variables were statistically significant at any time point. Both study treatments were safe and well tolerated by the volunteers.
Similar effects on the lipid and carbohydrate profiles were found for both preparations. The balanced one-third EE dose reduction in this new oral contraceptive caused slightly lower, but insignificant, changes in the lipid and carbohydrate variables compared with the reference treatment.
BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has a long half-life of 5-10 years in human beings as a result of its high lipophilicity, and little or no metabolism. We monitored TCDD, its form, distribution, and elimination in Victor Yushchenko after he presented with severe poisoning. METHODS: In late December, 2004, a patient presented with TCDD poisoning; the levels in his blood serum (108000 pg/g lipid weight) were more than 50 000-fold greater than those in the general population. We identified TCDD and its metabolites, and monitored their levels for 3 years using gas chromatography and high-resolution mass spectrometry in samples of blood serum, adipose tissue, faeces, skin, urine, and sweat, after they were extracted and cleaned with different organic solvents. FINDINGS: The amount of unmodified TCDD in the samples that were analysed accounted for about 60% of TCDD eliminated from the body during the same period. Two TCDD metabolites-2,3,7-trichloro-8-hydroxydibenzo-p-dioxin and 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin-were identified in the faeces, blood serum, and urine. The faeces contained the highest concentration of TCDD metabolites, and were the main route of elimination. Altogether, the different routes of elimination of TCDD and its metabolites accounted for 98% of the loss of the toxin from the body. The half-life of TCDD in our patient was 15.4 months. INTERPRETATION: This case of poisoning with TCDD suggests that the design of methods for routine assessment of TCDD metabolites in human beings should be a main aim of TCDD research in the metabolomic era. FUNDING: University of Geneva Dermatology Fund, and Swiss Centre for Applied Human Toxicology.
Comment In: Lancet. 2009 Oct 3;374(9696):1131-219660808
Homozygosity or mixed heterozygosity for mutations in the adenine phosphoribosyltransferase gene cause enzyme deficiency directing adenine through an alternative metabolic pathway. This results in the production of 2,8-dihydroxyadenine, which is actively secreted into the urine. 2,8-dihydroxyadenine is insoluble at physiological urinary pH but as marked supersaturation is possible the manifestations differ: there may be minimal consequences, there may be infiltration of the tubulointerstitial tissue with acute or chronic damage or there may be stone formation in the urinary tract. Effective treatment can be offered and therefore the prognosis depends upon the renal function at diagnosis. Treatment consists of adequate fluid intake, a low-purine diet and administration of allopurinol. Urinary 2,8-dihydroxyadenine crystals are easily recognized under a microscope. The diagnosis of 2,8-dihydroxyadeninuria can be confirmed by estimation of adenine phosphoribosyltransferase activity in erythrocyte lysates. More than 300 cases of 2,8-dihydroxyadeninuria have been diagnosed worldwide, most of them in Japan, France and Iceland. One case has been reported in Finland but there have been no reports from the Scandinavian peninsula or from Denmark. The relevant mutations may be very rare in these countries but underdiagnosis is also possible.
Over 45 years ago, Montreal Platelet Syndrome was first described as a rare inherited platelet disorder characterised by macrothrombocytopenia with spontaneous platelet clumping, abnormal platelet shape change upon stimulation and a defect in platelet calpain. This syndrome has now been reclassified as type 2B von Willebrand disease with the V1316M VWF mutation in the only kindred ever reported. We herein revisit the historical platelet characteristics originally described in Montreal Platelet Syndrome in light of the new diagnosis. This paper will review the 45-year saga of Montreal Platelet Syndrome, a story that highlights the value of revisiting a rare diagnosis to look for a more common explanation.