Arteriovenous Blood Metabolomics: A Readout of Intra-Tissue Metabostasis.

The human circulatory system consists of arterial blood that delivers nutrients to tissues, and venous blood that removes the metabolic by-products. Although it is well established that arterial blood generally has higher concentrations of glucose and oxygen relative to venous blood, a comprehensive biochemical characterization of arteriovenous differences has not yet been reported. Here we apply cutting-edge, mass spectrometry-based metabolomic technologies to provide a global characterization of metabolites that vary in concentration between the arterial and venous blood of human patients. Global profiling of paired arterial and venous plasma from 20 healthy individuals, followed up by targeted analysis made it possible to measure subtle (<2 fold), yet highly statistically significant and physiologically important differences in water soluble human plasma metabolome. While we detected changes in lactic acid, alanine, glutamine, and glutamate as expected from skeletal muscle activity, a number of unanticipated metabolites were also determined to be significantly altered including Krebs cycle intermediates, amino acids that have not been previously implicated in transport, and a few oxidized fatty acids. This study provides the most comprehensive assessment of metabolic changes in the blood during circulation to date and suggests that such profiling approach may offer new insights into organ homeostasis and organ specific pathology

Rapid detection of snakes modulates spatial orienting in infancy

Recent evidence for an evolved fear module in the brain comes from studies showing that adults, children and infants detect evolutionarily threatening stimuli such as snakes faster than non-threatening ones. A decisive argument for a threat detection system efficient early in life would come from data showing, in young infants, a functional threat-detection mechanism in terms of “what” and “where” visual pathways. The present study used a variant of Posner’s cuing paradigm, adapted to 7–11-month-olds. On each trial, a threat-irrelevant or a threat-relevant cue was presented (a flower or a snake, i.e., “what”). We measured how fast infants detected these cues and the extent to which they further influenced the spatial allocation of attention (“where”). In line with previous findings, we observed that infants oriented faster towards snake than flower cues. Importantly, a facilitation effect was found at the cued location for flowers but not for snakes, suggesting that these latter cues elicit a broadening of attention and arguing in favour of sophisticated “what–where” connections. These results strongly support the claim that humans have an early propensity to detect evolutionarily threat-relevant stimuli

Pharmacist Contributions to the U.S. Health Care System

Objective: The overall goal for this study was to conduct a segment analysis of the pharmacist workforce during 2009 based upon time spent in medication providing and in patient care services. Methods: Data for this study were obtained from the 2009 National Pharmacist Workforce Survey in which a random sample of 3,000 pharmacists was selected. Cluster analysis was used for identifying pharmacist segments and descriptive statistics were used for describing and comparing segments.Results: Of the 2,667 surveys that were presumed to be delivered to a pharmacist, 1,395 were returned yielding a 52.3% overall response rate. Of these, 1,200 responses were usable for cluster analysis. Findings from this study revealed five segments ofpharmacists: (1) Medication Providers, (2) Medication Providers who also Provide Patient Care, (3) Other Activity Pharmacists, (4) Patient Care Providers Who also Provide Medication, and (5) Patient Care Providers. The results showed that, in 2009, 41% of U.S. pharmacists were devoted wholly to medication providing (Medication Providers). Forty-three percent of pharmacists contributed significantly to patient care service provision (Medication Providers who also Provide Patient Care, Patient Care Providers who also Provide Medication, and Patient Care Providers) and the remaining 16% (Other Activity Pharmacists) contributed most of their time to business / organization management, research, education, and other health-system improvement activities. Conclusions: Based on the findings, we propose that the pharmacy profession currently has, and will continue to build, capacity for contributing to the U.S. health care system in new roles for which they have been identified. However, as shifts in professional roles occur, a great deal of capacity is required related to new service provision. Resources are scarce, so an understanding of the most appropriate timing for making such changes can lead to cost-effective use of limited resources for improving patient care

Rapid Identification of Hospitalized Patients at High Risk for MRSA Carriage

Patients who are asymptomatic carriers of methicillin-resistant Staphylococcus aureus (MRSA) are major reservoirs for transmission of MRSA to other patients. Medical personnel are usually not aware when these high-risk patients are hospitalized. We developed and tested an enterprise-wide electronic surveillance system to identify patients at high risk for MRSA carriage at hospital admission and during hospitalization. During a two-month study, nasal swabs from 153 high-risk patients were tested for MRSA carriage using polymerase chain reaction (PCR) of which 31 (20.3%) were positive compared to 12 of 293 (4.1%, p < 0.001) low-risk patients. The mean interval from admission to availability of PCR test results was 19.2 hours. Computer alerts for patients at high-risk of MRSA carriage were found to be reliable, timely and offer the potential to replace testing all patients. Previous MRSA colonization was the best predictor but other risk factors were needed to increase the sensitivity of the algorith

Defining Early-Onset Colon and Rectal Cancers

Background: Colorectal cancer (CRC) incidence is rising in the young, yet the age of those affected is not clearly defined. In this study, we identify such cohorts and define clinicopathological features of early-onset colon and rectal cancers.Methods: The Surveillance, Epidemiology and End Results Program (SEER) database was queried to compare clinicopathological characteristics of colon and rectal cancers diagnosed during 1973–1995 with those diagnosed during 1995–2014.Results: We identified 430,886 patients with colon and rectal cancers. From 1973–1995 to 1995–2014, colon cancer incidence increased in patients aged 20–44 years, while rectal cancer incidence increased in patients aged ≤54 years. The percent change of cancer incidence was greatest for rectal cancer with a 41.5% (95% confidence interval (CI): 37.4–45.8%) increase compared to a 9.8% (CI: 6.2–13.6%) increase in colon cancer. Colon cancer has increased in tumors located in ascending, sigmoid, and rectosigmoid locations. Adenocarcinoma histology has increased in both colon and rectal cancers (P &lt; 0.01), but mucinous and signet ring cell subtypes have not increased (P = 0.13 and 0.08, respectively). Incidence increases were race-specific, with rectal cancer seeing similar rises in white (38.4%, CI: 33.8–43.1%) and black populations (38.0%, CI: 26.2–51.2%), while colon cancer as a whole saw a rise in white (11.5%, CI: 7.2–15.9%) but not black populations (−6.8%, CI: −14.6–1.9%).Conclusions: Our study underscores the existence of key differences between early-onset colon (20–44 years) and rectal cancers (≤54 years) and provides evidence-based inclusion criteria for future investigations. We recommend that future research of CRC in the young should avoid investigating these cases as a single entity

ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF- levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF- levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D

Monitoring metabolic responses to chemotherapy in single cells and tumors using nanostructure-initiator mass spectrometry (NIMS) imaging

BACKGROUND: Tissue imaging of treatment-induced metabolic changes is useful for optimizing cancer therapies, but commonly used methods require trade-offs between assay sensitivity and spatial resolution. Nanostructure-Initiator Mass Spectrometry imaging (NIMS) permits quantitative co-localization of drugs and treatment response biomarkers in cells and tissues with relatively high resolution. The present feasibility studies use NIMS to monitor phosphorylation of 3(′)-deoxy-3(′)-fluorothymidine (FLT) to FLT-MP in lymphoma cells and solid tumors as an indicator of drug exposure and pharmacodynamic responses. METHODS: NIMS analytical sensitivity and spatial resolution were examined in cultured Burkitt’s lymphoma cells treated briefly with Rapamycin or FLT. Sample aliquots were dispersed on NIMS surfaces for single cell imaging and metabolic profiling, or extracted in parallel for LC-MS/MS analysis. Docetaxel-induced changes in FLT metabolism were also monitored in tissues and tissue extracts from mice bearing drug-sensitive tumor xenografts. To correct for variations in FLT disposition, the ratio of FLT-MP to FLT was used as a measure of TK1 thymidine kinase activity in NIMS images. TK1 and tumor-specific luciferase were measured in adjacent tissue sections using immuno-fluorescence microscopy. RESULTS: NIMS and LC-MS/MS yielded consistent results. FLT, FLT-MP, and Rapamycin were readily detected at the single cell level using NIMS. Rapid changes in endogenous metabolism were detected in drug-treated cells, and rapid accumulation of FLT-MP was seen in most, but not all imaged cells. FLT-MP accumulation in xenograft tumors was shown to be sensitive to Docetaxel treatment, and TK1 immunoreactivity co-localized with tumor-specific antigens in xenograft tumors, supporting a role for xenograft-derived TK1 activity in tumor FLT metabolism. CONCLUSIONS: NIMS is suitable for monitoring drug exposure and metabolite biotransformation with essentially single cell resolution, and provides new spatial and functional dimensions to studies of cancer metabolism without the need for radiotracers or tissue extraction. These findings should prove useful for in vitro and pre-clinical studies of cancer metabolism, and aid the optimization of metabolism-based cancer therapies and diagnostics

Actual and preferred contraceptive sources among young people: findings from the British National Survey of Sexual Attitudes and Lifestyles

OBJECTIVE: To describe actual and preferred contraceptive sources among young people in Britain and whether discordance between these is associated with markers of sexual risk behaviour or poor sexual health. DESIGN: Cross-sectional probability sample survey. SETTING: British general population. PARTICIPANTS: 3869 men and women aged 16-24 years interviewed for the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) between 2010 and 2012. MAIN OUTCOME MEASURES: Reported source of contraceptive method(s) and preferred source if all were available and easily accessible. RESULTS: Of the 75% of young people (aged 16-24) who were heterosexually active (1619 women, 1233 men), >86% reported obtaining contraceptives in the past year. Most common sources were general practice (women, 63%) and retail (men, 60%): using multiple sources was common (women 40%, men 45%). Healthcare sources were preferred by 81% of women and 57% of men. Overall, 32% of women and 39% of men had not used their preferred source. This discordance was most common among men who preferred general practice (69%) and women who preferred retail (52%). Likelihood of discordance was higher among women who usually used a less effective contraceptive method or had an abortion. It was less likely among men who usually used a less effective method of contraception and men who were not in a steady relationship. CONCLUSIONS: Most young people in Britain obtained contraception in the past year but one-third had not used their preferred source. Healthcare sources were preferred. Discordance was associated with using less effective contraception and abortion among young women. Meeting young people's preference for obtaining contraception from healthcare sources could improve uptake of effective contraception to reduce unwanted pregnancies

Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring.

BACKGROUND: Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. METHODOLOGY/PRINCIPAL FINDING: Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co-extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. CONCLUSIONS/SIGNIFICANCE: Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies