Prenatal exposures to phthalates among women in New York City and Krakow, Poland

Experimental evidence has shown that certain phthalates can disrupt endocrine function and induce reproductive and developmental toxicity. However, few data are available on the extent of human exposure to phthalates during pregnancy. As part of the research being conducted by the Columbia Center for Children's Environmental Health, we have measured levels of phthalates in 48-hr personal air samples collected from parallel cohorts of pregnant women in New York, New York, (n = 30) and in Krakow, Poland (n = 30). Spot urine samples were collected during the same 48-hr period from the New York women (n = 25). The following four phthalates or their metabolites were measured in both personal air and urine: diethyl phthalate (DEP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), and butyl benzyl phthalate (BBzP). All were present in 100% of the air and urine samples. Ranges in personal air samples were as follows: DEP (0.26-7.12 microg/m3), DBP (0.11-14.76 microg/m3), DEHP (0.05-1.08 microg/m3), and BBzP (0.00-0.63 microg/m3). The mean personal air concentrations of DBP, di-isobutyl phthalate, and DEHP are higher in Krakow, whereas the mean personal air concentration of DEP is higher in New York. Statistically significant correlations between personal air and urinary levels were found for DEP and monoethyl phthalate (r = 0.42, p < 0.05), DBP and monobutyl phthalate (r = 0.58, p < 0.01), and BBzP and monobenzyl phthalate (r = 0.65, p < 0.01). These results demonstrate considerable phthalate exposures during pregnancy among women in these two cohorts and indicate that inhalation is an important route of exposure.     

Muscle blood flow and mitochondrial function: influence of aging

Skeletal muscle mitochondrial capacity (mito), tissue blood flow (BF) capacity, and oxygen exchange capacity (e.g., DO2) appear to be well matched. The different skeletal muscle fiber types and muscle remodeled, due to inactivity (e.g., related to aging or disease) or exercise training, exhibit widely differing aerobic capacities (VO2max). Yet, there are remarkably coordinated alterations in these 3 parameters in each of these conditions. With such a balance, there is likely shared control among these parameters in limiting VO2max of muscle, although this is a matter of considerable debate. The reduction in aerobic capacity in elderly can be improved by submaximal aerobic exercise training; this is related to increases in muscle mitochondria concentration and capillarity, but probably not BF capacity, as this is limited by central cardiovascular function. Thus, exercise-induced biochemical adaptations and angiogenesis occur in the elderly. The increase in muscle capillarity likely contributes to the increased oxygen exchange capacity, typical of endurance type training. The increase in [mito] appears essential to realize the increased in muscle VO2max with training and amplifies the rate-limiting influence of the muscles oxygen exchange capacity. Further, vascular remodeling induced by exercise in the elderly could be effective at improving flow capacity, if limited by peripheral obstruction. Thus, the limits to aerobic function specific to aged muscle appear most influenced by inactivity, whereas central cardiovascular changes impact whole body performance. Some may consider the aged myocyte as a small, inactive, normal myocyte in need of activity!     

Validation of diving decompression tables

Research on the validation of decompression tables is one of the common subject areas of the co-operation undertaken between the Defence and Civil Institute of Environmental Medicine, Toronto, Canada, and The Naval Academy of Gdynia, Poland. For several years now, a systematic survey of diving technologies has been conducted among the target projects financed by the Polish State Committee for Scientific Research and the Polish Navy. Among the most important problems discussed have been various aspects of decompression safety. The present paper shows a study to standardise and unify validation procedures for decompression in the Polish Navy.     

Effect of cocaine and amphetamine on biosynthesis of proenkephalin and prodynorphin in some regions of the rat limbic system

A vast body of evidence points to the role of the limbic system in the mechanism of drug dependence. Opioid peptides localized in the limbic system may play a role in central effects of substances of abuse. The goal of the present study was to investigate the influence of acutely and chronically administered drugs of abuse, cocaine and amphetamine on biosynthesis of prodynorphin and proenkephalin in the rat amygdala, the structure involved in the mechanism of drug addiction. Acute injection of cocaine (20 mg/kg ip every hour for 3 h) or amphetamine (2.5 mg/kg) did not changed or decreased the level of proenkephalin mRNA in the central nucleus of the amygdala. In contrast, the level of prodynorphin mRNA was significantly increased in this structure after cocaine. Repeated cocaine administration (20 mg/kg ip every hour for 3 h, for 5 days) had no effect on the proenkephalin and prodynorphin mRNA in the central nucleus of the amygdala. Chronic amphetamine (2.5 mg/kg twice daily for 5 days) administration decreased proenkephalin and increased prodynorphin mRNA level in the central nucleus of the amygdala (at 24 and 48 h). Moreover, significant increase in prodynorphin mRNA level was observed in the hippocampal dentate gyrus after acute (cocaine) and chronic (cocaine, amphetamine) administration of the psychostimulants. The observed adaptive changes in the activity of two opioid systems in two structures of the limbic system, central nucleus of amygdala and hippocampus, may contribute to the neurochemical mechanism of drug addiction after psychostimulants. These studies also indicate that the changes in opioid gene expression in the central nucleus of the amygdala are not parallel to those observed in the nucleus accumbens after cocaine and amphetamine, which suggests that peptidergic systems in the structures of extended amygdala might be regulated by different neurochemical mechanisms after psychostymulant administration.     

Influence of new gamma-hydroxybutyric acid amide analogues on the central nervous system activity in mice

The present study investigates the activity of four gamma-hydroxybutyric acid amide analogues (BM-68, BM-74, BM-75 and BM-76) in two models of chemically induced seizures, i.e. picrotoxin- and pentetrazole-induced seizures and in the thiopental-induced sleep test. The results of pharmacological in vivo experiments with the gamma-hydroxybutyric acid amide analogues presented below show that the compounds possess variable influence on the central nervous system in mice.     

Inhibition of glutathione-related enzymes augments LPS-mediated cytokine biosynthesis: involvement of an IkappaB/NF-kappaB-sensitive pathway in the alveolar epithelium

The regulation of lipopolysaccharide (LPS)-mediated pro-inflammatory cytokine biosynthesis by reduction-oxidation (redox)-sensitive enzymes involved in maintaining intracellular glutathione homeostasis was investigated in fetal alveolar type II epithelial cells (fATII). Inhibition of glutathione-oxidized disulfide reductase, which recycles GSSG --> 2GSH, by the action of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) augmented LPS-dependent secretion of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha. BCNU increased [GSSG] concentration at the expense of [GSH], thereby favoring oxidation equilibrium. Inhibition of gamma-glutamylcysteine synthetase, the rate-limiting enzyme in the biosynthesis of GSH, by the action of L-buthionine-(S,R)-sulfoximine (BSO), potentiated LPS-induced IL-1beta, IL-6 and TNF-alpha production. Similar to BCNU, BSO depleted [GSH] and induced the accumulation of [GSSG]. BCNU and BSO reduced LPS-mediated phosphorylation of inhibitory-kappaB (IkappaB-alpha), allowing its cytosolic accumulation. This effect was associated with the inhibition of the nuclear translocation of selective nuclear factor (NF)-kappaB subunits: NF-kappaB1 (p50), RelA (p65), RelB (p68) and c-Rel (p75), but not NF-kappaB2 (p52). BCNU and BSO reduced LPS-induced NF-kappaB activation as determined by the electrophoretic mobility shift DNA-binding assay. Analytical analysis of the effect of modulating the dynamic redox ratio ([GSH]+[GSSG])/[GSSG] revealed a novel role for GSSG as a disulfhydryl compound which mediates an inhibitory effect on NF-kappaB activation. It is concluded that selective modulation of redox-sensitive enzymes has an immunopharmacological potential in regulating pro-inflammatory cytokines and that the TkappaB-alpha/NF-kappaB pathway is redox-sensitive and differentially involved in mediating redox-dependent regulation of cytokine signaling.     

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials—GPPAD‐02 study design and first results

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at‐risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD‐02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta‐cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single‐nucleotide polymorphisms (SNPs) or three SNPS and a first‐degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta‐cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta‐cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD‐02 study provides a unique path to primary prevention of beta‐cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta‐cell autoimmunity and T1D.     

Management of enteroatmospheric fistula with negative pressure wound therapy in open abdomen treatment: a multicentre observational study

The management of enteroatmospheric fistula (EAF) in open abdomen (OA) therapy is challenging and associated with a high mortality rate. The introduction of negative pressure wound therapy (NPWT) in open abdomen management significantly improved the healing process and increased spontaneous fistula closure. Retrospectively, we analysed 16 patients with a total of 31 enteroatmospheric fistulas in open abdomen management who were treated using NPWT in four referral centres between 2004 and 2014. EAFs were diagnosed based on clinical examination and confirmed with imaging studies and classified into low (<200 ml/day), moderate (200–500 ml/day) and high (>500 ml/day) output fistulas. The study group consisted of five women and 11 men with the mean age of 52·6 years [standard deviation (SD) 11·9]. Since open abdomen management was implemented, the mean number of re‐surgeries was 3·7 (SD 2·2). There were 24 EAFs located in the small bowel, while four were located in the colon. In three patients, EAF occurred at the anastomotic site. Thirteen fistulas were classified as low output (41·9%), two as moderate (6·5%) and 16 as high output fistulas (51·6%). The overall closure rate was 61·3%, with a mean time of 46·7 days (SD 43·4). In the remaining patients in whom fistula closure was not achieved (n = 12), a protruding mucosa was present. Analysing the cycle of negative pressure therapy, we surprisingly found that the spontaneous closure rate was 70% (7 of 10 EAFs) using intermittent setting of negative pressure, whereas in the group of patients treated with continuous pressure, 57% of EAFs closed spontaneously (12 of 21 EAFs). The mean number of NPWT dressing was 9 (SD 3·3; range 4–16). In two patients, we observed new fistulas that appeared during NPWT. Three patients died during therapy as a result of multi‐organ failure. NPWT is a safe and efficient method characterised by a high spontaneous closure rate. However, in patients with mucosal protrusion of the EAFs, spontaneous closure appears to be impossible to achieve.