Phenolic Glycolipid Facilitates Mycobacterial Escape from Microbicidal Tissue-Resident Macrophages

Mycobacterium tuberculosis (Mtb) enters the host in aerosol droplets deposited in lung alveoli, where the bacteria first encounter lung-resident alveolar macrophages. We studied the earliest mycobacterium-macrophage interactions in the optically transparent zebrafish. First-responding resident macrophages phagocytosed and eradicated infecting mycobacteria, suggesting that to establish a successful infection, mycobacteria must escape out of the initially infected resident macrophage into growth-permissive monocytes. We defined a critical role for mycobacterial membrane phenolic glycolipid (PGL) in engineering this transition. PGL activated the STING cytosolic sensing pathway in resident macrophages, inducing the production of the chemokine CCL2, which in turn recruited circulating CCR2+ monocytes towards infection. Transient fusion of infected macrophages with CCR2+ monocytes enabled bacterial transfer and subsequent dissemination, and interrupting this transfer so as to prolong mycobacterial sojourn in resident macrophages promoted clearing of infection. Human alveolar macrophages produced CCL2 upon Mtb infection, arguing for the potential of PGL-blocking interventions or PGL-targeting vaccine strategies in the prevention of tuberculosis.This work was supported by the NIH Director’s Pioneer Award, NIH grant R37AI054503, and a Wellcome Trust Principal Research Fellowship (L.R.), NIH training grant T32 AI55396 and a Damon Runyon Postdoctoral Fellowship (C.J.C.), the Health Research Board of Ireland (S.M.O., M.P.O., and J.K.), and The Royal City of Dublin Hospital Trust (J.K.)

A Multicriteria Decision Analysis Comparing Pharmacotherapy for Chronic Neuropathic Pain, Including Cannabinoids and Cannabis-Based Medical Products

BACKGROUND: Pharmacological management of chronic neuropathic pain (CNP) still represents a major clinical challenge. Collective harnessing of both the scientific evidence base and clinical experience (of clinicians and patients) can play a key role in informing treatment pathways and contribute to the debate on specific treatments (e.g., cannabinoids). A group of expert clinicians (pain specialists and psychiatrists), scientists, and patient representatives convened to assess the relative benefit–safety balance of 12 pharmacological treatments, including orally administered cannabinoids/cannabis-based medicinal products, for the treatment of CNP in adults. METHODS: A decision conference provided the process of creating a multicriteria decision analysis (MCDA) model, in which the group collectively scored the drugs on 17 effect criteria relevant to benefits and safety and then weighted the criteria for their clinical relevance. FINDINGS: Cannabis-based medicinal products consisting of tetrahydrocannabinol/cannabidiol (THC/CBD), in a 1:1 ratio, achieved the highest overall score, 79 (out of 100), followed by CBD dominant at 75, then THC dominant at 72. Duloxetine and the gabapentinoids scored in the 60s, amitriptyline, tramadol, and ibuprofen in the 50s, methadone and oxycodone in the 40s, and morphine and fentanyl in the 30s. Sensitivity analyses showed that even if the pain reduction and quality-of-life scores for THC/CBD and THC are halved, their benefit–safety balances remain better than those of the noncannabinoid drugs. INTERPRETATION: The benefit–safety profiles for cannabinoids were higher than for other commonly used medications for CNP largely because they contribute more to quality of life and have a more favorable side effect profile. The results also reflect the shortcomings of alternative pharmacological treatments with respect to safety and mitigation of neuropathic pain symptoms. Further high-quality clinical trials and systematic comprehensive capture of clinical experience with cannabinoids is warranted. These results demonstrate once again the complexity and multimodal mechanisms underlying the clinical experience and impact of chronic pain

Waiting times for systemic cancer therapy in the United Kingdom in 2006

This audit was conducted to measure waiting times for systemic cancer therapy across the United Kingdom. All patients, aged 16 years or older, commencing their first course of systemic therapy between 13 November and 19 November 2006 were eligible for inclusion. Data on 936 patients from 81 hospital sources were collected. Systemic therapy is largely given in compliance with national waiting time targets. In terms of the Joint Council for Clinical Oncology (JCCO) targets, 84% of patients commence treatment within 21 days and 98% of patients complied with the Department of Health target that treatment should follow within 31 days of the decision being agreed with the patient. Only 76% complied with the Department of Health 62-day target from GP referral to first definitive treatment. However, the date of urgent referral by the GP was not submitted for most patients in our survey, leaving a sample of only 84 out of 936 patients (9% of total) suitable for this analysis. There was only a 3- to 5-day difference between the waiting times for systemic therapy for patients categorised as urgent compared with routine. Locally agreed definitions had little impact on patients' priority for treatment. This audit has established a baseline measurement of waiting times for systemic therapy across the United Kingdom. The continuing introduction of novel therapies is likely to have a significant effect on the service and we recommend that service managers model the likely impact on resource requirements. In addition, urgent treatment should be clearly defined as that required within 24 h (maximum 48 h) to avoid the risk of clinical deterioration, particularly in patients with acute leukaemia, lymphoma or germ cell tumour

The differential effects of core stabilization exercise regime and conventional physiotherapy regime on postural control parameters during perturbation in patients with movement and control impairment chronic low back pain

<p>Abstract</p> <p>Background</p> <p>The purpose of the present study was to examine the differential effect of core stability exercise training and conventional physiotherapy regime on altered postural control parameters in patients with chronic low back pain (CLBP). As heterogeneity in CLBP population moderates the effect of intervention on outcomes, in this study, interventions approaches were used based on sub-groups of CLBP.</p> <p>Methods</p> <p>This was an allocation concealed, blinded, sequential and pragmatic control trial. Three groups of participants were investigated during postural perturbations: 1) CLBP patients with movement impairment (n = 15, MI group) randomized to conventional physiotherapy regime 2) fifteen CLBP patients with control impairment randomized to core stability group (CI group) and 3) fifteen healthy controls (HC).</p> <p>Results</p> <p>The MI group did not show any significant changes in postural control parameters after the intervention period however they improved significantly in disability scores and fear avoidance belief questionnaire work score (P < 0.05). The CI group showed significant improvements in Fx, Fz, and My variables (p < 0.013, p < 0.006, and p < 0.002 respectively with larger effect sizes: Hedges's g > 0.8) after 8 weeks of core stability exercises for the adjusted p values. Postural control parameters of HC group were analyzed independently with pre and post postural control parameters of CI and MI group. This revealed the significant improvements in postural control parameters in CI group compared to MI group indicating the specific adaptation to the core stability exercises in CI group. Though the disability scores were reduced significantly in CI and MI groups (p < 0.001), the post intervention scores between groups were not found significant (p < 0.288). Twenty percentage absolute risk reduction in flare-up rates during intervention was found in CI group (95% CI: 0.69-0.98).</p> <p>Conclusions</p> <p>In this study core stability exercise group demonstrated significant improvements after intervention in ground reaction forces (Fz, Mz; g > 0.8) indicating changes in load transfer patterns during perturbation similar to HC group.</p> <p>Trial registration</p> <p>UTRN095032158-06012009423714</p

The relationship between the systemic inflammatory response, tumour proliferative activity, T-lymphocytic and macrophage infiltration, microvessel density and survival in patients with primary operable breast cancer

The significance of the inter-relationship between tumour and host local/systemic inflammatory responses in primary operable invasive breast cancer is limited. The inter-relationship between the systemic inflammatory response (pre-operative white cell count, C-reactive protein and albumin concentrations), standard clinicopathological factors, tumour T-lymphocytic (CD4+ and CD8+) and macrophage (CD68+) infiltration, proliferative (Ki-67) index and microvessel density (CD34+) was examined using immunohistochemistry and slide-counting techniques, and their prognostic values were examined in 168 patients with potentially curative resection of early-stage invasive breast cancer. Increased tumour grade and proliferative activity were associated with greater tumour T-lymphocyte (P&lt;0.05) and macrophage (P&lt;0.05) infiltration and microvessel density (P&lt;0.01). The median follow-up of survivors was 72 months. During this period, 31 patients died; 18 died of their cancer. On univariate analysis, increased lymph-node involvement (P&lt;0.01), negative hormonal receptor (P&lt;0.10), lower albumin concentrations (P&lt;0.01), increased tumour proliferation (P&lt;0.05), increased tumour microvessel density (P&lt;0.05), the extent of locoregional control (P&lt;0.0001) and limited systemic treatment (Pless than or equal to0.01) were associated with cancer-specific survival. On multivariate analysis of these significant covariates, albumin (HR 4.77, 95% CI 1.35–16.85, P=0.015), locoregional treatment (HR 3.64, 95% CI 1.04–12.72, P=0.043) and systemic treatment (HR 2.29, 95% CI 1.23–4.27, P=0.009) were significant independent predictors of cancer-specific survival. Among tumour-based inflammatory factors, only tumour microvessel density (P&lt;0.05) was independently associated with poorer cancer-specific survival. The host inflammatory responses are closely associated with poor tumour differentiation, proliferation and malignant disease progression in breast cancer

Disease knowledge after an educational program in patients with GERD – a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Patient education has proved beneficial in several but not all chronic disease. Inconsistent findings may rely on varying educational effects of various programs and differential effects on subgroups of patients. Patients' increase in disease knowledge may serve as a feedback to the educator on how well the education program works – but may not be associated to relevant clinical outcomes like quality of life (QoL). This study aimed to investigate the effects of a group based education program for patients with gastroesophageal reflux disease (GERD) on disease knowledge and the association between knowledge and QoL.</p> <p>Methods</p> <p>Patients with GERD were randomly allocated to education (102 patients) or control (109 patients). The education program was designed as a structured dialogue conveying information about pathophysiology, pharmacological and non-pharmacological treatment of GERD, patients' rights and use of healthcare. Outcomes were a 24 item knowledge test on GERD (score 0 – 24) 2 and 12 months after the educational program and disease specific and general QoL (Digestive symptoms and disease impact, DSIQ, and General Health Questionnaire, GHQ).</p> <p>Results</p> <p>Patients allocated to education achieved higher knowledge test scores than controls at 2 months (17.0 vs. 13.1, p < 0.001) and at 12 months (17.1 vs. 14.0, p < 0.001) follow-up. Knowledge test score was positively associated with having completed advanced school and inversely related to psychiatric illness and poor QoL as perceived by the patients at the time of inclusion. Overall, changes in knowledge test score were not associated with change in QoL.</p> <p>Conclusion</p> <p>A group based education program for patients with GERD designed as a structured dialogue increased patients' disease knowledge, which was retained after 1 year. Changes in GERD-knowledge were not associated with change in QoL.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: NCT0061850</p

Dry weather induces outbreaks of human West Nile virus infections

<p>Abstract</p> <p>Background</p> <p>Since its first occurrence in the New York City area during 1999, West Nile virus (WNV) has spread rapidly across North America and has become a major public health concern in North America. By 2002, WNV was reported in 40 states and the District of Columbia with 4,156 human and 14,539 equine cases of infection. Mississippi had the highest human incidence rate of WNV during the 2002 epidemic in the United States. Epidemics of WNV can impose enormous impacts on local economies. Therefore, it is advantageous to predict human WNV risks for cost-effective controls of the disease and optimal allocations of limited resources. Understanding relationships between precipitation and WNV transmission is crucial for predicting the risk of the human WNV disease outbreaks under predicted global climate change scenarios.</p> <p>Methods</p> <p>We analyzed data on the human WNV incidences in the 82 counties of Mississippi in 2002, using standard morbidity ratio (SMR) and Bayesian hierarchical models, to determine relationships between precipitation and human WNV risks. We also entertained spatial autocorrelations of human WNV risks with conditional autocorrelative (CAR) models, implemented in WinBUGS 1.4.3.</p> <p>Results</p> <p>We observed an inverse relationship between county-level human WNV incidence risk and total annual rainfall during the previous year. Parameters representing spatial heterogeneity in the risk of human exposure to WNV improved model fit. Annual precipitation of the previous year was a predictor of spatial variation of WNV risk.</p> <p>Conclusions</p> <p>Our results have broad implications for risk assessment of WNV and forecasting WNV outbreaks. Assessing risk of vector-born infectious diseases will require understanding of complex ecological relationships. Based on the climatologically characteristic drought occurrence in the past and on climate model predictions for climate change and potentially greater drought occurrence in the future, we suggest that the frequency and relative risk of WNV outbreaks could increase.</p

Modification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection

Human CD4+ αβ T cells are activated via T-cell receptor recognition of peptide epitopes presented by major histocompatibility complex (MHC) class II (MHC-II). The open ends of the MHC-II binding groove allow peptide epitopes to extend beyond a central nonamer core region at both the amino- and carboxy-terminus. We have previously found that these non-bound C-terminal residues can alter T cell activation in an MHC allele-transcending fashion, although the mechanism for this effect remained unclear. Here we show that modification of the C-terminal peptide-flanking region of an influenza hemagglutinin (HA305−320) epitope can alter T-cell receptor binding affinity, T-cell activation and repertoire selection of influenza-specific CD4+ T cells expanded from peripheral blood. These data provide the first demonstration that changes in the C-terminus of the peptide-flanking region can substantially alter T-cell receptor binding affinity, and indicate a mechanism through which peptide flanking residues could influence repertoire selection

How about your peers? Cystic fibrosis questionnaire data from healthy children and adolescents

Contains fulltext : 97967.pdf (publisher's version ) (Open Access)BACKGROUND: The Cystic Fibrosis Questionnaire (CFQ) is widely used in research as an instrument to measure quality of life in patients with cystic fibrosis (CF). In routine patient care however, measuring quality of life is still not implemented in guidelines. One of the reasons might be the lack of consensus on how to interpret CFQ scores of an individual patient, because appropriate reference data are lacking. The question which scores reflect normal functioning and which scores reflect clinically relevant problems is still unanswered. Moreover, there is no knowledge about how healthy children and adolescents report on their quality of life (on the CFQ). With regard to quality of life the effect of normal development should be taken into account, especially in childhood and adolescence. Therefore, it is important to gain more knowledge about how healthy children and adolescents report on their quality of life and if there are any difference in a healthy populations based on age or gender. Without these data we cannot adequately interpret the CFQ as a tool in clinical care to provide patient-tailored care. Therefore this study collected data of the CFQ in healthy children and adolescents with the aim to refer health status of CF youngsters to that of healthy peers. METHODS: The CFQ was completed by 478 healthy Dutch children and adolescents (aged 6-20) in a cross-sectional study. RESULTS: The majority of healthy children (over 65%) did not reach maximum scores on most domains of the CFQ. Median CFQ-scores of healthy children and adolescents ranged from 67 to 100 (on a scale of 0-100) on the different CFQ-domains. Significant differences in quality of life exist among healthy children and adolescents, and these depend on age and gender. CONCLUSIONS: Reference data of quality of life scores from a healthy population are essential for adequate interpretation of quality of life in young patients with CF. Clinicians should be aware that the perception of health-related quality of life is not as disease-specific as one might think and also relies on factors such as age, normal maturation and gender

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty