Endocrine disruptors: Challenges and future directions in epidemiologic research.

Public concern about the impact of endocrine disrupting chemicals (EDCs) on both humans and the environment is growing steadily. Epidemiologic research provides key information towards our understanding of the relationship between environmental exposures like EDCs and human health outcomes. Intended for researchers in disciplines complementary to epidemiology, this paper highlights the importance and challenges of epidemiologic research in order to present the key elements pertaining to the design and interpretation of an epidemiologic study on EDCs. The conduct of observational studies on EDCs derives from a thoughtful research question, which will help determine the subsequent methodological choices surrounding the careful selection of the study population (including the comparison group), the adequate ascertainment of exposure(s) and outcome(s) of interest, and the application of methodological and statistical concepts more specific to epidemiology. The interpretation of epidemiologic results may be arduous due to the latency occurring between EDC exposure and certain outcome(s), the complexity in capturing EDC exposure(s), and traditional methodological and statistical issues that also deserve consideration (e.g., confounding, effect modification, non-monotonic responses). Moving forward, we strongly advocate for an integrative approach of expertise in the fields of epidemiology, exposure science, risk assessment and toxicology to adequately study the health risks associated with EDCs while tackling their challenges.

Grouping of PFAS for human health risk assessment: Findings from an independent panel of experts.

An expert panel was convened to provide insight and guidance on per- and polyfluoroalkyl substances (PFAS) grouping for the purposes of protecting human health from drinking water exposures, and how risks to PFAS mixtures should be assessed. These questions were addressed through multiple rounds of blind, independent responses to charge questions, and review and comments on co-panelists responses. The experts agreed that the lack of consistent interpretations of human health risk for well-studied PFAS and the lack of information for the vast majority of PFAS present significant challenges for any mixtures risk assessment approach. Most experts agreed that "all PFAS" should not be grouped together, persistence alone is not sufficient for grouping PFAS for the purposes of assessing human health risk, and that the definition of appropriate subgroups can only be defined on a case-by-case manner. Most panelists agreed that it is inappropriate to assume equal toxicity/potency across the diverse class of PFAS. A tiered approach combining multiple lines of evidence was presented as a possible viable means for addressing PFAS that lack analytical and/or toxicological studies. Most PFAS risk assessments will need to employ assumptions that are more likely to overestimate risk than to underestimate risk, given the choice of assumptions regarding dose-response model, uncertainty factors, and exposure information.

[The EDEC curriculum-the path to advanced echocardiography in the intensive care unit]. / Das EDEC-Curriculum ­ der Weg zur fortgeschrittenen Echokardiographie auf der Intensivstation.

Good knowledge of echocardiography is essential for modern intensive care medicine. A standardized curriculum for acquiring the expertise to perform TTE and TEE is a good way to strengthen one's own diagnostic skills.The EDEC curriculum from ESICM, which has been established for years, offers a good opportunity for structural further training at the advanced level in combination with gaining a high level of professional competence.

An approach to classifying occupational exposures to endocrine disrupting chemicals by sex hormone function using an expert judgment process.

Endocrine disrupting chemicals (EDCs) are exogenous substances that interfere with the endocrine system and cause adverse effects. We aimed to classify the effects of 24 known EDCs, prevalent in certain occupations, according to four modes of action (estrogenic, antiestrogenic, androgenic, and/or antiandrogenic). A literature search, stratified into four types of literature was conducted (namely: national and international agency reports; review articles; primary studies; ToxCastTM). The state of the evidence of each EDC on sex hormone function was summarized and reviewed by an expert panel. For each mode of action, the experts evaluated the likelihood of endocrine disruption in five categories: "No", "Unlikely", "Possibly", "Probably", and "Yes". Seven agents were categorized as "Yes," or having strong evidence for their effects on sex hormone function (antiandrogenic: lead, arsenic, butylbenzyl phthalate, dibutyl phthalate, dicyclohexyl phthalate; estrogenic: nonylphenol, bisphenol A). Nine agents were categorized as "Probable," or having probable evidence (antiandrogenic: bis(2-ethylhexyl)phthalate, nonylphenol, toluene, bisphenol A, diisononyl phthalate; androgenic: cadmium; estrogenic: copper, cadmium and; anti-estrogenic: lead). Two agents (arsenic, polychlorinated biphenyls) had opposing conclusions supporting both "probably" estrogenic and antiestrogenic effects. This synthesis will allow researchers to evaluate the health effects of selected EDCs with an added level of precision related to the mode of action.

High concentrations of commonly used drugs can inhibit the in vitro glucuronidation of bisphenol A and nonylphenol in rats.

4-n-Nonylphenol and bisphenol A are endocrine disrupting chemicals that are mainly detoxified through glucuronidation. A factor that may modulate their glucuronidation rates is co-exposure to pharmaceuticals. This study aimed to identify and characterize the potential metabolic interactions between 14 drugs and these two endocrine disruptors. Nonylphenol and bisphenol A were co-incubated in freshly isolated rat hepatocytes with, drugs at a high concentration. Statistically significant metabolic inhibition of bisphenol A and nonylphenol biotransformation was observed with nine drugs (>50% inhibition by naproxen, salicylic acid, carbamazepine and mefenamic acid). Inhibition assays of UGT activity in rat liver microsomes revealed: 1) competitive inhibition by naproxen (K(i)(app) = 848.3 microM) and carbamazepine (K(i)(app) = 1023.1 microM), 2) no inhibition by salicylic acid suggesting another mechanism of inhibition. Detoxification of nonylphenol and bisphenol A was shown to be impaired by excessive concentrations of many drugs and health risk assessment should therefore address this issue.

[A comparison of operative invasiveness in minimally invasive anterolateral hip replacement (MIS-AL) and standard hip procedure, using biochemical markers]. / Biochemické porovnání invazivity TEP MIS-AL a standardní TEP kycelního kloubu.

PURPOSE OF THE STUDY: The aim of this prospective randomized study was to compare, by means of biochemical markers, the operative invasiveness of the standard total hip replacement with that of the minimally invasive anterolateral (MIS-AL) approach. MATERIAL: Twenty-six randomly assigned patients with standard and 22 patients with MIS-AL total hip replacement were included in the study. Patients with elevated pre-operative levels of the markers evaluated or patients taking medication that might affect marker levels were not included. METHODS: Creatine phosphokinase (CPK) and C-reactive protein (CRP) were chosen as markers of muscle damage and post-operative inflammatory changes, respectively. Blood samples were drawn before surgery (less than 24 hours) and after surgery at 24, 48 and 96 hours, which respected biological half-lives of the markers and permitted us to study their dynamics. The results were evaluated and statistically analyzed at the department of biochemistry, using the two sample t-test. RESULTS: Statistically significant differences between the two groups of patients were found for both markers. The average CRP values differed significantly (p < 0.05) at 48 and 96 hours post-operatively, being higher for the standard than MIS-AL total hip replacement by 28% and 44%, respectively. The average CPK values showed the most marked difference at 48 hours after surgery, when the level was higher by 62.5% in the standard than MIS-AL total hip replacement (p < 0.05). DISCUSSION: Our objective evaluation of the invasiveness of surgery in total hip replacement was based on the most frequently recommended markers for assessment of muscle tissue damage and post-operative inflammatory changes. The study was focused on the invasiveness of surgery only and neither subjective nor objective outcomes of implantation were evaluated. The use of the muscle sparing approach MIS-AL results in minimal damage to muscle tissue and, consequently, a lower degree of post-operative inflammation than is recorded in traditional hip replacement surgery. CONCLUSIONS: In the patients undergoing MIS-AL total hip replacement, post-operative levels of CPK and CRP were significantly lower than in the patients with standard total hip replacement. The MIS-AL technique evidently provides a more sparing approach to soft tissues.

Role of imaging in the diagnosis of acute appendicitis in children.

The aim of the study was to investigate the place of imaging in the diagnosis and treatment of acute appendicitis. The files of 2,427 children with suspected acute appendicitis were reviewed for clinical management and operative findings. The sample was divided into 3 groups at time of admission: (1) before diagnostic imaging was available in our department (1991-1994); (2) after the introduction of imaging studies on a random basis in equivocal cases (1995-1998); and (3) after a policy was formulated for ultrasound use in all equivocal cases followed by computed tomography if necessary (1999-2000). Results showed that the rate of misdiagnosis decreased from 13.2% in group 1 to 6.5% in group 2 and 6.1% in group 3. False-positive findings (normal appendix with positive scan) were noted in 16.7% of group 2 and 25% of group 3; false-negative findings (appendicitis at surgery with negative scan) in 23.8% and 9.5%, respectively. Computed tomography was performed in 8 children and prevented unnecessary surgery in 4 of them. We conclude that in equivocal cases of acute appendicitis, imaging studies performed by skilled operators can improve the accuracy of diagnosis, saving patients unnecessary surgery, and identifying other conditions that mimic appendicitis.

Fertility of dairy cows in Northern Ireland.

A comprehensive database was established on the milk production and reproductive performance of dairy cows in 19 selected herds in Northern Ireland, varying in size, management system and genetic merit. Data were obtained for 2471 cows, 1775 of which calved in a second year, and 693 were culled from the herd for specific reasons. The estimated mean rate of heat detection (assessed by the interheat interval during the main breeding season) in all the herds was 71 per cent, with a range from 53 to 92 per cent The average conception rate to first insemination was 37.1 per cent (range 21 to 66 per cent). The average calving interval for the retained cows was 407.2 days (range 359 to 448 days). Twenty-eight per cent of the cows that calved were culled, with infertility being the largest single reason (26.8 per cent of the cows culled). There were major differences in reproductive performance between the herds, but heat detection rate, conception rate and calving interval did not appear to be affeded by a herd's genetic merit. The herds with shorter calving intervals were characterised by better heat detection efficiency (83 v 61 per cent, P<0.01), a shorter interval from calving to first insemination (74 v 97 days; P<0.05), a higher conception rate to first insemination (45 v 34 per cent, P>0.10) and a lower removal rate (23 v 37 per cent, P<0.01). Furthermore, the cows in these herds had lower body condition scores (BCS) in the dry period (3.0 v 3.3; P<0.05) but lost less body condition in early lactation (0.3 v 0.6 BCS units, P<0.05). These results show that dairy herd fertility in Northern Ireland is generally low and similar to that previously reported for England and the USA, but that in some herds changes in herd management practices improved the cows' fertility.

[Influence of antenatal administration of corticoids on heart activity--case report]. / Vliv antenatálne aplikovaných kortikoidu na srdecní aktivitu--kazuistika.

OBJECTIVE: to draw attention to possible influencing of cardiotocographic recording of antenatal administration of corticoids, on the use of Doppler ultrasonographic parameters in the diagnostics of hypoxia-endangered fetus. DESIGN: Case report. SETTING: Mother and Child Care Institute of Prague. METHOD: Case report. CONCLUSION: Antenatal administration of corticoids is presently an inherent part of therapeutic management of premature delivery. This administration significantly diminishes morbidity and mortality of immature newborns. Nevertheless, their administration results in changing intrauterine behavior of the fetus and his/her heart activity. These changes may be mistakenly diagnosed as signs of evolving hypoxia. For the evaluation of acute condition of the fetus and obtaining help in decision making how the further management of delivery should be done, Doppler ultrasonographic examination of maternal, fetus-maternal and fetal circulation may prove useful.

Alteration of infant attention and activity by polychlorinated biphenyls: unravelling critical windows of susceptibility using physiologically based pharmacokinetic modeling.

Pre- and postnatal exposure to polychlorinated biphenyls (PCBs) can impair behavioural function in animal models at doses within the range at which humans are commonly exposed. Yet, epidemiologic studies conducted in the US and Europe are inconsistent with regard to the developmental effects of lactational exposure to these chemicals. This inconsistency may be due to limitations in the current methodological approaches for assessing postnatal exposure to PCBs. Our study used a physiologically based pharmacokinetic (PBPK) model to simulate blood PCB levels during specific pre- and postnatal periods and to evaluate the relation of those levels to infant behaviour. A previously validated PBPK model was used to simulate infant blood PCB-153 levels at delivery and on a month-by-month basis during the first year of life for Inuit infants enrolled in a longitudinal birth cohort. Infant behaviour was assessed using the Behaviour Rating Scales (BRS) of the Bayley Scales of Infant Development (BSID-II) at 11 months of age and video coding of inattention and activity measured during the administration of the mental development subscale of the BSID-II. The estimated pre- and postnatal PCB exposure measures predicted significant increases in inattention and activity at 11 months. Whereas inattention was related to prenatal exposure, activity level, measured by non-elicited activity, was best predicted by postnatal exposure, with the strongest association obtained for simulated PCB levels during the 4th month of life. These findings are consistent with previous reports indicating PCB-induced behavioural alteration in attention and activity level. Simulated infant toxicokinetic profiles for the first year of life revealed windows of susceptibility during which PCBs may impair infant attention and activity.

Associations between genetic merit for milk production and animal parameters and the fertility performance of dairy cows.

Relationships between genetic merit for milk production and animal parameters and various parameters of reproductive performance were examined using multilevel binary response analysis in a study of 19 dairy herds for three successive years, representing approximately 2500 cows per year. The proportion of cows intended for rebreeding that were back in-calf again within 100 days of calving (ICR-100) and the proportion of cows that reappeared again with 365 (RR-365) and 400 days (RR-400) of a previous calving were considered in addition to the traditional measures of reproductive performance. Each 100-kg increase in genetic merit for milk yield was associated with an increased interval to first service (IFS) and calving index (CI) of 1.4 ( P < 0.001) and 1.8 days ( P < 0.001), respectively, a 0.5% increase ( P < 0.05) in calving rate to first insemination (CR-1) and 0.8% increase in RR-400. Each £10 increase in £PIN (the economically weighted yield selection index used in the UK that takes account of butterfat and protein yields) was associated with an increased IFS and CI of 1.5 ( P < 0.001) and 3.0 days ( P < 0.001), respectively. Cows with increased genetic merit for milk yield and £PIN were more likely to re-calve (RR-overall; P < 0.001). Each 1000-kg increase in 305-day milk yield was associated with an increased IFS and CI of 3.2 ( P < 0.001) and 7.8 days ( P < 0.001), respectively, and a 13.6 ( P < 0.001), 22.4 ( P < 0.001), 19.9 ( P < 0.001) and 19.0% ( P < 0.001) decrease in CR-1, ICR-100, RR-365 and RR-400, respectively. A 10-kg increase in maximum yield was associated with a 6.6-day increase in CI ( P < 0.001) and a 14.9 ( P < 0.001), 18.3 ( P < 0.001), 9.6 ( P < 0.05) and 14.2% ( P < 0.001) decrease in CR-1, ICR-100, RR-365 and RR-400, respectively. Fertility performance was also associated with season of calving, lactation number and dystocia score. Level of production had a larger effect on fertility performance than genetic merit for milk production suggesting that infertility at an individual cow level is more likely to be associated with increased production and an inability to meet the nutritional requirements of the cow.

Intracytoplasmic sperm injection combined with preimplantation genetic diagnosis for the prevention of recurrent gestational trophoblastic disease.

A strategy for the prevention of repeated molar pregnancies by using intracytoplasmic sperm injection (ICSI) coupled with preimplantation genetic diagnosis (PGD) with fluorescence in-situ hybridization (FISH) was developed. In this approach, complete moles which arise from dispermic fertilization are avoided by the use of ICSI. ICSI is followed by preimplantation selection against the transfer of 46,XX embryos, thus preventing complete moles resulting from a fertilization of an inactive oocyte, by a haploid X-bearing spermatozoon which subsequently duplicates. Triploid partial moles which arise mainly from dispermic fertilization may also be prevented by ICSI. The preimplantation confirmation of diploidy by FISH guards against triploid partial moles which may result from mechanisms other than dispermic fertilization. The employment of this strategy in an attempt to prevent a repeated event of molar pregnancy in a patient with a history of two previous episodes of gestational trophoblastic disease is reported.

Phylogenetic analysis of the Saccharomyces cerevisiae group based on polymorphisms of rDNA spacer sequences.

The phylogenetic relationships between species of yeasts assigned to the Saccharomyces sensu stricto group, which includes Saccharomyces cerevisiae and Saccharomyces bayanus, were studied together with Saccharomyces pastorianus and Saccharomyces paradoxus. The experimental approaches used were RFLP analysis of the PCR-amplified rDNA internal transcribed spacer (ITS) and intergenic spacer, and total ITS sequence analysis. Both RFLP and sequence analyses gave fairly similar results. The gene trees generated with either of the two data sets showed the distribution of the yeasts into two major, well-separated, phylogenetic clusters called 'cerevisiae' and 'bayanus'. The 'cerevisiae' cluster included the S. cerevisiae type strain, together with most of the species (16 out of 23), whereas the 'bayanus' cluster included the remaining seven type strains. Therefore, analysis of rDNA sequences confirmed S. cerevisiae and S. bayanus as two well-defined taxa. However, S. pastorianus and S. paradoxus, the two other usually accepted taxa of the now-defined Saccharomyces sensu stricto complex, could not be clearly separated from S. bayanus and S. cerevisiae, respectively. However, in both PCR-RFLP and ITS sequence analyses, S. paradoxus had the outermost position in the 'cerevisiae' cluster. PCR-RFLP analysis of the ribosomal spacer sequences was also carried out on 26 Saccharomyces strains isolated in various wine-growing regions of France in an attempt to clarify their positions in the Saccharomyces phylogenetic tree. Compared to the diversity of the Saccharomyces type strains, less genetic diversity was detected among these yeasts and several of them exhibited identical RFLP patterns. Most of the wine yeast strains (16 out of 26) were closely related to each other and were found within the 'cerevisiae' cluster. The remaining 10 wine yeast strains branched within the 'bayanus' cluster. PCR-RFLP analysis of ribosomal spacer sequences thus appears to be a useful and appropriate method for the correct characterization of Saccharomyces yeast strains used in food processing.

Frequent involvement of the internal cuff segment in CAPD peritonitis and exit-site infection - an ultrasound study.

BACKGROUND: The extent of involvement of the subcutaneous Tenckhoff catheter tract in CAPD peritonitis and catheter-related infections is of major therapeutic importance. By definition, both peritonitis and exit-site infections do not involve the catheter tract. However, diagnosis of these infections as well as the more sinister tunnel infection is based mainly on clinical signs. METHODS: We examined the usefulness of ultrasound examination (US) of the catheter tract in delineating catheter-related (exit-site and tunnel) infections, and their relationship to each other and to peritonitis. CAPD patients with no evidence of peritonitis or catheter-related infections for 6 months prior to examination served as controls. US were performed by one of two experienced radiologists using the Acuson 128XP/10 scanner with a 7-MHz linear transducer. A positive US was defined as an area of hypoechogenicity (indicative of fluid collection) >2 mm in width along any portion of the catheter tract. Findings were localized into segments(S) as follows: S1, limited to external cuff; S2, intercuff segment adjacent to the external cuff; S3, intercuff segment adjacent to the internal cuff; S4, limited to the internal cuff; and S5, involvement extending throughout the catheter tract. RESULTS: Between March 1993 and January 1995, 39 CAPD patients, all with a double-cuff straight Tenckhoff catheter with the exit site situated above the point of entry into the peritoneum were studied. A total of 56 US were performed divided among 26 episodes of peritonitis, four tunnel infections, 13 exit-site infections,and 13 controls. There were 30 positive US distributed among 16 peritonitis, four tunnel, eight exit site infections and two control patients. The two positive controls went on to develop peritonitis within 1 month of the US. The majority of the US findings (13/16 in episodes of peritonitis and 5/8 exit site infections were localized to segment 4, that is, to the internal cuff region. Apart from a significant increase in width in all infected segments versus a normal tunnel, no differences in size were seen between peritonitis, exit-site, or tunnel infections, nor were there any differences in size and localization in these infections when comparing the offending organism (Gram-positive, negative, or culture negative). CONCLUSIONS: We conclude that peritonitis and exit-site infections are frequently accompanied by involvement of the catheter tract. The localization of infection to the internal cuff region in cases of exit-site infection probably occurred as a result of downward migration along the catheter tract. This supports the notion that ideally the exit site should be pointing caudally or that the peritoneal catheter have a swan-neck configuration. With regard to peritonitis, infection within the peritoneal cavity appears to extend and involve the internal cuff region. Thus both the internal and external cuffs do not seem to pose an effective barrier against the spread of infection.. Based on our data, we recommend that US be performed as a routine investigation in all cases of exit-site infection and in cases of refractory or relapsing peritonitis.