The Balance of Apoptotic and Necrotic Cell Death in Mycobacterium tuberculosis Infected Macrophages Is Not Dependent on Bacterial Virulence

An important mechanism of Mycobacterium tuberculosis pathogenesis is the ability to control cell death pathways in infected macrophages: apoptotic cell death is bactericidal, whereas necrotic cell death may facilitate bacterial dissemination and transmission

Measurement of urinary collagen cross-links indicate response to therapy in patients with breast cancer and bone metastases

Objective assessment of response in bone metastases from breast cancer using radiological techniques takes up to 6 months of treatment to be certain of a response, and sclerotic metastases are not evaluable. Standard serum and urinary tumour markers may not always be utilized to predict response, as they may not be elevated, and therefore may not change on treatment. The development of the urinary pyridinoline cross-link assays which measure mature bone breakdown products have been shown to be highly sensitive and specific as a measure of bone change in osteoporosis. We have measured pyridinoline (Pyr) and deoxypyridinoline (Dpyr) cross-links sequentially in 36 breast cancer patients with bone metastases, to determine if the measurement of these analytes predicts response at an earlier stage than radiological assessment. Response was assessed by UICC criteria. Seventeen women responded to hormonal therapy, whilst 19 developed progressive disease. Both Pyr and Dpyr increased sequentially in women with progressive disease with changes becoming apparent by 8 weeks (P < 0.03). In responding women, cross-link levels did not change significantly. Pyr and Dpyr were more sensitive and specific than the standard serum tumour marker CA 15-3. Urinary cross-link measurements provide a novel objective method of assessing response to treatment in women with bone metastases. Initial elevated urinary cross-link markers identify patients who tend not to respond to changes in hormonal therap

Milling plant and soil material in plastic tubes over-estimates carbon and under-estimates nitrogen concentrations

Peer reviewedPostprin

Reduction of T-Helper Cell Responses to Recall Antigen Medicated by Codelivery with Peptidoglycan via the Intestinal Nanomineral-Antigen Pathway

Naturally occurring intestinal nanomineral particles constituently form in the mammalian gut and trap luminal protein and microbial components. These cargo loaded nanominerals are actively scavenged by M cells of intestinal immune follicles, such as Peyer’s patches and are passed to antigen-presenting cells. Using peripheral blood mononuclear cell populations as an in vitro model of nanomineral uptake and antigen presentation, we show that monocytes avidly phagocytose nanomineral particles bearing antigen and peptidoglycan (PGN), and that the presence of PGN within particles downregulates their cell surface MHC class II and upregulates programmed death receptor ligand 1. Nanomineral delivery of antigen suppresses antigen-specific CD4+ T cell responses, an effect that is enhanced in the presence of PGN. Blocking the interleukin-10 receptor restores CD4+ T cell responses to antigen codelivered with PGN in nanomineral form. Using human intestinal specimens, we have shown that the in vivo nanomineral pathway operates in an interleukin-10 rich environment. Consequently, the delivery of a dual antigen–PGN cargo by endogenous nanomineral in vivo is likely to be important in the establishment of intestinal tolerance, while their synthetic mimetics present a potential delivery system for therapeutic applications targeting the modulation of Peyer’s patch T cell responses

Genetic testing of children for adult-onset conditions: opinions of the British adult population and implications for clinical practice

This study set out to explore the attitudes of a representative sample of the British public towards genetic testing in children to predict disease in the future. We sought opinions about genetic testing for adult-onset conditions for which no prevention/treatment is available during childhood, and about genetic 'carrier' status to assess future reproductive risks. The study also examined participants' level of agreement with the reasons professional organisations give in favour of deferring such testing. Participants (n=2998) completed a specially designed questionnaire, distributed by email. Nearly half of the sample (47%) agreed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. This runs contrary to professional guidance about genetic testing in children. Testing for carrier status was supported by a larger proportion (60%). A child's future ability to decide for her/himself if and when to be tested was the least supported argument in favour of deferring testing.European Journal of Human Genetics advance online publication, 5 November 2014; doi:10.1038/ejhg.2014.221

A cavity expansion–based solution for interpretation of CPTu data in soils under partially drained conditions

A cavity expansion–based solution is proposed in this paper for the interpretation of CPTu data under a partially drained condition. Variations of the normalized cone tip resistance, cone factor, and undrained‐drained resistance ratio are examined with different initial specific volume and overconsolidation ratio, based on the exact solutions of both undrained and drained cavity expansion in CASM, which is a unified state parameter model for clay and sand. A drainage index is proposed to represent the partially drained condition, and the critical state after expansion and stress paths of cavity expansion are therefore predicted by estimating a virtual plastic region and assuming a drainage‐index–based mapping technique. The stress paths and distributions of stresses and specific volume are investigated for different values of drainage index, which are also related to the penetration velocity with comparisons of experimental data and numerical results. The subsequent consolidation after penetration is thus predicted with the assumption of constant deviatoric stress during dissipation of the excess pore pressure. Both spherical and cylindrical consolidations are compared for dissipation around the cone tip and the probe shaft, respectively. The effects of overconsolidation ratio on the stress paths and the distributions of excess pore pressure and specific volume are then thoroughly investigated. The proposed solution and the findings would contribute to the interpretation of CPTu tests under a random drained condition, as well as the analysis of pile installation and the subsequent consolidation

A Visual Metaphor Describing Neural Dynamics in Schizophrenia

Background: In many scientific disciplines the use of a metaphor as an heuristic aid is not uncommon. A well known example in somatic medicine is the 'defense army metaphor' used to characterize the immune system. In fact, probably a large part of the everyday work of doctors consists of 'translating' scientific and clinical information (i.e. causes of disease, percentage of succes versus risk of side-effects) into information tailored to the needs and capacities of the individual patient. The ability to do so in an effective way is at least partly what makes a clinician a good communicator. Schizophrenia is a severe psychiatric disorder which affects approximately 1% of the population. Over the last two decades a large amount of molecular-biological, imaging and genetic data have been accumulated regarding the biological underpinnings of schizophrenia. However, it remains difficult to understand how the characteristic symptoms of schizophrenia such as hallucinations and delusions are related to disturbances on the molecular-biological level. In general, psychiatry seems to lack a conceptual framework with sufficient explanatory power to link the mental- and molecular-biological domains. Methodology/Principal Findings: Here, we present an essay-like study in which we propose to use visualized concepts stemming from the theory on dynamical complex systems as a 'visual metaphor' to bridge the mental- and molecular-biological domains in schizophrenia. We first describe a computer model of neural information processing; we show how the information processing in this model can be visualized, using concepts from the theory on complex systems. We then describe two computer models which have been used to investigate the primary theory on schizophrenia, the neurodevelopmental model, and show how disturbed information processing in these two computer models can be presented in terms of the visual metaphor previously described. Finally, we describe the effects of dopamine neuromodulation, of which disturbances have been frequently described in schizophrenia, in terms of the same visualized metaphor. Conclusions/Significance: The conceptual framework and metaphor described offers a heuristic tool to understand the relationship between the mental- and molecular-biological domains in an intuitive way. The concepts we present may serve to facilitate communicatio

A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: luteinising hormone-releasing hormone agonists versus transdermal oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100μg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784)

Measuring the effect of enhanced cleaning in a UK hospital : a prospective cross-over study

Increasing hospital-acquired infections have generated much attention over the last decade. There is evidence that hygienic cleaning has a role in the control of hospital-acquired infections. This study aimed to evaluate the potential impact of one additional cleaner by using microbiological standards based on aerobic colony counts and the presence of Staphylococcus aureus including meticillin-resistant S. aureus. We introduced an additional cleaner into two matched wards from Monday to Friday, with each ward receiving enhanced cleaning for six months in a cross-over design. Ten hand-touch sites on both wards were screened weekly using standardised methods and patients were monitored for meticillin-resistant S. aureus infection throughout the year-long study. Patient and environmental meticillin-resistant S. aureus isolates were characterised using molecular methods in order to investigate temporal and clonal relationships. Enhanced cleaning was associated with a 32.5% reduction in levels of microbial contamination at handtouch sites when wards received enhanced cleaning (P < 0.0001: 95% CI 20.2%, 42.9%). Near-patient sites (lockers, overbed tables and beds) were more frequently contaminated with meticillin-resistant S. aureus/S. aureus than sites further from the patient (P = 0.065). Genotyping identified indistinguishable strains from both handtouch sites and patients. There was a 26.6% reduction in new meticillin-resistant S. aureus infections on the wards receiving extra cleaning, despite higher meticillin-resistant S. aureus patient-days and bed occupancy rates during enhanced cleaning periods (P = 0.032: 95% CI 7.7%, 92.3%). Adjusting for meticillin-resistant S. aureus patient-days and based upon nine new meticillin-resistant S. aureus infections seen during routine cleaning, we expected 13 new infections during enhanced cleaning periods rather than the four that actually occurred. Clusters of new meticillin-resistant S. aureus infections were identified 2 to 4 weeks after the cleaner left both wards. Enhanced cleaning saved the hospital £30,000 to £70,000.Introducing one extra cleaner produced a measurable effect on the clinical environment, with apparent benefit to patients regarding meticillin-resistant S. aureus infection. Molecular epidemiological methods supported the possibility that patients acquired meticillin-resistant S. aureus from environmental sources. These findings suggest that additional research is warranted to further clarify the environmental, clinical and economic impact of enhanced hygienic cleaning as a component in the control of hospital-acquired infection