B cell mediated priming following pneumococcal colonization

The primary reservoir for Streptococcus pneumoniae is the human nasopharynx, and colonization is often the initial step in pathogenesis. Recently we have demonstrated that pneumococcal colonization primes the immune response to subsequent vaccination with the pneumococcal conjugate vaccine (CPV). In this study we wished to determine if colonization stimulates the production of B cell memory that is activated following vaccination with CPV. To test this hypothesis, we colonized mice with S. pneumoniae serotype 14, adoptively transferred their B cells and CD4+ T cells into na?ve recipients, and vaccinated the recipients with CPV. Our results indicate that pneumococcal colonization stimulates the production of memory B cells which are responsible for enhancing the immune response to CPV vaccination.     

The influence of the environment on participation subsequent to rehabilitation as experienced by elderly people in Norway

The aim of this study was to illuminate how the environment may influence participation among elderly people who have undergone community-based rehabilitation in Norway, after an acute illness or accident. Fourteen persons over 65 years of age were selected with the specific intention of gaining a variety of ages, both genders, and people living in different kinds of housing. Three focus groups were established and repeated interviews were held with each group. A constant comparative analysis was used to analyse the data. The main finding was that the participants experienced pressure from their environment to concentrate on performing the most necessary daily activities rather than on participation. Three main encounters with environments seemed to be important for this: encountering people and society, encountering private and formal assistance, and encountering occupation. The support that the participants received from family and friends was more important for their participation than having accessible physical environments. The findings suggest that occupational therapists must consider themselves to be part of a societal environment that can hinder participation.     

Risk factors for Age-related Macular Degeneration in a Greek population: The Thessaloniki Eye Study

Purpose: To assess the association of potential risk factors with early and late age-related macular degeneration (AMD) in the Thessaloniki Eye Study (TES) population

Design: Population-based, cross-sectional study of subjects over age of 60 living in Thessaloniki, Greece

Methods: Subjects without any AMD features and subjects with early and late AMD (neovascular AMD or geographic atrophy) were identified in the TES cohort using standardized procedures and masked grading of stereo color fundus photos. Demographic, lifestyle, systemic and other ophthalmic covariates were also collected during a detailed examination process. Their association with AMD was investigated using univariate and multivariate adjusted logistic regression models.

Results: Among the 2108 participants with gradable photos, the grading process identified 1204 subjects with no AMD, 848 subjects with early AMD, and 56 subjects with late AMD (24 with geographic atrophy and 32 with neovascular AMD). In multivariate analysis, compared to no AMD, late AMD was positively associated with older age (OR:1.16; 95%CI:1.10–1.22 per year of age), current smoking (smoking vs. never smoking, OR:2.34; 95%CI:1.12–4.90), prior cataract surgery (cataract surgery vs. no cataract surgery OR:2.06; 95%CI:0.96–4.40), marital status (divorced/separated vs. married, OR:3.10; 95%CI:1.08–8.93) and with 60% lower odds when sleeping in the afternoon (yes vs. no, OR:0.40; 95%CI:0.22–0.72). Early AMD was positively associated with older age (OR: 1.03; 95%CI:1.01–1.05 per year of age) and negatively with higher pulse pressure (OR:0.99; 95%CI:0.98–0.99 per mmHg).

Conclusions: In TES, apart for well-known risk factors for AMD like age, smoking, and cataract surgery, two novel behavioral risk factors for prevalent late AMD were suggested. Sleeping in the afternoon was associated with 60% decreased odds for late AMD and 67% decreased odds for neovascular AMD. Being divorced/separated compared to married was associated with 3-fold higher odds for late AMD. Large longitudinal population-based studies will be necessary to further establish the potential late AMD risk effects of these two novel factors, to demonstrate potential implications of underlying pathogenetic mechanisms, and to explore preventive measures and therapeutic targets.     

Relevance of mitogen activated protein kinase (MAPK) and phosphotidylinositol-3-kinase/protein kinase B (PI3K/PKB) pathways to induction of apoptosis by curcumin in breast cells

Following observations that curcumin inhibited proliferation (IC(50)=1-5 microM), invasiveness and progression through S/G2/M phases of the cell cycle in the non-tumourigenic HBL100 and tumourigenic MDA-MB-468 human breast cell lines, it was noted that apoptosis was much more pronounced in the tumour line. Therefore, the ability of curcumin to modulate signalling pathways which might contribute to cell survival was investigated. After pre-treatment of cells for 20 min, curcumin (40 microM) inhibited EGF-stimulated phosphorylation of the EGFR in MDA-MB-468 cells and phosphorylation of extracellular signal regulated kinases (ERKs) 1 and 2, as well as ERK activity and levels of nuclear c-fos in both cell lines. At a lower dose (10 microM), it also inhibited the ability of anisomycin to activate JNK, resulting in decreased c-jun phosphorylation, although it did not inhibit JNK activity directly. In contrast, the activation of p38 mitogen activated protein kinase (MAPK) by anisomycin was not inhibited. Curcumin inhibited basal phosphorylation of Akt/protein kinase B (PKB) in both cell lines, but more consistently and to a greater extent in the MDA-MB-468 cells. The MAPK kinase (MKK) inhibitor U0126 (10 microM), while preventing ERK phosphorylation in MDA-MB-468 cells, did not induce apoptosis. The PI3K inhibitor LY294002 (50 microM) inhibited PKB phosphorylation in both cells lines, but only induced apoptosis in the MDA-MB-468 line. These results suggest that while curcumin has several different molecular targets within the MAPK and PI3K/PKB signalling pathways that could contribute to inhibition of proliferation and induction of apoptosis, inhibition of basal activity of Akt/PKB, but not ERK, may facilitate apoptosis in the tumour cell line.     

Heterogeneity of chemosensitivity of esophageal and gastric carcinoma

Esophageal and gastric cancer have a poor prognosis, and chemotherapy is rarely of long-term benefit. This may be related in part to heterogeneity of chemosensitivity and to constitutive resistance to individual cytotoxic drugs. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity between tumors. We have examined the heterogeneity of chemosensitivity in esophageal and gastric cancer specimens (n=85) using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). A variety of chemotherapeutic agents were tested. Sixty-four specimens were endoscopic biopsy samples; the remainder were from resection specimens. Cells were obtained from 62 specimens (73%). Eight assays were infected due to contamination/infection of the biopsy material, giving an evaluability rate of 87%. Analysis of the data showed considerable heterogeneity of chemosensitivity. The most active single agents identified by the assay were mitomycin C (56% sensitivity) and 5-fluorouracil (5-FU; 42% sensitivity). Exposure of tumor cells to combinations of drugs showed ECF (epirubicin, cisplatin, 5-FU) and mitomycin C+5-FU to be moderately active regimens. Other experimental drug combinations showed greater activity. There is a marked heterogeneity of chemosensitivity in esophageal and gastric cancers. The degree of heterogeneity observed suggests that the ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients. This approach provides the rationale for a trial of ATP-TCA-directed therapy to determine whether individualization of chemotherapy might improve patient response and survival.     

Tolerogenic role of Kupffer cells in allergic reactions

Drug-induced allergic reactions (DIARs), including allergic hepatitis, cutaneous reactions, and blood dyscrasias, are unpredictable and can be life threatening. Although current studies suggest that DIARs are caused by immunogenic drug-protein adducts, it remains unclear what factors determine the susceptibility to DIARs. We hypothesized that most individuals may be resistant to DIARs in part because they become immunologically tolerant to drug-protein adducts in the liver, an organ with tolerogenic properties. Because animal models of DIARs are elusive, we tested this hypothesis using a murine model of 2,4-dinitrochlorobenzene (DNCB)-induced delayed type hypersensitivity reaction that is mediated by immunogenic 2,4-dinitrophenylated (DNP)-protein adducts. Intravenous pretreatment of mice with DNP-BSA led to its accumulation in hepatic Kupffer cells (KC) and induced immunological tolerance to subsequent DNCB sensitization. Tolerance could be abrogated by prior depletion of KC or induced in na?ve mice by transferring a T cell-depleted, KC-enriched fraction of liver nonparenchymal cells from mice tolerized 1 month earlier by DNP-BSA pretreatment. These findings implicate KC as a primary and sustained inducer of tolerance against DNP-protein adducts and suggest a similar role in modulating allergic reactions against drug-protein adducts. Perhaps genetic and/or environmental factors affecting the activities of these cells may play a role in determining individual susceptibility to DIARs.     

Social inequalities in health. A partnership of research and education

The Chair on Health Inequality is one of the 12 Chairs created by the CHSRF. Resulting from a partnership between l'Université de Montréal, together with the Direction de la santé publique of the Régie régionale de la santé et des services sociaux Montréal-centre, the Chair will create a research program that will document and assess the role of public health programs based on social development in urban districts, in reducing social health inequality. This research infrastructure will support two training programs: 1) a post-doctoral training program that will introduce newly minted social science PhDs to collaborative research in public health; and 2) a professional doctorate program for public health professionals. The decision-makers and policy-makers targeted by the Chair's knowledge diffusion program are Directors of public health organizations.     

The risk of Ross River and Barmah Forest virus disease in Queensland: implications for New Zealand

OBJECTIVES: To describe the incidence of Ross River (RR) and Barmah Forest (BF) virus disease in Queensland and determine the risk of importation of RR virus from Queensland into New Zealand (NZ) via viraemic travellers. METHODS: Based on routine RR and BF virus notification data of seven major urban tropical and subtropical Queensland populations, incidence rates adjusted for age, sex, season and a baseline level of immunity were used to examine the annual and seasonal risk of disease in the specific populations and selected subgroups. The risk for NZ was determined by estimating the number of infections among major visitor groups travelling from Queensland to NZ, using seroconversion rates. RESULTS: In Queensland, annual rates of RR and BF virus disease ranged between 31.5-288.3 and 3.4-37.4/100,000 person years respectively and increased to between 48.4-423.5 and 3.8-40.4/100,000 person years at risk when adjusted for immunity. Our estimates indicate that more than 100 viraemic travellers may enter NZ from Queensland each year. Estimates were greatest among New Zealanders returning home. CONCLUSIONS AND IMPLICATIONS: Usefulness of notification data could be maximised by presenting more detailed information to the local governments responsible for the control and public health awareness of these pathogens. Given the high number of viraemic persons entering NZ, the abundance of possums and the emergence of Oc. camptorhynchus, transmission of RR virus within NZ is probable. Health authorities should prepare for a virgin soil epidemic of RR virus by initiating serological and clinical surveillance in key areas, enhance public and professional awareness and elevate national resources necessary to invoke emergency vector control and case management.     

Environmental organochlorines and semen quality: results of a pilot study

There have been numerous studies that suggest that sperm concentrations (sperm counts) are declining in men. However, other studies suggest that sperm counts are not declining or may be increasing in some areas. Although there is disagreement on whether there is a downward temporal trend in sperm counts, the studies provide evidence that sperm counts vary by geographic location. It has been hypothesized that the geographic variation in sperm concentrations may be due to environmental exposures, lifestyle factors, or some unknown causes. To determine whether contemporary ambient levels of polychlorinated biphenyls (PCBs) and p,p-DDE are associated with altered semen quantity and quality, we selected a study population without specific exposure to PCBs or p,p-DDE. The present study presents the results from a pilot study on the relationship between serum PCBs and p,p-DDE and semen quality in 29 subjects recruited from the Massachusetts General Hospital Andrology Laboratory. Of the 29 subjects, 3 had sperm concentrations < 20 million/mL, 7 had < 50% motile sperm, 9 had < 4% normal morphology, and 6 were below normal in more than one semen parameter. The 18 subjects with normal spermatozoa concentration, motility, and morphology were used as comparison subjects. The mean (SE) concentration of the sum of PCBs and p,p-DDE was 242 ng/g lipids (34.0) and 354 ng/g lipids (120), respectively, for men with below normal motility as compared to 202 ng/g lipids (16.6) and 240 ng/g lipids (31.1), respectively, for the comparison subjects. The data showed general trends that were suggestive of an association between PCBs and p,p-DDE and abnormal motility, as well as with sperm concentration and morphology. A full-scale study is currently in progress.