The discovery of a novel antibiotic for the treatment of Clostridium difficile infections: a story of an effective academic-industrial partnership

Academic drug discovery is playing an increasingly important role in the identification of new therapies for a wide range of diseases. There is no one model that guarantees success. We describe here a drug discovery story where chance, the ability to capitalise on chance, and the assembling of a range of expertise, have all played important roles in the discovery and subsequent development of an antibiotic chemotype based on the bis-benzimidazole scaffold, with potency against a number of current therapeutically challenging diseases. One compound in this class, SMT19969, has recently entered Phase 2 human clinical trials for the treatment of Clostridium difficile infections

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND:Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS:From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS:The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS:Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk

The effects of moderate alcohol supplementation on estrone sulfate and DHEAS in postmenopausal women in a controlled feeding study

BACKGROUND: We have demonstrated that moderate alcohol consumption (15 g/d, 30 g/d) for 8 weeks resulted in significantly increased levels of serum estrone sulfate and DHEAS in 51 postmenopausal women in a randomized, placebo-controlled trial. We now report on the relationships between serum estrone sulfate and dehydroepiandrosterone sulfate (DHEAS) levels after 4 weeks of moderate alcohol supplementation, and compare the results to the 8 weeks data to elucidate time-to-effect differences. METHODS: Postmenopausal women (n = 51) consumed 0 (placebo), 15 (1 drink), and 30 (2 drinks) g alcohol (ethanol)/ day for 8 weeks as part of a controlled diet in a randomized crossover design. Blood samples were drawn at baseline, at 4 weeks and at 8 weeks. Changes in estrone sulfate and DHEAS levels from placebo to 15 g and 30 g alcohol per day were estimated using linear mixed models. RESULTS AND DISCUSSION: At week 4, compared to the placebo, estrone sulfate increased an average 6.9% (P = 0.24) when the women consumed 15 g of alcohol per day, and 22.2% (P = 0.0006) when they consumed 30 g alcohol per day. DHEAS concentrations also increased significantly by an average of 8.0% (P < 0.0001) on 15 g of alcohol per day and 9.2% (P < 0.0001) when 30 g alcohol was consumed per day. Trend tests across doses for both estrone sulfate (P = 0.0006) and DHEAS (P < 0.0001) were significant. We found no significant differences between the absolute levels of serum estrone sulfate at week 4 versus week 8 (P = 0.32) across all doses. However, absolute DHEAS levels increased from week 4 to week 8 (P < 0.0001) at all three dose levels. CONCLUSIONS: These data indicate that the hormonal effects due to moderate alcohol consumption are seen early, within 4 weeks of initiation of ingestion

Understanding the Challenges of Reducing Cancer in Appalachia: Addressing a Place-Based Health Disparity Population

The Appalachian region of the United States has long been recognized for its poor economic and social indicators. Only during the past decade have multi-state data become more accessible to describe the regions’ poor health status and resulting outcomes. A recent community-based participatory study engaged rural Appalachians to describe “what makes Appalachia different?” from other geographic areas and cultural groups in the United States and identify those characteristics that influence the region’s health. This article summarizes the community interpretation of these findings

High-resolution computed tomography reconstructions of invertebrate burrow systems

The architecture of biogenic structures can be highly influential in determining species contributions to major soil and sediment processes, but detailed 3-D characterisations are rare and descriptors of form and complexity are lacking. Here we provide replicate high-resolution micro-focus computed tomography (μ-CT) data for the complete burrow systems of three co-occurring, but functionally contrasting, sediment-dwelling inter-tidal invertebrates assembled alone, and in combination, in representative model aquaria. These data (≤2,000 raw image slices aquarium−1, isotropic voxel resolution, 81 μm) provide reference models that can be used for the development of novel structural analysis routines that will be of value within the fields of ecology, pedology, geomorphology, palaeobiology, ichnology and mechanical engineering. We also envisage opportunity for those investigating transport networks, vascular systems, plant rooting systems, neuron connectivity patterns, or those developing image analysis or statistics related to pattern or shape recognition. The dataset will allow investigators to develop or test novel methodology and ideas without the need to generate a complete three-dimensional computation of exemplar architecture

Gas sorption in poly(lactic acid) and packaging materials

Abstract The solubility of nitrogen, oxygen, carbon dioxide and water in poly(lactic acid) (PLA) was measured using a quartz crystal microbalance (QCM). For that purpose an apparatus based on the quartz crystal microbalance technique was built. This apparatus was calibrated with the system carbon dioxide in atactic polystyrene and the determined precision was of 3%. Measurements were performed up to atmospheric pressure and in the temperature region from 293.2 to 313.2 K. A study of the solubility of carbon dioxide in PLA over a temperature range from 283.2 to 313.2 K and at pressures bellow the atmospheric will be presented. The experimental results obtained were correlated with the Flory-Huggins model with an overall AAD of 6%

The challenge of measuring circulating estradiol at low concentrations

Demand for measuring estradiol at low concentrations is increasing, and the widely used 'direct' radioimmunoassays that do not require a preliminary organic purification step may be inadequate in patient care because of their limited accuracy. In observational epidemiology, however, the main concern is to obtain a correct ranking of individuals' hormone concentration relative to the true level (as determined through a 'gold standard'). Despite differences in the absolute scale of measured and true concentrations, correct ranking will permit calculation of unbiased estimates of hormone–disease associations. In prospective studies, the major concerns are the limited volume of often irreplaceable specimens and the need to perform a large number of assays within a reasonable period of time. Organic purification is often not feasible because of sample volume requirements and logistic difficulties, and so the development of accurate, rapid and inexpensive methods to measure sex steroids at low concentrations would represent a valuable new research tool for both clinicians and epidemiologists

Higher self-reported physical activity Is associated with lower systolic blood pressure: The Dietary Intervention Study in Childhood (DISC)

Objective: Children participating in a dietary clinical trial were studied to assess physical activity patterns in boys and girls longitudinally from late childhood through puberty; and to determine the association of level of physical activity on systolic blood pressure (SBP), low density lipoprotein (LDL) cholesterol, and body mass index (BMI). Patients and Methods: In the Dietary Intervention Study in Childhood (DISC), a randomized clinical trial of a reduced saturated fat and cholesterol diet in 8-10 year olds with elevated LDL, a questionnaire that determined time spent in five intensity levels of physical activity was completed at baseline and at 1 and 3 years. A MET score was calculated for weekly activity; hours per week were calculated for intense activities. We hypothesized that weekly self-reported physical activity would be associated with lower SBP, LDL, and BMI over three years. Longitudinal data analyses were performed for each outcome (SBP, LDL, and BMI) using generalized estimating equations with MET score per week as the independent variable adjusted for visit, gender, and Tanner stage (BMI was included in models for SBP and LDL). Results: The initial study cohort comprised 663 youths (362 male; age 9.7 years, 301 female; age 9.0 years) of whom 623 (94%) completed the 3-year visit. For every 100 MET-hours of physical activity, there was a decrease of 1.15 mmHg of SBP (p=0.0038). There was a 1.28 mg/dl decline in LDL (p=0.10) for a similar energy expenditure. For BMI, an analysis of intense physical activity showed that for every 10 hours of intense activity, there was a trend toward significance with a 0.2 kg/m2 decrease (p=0.06). Conclusion: Children with elevated cholesterol who lead a more physically active lifestyle have lower SBP and a trend toward lower LDL over a 3-year interval. Long-term participation in intense physical activity may reduce BMI as well