Reasons why osteoarthritis predicts mortality:Path analysis within a Cox proportional hazards model

Objectives To identify potentially modifiable factors that mediate the association between symptomatic osteoarthritis (OA) and premature mortality. Methods A population-based prospective cohort study; primary care medical record data were linked to self-report information collected by questionnaire in adults aged 50 years and over (n=10 415). OA was defined by primary care consultation and moderate-to-severe pain interference in daily life. A Cox proportional hazards analysis determined the total effect (TE) of OA on mortality after adjustment for potential confounders. Within the Cox model, path analysis was used to decompose the TE to assess the indirect and direct effects for selected potential mediators (anxiety, depression, unrefreshed sleep and walking frequency). Results are expressed as HRs with 95% CIs derived from bootstrap resampling. Results OA was significantly associated with mortality (TE-adjusted HR 1.14; 95% CI 1.00 to 1.29). The indirect effects for walking frequency were 1.05 (95% CI 1.04 to 1.06), depression 1.02 (95% CI 1.02 to 1.03), anxiety 1.01 (95% CI 1.00 to 1.02) and unrefreshed sleep 1.01 (95% CI 1.00 to 1.01). Conclusions The analysis indicates that encouraging people to walk and get out and about' in addition to targeting OA could be protective against excessive mortality. The findings also suggest that depression, anxiety and unrefreshed sleep have a role in premature mortality for people with OA; however, this has low clinical significance

Crystallization and X-ray diffraction analysis of the N-terminal domain of the Toll-like receptor signalling adaptor protein TRIF/TICAM-1

As part of the mammalian innate immune response, Toll-like receptors 3 and 4 can signal via the adaptor protein TRIF/TICAM-1 to elicit the production of type-I interferons and cytokines. Recent studies have suggested an auto-inhibitory role for the N-terminal domain (NTD) of TRIF. This domain has no significant sequence similarity to proteins of known structure. In this paper, the crystallization and X-ray diffraction analysis of TRIF-NTD and its selenomethionine-labelled mutant TRIF-NTDA66M/L113M are reported. Thin plate-like crystals of native TRIF-NTD obtained using polyethylene glycol 3350 as precipitant diffracted X-rays to 1.9 Å resolution. To facilitate phase determination, two additional methionines were incorporated into the protein at positions chosen based on the occurrence of methionines in TRIF homologues in different species. Crystals of the selenomethionine-labelled protein were obtained under conditions similar to the wild-type protein; these crystals diffracted X-rays to 2.5 Å resolution. The TRIF-NTD and TRIF-NTDA66M/L113M crystals have the symmetry of space groups P2 12121 and P1, and most likely contain two and four molecules in the asymmetric unit, respectively. These results provide a sound foundation for the future structure determination of this novel domain

Formal Modeling and Analysis of the MAL-Associated Biological Regulatory Network: Insight into Cerebral Malaria

The discrete modeling formalism of René Thomas is a well known approach for the modeling and analysis of Biological Regulatory Networks (BRNs). This formalism uses a set of parameters which reflect the dynamics of the BRN under study. These parameters are initially unknown but may be deduced from the appropriately chosen observed dynamics of a BRN. The discrete model can be further enriched by using the model checking tool HyTech along with delay parameters. This paves the way to accurately analyse a BRN and to make predictions about critical trajectories which lead to a normal or diseased response. In this paper, we apply the formal discrete and hybrid (discrete and continuous) modeling approaches to characterize behavior of the BRN associated with MyD88-adapter-like (MAL) – a key protein involved with innate immune response to infections. In order to demonstrate the practical effectiveness of our current work, different trajectories and corresponding conditions that may lead to the development of cerebral malaria (CM) are identified. Our results suggest that the system converges towards hyperinflammation if Bruton's tyrosine kinase (BTK) remains constitutively active along with pre-existing high cytokine levels which may play an important role in CM pathogenesis

Implications of Inflammatory Bowel Disease for reconstructive surgery in non-malignant urinary tract dysfunction:an International Continence Society working group report

Potential consequences of inflammatory bowel disease (IBD) need evaluation for patients considering urinary tract reconstruction for benign disease. A working group was formed by the International Continence Society, which considered urinary tract reconstruction in IBD.Methods Nominal group technique was used to derive consensus. Principal aspects of IBD assessment and surgery decision-making were agreed. A questionnaire was used to facilitate the generation of statements by a core focus group of experts, which were modified and ratified by the wider working group. This was followed by final voting by the full working group.Results General considerations included identification importance of the specialist IBD multi-disciplinary team. Peri-operative considerations recommended avoiding pre-operative fasting from midnight and using an enhanced recovery after surgery (ERAS) protocol. Selection of bowel segment, pre-operative optimisation and post-operative issues were considered for both Ulcerative colitis (UC) and Crohn’s disease. UC is not an absolute contraindication to urinary tract reconstruction using small or large bowel. Elective reconstructive surgery should wait at least three months following resolution of any acute UC flare-up to correct all abnormalities. Crohn’s disease is a high-risk disease for urinary tract reconstruction, even if in remission. In Crohn’s, reconstructive surgical options are limited by the location and extent of gastrointestinal segment(s) affected and the phenotype of disease.Conclusion The consensus opinion indicates that urinary tract reconstruction using bowel segments is feasible in carefully selected and optimised patients with IBD lacking alternative management options, provided there is access to appropriate multidisciplinary skills. UC is relatively low risk for surgical procedures, whereas Crohn’s has considerably increased risk of morbidity. The potential risks must be properly discussed with patients considering reconstructive urological procedures. Outcomes should be carefully monitored and published to identify the safety and efficacy of reconstructive surgery in IBD, including full description of the disease status

Risk factors for acquisition of hepatitis C virus infection: a case series and potential implications for disease surveillance

BACKGROUND: Transmission of hepatitis C vims (HCV) is strongly associated with use of contaminated blood products and injection drugs. Other "non-parental" modes of transmission including sexual activity have been increasingly recognized. We examined risk factors for acquiring HCV in patients who were referred to two tertiary care centers and enrolled in an antiviral therapy protocol. METHODS: Interviews of 148 patients were conducted apart from their physician evaluation using a structured questionnaire covering demographics and risk factors for HCV acquisition. RESULTS: Risk factors (blood products, injection/intranasal drugs, razor blades/ toothbrushes, body/ear piercing, occupational exposure, sexual activity) were identified in 141 (95.3%) of participants; 23 (15.5%) had one (most frequently blood or drug exposure), 41 (27.7%) had two, and 84 (53.4%) had more than two risk factors. No patient reported sexual activity as a sole risk factor. Body piercing accounted for a high number of exposures in women. Men were more likely to have exposure to street drugs but less exposure to blood products than women. Blood product exposure was less common in younger than older HCV patients. CONCLUSION: One and often multiple risk factors could be identified in nearly all HCV-infected patients seen in a referral practice. None named sexual transmission as the sole risk factor. The development of a more complete profile of factors contributing to transmission of HCV infection may assist in clinical and preventive efforts. The recognition of the potential presence of multiple risk factors may have important implications in the approach to HCV surveillance, and particularly the use of hierarchical algorithms in the study of risk factors

Red Cabbage Juice-Mediated Gut Microbiota Modulation Improves Intestinal Epithelial Homeostasis and Ameliorates Colitis

Gut microbiota plays a crucial role in inflammatory bowel diseases (IBD) and can potentially prevent IBD through microbial-derived metabolites, making it a promising therapeutic avenue. Recent evidence suggests that despite an unclear underlying mechanism, red cabbage juice (RCJ) alleviates Dextran Sodium Sulfate (DSS)-induced colitis in mice. Thus, the study aims to unravel the molecular mechanism by which RCJ modulates the gut microbiota to alleviate DSS-induced colitis in mice. Using C57BL/6J mice, we evaluated RCJ’s protective role in DSS-induced colitis through two cycles of 3% DSS. Mice were daily gavaged with PBS or RCJ until the endpoint, and gut microbiota composition was analyzed via shotgun metagenomics. RCJ treatment significantly improved body weight (p ≤ 0.001), survival in mice (p \u3c 0.001) and reduced disease activity index (DAI) scores. Further, RCJ improved colonic barrier integrity by enhancing the expression of protective colonic mucins (p \u3c 0.001) and tight junction proteins (p ≤ 0.01) in RCJ + DSS-treated mice compared to the DSS group. Shotgun metagenomic analysis revealed an enrichment of short-chain fatty acids (SCFAs)-producing bacteria (p \u3c 0.05), leading to increased Peroxisome Proliferator-Activated Receptor Gamma (PPAR-ү ) activation (p ≤ 0.001). This, in turn, resulted in repression of the nuclear factor кB (NFкB) signaling pathway, causing decreased production of inflammatory cytokines and chemokines. Our study demonstrates colitis remission in a DSS-induced mouse model, showcasing RCJ as a potential modulator for gut microbiota and metabolites, with promising implications for IBD prevention and treatment

The impact of thought speed and variability on psychological state and threat perception: Further exploration of the theory of mental motion.

Thought speed and variability are purportedly common features of specific psychological states, such as mania and anxiety. The present study explored the independent and combinational influence of these variables upon condition-specific symptoms and affective state, as proposed by Pronin and Jacobs’ (2008) theory of mental motion. A general population sample was recruited online (N = 263). Participants completed a thought speed and variability manipulation task, inducing a combination of fast/slow and varied/repetitive thought. Change in mania and anxiety symptoms was assessed through direct self-reported symptom levels and indirect, processing bias assessment (threat interpretation). Results indicated that fast and varied thought independently increased self-reported mania symptoms. Affect was significantly less positive and more negative during slow thought. No change in anxiety symptoms or threat interpretation was found between manipulation conditions. No evidence for the proposed combinational influence of speed and variability was found. Implications and avenues for therapeutic intervention are discussed

Cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of the TIR domain from the Brucella melitensis TIR-domain-containing protein TcpB

In mammals, Toll-like receptors (TLRs) recognize conserved microbial molecular signatures and induce an early innate immune response in the host. TLR signalling is mediated by interactions between the cytosolic TIR (Toll/interleukin-1 receptor) domains of the receptor and the adaptor proteins. Increasingly, it is apparent that pathogens target this interaction via pathogen-expressed TIR-domain-containing proteins to modulate immune responses. A TIR-domain-containing protein TcpB has been reported in the pathogenic bacterium Brucella melitensis. Studies have shown that TcpB interferes with the TLR2 and TLR4 signalling pathways to inhibit TLR-mediated inflammatory responses. Such interference may involve TIR-TIR-domain interactions between bacterial and mammalian proteins, but there is a lack of information about these interactions at the molecular level. In this study, the cloning, expression, purification, crystallization and preliminary X-ray crystallographic analysis of the protein construct corresponding to the TIR domain of TcpB (residues 120-250) are reported. The crystals diffracted to 2.6 angstrom resolution, have the symmetry of the monoclinic space group P2(1) and are most likely to contain four molecules in the asymmetric unit. The structure should help in understanding the molecular basis of how TcpB affects the innate immunity of the host