Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth

The Columbia Center for Children's Environmental Health is using a combination of environmental and biologic measures to evaluate the effects of prenatal insecticide exposures among urban minorities in New York City. Of the 571 women enrolled, 85% report using some form of pest control during pregnancy and 46% report using exterminators, can sprays, and/or pest bombs. Chlorpyrifos, diazinon, and propoxur were detected in 99.7-100% of 48-h personal air samples collected from the mothers during pregnancy (n = 394) and in 39-70% of blood samples collected from the mothers (n = 326) and/or newborns (n = 341) at delivery. Maternal and newborn blood levels are similar and highly correlated (r = 0.4-08, P < 0.001). Levels of insecticides in blood samples and/or personal air samples decreased significantly following the 2000-2001 U.S. Environmental Protection Agency's regulatory actions to phase out residential use of chlorpyrifos and diazinon. Among infants born prior to 1/1/01, birth weight decreased by 67.3 g (95% confidence interval (CI) -116.6 to -17.8, P = 0.008) and birth length decreased by 0.43 centimeters (95% CI, -0.73 to -0.14, P = 0.004) for each unit increase in log-transformed cord plasma chlorpyrifos levels. Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (P 0.8). Results support recent regulatory action to phase out residential uses of these insecticides.     

Pediatric renal allograft transplantation does not normalize the increased cortisol/cortisone ratios of chronic renal failure

OBJECTIVE: The conversion of cortisol (F) to cortisone (E) is catalyzed by 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). Children suffering from chronic renal failure (CRF) have a decreased activity of 11beta-HSD2 contributing to increased arterial blood pressure. The objective was to investigate whether a normal conversion of F to E is achieved after renal transplantation (TX) in children. METHODS: Fifteen children with CRF, 17 children with steroid-free immunosuppression after TX, and 18 healthy controls (CO) were enrolled. The activity of 11beta-HSD2 in plasma was calculated using the ratio of F/E determined by tandem mass spectrometry, the ratio of tetrahydrocortisol (THF) +5alpha-tetrahydrocortisol (5alphaTHF) in urine determined by gas chromatography/mass spectrometry, and the ratio of (THF +5alphaTHF)/tetrahydrocortisone (THE) in urine determined by tandem mass spectrometry. RESULTS: The F/E ratio (mean +/- S.D./S.E.M.) was significantly higher in CRF and TX (5.6 +/- 1.9/0.6, 7.12 +/- 3.1/0.9) than in CO (1.18 +/- 0.2/0.03, P < 0.0001) groups. The (THF + 5alphaTHF)/THE ratio in CRF (1.19 +/- 1.1/0.5) and TX (1.19 +/- 0.1/0.5) groups was significantly higher than in controls (0.21 +/- 0.05/0.18, P < 0.0001). Positive correlations between plasma and urinary ratios (P = 0.0004. R(2) = 0.73 in CRF, P = 0.0013, R(2) = 0.56 in TX, P < 0.0001, R(2) = 0.66 in CO) were found, whereas significant correlations between F/E or (THF + 5alphaTHF)/THE ratios and blood pressure, the number of antihypertensive drugs taken or creatinine clearance could not be found. CONCLUSIONS: In all children with chronic renal failure plasma and urinary cortisol/cortisone ratios are elevated and do not return to normal levels after renal allograft transplantation. This suggests that renal transplantation does not normalize 11beta-HSD2 activity.     

Eating behaviors of children in the context of their family environment

Both a family history of obesity and early childhood obesity have been identified as strong predictors of adult obesity risk. The finding that parental obesity, maternal obesity in particular, increases a child's risk for developing obesity suggests that either shared genes, or environment, or likely a combination of both may promote overeating and excessive weight gain in children. Parents not only create food environments for children's early experiences with food and eating, but they also influence their children's eating by modeling their own eating behaviors, taste preferences, and food choices. Thus, it is important to identify intermediary behavioral eating traits which promote overeating and obesity in children and to determine the extent to which associations between eating traits and excessive weight gain in children may be influenced by genetic factors, environmental factors, or both. Behavioral genetic methods can be used to help partition genetic and environmental sources of variability in behavioral traits. The focus of this paper is to review and discuss findings from both short-term experimental and prospective cohort studies on eating behaviors of children at various stages in their lives. Select child eating traits and parent-child resemblances in eating will be further examined in the context of children's home environment and their familial predisposition to obesity.The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.     

Proteus in the World of Proteins: Conformational Changes in Protein Kinases

The 512 protein kinases encoded by the human genome are a prime example of nature's ability to create diversity by introducing variations to a highly conserved theme. The activity of each kinase domain is controlled by layers of regulatory mechanisms involving different combinations of post‐translational modifications, intramolecular contacts, and intermolecular interactions. Ultimately, they all achieve their effect by favoring particular conformations that promote or prevent the kinase domain from catalyzing protein phosphorylation. The central role of kinases in various diseases has encouraged extensive investigations of their biological function and three‐dimensional structures, yielding a more detailed understanding of the mechanisms that regulate protein kinase activity by conformational changes. In the present review, we discuss these regulatory mechanisms and show how conformational changes can be exploited for the design of specific inhibitors that lock protein kinases in inactive conformations. In addition, we highlight recent developments to monitor ligand‐induced structural changes in protein kinases and for screening and identifying inhibitors that stabilize enzymatically incompetent kinase conformations.     

The role of genetic breast cancer susceptibility variants as prognostic factors

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09-1.35, P=0.0002 and HR=1.29; 95% CI: 1.12-1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.     

Diabetes and prognosis in a breast cancer cohort

Purpose

Epidemiological studies indicated that type 2 diabetes mellitus may increase breast cancer risk and mortality. The aim of this retrospective cohort study was to examine the effect of diabetes on the clinical course and the prognosis of early stage breast cancer in relation to tumour and patient characteristics.

Methods

The cohort analyzed in this study consisted of 4,056 patients with invasive primary breast cancer. We compared overall survival, distant metastasis-free survival and local recurrence free survival between breast cancer patients with and without diabetes.

Results

In our cohort 276 breast cancer patients (6.8%) were affected by diabetes compared to 3,780 patients (93.2%) without diabetes. Women with diabetes were significantly older, had larger tumours, and a higher rate of lymph node involvement. After a follow-up period of 5?years, stratification for age and adjustment for other prognostic factors, overall mortality following breast cancer was significantly higher in diabetic breast cancer patients (hazard ratio, HR 1.92; 95% confidence interval, CI 1.49?C2.48). We found no significant differences in distant metastasis-free survival and local recurrence free survival between the two groups, but we found a slightly significant higher rate of distant metastasis in the group of patients with diabetes and oestrogen receptor negative tumours (HR 2.28; CI 1.31?C3.97).

Conclusion

In this study, patients with diabetes and oestrogen receptor negative breast cancer had a more than 2-fold higher risk for distant metastasis compared to patients without diabetes. Diabetes was also associated with an almost 2-fold increase in mortality within the 5?years follow-up period.     

Verbesserte Qualität gelagerter Erythrozytenkonzentrate durch maschinelle Autotransfusion

Die Anaesthesiologie - Die Transfusion von Erythrozytenkonzentraten (EK) ist mit verschiedenen Nebenwirkungen assoziiert, die u. a. durch Lagerungsschäden an Erythrozyten hervorgerufen...     

Hope and Disappointment: Covalent Inhibitors to Overcome Drug Resistance in Non-Small Cell Lung Cancer

In the last five years, the detailed understanding of how to overcome T790M drug resistance in non-small cell lung cancer (NSCLC) has culminated in the development of a third-generation of covalent EGFR inhibitors with excellent clinical outcomes. However, the emergence of a newly discovered acquired drug resistance challenges the concept of small molecule targeted cancer therapy in NSCLC.