Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC

Patient satisfaction with healthcare provided by family doctors: primary dimensions and an attempt at typology

<p>Abstract</p> <p>Background</p> <p>Patient satisfaction is a complex and difficult concept to measure, thus precluding the use of exclusively quantitative methods for its description. The purpose of this survey was firstly to identify particular healthcare dimensions that determine a patient's satisfaction or dissatisfaction; and secondly to attempt to typologise the patients' responses based on their evaluation of healthcare.</p> <p>Methods</p> <p>Using a qualitative research design, thirty-six in-depth interviews with patients of family physicians were conducted: four patients from each of 9 family practices in different regions of Poland were interviewed. The main outcome measure was factors associated with patient satisfaction/dissatisfaction.</p> <p>Results</p> <p>In their evaluations of their contacts with family doctors, the patients cited mostly issues concerning interpersonal relationships with the doctor. Nearly 40% of the statements referred to this aspect of healthcare, with nearly equal proportions of positive and negative comments. The second most frequent category of responses concerned contextual factors (21%) that related to conditions of medical service, with two-thirds of the evaluations being negative. Statements concerning the doctor's competencies (12.9%) and personal qualities (10.5%) were less common.</p> <p>Conclusion</p> <p>To improve the quality of healthcare, family doctors should take special care to ensure the quality of their interactions with patients.</p

Association between skin diseases and severe bacterial infections in children: case-control study

BACKGROUND: Sepsis or bacteraemia, however rare, is a significant cause of high mortality and serious complications in children. In previous studies skin disease or skin infections were reported as risk factor. We hypothesize that children with sepsis or bacteraemia more often presented with skin diseases to the general practitioner (GP) than other children. If our hypothesis is true the GP could reduce the risk of sepsis or bacteraemia by managing skin diseases appropriately. METHODS: We performed a case-control study using data of children aged 0–17 years of the second Dutch national survey of general practice (2001) and the National Medical Registration of all hospital admissions in the Netherlands. Cases were defined as children who were hospitalized for sepsis or bacteraemia. We selected two control groups by matching each case with six controls. The first control group was randomly selected from the GP patient lists irrespective of hospital admission and GP consultation. The second control group was randomly sampled from those children who were hospitalized for other reasons than sepsis or bacteraemia. We calculated odds ratios and 95% confidence intervals (CI). A two-sided p-value less than 0.05 was considered significant in all tests. RESULTS: We found odds ratios for skin related GP consultations of 3.4 (95% CI: [1.1–10.8], p = 0.03) in cases versus GP controls and 1.4 (95% CI: [0.5–3.9], p = 0.44) in cases versus hospital controls. Children younger than three months had an odds ratio (cases/GP controls) of 9.2 (95% CI: [0.81–106.1], p = 0.07) and 4.0 (95% CI: [0.67–23.9], p = 0.12) among cases versus hospital controls. Although cases consulted the GP more often with skin diseases than their controls, the probability of a GP consultation for skin disease was only 5% among cases. CONCLUSION: There is evidence that children who were admitted due to sepsis or bacteraemia consulted the GP more often for skin diseases than other children, but the differences are not clinically relevant indicating that there is little opportunity for GPs to reduce the risk of sepsis and/or bacteraemia considerably by managing skin diseases appropriately

Heterogeneity of Multifunctional IL-17A Producing S. Typhi-Specific CD8+ T Cells in Volunteers following Ty21a Typhoid Immunization

Salmonella enterica serovar Typhi (S. Typhi), the causative agent of typhoid fever, continues to cause significant morbidity and mortality world-wide. CD8+ T cells are an important component of the cell mediated immune (CMI) response against S. Typhi. Recently, interleukin (IL)-17A has been shown to contribute to mucosal immunity and protection against intracellular pathogens. To investigate multifunctional IL-17A responses against S. Typhi antigens in T memory subsets, we developed multiparametric flow cytometry methods to detect up to 6 cytokines/chemokines (IL-10, IL-17A, IL-2, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1β (MIP-1β)) simultaneously. Five volunteers were immunized with a 4 dose regimen of live-attenuated S. Typhi vaccine (Ty21a), peripheral blood mononuclear cells (PBMC) were isolated before and at 11 time points after immunization, and CMI responses were evaluated. Of the 5 immunized volunteers studied, 3 produced detectable CD8+ T cell responses following stimulation with S. Typhi-infected autologous B lymphoblastoid cell lines (B-LCL). Additionally, 2 volunteers had detectable levels of intracellular cytokines in response to stimulation with S. Typhi-infected HLA-E restricted cells. Although the kinetics of the responses differed among volunteers, all of the responses were bi- or tri-phasic and included multifunctional CD8+ T cells. Virtually all of the IL-17A detected was derived from multifunctional CD8+ T cells. The presence of these multifunctional IL-17A+ CD8+ T cells was confirmed using an unsupervised analysis program, flow cytometry clustering without K (FLOCK). This is the first report of IL-17A production in response to S. Typhi in humans, indicating the presence of a Tc17 response which may be important in protection. The presence of IL-17A in multifunctional cells co-producing Tc1 cytokines (IL-2, IFN-γ and TNF-α) may also indicate that the distinction between Tc17 and Tc1 responses in humans is not as clearly delineated as suggested by in vitro experiments and animal models

The family as a determinant of stunting in children living in conditions of extreme poverty: a case-control study

BACKGROUND: Malnutrition in children can be a consequence of unfavourable socioeconomic conditions. However, some families maintain adequate nutritional status in their children despite living in poverty. The aim of this study was to ascertain whether family-related factors are determinants of stunting in young Mexican children living in extreme poverty, and whether these factors differ between rural or urban contexts. METHODS: A case-control study was conducted in one rural and one urban extreme poverty level areas in Mexico. Cases comprised stunted children aged between 6 and 23 months. Controls were well-nourished children. Independent variables were defined in five dimensions: family characteristics; family income; household allocation of resources and family organisation; social networks; and child health care. Information was collected from 108 cases and 139 controls in the rural area and from 198 cases and 211 controls in the urban area. Statistical analysis was carried out separately for each area; unconditional multiple logistic regression analyses were performed to obtain the best explanatory model for stunting. RESULTS: In the rural area, a greater risk of stunting was associated with father's occupation as farmer and the presence of family networks for child care. The greatest protective effect was found in children cared for exclusively by their mothers. In the urban area, risk factors for stunting were father with unstable job, presence of small social networks, low rate of attendance to the Well Child Program activities, breast-feeding longer than six months, and two variables within the family characteristics dimension (longer duration of parents' union and migration from rural to urban area). CONCLUSIONS: This study suggests the influence of the family on the nutritional status of children under two years of age living in extreme poverty areas. Factors associated with stunting were different in rural and urban communities. Therefore, developing and implementing health programs to tackle malnutrition should take into account such differences that are consequence of the social, economic, and cultural contexts in which the family lives

Prediction of chronic disability in work-related musculoskeletal disorders: a prospective, population-based study

BACKGROUND: Disability associated with work-related musculoskeletal disorders is an increasingly serious societal problem. Although most injured workers return quickly to work, a substantial number do not. The costs of chronic disability to the injured worker, his or her family, employers, and society are enormous. A means of accurate early identification of injured workers at risk for chronic disability could enable these individuals to be targeted for early intervention to promote return to work and normal functioning. The purpose of this study is to develop statistical models that accurately predict chronic work disability from data obtained from administrative databases and worker interviews soon after a work injury. Based on these models, we will develop a brief instrument that could be administered in medical or workers' compensation settings to screen injured workers for chronic disability risk. METHODS: This is a population-based, prospective study. The study population consists of workers who file claims for work-related back injuries or carpal tunnel syndrome (CTS) in Washington State. The Washington State Department of Labor and Industries claims database is reviewed weekly to identify workers with new claims for work-related back injuries and CTS, and these workers are telephoned and invited to participate. Workers who enroll complete a computer-assisted telephone interview at baseline and one year later. The baseline interview assesses sociodemographic, employment-related, biomedical/health care, legal, and psychosocial risk factors. The follow-up interview assesses pain, disability, and work status. The primary outcome is duration of work disability over the year after claim submission, as assessed by administrative data. Secondary outcomes include work disability status at one year, as assessed by both self-report and work disability compensation status (administrative records). A sample size of 1,800 workers with back injuries and 1,200 with CTS will provide adequate statistical power (0.96 for low back and 0.85 for CTS) to predict disability with an alpha of .05 (two-sided) and a hazard ratio of 1.2. Proportional hazards regression models will be constructed to determine the best combination of predictors of work disability duration at one year. Regression models will also be developed for the secondary outcomes

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma

<p>Abstract</p> <p>Background</p> <p>Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene <it>PON1</it>, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous <it>PON1 </it>polymorphisms and the risk of developing astrocytoma and meningioma.</p> <p>Methods</p> <p>Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous <it>PON1 </it>genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain.</p> <p>Results</p> <p>The frequencies of the <it>PON1 </it>genotypes and allelic variants of the polymorphisms <it>PON1 </it>L55M and <it>PON1 </it>Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: <it>PON1 </it>55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; <it>PON1 </it>192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the <it>p </it>values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma.</p> <p>Conclusions</p> <p>Common nonsynonymous <it>PON1 </it>polymorphisms are not related with the risk of developing astrocytoma and meningioma.</p