Disease-specific extracellular matrix composition regulates placental trophoblast fusion efficiency.

The placental syncytiotrophoblast is a multinucleated layer that regulates transport between the mother and fetus. Fusion of trophoblasts is essential to form this layer, but this process can be disrupted in pregnancy-related disorders such as preeclampsia. Disease progression is also associated with changes in the extracellular matrix (ECM), but whether disease-specific ECM compositions play any causal role in establishing syncytiotrophoblast disease phenotypes remains unknown. Here, we develop a decellularization-based platform to isolate and characterize the role of human placental ECM composition on cell function, while controlling for the confounding effects of matrix structure and mechanics that can arise in conventional tissue decellularization/recellularization experiments. Using this approach, we demonstrate that ECM compositional changes that occur in preeclampsia have a statistically significant effect on adhesion, spreading, and fusion of placental trophoblasts. Proteomic analysis of ECM content then allowed us to identify and recreate selected differences in matrix composition; indicating that replacement of normally present Type IV Collagen by Type I Collagen in preeclampsia significantly affects fusion efficiency. These results indicate that disease-specific matrix compositions can play an important role in trophoblast fusion, suggesting novel matrix-targeting therapeutic strategies for pregnancy-related disorders. More broadly, this work demonstrates the utility of a decellularization-based approach in understanding the functional contributions of matrix composition in driving cellular disease phenotypes.

Contrasting Effects of Adipokines on the Cytokine Production by Primary Human Bronchial Epithelial Cells: Inhibitory Effects of Adiponectin.

BACKGROUND: Obesity is associated with an elevated risk of respiratory infections and inflammatory lung diseases. The objective was to investigate (i) the effects of adipokines (adiponectin (APN), leptin, chemerin, and visfatin) on the production of cytokines by unstimulated and poly(I:C)- and TNF-α-activated human primary bronchial epithelial cells (hBECs), (ii) the cells' expression of the APN receptors (AdipoR1 and AdipoR2), and (iii) the cells' production of APN. METHODS: The hBECs were isolated from patients undergoing surgery for lung carcinoma. The cells were then cultured with human recombinant adipokines in the absence or presence of TNF-α or poly(I:C) for 24 h. Supernatant levels of cytokines (IL-6, CCL2, CCL5, CCL20, CXCL1, CXCL8) and APN were measured using ELISAs. The mRNA levels of AdipoR1 and AdipoR2 in hBECs were determined using a real-time quantitative PCR. RESULTS: Of the four adipokines tested, only APN significantly influenced the basal production and the TNF-α poly(I:C)-induced production of cytokines by hBECs. APN (3-30 µg.ml-1) was associated with greater basal production of IL-6, CCL20, and CXCL8, lower basal production of CCL2 and CXCL1 and no difference in CCL5 production. APN inhibited the poly(I:C)-induced production of these five cytokines and the TNF-α-induced production of CCL2 and CXCL1. AdipoR1 and AdipoR2 were both expressed in hBECs. In contrast to human bronchial explants, isolated hBECs did not produce APN. CONCLUSIONS: The APN concentrations are abnormally low in obese individuals, and this fall may contribute to the susceptibility to viral lung infections and the severity of these infections in obese individuals.

Adherence to colorectal cancer screening guidelines in Canada.

BACKGROUND: To identify correlates of adherence to colorectal cancer (CRC) screening guidelines in average-risk Canadians. METHODS: 2003 Canadian Community Health Survey Cycle 2.1 respondents who were at least 50 years old, without past or present CRC and living in Ontario, Newfoundland, Saskatchewan, and British Columbia were included. Outcomes, defined according to current CRC screening guidelines, included adherence to: i) fecal occult blood test (FOBT) (in prior 2 years), ii) endoscopy (colonoscopy/sigmoidoscopy) (prior 10 years), and iii) adherence to CRC screening guidelines, defined as either (i) or (ii). Generalized estimating equations regression was employed to identify correlates of the study outcomes. RESULTS: Of the 17,498 respondents, 70% were non-adherent CRC screening to guidelines. Specifically, 85% and 79% were non-adherent to FOBT and endoscopy, respectively. Correlates for all outcomes were: having a regular physician (OR = (i) 2.68; (ii) 1.91; (iii) 2.39), getting a flu shot (OR = (i) 1.59; (ii) 1.51; (iii) 1.55), and having a chronic condition (OR = (i) 1.32; (ii) 1.48; (iii) 1.43). Greater physical activity, higher consumption of fruits and vegetables and smoking cessation were each associated with at least 1 outcome. Self-perceived stress was modestly associated with increased odds of adherence to endoscopy and to CRC screening guidelines (OR = (ii) 1.07; (iii) 1.06, respectively). CONCLUSION: Healthy lifestyle behaviors and factors that motivate people to seek health care were associated with adherence, implying that invitations for CRC screening should come from sources that are independent of physicians, such as the government, in order to reduce disparities in CRC screening.

Do physician recommendations for colorectal cancer screening differ by patient age?

Colorectal cancer screening is underutilized, resulting in preventable morbidity and mortality. In the present study, age-related and other disparities associated with physicians' delivery of colorectal cancer screening recommendations were examined. The present cross-sectional study included 43 physicians and 618 of their patients, aged 50 to 80 years, without past or present colorectal cancer. Of the 285 screen-eligible patients, 45% received a recommendation. Multivariate analyses revealed that, compared with younger nondepressed patients, older depressed patients were less likely to receive fecal occult blood test recommendations, compared with no recommendation (OR=0.31, 95% CI 0.09 to 1.02), as well as less likely to receive colonoscopy recommendations, compared with no recommendation (OR=0.14; 95% CI 0.03 to 0.66). Comorbidity and marital status were associated with delivery of fecal occult blood test and colonoscopy recommendations, respectively, compared with no recommendation. In summary, patient age and other characteristics appeared to influence physicians' delivery of colorectal cancer screening and choice of modality.

Exploration of health-related quality of life areas that may distinguish between continent diversion and ileal conduit patients.

OBJECTIVES: We explored the specific impact of urinary diversion type on HRQOL in men after cystectomy for bladder cancer. Our intent was to provide a basis for the development of a diversion-specific instrument. METHODS: We invited 13 ileal conduit and 12 orthotopic urinary diversion (neo-bladder) male patients to several open-ended interviews. We explored HRQOL domains that may have been affected by cystectomy and urinary diversion, and that could then be used to form a basis for a diversion-specific HRQOL measure. RESULTS: The average age of neo-bladder patients was 59 versus 65 years for ileal conduit patients. We identified 10 HRQOL domains, ranging from involuntary urine leakage to dietary modifications, which were recognized as important by ileal conduit and neobladder patients. Within each domain, a sufficient amount of overlap existed to allow developing a measure that might be applied to both groups of patients. CONCLUSIONS: Ten HRQOL domains were identified as important by ileal conduit and neobladder patients. These demonstrated a significant amount of overlap between conduit and neobladder patients. Potentially, these domains could be used to develop scales for distinguishing between conduit and neobladder-specific HRQOL detriments.