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

Cellular population dynamics control the robustness of the stem cell niche.

Within populations of cells, fate decisions are controlled by an indeterminate combination of cell-intrinsic and cell-extrinsic factors. In the case of stem cells, the stem cell niche is believed to maintain 'stemness' through communication and interactions between the stem cells and one or more other cell-types that contribute to the niche conditions. To investigate the robustness of cell fate decisions in the stem cell hierarchy and the role that the niche plays, we introduce simple mathematical models of stem and progenitor cells, their progeny and their interplay in the niche. These models capture the fundamental processes of proliferation and differentiation and allow us to consider alternative possibilities regarding how niche-mediated signalling feedback regulates the niche dynamics. Generalised stability analysis of these stem cell niche systems enables us to describe the stability properties of each model. We find that although the number of feasible states depends on the model, their probabilities of stability in general do not: stem cell-niche models are stable across a wide range of parameters. We demonstrate that niche-mediated feedback increases the number of stable steady states, and show how distinct cell states have distinct branching characteristics. The ecological feedback and interactions mediated by the stem cell niche thus lend (surprisingly) high levels of robustness to the stem and progenitor cell population dynamics. Furthermore, cell-cell interactions are sufficient for populations of stem cells and their progeny to achieve stability and maintain homeostasis. We show that the robustness of the niche - and hence of the stem cell pool in the niche - depends only weakly, if at all, on the complexity of the niche make-up: simple as well as complicated niche systems are capable of supporting robust and stable stem cell dynamics

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

Hippocampal - diencephalic - cingulate networks for memory and emotion: An anatomical guide

This review brings together current knowledge from tract tracing studies to update and reconsider those limbic connections initially highlighted by Papez for their presumed role in emotion. These connections link hippocampal and parahippocampal regions with the mammillary bodies, the anterior thalamic nuclei, and the cingulate gyrus, all structures now strongly implicated in memory functions. An additional goal of this review is to describe the routes taken by the various connections within this network. The original descriptions of these limbic connections saw their interconnecting pathways forming a serial circuit that began and finished in the hippocampal formation. It is now clear that with the exception of the mammillary bodies, these various sites are multiply interconnected with each other, including many reciprocal connections. In addition, these same connections are topographically organised, creating further subsystems. This complex pattern of connectivity helps explain the difficulty of interpreting the functional outcome of damage to any individual site within the network. For these same reasons, Papez’s initial concept of a loop beginning and ending in the hippocampal formation needs to be seen as a much more complex system of hippocampal–diencephalic–cingulate connections. The functions of these multiple interactions might be better viewed as principally providing efferent information from the posterior medial temporal lobe. Both a subcortical diencephalic route (via the fornix) and a cortical cingulate route (via retrosplenial cortex) can be distinguished. These routes provide indirect pathways for hippocampal interactions with prefrontal cortex, with the preponderance of both sets of connections arising from the more posterior hippocampal regions. These multi-stage connections complement the direct hippocampal projections to prefrontal cortex, which principally arise from the anterior hippocampus, thereby creating longitudinal functional differences along the anterior–posterior plane of the hippocampus

Nutrition and lung cancer: a case control study in Iran

Background: Despite many prospective and retrospective studies about the association of dietary habit and lung cancer, the topic still remains controversial. So, this study aims to investigate the association of lung cancer with dietary factors. Method: In this study 242 lung cancer patients and their 484 matched controls on age, sex, and place of residence were enrolled between October 2002 to 2005. Trained physicians interviewed all participants with standardized questionnaires. The middle and upper third consumer groups were compared to the lower third according to the distribution in controls unless the linear trend was significant across exposure groups. Result: Conditional logistic regression was used to evaluate the association with lung cancer. In a multivariate analysis fruit (Ptrend < 0.0001), vegetable (P = 0.001) and sunflower oil (P = 0.006) remained as protective factors and rice (P = 0.008), bread (Ptrend = 0.04), liver (P = 0.004), butter (Ptrend = 0.04), white cheese (Ptrend < 0.0001), beef (Ptrend = 0.005), vegetable ghee (P < 0.0001) and, animal ghee (P = 0.015) remained as risk factors of lung cancer. Generally, we found positive trend between consumption of beef (P = 0.002), bread (P < 0.0001), and dairy products (P < 0.0001) with lung cancer. In contrast, only fruits were inversely related to lung cancer (P < 0.0001). Conclusion: It seems that vegetables, fruits, and sunflower oil could be protective factors and bread, rice, beef, liver, dairy products, vegetable ghee, and animal ghee found to be possible risk factors for the development of lung cancer in Iran

Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature

ackground: Omega-3 (n-3) fatty acid supplementation is becoming increasingly popular. However given its antithrombotic properties the potential for severe adverse events (SAE) such as bleeding has safety implications, particularly in an older adult population. A systematic review of randomized control trials (RCT) was conducted to explore the potential for SAE and non-severe adverse events (non-SAE) associated with n-3 supplementation in older adults. Methods: A comprehensive search strategy using Medline and a variety of other electronic sources was conducted. Studies investigating the oral administration of n-3 fish oil containing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or both against a placebo were sourced. The primary outcome of interest included reported SAE associated with n-3 supplementation. Chi-square analyses were conducted on the pooled aggregate of AEs. Results: Of the 398 citations initially retrieved, a total of 10 studies involving 994 older adults aged ≥60 years were included in the review. Daily fish oil doses ranged from 0.03 g to 1.86 g EPA and/or DHA with study durations ranging from 6 to 52 weeks. No SAE were reported and there were no significant differences in the total AE rate between groups (n-3 intervention group: 53/540; 9.8%; placebo group: 28/454; 6.2%; p= 0.07). Non-SAE relating to gastrointestinal (GI) disturbances were the most commonly reported however there was no significant increase in the proportion of GI disturbances reported in participants randomized to the n-3 intervention (n-3 intervention group: 42/540 (7.8%); placebo group: 24/454 (5.3%); p= 0.18). Conclusions: The potential for AEs appear mild-moderate at worst and are unlikely to be of clinical significance. The use of n-3 fatty acids and the potential for SAE should however be further researched to investigate whether this evidence is consistent at higher doses and in other populations. These results also highlight that well-documented data outlining the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. A more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve n-3 supplementation is required.The authors would like to acknowledge funding provided for the ongoing ATLANTIC randomized controlled trial supported by the National Health and Medical Research Council (NHMRC), Australia

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

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

Updated fracture incidence rates for the US version of FRAX®

# The Author(s) 2009. This article is published with open access at Springerlink.com Summary On the basis of updated fracture and mortality data, we recommend that the base population values used in the US version of FRAX ® be revised. The impact of suggested changes is likely to be a lowering of 10-year fracture probabilities. Introduction Evaluation of results produced by the US version of FRAX ® indicates that this tool overestimates the likelihood of major osteoporotic fracture. In an attempt to correct this, we updated underlying fracture and mortality rates for the model. Methods We used US hospital discharge data from 2006 t