Through-Solvent Tunneling in Donor-Bridge-Acceptor Molecules Containing a Molecular Cleft.

Photoinduced electron transfer is used to investigate the solvent-mediated electron tunneling between electron donor and acceptor groups in polar solvents. Bis-peptide scaffolds are used to control the spatial positioning of electron donor and acceptor groups and create a molecular cleft. The photoinduced electron transfer is studied for two different cleft sizes, and the electronic coupling is found to be controlled by the nature of the solvent and the ability of the molecular cleft to accommodate it, as well as interact directly with it. These studies demonstrate the importance of electron tunneling through nonbonded contacts and reveal a strategy for examining such tunneling pathways in polar solvents.

Hematopoietic androgen receptor deficiency promotes visceral fat deposition in male mice without impairing glucose homeostasis.

Androgen deficiency in men increases body fat, but the mechanisms by which testosterone suppresses fat deposition have not been elucidated fully. Adipose tissue macrophages express the androgen receptor (AR) and regulate adipose tissue remodeling. Thus, testosterone signaling in macrophages could alter the paracrine function of these cells and thereby contribute to the metabolic effects of androgens in men. A metabolic phenotyping study was performed to determine whether the loss of AR signaling in hematopoietic cells results in greater fat accumulation in male mice. C57BL/6J male mice (ages 12-14 weeks) underwent bone marrow transplant from either wild-type (WT) or AR knockout (ARKO) donors (n = 11-13 per group). Mice were fed a high-fat diet (60% fat) for 16 weeks. At baseline, 8 and 16 weeks, glucose and insulin tolerance tests were performed, and body composition was analyzed with fat-water imaging by MRI. No differences in body weight were observed between mice transplanted with WT bone marrow [WT(WTbm)] or ARKO bone marrow [WT(ARKObm)] prior to initiation of the high-fat diet. After 8 weeks of high-fat feeding, WT(ARKObm) mice exhibited significantly more visceral and total fat mass than WT(WTbm) animals. Despite this, no differences between groups were observed in glucose tolerance, insulin sensitivity, or plasma concentrations of insulin, glucose, leptin, or cholesterol, although WT(ARKObm) mice had higher plasma levels of adiponectin. Resultant data indicate that AR signaling in hematopoietic cells influences body fat distribution in male mice, and the absence of hematopoietic AR plays a permissive role in visceral fat accumulation. These findings demonstrate a metabolic role for AR signaling in marrow-derived cells and suggest a novel mechanism by which androgen deficiency in men might promote increased adiposity. The relative contributions of AR signaling in macrophages and other marrow-derived cells require further investigation.

Quantitative proteomics in resected renal cancer tissue for biomarker discovery and profiling.

BACKGROUND: Proteomics-based approaches for biomarker discovery are promising strategies used in cancer research. We present state-of-art label-free quantitative proteomics method to assess proteome of renal cell carcinoma (RCC) compared with noncancer renal tissues. METHODS: Fresh frozen tissue samples from eight primary RCC lesions and autologous adjacent normal renal tissues were obtained from surgically resected tumour-bearing kidneys. Proteins were extracted by complete solubilisation of tissues using filter-aided sample preparation (FASP) method. Trypsin digested proteins were analysed using quantitative label-free proteomics approach followed by data interpretation and pathways analysis. RESULTS: A total of 1761 proteins were identified and quantified with high confidence (MASCOT ion score threshold of 35 and P-value <0.05). Of these, 596 proteins were identified as differentially expressed between cancer and noncancer tissues. Two upregulated proteins in tumour samples (adipose differentiation-related protein and Coronin 1A) were further validated by immunohistochemistry. Pathway analysis using IPA, KOBAS 2.0, DAVID functional annotation and FLink tools showed enrichment of many cancer-related biological processes and pathways such as oxidative phosphorylation, glycolysis and amino acid synthetic pathways. CONCLUSIONS: Our study identified a number of differentially expressed proteins and pathways using label-free proteomics approach in RCC compared with normal tissue samples. Two proteins validated in this study are the focus of on-going research in a large cohort of patients.

Cervical intramedullary melanocytoma: a case report and review of literature.

Meningeal melanocytomas are rare tumours of the central nervous system, most commonly found in the intracranial compartment (posterior cranial fossa). Spinal lesions are uncommon, with the majority being intradural, extramedullary lesions. Intramedullary melanocytomas are extremely rare and are most commonly found in the thoracic region. We report a patient with cervical intramedullary melanocytoma and review the available literature regarding this rare pathology.

Pre-treatment plasma proteomic markers associated with survival in oesophageal cancer.

BACKGROUND: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy can improve survival, but prognostic and predictive biomarkers are required. This study built upon preclinical approaches to identify prognostic plasma proteomic markers in oesophageal cancer. METHODS: Plasma samples collected before and during the treatment of oesophageal cancer and non-cancer controls were analysed by surface-enhanced laser desorption/ionisation time-of-flight (SELDI-TOF) mass spectroscopy (MS). Protein peaks were identified by MS in tryptic digests of purified fractions. Associations between peak intensities obtained in the spectra and clinical endpoints (survival, disease-free survival) were tested by univariate (Fisher's exact test) and multivariate analysis (binary logistic regression). RESULTS: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the oesophageal cancer and control groups at baseline. Three peaks, confirmed as apolipoprotein A-I, serum amyloid A and transthyretin, in baseline (pre-treatment) samples were associated by univariate and multivariate analysis with disease-free survival and overall survival. CONCLUSION: Plasma proteins can be detected prior to treatment for oesophageal cancer that are associated with outcome and merit testing as prognostic and predictive markers of response to guide chemotherapy in oesophageal cancer.

Toward automated consumer question answering: automatically separating consumer questions from professional questions in the healthcare domain.

OBJECTIVE: Both healthcare professionals and healthcare consumers have information needs that can be met through the use of computers, specifically via medical question answering systems. However, the information needs of both groups are different in terms of literacy levels and technical expertise, and an effective question answering system must be able to account for these differences if it is to formulate the most relevant responses for users from each group. In this paper, we propose that a first step toward answering the queries of different users is automatically classifying questions according to whether they were asked by healthcare professionals or consumers. DESIGN: We obtained two sets of consumer questions (~10,000 questions in total) from Yahoo answers. The professional questions consist of two question collections: 4654 point-of-care questions (denoted as PointCare) obtained from interviews of a group of family doctors following patient visits and 5378 questions from physician practices through professional online services (denoted as OnlinePractice). With more than 20,000 questions combined, we developed supervised machine-learning models for automatic classification between consumer questions and professional questions. To evaluate the robustness of our models, we tested the model that was trained on the Consumer-PointCare dataset on the Consumer-OnlinePractice dataset. We evaluated both linguistic features and statistical features and examined how the characteristics in two different types of professional questions (PointCare vs. OnlinePractice) may affect the classification performance. We explored information gain for feature reduction and the back-off linguistic category features. RESULTS: The 10-fold cross-validation results showed the best F1-measure of 0.936 and 0.946 on Consumer-PointCare and Consumer-OnlinePractice respectively, and the best F1-measure of 0.891 when testing the Consumer-PointCare model on the Consumer-OnlinePractice dataset. CONCLUSION: Healthcare consumer questions posted at Yahoo online communities can be reliably classified from professional questions posted by point-of-care clinicians and online physicians. The supervised machine-learning models are robust for this task. Our study will significantly benefit further development in automated consumer question answering.

Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenografts in response to chemotherapy.

BACKGROUND: The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy may improve survival, but targeting treatment to patients who respond to chemotherapy could be improved by the availability of markers of response. This study sought proteomic markers of therapeutic response using an adenocarcinoma xenograft model. METHODS: Epirubicin, cisplatin or 5-fluorouracil was administered to severe combined immune-deficient mice bearing OE19 oesophageal adenocarcinoma xenografts. Murine plasma samples from treated and untreated xenografts were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectroscopy, and panels of peaks were found using class prediction models that distinguished treatment groups. Proteins in these peaks were identified by mass spectroscopy in tryptic digests of purified fractions. Five paired samples from oesophageal cancer patients before and after chemotherapy were analysed using the same methodology. RESULTS: Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the treated xenograft and control groups. Marker panels predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86-100% and test efficiencies of 89-100%. Three of the proteins identified in these panels, apolipoprotein A-I, serum amyloid A and transthyretin were confirmed in the clinical samples. CONCLUSION: Plasma protein markers can be detected in response to chemotherapy in oesophageal adenocarcinoma xenografts and in clinical samples, and have the potential to monitor response and guide chemotherapy in oesophageal adenocarcinoma.

Behavior of cellular slime molds in the soil.

Cellular slime molds are soil organisms, yet since they were discovered in 1869 they have been studied on agar surfaces. Here the behavior of a number of species is examined and it is evident that they have different responses to directional light and they all thrive in the presence of soil. While phototaxis clearly plays a significant role in their ability to come to the soil surface for dispersal, even more important are gradients in the soil: both temperature gradients known from earlier studies, and as we show here gas gradients, presumably ammonia as a repellent and oxygen as an attractant. There are numerous differences in both morphology and behavior among slime mold species, some of which are likely to be the result of natural selection to particular habitats, while others could be explained more easily by neutral phenotypic variation.

A lifecourse study of risk for hyperinsulinaemia, dyslipidaemia and obesity (the central metabolic syndrome) at age 49-51 years.

AIMS: Suboptimal maternal nutrition and catch-up growth in early childhood predispose to insulin resistance and other components of metabolic syndrome in later life. A central metabolic syndrome (CMS) has been identified comprising obesity, dyslipidaemia and insulin resistance. This study was designed to investigate determinants of risk for CMS. METHODS: Persons born in Newcastle in May and June 1947 (n = 358) were followed to 1996-1998. A lifecourse approach was used to estimate the proportion of variance in a summary measure of CMS at age 49-51 years accounted for by factors operating at different stages of life. RESULTS: After adjustment for other early life variables, childhood catch-up growth in men accounted for significant variation in the CMS score independent of adult lifestyle. In adulthood, exercise level in men and smoking in both genders were independently associated with CMS. Over two-thirds of explained variation in the CMS score in women, and almost half in men, was accounted for exclusively by factors measured in adulthood. CONCLUSIONS: While risk for CMS in men is compounded by early life disadvantage, promotion of a healthier adult lifestyle and a reduction in the number of people taking up smoking would appear to be the public health interventions most likely to reduce the prevalence of CMS in middle age.

AHEC in West Virginia: a case study. Area health education centers.

This case study describes the area health education centers (AHEC) program in West Virginia, spanning 30 years from a first-generation project at Charleston in 1972 (AHEC 1) to a newly funded statewide program (AHEC 2). The outcome is an evolving university-community partnership designed to meet changing work-force and community health needs in the heart of rural Appalachia. West Virginia University's (WVU's) application of the original Carnegie Commission AHEC recommendations (1970) resulted in the Charleston AHEC, now part of the Robert C. Byrd Health Sciences Center of WVU. AHEC today trains more than 135 residents and interns, and one-third of the third-year and fourth-year WVU medical students. Charleston offers clinical and continuing education for nurses, dentists, pharmacists, and allied health professionals. A health sciences library, distance learning, and a network of primary care clinics help define Charleston's unique AHEC role. This AHEC hub continues to meet the classic Carnegie goals of recruiting and retaining health professionals, and providing access to care in the original service area and statewide. Based on the Charleston experience, four new federally funded AHECs are being developed to link rural primary care residencies with the state-funded West Virginia rural health education partnerships. These rural consortia AHECs are applying the concept of community competency, a performance-based methodology, to integrate learning while achieving the goals of Healthy People 2010.

Implications of childhood obesity for adult health: findings from thousand families cohort study.

OBJECTIVE: To determine whether being overweight in childhood increases adult obesity and risk of disease. DESIGN: Prospective cohort study. SETTING: City of Newcastle upon Tyne. PARTICIPANTS: 932 members of thousand families 1947 birth cohort, of whom 412 attended for clinical examination age 50. MAIN OUTCOME MEASURES: Blood pressure; carotid artery intima-media thickness; fibrinogen concentration; total, low density lipoprotein, and high density lipoprotein cholesterol concentrations; triglyceride concentration; fasting insulin and 2 hour glucose concentrations; body mass index; and percentage body fat. RESULTS: Body mass index at age 9 years was significantly correlated with body mass index age 50 (r=0.24, P<0.001) but not with percentage body fat age 50 (r=0.10, P=0.07). After adult body mass index had been adjusted for, body mass index at age 9 showed a significant inverse association with measures of lipid and glucose metabolism in both sexes and with blood pressure in women. However, after adjustment for adult percentage fat instead of body mass index, only the inverse associations with triglycerides (regression coefficient= -0.21, P<0.01) and total cholesterol (-0.17, P<0.05) in women remained significant. CONCLUSIONS: Little tracking from childhood overweight to adulthood obesity was found when using a measure of fatness that was independent of build. Only children who were obese at 13 showed an increased risk of obesity as adults. No excess adult health risk from childhood or teenage overweight was found. Being thin in childhood offered no protection against adult fatness, and the thinnest children tended to have the highest adult risk at every level of adult obesity.

Randomized trial of a "stage-of-change" oriented smoking cessation intervention in infertile and pregnant women.

OBJECTIVE: To assess a "stage-of-change" oriented smoking cessation intervention for infertile and pregnant women, compared with standard of care. DESIGN: Randomized controlled trial. SETTING: Three university teaching hospitals in Hamilton, Ontario, Canada. PATIENT(S): Infertile women at their first visit to a tertiary referral infertility clinic (n = 94) and new patients seeking pre-natal care (n = 110) who had smoked >/= 3 cigarettes in the past six months. INTERVENTION(S): A three to five minute scripted intervention and booklet specific to the woman's "stage-of-change" in the smoking continuum, versus standard of care. Exhaled carbon-monoxide (CO) monitoring was used to validate exposure in both groups. MAIN OUTCOME MEASURE(S): Delta "stage-of-change" and rate of maintained cessation at 12 months post follow-up. RESULT(S): Intervention and control were similarly effective for infertile women: the rate of maintained cessation rose significantly from 4% to 24% over twelve months, with a mean delta "stage-of-change" 0.28. In prenatal women, neither approach was effective. Maintained cessation did not significantly change from 0 to 12 months (19% to 18%). Mean delta "stage-of-change" declined by -0.62. CONCLUSION(S): For infertile women, basic information describing the impact of smoking on fertility, along with exhaled CO monitoring and a more intensive intervention were both highly effective. In pregnant women neither approach was beneficial, with some evidence of post-partum relapse.

Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease.

OBJECTIVES: This study compared coronary artery calcium (CC) as detected by electron beam computed tomography (EBCT) with conventional stress testing in the evaluation of patients with symptoms suggestive of coronary artery disease (CAD). BACKGROUND: Exercise electrocardiogram treadmill stress testing (treadmill-ECG) is limited by its requirement of a normal resting ECG and the ability of the patient to exercise adequately. The addition of myocardial imaging agents such as technetium improves the sensitivity and specificity but substantially increases the cost and prolongs the testing time. The use of EBCT provides a noninvasive and rapid method for identifying the presence and amount of CC, which has been shown to be related to atherosclerosis, and may provide additional information in combination with more traditional noninvasive testing methods. METHODS: A total of 97 patients underwent technetium stress testing (technetium-stress), treadmill-ECG, and EBCT coronary scanning within three months of coronary angiography for the evaluation of chest pain. RESULTS: The relative risk (RR) of obstructive angiographic CAD for an abnormal test was higher for EBCT (4.53) than either treadmill-ECG (1.72) or technetium-stress (1.96). The low specificity of EBCT (47%) was improved by the addition of treadmill-ECG (83%, p < 0.05). CONCLUSIONS: Electron beam computed tomography has a higher diagnostic ability than either treadmill-ECG or technetium-stress for the detection of obstructive angiographic CAD. Electron beam computed tomography is an accurate and noninvasive alternative to traditional stress testing for the detection of obstructive CAD in symptomatic patients.

Risk of cardiovascular disease measured by carotid intima-media thickness at age 49-51: lifecourse study.

OBJECTIVE: To quantify the direct and indirect effects of fetal life, childhood, and adult life on risk of cardiovascular disease at age 49-51 years. DESIGN: Follow up study of the "Newcastle thousand families" birth cohort established in 1947. PARTICIPANTS: 154 men and 193 women who completed a health and lifestyle questionnaire and attended for clinical examination between October 1996 and December 1998. MAIN OUTCOME MEASURES: Correlations between mean intima-media thickness of the carotid artery (carotid intima-media thickness) and family history, birth weight, and socioeconomic position around birth; socioeconomic position, growth, illness, and adverse life events in childhood; and adult socioeconomic position, lifestyle, and biological risk markers. Proportions of variance in carotid intima-media thickness that were accounted for by each stage of the lifecourse. RESULTS: Socioeconomic position at birth and birth weight were negatively associated with carotid intima-media thickness, although only social class at birth in women was a statistically significant covariate independent of adult lifestyle. These early life variables accounted directly for 2.2% of total variance in men and 2.0% in women. More variation in carotid intima-media thickness was explained by adult socioeconomic position and lifestyle, which accounted directly and indirectly for 3.4% of variance in men (95% confidence interval 0.5% to 6.2%) and 7.6% in women (2.1% to 13.0%). Biological risk markers measured in adulthood independently accounted for a further 9.5% of variance in men (2.4% to 14.2%) and 4.9% in women (1.6% to 7.4%). CONCLUSIONS: Adult lifestyle and biological risk markers were the most important determinants of the cardiovascular health of the study members of the Newcastle thousand families cohort at age 49-51 years. The limited overall effect of early life factors may reflect the postwar birth year of this cohort.

Diagnosis and treatment of severe dysplastic spondylolisthesis.

Spondylolisthesis, the anterior or posterior displacement of one vertebra on another, usually affects the lumbar region. Five percent of the population has one of the five classes of spondylolisthesis, which include dysplastic, isthmic, degenerative, traumatic, and pathologic spondylolisthesis. This article focuses on the dysplastic type, which makes up 14% to 21% of all spondylolisthesis. Dysplastic spondylolisthesis usually causes no symptoms in children; pain usually begins in adolescence. The key to diagnosis is the appropriate use of radiography in the evaluation of low back pain. This report describes a case involving a 21-year-old woman presenting with back pain to the family physician. Also, it details how the diagnosis was achieved and evaluates conservative and aggressive treatment options.