Multivariate linkage scan for metabolic syndrome traits in families with type 2 diabetes

The purpose of this study was to evaluate evidence for linkage to interrelated quantitative features of the metabolic syndrome (MetS). Data on eight quantitative MetS traits (body weight, waist circumference, systolic and diastolic blood pressure, high‐density lipoprotein (HDL) cholesterol, triglycerides (TGs), and fasting glucose and insulin measurements) and a 10 cM genome scan were available for 78 white families (n = 532 subjects). These data were used to conduct multipoint, multivariate linkage analyses, including tests for coincident linkage and complete pleiotropy. The strongest evidence for linkage from the bivariate analyses was observed on chromosome 1 (1p22.2) (HDL‐TG; univariate lod score equivalent (lod_eq = 3.99)) with stronger results from the trivariate analysis at the same location (HDL‐TG‐Insulin; lod_eq = 4.32). Seven additional susceptibility regions (lod_eq scores >1.9) were observed (1p36, 1q23, 2q21.2, 8q23.3, 14q23.2, 14q32.11, and 20p11.21). The results from this study indicate that several correlated traits of the MetS are influenced by the same gene(s) that account for some of the clustering of the MetS features.     

Selection of microbial mutants tolerant to extreme environmental stress using continuous culture-control design

The design of controllers for a continuous selection technique (BOICS; Brown and Oliver, 1982) is considered. This technique is used to obtain microbial mutants that are tolerant to extreme environmental stress. Applications of BOICS have been hampered by the problem of controller design. In this paper, a modified implementation of BOICS is considered which has a number of practical advantages. A model-based approach to controller design is taken. The case in which the stress is due to an inhibitory substance in the growth environment is considered. The analysis is intended to be applicable to any reasonable combination of organism and inhibitor. Conventional linear and time-invariant controllers are considered. Guidelines for the selection of controller parameters' values are suggested. The application of these guidelines requires that certain process parameters' values be identified. Methods by which these parameters' values can be identified are suggested. Simulation results indicate that the resulting controllers perform satisfactorily. This is confirmed by experimental data from a model selection experiment. A recipe for the design of controllers is a necessary part of a protocol for BOICS. It is hoped that the solution to the controller design problem that is offered in this paper will encourage further applications for the technique.     

Best Practice Updates for Surgical Care in Weight Loss Surgery

To update evidence‐based best practice guidelines for surgical care in weight loss surgery (WLS). Systematic search of English‐language literature on WLS in MEDLINE, EMBASE, and the Cochrane Library between April 2004 and May 2007. Use of key words to narrow the search for a selective review of abstracts, retrieval of full articles, and grading of evidence according to systems used in established evidence‐based models. Evidence‐based best practice recommendations from the most recent literature on surgical methods and technologies, risks and benefits, outcomes, and surgeon qualifications and credentialing. We identified >135 articles; the 65 most relevant were reviewed in detail. Regular updates of evidence‐based recommendations for best practices in WLS are required to address rapid changes in surgical techniques and patient demographics. Key factors in patient safety include surgical risk factors, type of procedure, surgeon training, and facility certification.     

Positive correlation between cellular glutathione and acquired cisplatin resistance in human ovarian cancer cells

While multiple changes are frequently found to be associated with cisplatin resistance in a variety of tumor cell lines, a cause-effect relationship of these alterations with the resistant phenotype has not been established. In order to identify the resistance-relevant determinants, a series of cisplatinresistant sublines with different degrees of resistance to cisplatin was developed in a human ovarian carcinoma cell line (O-129). Three derived resistant cell lines displayed 2.1-fold (O-129/DDP₄, low), 4.1-fold (O-129/DDP₈, moderate) and 6.3-fold (O-129/DDP₁₆, high) resistance, respectively, to cisplatin, compared with the sensitive parental line O-129. While the activity of poly(ADP-ribose) polymerase, an enzyme proposed to be involved in DNA repair, was elevated in all three resistant lines, a significant karyotypic change was observed only in the high-resistance line with the karyotype alteration from near diploidy to heteroploidy. The moderate (4.1-fold) and high (6.3-fold) DDP resistance was associated with a slow proliferation rate in drug-free medium, but cellular glutathione level was highly correlated with DDP sensitivity in all four cell lines. Taken together, the present studies establish that while many changes at cellular level can occur with development of cisplatin resistance, only elevation of intracellular glutathione concentration appears to be related to the resistance phenotype in these human ovarian cancer cells.Abbreviations DDP cisplatin - FBS fetal bovine serum - GSH glutathione - IC₅₀ drug concentration required to result in 50% growth inhibition - PARP poly(ADP-ribose) polymerase     

Synthesis of pyrophosphates for in vitro selection of catalytic RNA molecules

Reported here are synthetic routes to pyrophosphates linking riboflavin with various nucleosides. The focus is on a flavin-uracil dinucleotide having a biotin tag on the uracil, a molecule that has potential value in the selection of RNA enzymes that catalyze the template-directed polymerization of RNA in the 3'-to-5' direction, which is the direction opposite that catalyzed by standard protein polymerases. Two detailed procedures are presented to prepare this new compound, as well as one procedure to prepare the new flavin-2,6-diaminopurine dinucleotide.     

Training-specific changes in cardiac structure and function: a prospective and longitudinal assessment of competitive athletes.

This prospective, longitudinal study examined the effects of participation in team-based exercise training on cardiac structure and function. Competitive endurance athletes (EA, n = 40) and strength athletes (SA, n = 24) were studied with echocardiography at baseline and after 90 days of team training. Left ventricular (LV) mass increased by 11% in EA (116 +/- 18 vs. 130 +/- 19 g/m(2); P < 0.001) and by 12% in SA (115 +/- 14 vs. 132 +/- 11 g/m(2); P < 0.001; P value for the compared Delta = NS). EA experienced LV dilation (end-diastolic volume: 66.6 +/- 10.0 vs. 74.7 +/- 9.8 ml/m(2), Delta = 8.0 +/- 4.2 ml/m(2); P < 0.001), enhanced diastolic function (lateral E': 10.9 +/- 0.8 vs. 12.4 +/- 0.9 cm/s, P < 0.001), and biatrial enlargement, while SA experience LV hypertrophy (posterior wall: 4.5 +/- 0.5 vs. 5.2 +/- 0.5 mm/m(2), P < 0.001) and diminished diastolic function (E' basal lateral LV: 11.6 +/- 1.3 vs. 10.2 +/- 1.4 cm/s, P < 0.001). Further, EA experienced right ventricular (RV) dilation (end-diastolic area: 1,460 +/- 220 vs. 1,650 +/- 200 mm/m(2), P < 0.001) coupled with enhanced systolic and diastolic function (E' basal RV: 10.3 +/- 1.5 vs. 11.4 +/- 1.7 cm/s, P < 0.001), while SA had no change in RV parameters. We conclude that participation in 90 days of competitive athletics produces significant training-specific changes in cardiac structure and function. EA develop biventricular dilation with enhanced diastolic function, while SA develop isolated, concentric left ventricular hypertrophy with diminished diastolic relaxation.     

Ligand-dependent differences in estrogen receptor beta-interacting proteins identified in lung adenocarcinoma cells corresponds to estrogenic responses

Background

A recent epidemiological study demonstrated a reduced risk of lung cancer mortality in breast cancer patients using antiestrogens. These and other data implicate a role for estrogens in lung cancer, particularly nonsmall cell lung cancer (NSCLC). Approximately 61% of human NSCLC tumors express nuclear estrogen receptor β (ERβ); however, the role of ERβ and estrogens in NSCLC is likely to be multifactorial. Here we tested the hypothesis that proteins interacting with ERβ in human lung adenocarcinoma cells that respond proliferatively to estradiol (E₂) are distinct from those in non-E₂-responsive cells.

Methods

FLAG affinity purification of FLAG-ERβ-interacting proteins was used to isolate ERβ-interacting proteins in whole cell extracts from E₂ proliferative H1793 and non-E₂-proliferative A549 lung adenocarcinoma cell lines. Following trypsin digestion, proteins were identified using liquid chromatography electrospray ionization tandem mass spectrometry (LC-MS/MS). Proteomic data were analyzed using Ingenuity Pathway Analysis. Select results were confirmed by coimmunoprecipitation.

Results

LC-MS/MS identified 27 non-redundant ERβ-interacting proteins. ERβ-interacting proteins included hsp70, hsp60, vimentin, histones and calmodulin. Ingenuity Pathway Analysis of the ERβ-interacting proteins revealed differences in molecular and functional networks between H1793 and A549 lung adenocarcinoma cells. Coimmunoprecipitation experiments in these and other lung adenocarcinoma cells confirmed that ERβ and EGFR interact in a gender-dependent manner and in response to E₂ or EGF. BRCA1 interacted with ERβ in A549 cell lines and in human lung adenocarcinoma tumors, but not normal lung tissue.

Conclusion

Our results identify specific differences in ERβ-interacting proteins in lung adenocarcinoma cells corresponding to ligand-dependent differences in estrogenic responses.