Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

The Blister Score: A Novel, Externally Validated Tool for Predicting Cardiac Implantable Electronic Device Infections, and Its Cost-utility Implications for Antimicrobial Envelope Use.

Background: Antimicrobial envelopes reduce the incidence of cardiac implantable electronic device (CIED) infections, but their cost restricts routine use in the UK. Risk scoring could help identify which patients would most benefit from this technology. Methods: A novel risk score (BLISTER) was derived from multivariate analysis of factors associated with CIED infection. Diagnostic utility was assessed against the existing PADIT score in both standard and high-risk external validation cohorts, and cost-utility models examined different BLISTER and PADIT score thresholds for TYRXTM antimicrobial envelope (AE) allocation. Results: In a derivation cohort (n=7,383), CIED infection occurred in 59 individuals within 12 months of a procedure (event rate: 0.8%). In addition to the PADIT score constituents, lead extraction (HR 3.3 (1.9-6.1), p50mg/l (HR 3.0 (1.4-6.4), p=0.005), re-intervention within two years (HR 10.1 (5.6-17.9), p<0.0001), and top-quartile procedure duration (HR 2.6 (1.6-4.1), p=0.001) were independent predictors of infection. The BLISTER score demonstrated superior discriminative performance versus PADIT in the standard-risk (n=2,854, event rate: 0.8%, AUC 0.82 vs 0.71, p=0.001) and high-risk validation cohorts (n=1,961, event rate: 2.0%, AUC 0.77 vs 0.69, p=0.001), and in all patients (n=12,198, event rate: 1%, AUC 0.8 vs 0.75, p=0.002). In decision-analytic modelling, the optimum scenario assigned AEs to patients with BLISTER scores ≥ 6 (10.8%), delivering a significant reduction in infections (relative risk reduction: 30%, p=0.036) within the NICE cost-utility thresholds (ICER: ￡18,446). Conclusions: The BLISTER score (https://qxmd.com/calculate/calculator_876/the-blister-score-for-cied-infection) was a valid predictor of CIED infection, and could facilitate cost-effective AE allocation to high-risk patients

Safety of bazedoxifene in a randomized, double-blind, placebo- and active-controlled phase 3 study of postmenopausal women with osteoporosis

Background. We report the safety findings from a 3-year phase 3 study (NCT00205777) of bazedoxifene, a novel selective estrogen receptor modulator under development for the prevention and treatment of postmenopausal osteoporosis. Methods. Healthy postmenopausal osteoporotic women (N = 7,492; mean age, 66.4 years) were randomized to daily doses of bazedoxifene 20 or 40 mg, raloxifene 60 mg, or placebo for 3 years. Safety and tolerability were assessed by adverse event (AE) reporting and routine physical, gynecologic, and breast examination. Results. Overall, the incidence of AEs, serious AEs, and discontinuations due to AEs in the bazedoxifene groups was not different from that seen in the placebo group. The incidence of hot flushes and leg cramps was higher with bazedoxifene or raloxifene compared with placebo. The rates of cardiac disorders and cerebrovascular events were low and evenly distributed among groups. Venous thromboembolic events, primarily deep vein thromboses, were more frequently reported in the active treatment groups compared with the placebo group; rates were similar with bazedoxifene and raloxifene. Bazedoxifene showed a neutral effect on the breast and an excellent endometrial safety profile. The incidence of fibrocystic breast disease was lower with bazedoxifene 20 and 40 mg versus raloxifene or placebo. Reductions in total and low-density lipoprotein levels and increases in high-density lipoprotein levels were seen with bazedoxifene versus placebo; similar results were seen with raloxifene. Triglyceride levels were similar among groups. Conclusion. Bazedoxifene showed a favorable safety and tolerability profile in women with postmenopausal osteoporosis. © 2010 Christiansen et al; licensee BioMed Central Ltd.link_to_subscribed_fulltex

Bioavailability in soils

The consumption of locally-produced vegetables by humans may be an important exposure pathway for soil contaminants in many urban settings and for agricultural land use. Hence, prediction of metal and metalloid uptake by vegetables from contaminated soils is an important part of the Human Health Risk Assessment procedure. The behaviour of metals (cadmium, chromium, cobalt, copper, mercury, molybdenum, nickel, lead and zinc) and metalloids (arsenic, boron and selenium) in contaminated soils depends to a large extent on the intrinsic charge, valence and speciation of the contaminant ion, and soil properties such as pH, redox status and contents of clay and/or organic matter. However, chemistry and behaviour of the contaminant in soil alone cannot predict soil-to-plant transfer. Root uptake, root selectivity, ion interactions, rhizosphere processes, leaf uptake from the atmosphere, and plant partitioning are important processes that ultimately govern the accumulation ofmetals and metalloids in edible vegetable tissues. Mechanistic models to accurately describe all these processes have not yet been developed, let alone validated under field conditions. Hence, to estimate risks by vegetable consumption, empirical models have been used to correlate concentrations of metals and metalloids in contaminated soils, soil physico-chemical characteristics, and concentrations of elements in vegetable tissues. These models should only be used within the bounds of their calibration, and often need to be re-calibrated or validated using local soil and environmental conditions on a regional or site-specific basis.Mike J. McLaughlin, Erik Smolders, Fien Degryse, and Rene Rietr

Maternal Environmental Contribution to Adult Sensitivity and Resistance to Obesity in Long Evans Rats

The OLETF rat is an animal model of early onset hyperphagia induced obesity, presenting multiple pre-obese characteristics during the suckling period. In the present study, we used a cross-fostering strategy to assess whether interactions with obese dams in the postnatal environment contributed to the development of obesity.On postnatal Day (PND)-1 OLETF and control LETO pups were cross-fostered to same or opposite strain dams. An independent ingestion test was performed on PND11 and a nursing test on PND18. Rats were sacrificed at weaning or on PND90, and plasma leptin, insulin, cholesterol, triglycerides and alanine aminotransferase (ALT) were assayed. Fat pads were collected and weighed and adipocyte size and number were estimated. Body weight and intake, as well as the estrous cycle of the female offspring were monitored.During the suckling period, the pups' phenotype was almost completely determined by the strain of the mother. However, pups independently ingested food according to their genotype, regardless of their actual phenotype. At adulthood, cross fostered males of both strains and LETO females were affected in regard of their adiposity levels in the direction of the foster dam. On the other hand, OLETF females showed almost no alterations in adiposity but were affected by the strain of the dams in parameters related to the metabolic syndrome. Thus, OLETF females showed reduced liver adiposity and circulating levels of ALT, while LETO females presented a disrupted estrous cycle and increased cholesterol and triglycerides in the long term.The present study provides further support for the early postnatal environment playing a sex-divergent role in programming later life phenotype. In addition, it plays a more central role in determining the functioning of mechanisms involved in energy balance that may provide protection from or sensitivity to later life obesity and pathologies related to the metabolic syndrome

Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells

<p>Abstract</p> <p>Background</p> <p>Chloroquine (CQ), the worldwide used anti-malarial drug, has recently being focused as a potential anti-cancer agent as well as a chemosensitizer when used in combination with anti-cancer drugs. It has been shown to inhibit cell growth and/or to induce cell death in various types of cancer. 5-Fluorouracil (5-FU) is the chemotherapeutic agent of first choice in colorectal cancer, but in most cases, resistance to 5-FU develops through various mechanisms. Here, we focused on the combination of CQ as a mechanism to potentiate the inhibitory effect of 5-FU on human colon cancer cells.</p> <p>Methods</p> <p>HT-29 cells were treated with CQ and/or 5-FU, and their proliferative ability, apoptosis and autophagy induction effects, and the affection of the cell cycle were evaluated. The proliferative ability of HT-29 was analyzed by the MTS assay. Apoptosis was quantified by flow-cytometry after double-staining of the cells with AnnexinV/PI. The cell cycle was evaluated by flow-cytometry after staining of cells with PI. Autophagy was quantified by flow-cytometry and Western blot analysis. Finally, to evaluate the fate of the cells treated with CQ and/or 5-FU, the colony formation assay was performed.</p> <p>Results</p> <p>5-FU inhibited the proliferative activity of HT-29 cells, which was mostly dependent on the arrest of the cells to the G0/G1-phase but also partially on apoptosis induction, and the effect was potentiated by CQ pre-treatment. The potentiation of the inhibitory effect of 5-FU by CQ was dependent on the increase of p21^Cip1and p27^Kip1and the decrease of CDK2. Since CQ is reported to inhibit autophagy, the catabolic process necessary for cell survival under conditions of cell starvation or stress, which is induced by cancer cells as a protective mechanism against chemotherapeutic agents, we also analyzed the induction of autophagy in HT-29. HT-29 induced autophagy in response to 5-FU, and CQ inhibited this induction, a possible mechanism of the potentiation of the anti-cancer effect of 5-FU.</p> <p>Conclusion</p> <p>Our findings suggest that the combination therapy with CQ should be a novel therapeutic modality to improve efficacy of 5-FU-based chemotherapy, possibly by inhibiting autophagy-dependent resistance to chemotherapy.</p

Illness meanings and experiences for pre-ulcer and ulcer conditions of Buruli ulcer in the Ga-West and Ga-South Municipalities of Ghana

ABSTRACT: BACKGROUND: Ghana is a Buruli ulcer (BU) endemic country yet there is paucity of socio-cultural research on BU. Examining distinctive experiences and meanings for pre-ulcers and ulcers of BU may clarify the disease burden, illness experience and local perceptions of causes and spread, and environmental features of BU, which are useful to guide public health programmes and future research. This study aimed to explain local meanings and experiences of BU for persons with pre-ulcers and ulcers in the Ga-West and Ga-South municipalities in Accra. METHODS: Semi-structured interviews based on the Explanatory Model Interview Catalogue framework were administered to 181 respondents comprising 15 respondents with pre-ulcers and 166 respondents with ulcers. The Wilcoxon rank-sum test was used to compare categories of illness experiences (PD) and perceived causes (PC) among respondents with pre-ulcer and ulcer conditions. The Fisher's exact test was used to compare the most troubling PD and the most important PC variables. Qualitative phenomenological analysis of respondents' narratives clarified illness experiences and meanings with reference to PC and PD variables. RESULTS: Families of respondents with pre-ulcers and the respondents themselves were often anxious about disease progression, while families of respondents with ulcers, who had to give care, worried about income loss and disruption of school attendance. Respondents with pre-ulcers frequently reported swimming in ponds and rivers as a perceived cause and considered it as the most important PC (53.3%). Respondents with ulcers frequently attributed their BU illness to witchcraft (64.5%) and respondents who claimed they had no water contact, questioned the credibility of health messages CONCLUSIONS: Affected persons with pre-ulcers are likely to delay treatment because of social and financial constraints and the absence of pain. Scepticism on the role of water in disease contagion and prolonged healin is perceived to make ideas of witchcraft as a PC more credible, among respondents with ulcers. Health messages should address issues of locally perceived risk and vulnerability. Guided by study findings, further research on the role of environmental, socio-cultural and genetic factors in BU contagion, is also needed to clarify and formulate health messages and strengthen public health initiative

Simulated-Physiological Loading Conditions Preserve Biological and Mechanical Properties of Caprine Lumbar Intervertebral Discs in Ex Vivo Culture

Low-back pain (LBP) is a common medical complaint and associated with high societal costs. Degeneration of the intervertebral disc (IVD) is assumed to be an important causal factor of LBP. IVDs are continuously mechanically loaded and both positive and negative effects have been attributed to different loading conditions

New Detection Systems of Bacteria Using Highly Selective Media Designed by SMART: Selective Medium-Design Algorithm Restricted by Two Constraints

Culturing is an indispensable technique in microbiological research, and culturing with selective media has played a crucial role in the detection of pathogenic microorganisms and the isolation of commercially useful microorganisms from environmental samples. Although numerous selective media have been developed in empirical studies, unintended microorganisms often grow on such media probably due to the enormous numbers of microorganisms in the environment. Here, we present a novel strategy for designing highly selective media based on two selective agents, a carbon source and antimicrobials. We named our strategy SMART for highly Selective Medium-design Algorithm Restricted by Two constraints. To test whether the SMART method is applicable to a wide range of microorganisms, we developed selective media for Burkholderia glumae, Acidovorax avenae, Pectobacterium carotovorum, Ralstonia solanacearum, and Xanthomonas campestris. The series of media developed by SMART specifically allowed growth of the targeted bacteria. Because these selective media exhibited high specificity for growth of the target bacteria compared to established selective media, we applied three notable detection technologies: paper-based, flow cytometry-based, and color change-based detection systems for target bacteria species. SMART facilitates not only the development of novel techniques for detecting specific bacteria, but also our understanding of the ecology and epidemiology of the targeted bacteria