Cytoadherence and virulence - the case of Plasmodium knowlesi malaria.

BACKGROUND: Cytoadherence of infected red blood cells to brain endothelium is causally implicated in malarial coma, one of the severe manifestations of falciparum malaria. Cytoadherence is mediated by specific binding of variant parasite antigens, expressed on the surface of infected erythrocytes, to endothelial receptors including, ICAM-1, VCAM and CD36. In fatal cases of severe falciparum malaria with coma, blood vessels in the brain are characteristically congested with infected erythrocytes. Brain sections from a fatal case of knowlesi malaria, but without coma, were similarly congested with infected erythrocytes. The objective of this study was to determine the binding phenotype of Plasmodium knowlesi infected human erythrocytes to recombinant human ICAM-1, VCAM and CD36. METHODS: Five patients with PCR-confirmed P. knowlesi malaria were recruited into the study with consent between April and August 2010. Pre-treatment venous blood was washed and cultured ex vivo to increase the proportion of schizont-infected erythrocytes. Cultured blood was seeded into Petri dishes with triplicate areas coated with ICAM-1, VCAM and CD36. Following incubation at 37°C for one hour the dishes were washed and the number of infected erythrocytes bound/mm2 to PBS control areas and to recombinant human ICAM-1 VCAM and CD36 coated areas were recorded. Each assay was performed in duplicate. Assay performance was monitored with the Plasmodium falciparum clone HB3. RESULTS: Blood samples were cultured ex vivo for up to 14.5 h (mean 11.3 ± 1.9 h) to increase the relative proportion of mature trophozoite and schizont-infected red blood cells to at least 50% (mean 65.8 ± 17.51%). Three (60%) isolates bound significantly to ICAM-1 and VCAM, one (20%) isolate bound to VCAM and none of the five bound significantly to CD36. CONCLUSIONS: Plasmodium knowlesi infected erythrocytes from human subjects bind in a specific but variable manner to the inducible endothelial receptors ICAM-1 and VCAM. Binding to the constitutively-expressed endothelial receptor CD36 was not detected. Further work will be required to define the pathological consequences of these interactions

Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women

<p>Abstract</p> <p>Background</p> <p>Considerably little is known about the biological role and clinical significance of androgen receptor expression in breast cancer. The objectives of this study were to characterize <it>AR</it>-CAG repeat genotypes in a cohort of women with breast cancer and to determine the influence of AR on response to neoadjuvant chemotherapy and clinical outcome.</p> <p>Materials and methods</p> <p>Genotyping of the <it>AR </it>CAG repeat region was done on 70 patients and 80 healthy aged- matched female controls. To assess response to NACT, tissue samples from 30 LABC cases were evaluated quantitatively by real time for AR mRNA expression. The clinical response was correlated with both the pre and post chemotherapy AR expression. The CAG alleles did not show differences between cases and controls when the mean of short, long and average length of both CAG alleles was considered. However, analysis when done defining short allele as CAGn < 20 (AR1) and the long as CAGn ≥ 20 (AR2), risk was found associated with AR2 allele with marginal significance (P = 0.09). Stratification by age of onset, FH, stage, grade ER and AR status failed to reveal any association with breast cancer risk. Genotype carriers with ≥20 CAGn showed decrease of AR mRNA expression although significance could not be established (P = 0.47). Tumours in responders had the higher AR mRNA expression levels in pre neo-adjuvant chemotherapy condition (p < 0.02) which got reduced after neoadjuvant chemotherapy and the difference was found to be significant (P = 0.014).</p> <p>Conclusions</p> <p>Although, expansion of the CAGn in the <it>AR </it>gene doesn't show any major effect on breast cancer risk, patients with positive AR expression, pre neoadjuvant chemotherapy, were found to be good responders and a decrease in mRNA level of <it>AR </it>gene related to the chemotherapy-induced apoptosis could serve as an important independent predictor of response to NACT.</p

Degree bounded matroids and submodular flows

We consider two related problems, the Minimum Bounded Degree Matroid Basis problem and the Minimum Bounded Degree Submodular Flow problem. The first problem is a generalization of the Minimum Bounded Degree Spanning Tree problem: We are given a matroid and a hypergraph on its ground set with lower and upper bounds f(e)≤g(e) for each hyperedge e. The task is to find a minimum cost basis which contains at least f(e) and at most g(e) elements from each hyperedge e. In the second problem we have a submodular flow problem, a lower bound f(v) and an upper bound g(v) for each node v, and the task is to find a minimum cost 0-1 submodular flow with the additional constraint that the sum of the incoming and outgoing flow at each node v is between f(v) and g(v). Both of these problems are NP-hard (even the feasibility problems are NP-complete), but we show that they can be approximated in the following sense. Let opt be the value of the optimal solution. For the first problem we give an algorithm that finds a basis B of cost no more than opt such that f(e)-2Δ+1≤|B∩e|≤g(e)+2Δ-1 for every hyperedge e, where Δ is the maximum degree of the hypergraph. If there are only upper bounds (or only lower bounds), then the violation can be decreased to Δ-1. For the second problem we can find a 0-1 submodular flow of cost at most opt where the sum of the incoming and outgoing flow at each node v is between f(v)-1 and g(v)+1. These results can be applied to obtain approximation algorithms for several combinatorial optimization problems with degree constraints, including the Minimum Crossing Spanning Tree problem, the Minimum Bounded Degree Spanning Tree Union problem, the Minimum Bounded Degree Directed Cut Cover problem, and the Minimum Bounded Degree Graph Orientation problem. © 2012 János Bolyai Mathematical Society and Springer-Verlag Berlin Heidelberg

A protocol for co-creating research project lay summaries with stakeholders:Guideline development for Canada's AGE-WELL Network

Background Funding bodies increasingly require researchers to write lay summaries to communicate projects’ real-world relevance to the public in an accessible way. However, research proposals and findings are generally not easily readable or understandable by non-specialist readers. Many researchers find writing lay summaries difficult because they typically write for fellow subject specialists or academics rather than the general public or a non-specialist audience. The primary objective of our project is to develop guidelines for researchers in Canada’s AGE-WELL Network of Centres of Excellence, and ultimately various other disciplines, sectors, and institutions, to co-create lay summaries of research projects with stakeholders. To begin, we produced a protocol for co-creating a lay summary based on workshops we organized and facilitated for an AGE-WELL researcher. This paper presents the lay summary co-creation protocol that AGE-WELL researchers will be invited to use. Methods Eligible participants in this project will be 24 AgeTech project researchers who are funded by the AGE-WELL network in its Core Research Program 2020. If they agree to participate in this project, we will invite them to use our protocol to co-produce a lay summary of their respective projects with stakeholders. The protocol comprises six steps: Investigate principles of writing a good lay summary, identify the target readership, identify stakeholders to collaborate with, recruit the identified stakeholders to work on a lay summary, prepare for workshop sessions, and execute the sessions. To help participants through the process, we will provide them with a guide to developing an accessible, readable research lay summary, help them make decisions, and host, and facilitate if needed, their lay summary co-creation workshops. Discussion Public-facing research outputs, including lay summaries, are increasingly important knowledge translation strategies to promote the impact of research on real-world issues. To produce lay summaries that include information that will interest a non-specialist readership and that are written in accessible language, stakeholder engagement is key. Furthermore, both researchers and stakeholders benefit by participating in the co-creation process. We hope the protocol helps researchers collaborate with stakeholders effectively to co-produce lay summaries that meet the needs of both the public and project funders

Ear, nose and throat injuries at Bugando Medical Centre in northwestern Tanzania: a five-year prospective review of 456 cases.

Injuries to the ear, nose and throat (ENT) regions are not uncommon in clinical practice and constitute a significant cause of morbidity and mortality in our setting. There is dearth of literature on this subject in our environment. This study was conducted to describe the causes, injury pattern and outcome of these injuries in our setting and proffer possible preventive measures. This was a descriptive prospective study of patients with ear, nose and throat injuries managed at Bugando Medical Centre between May 2007 and April 2012. Ethical approval to conduct the study was sought from relevant authorities. Statistical data analysis was performed using SPSS computer software version 17.0. A total of 456 patients were studied. The median age of patients at presentation was 18 years (range 1 to 72 years). The male to female ratio was 2:1. The commonest cause of injury was foreign bodies (61.8%) followed by road traffic accidents (22.4%). The ear was the most common body region injured accounting for 59.0% of cases. The majority of patients (324, 71.1%) were treated as an outpatient and only 132(28.9%) patients required admission to the ENT wards after definitive treatment. Foreign body removal and surgical wound debridement were the most common treatment modalities performed in 61.9% and 16.2% of cases respectively. Complication rate was 14.9%. Suppurative otitis media (30.9%) was the commonest complication in the ear while traumatic epistaxis (26.5%) and hoarseness of voice (11.8%) in the aero-digestive tract were commonest in the nose and throat. The overall median length of hospital stay for in-patients was 8 days (range 1 to 22 days). Patients who developed complications and those who had associated injuries stayed longer in the hospital (P < 0.001).Mortality rate related to isolated ENT injuries was 1.3% (6 deaths). The majority of patients (96.9%) were treated successfully and only 3.1% of cases were discharged with permanent disabilities. Injuries to the ENT regions are not uncommon in our environment and foreign bodies constitute a significant cause of injury. Majority of these injuries can be prevented through public enlightenment campaigns

Direct intra-tumoral injection of zinc-acetate halts tumor growth in a xenograft model of prostate cancer

Intracellular levels of zinc have shown a strong inverse correlation to growth and malignancy of prostate cancer. To date, studies of zinc supplementation in prostate cancer have been equivocal and have not accounted for bioavailability of zinc. Therefore, we hypothesized that direct intra-tumoral injection of zinc could impact prostate cancer growth. In this study, we evaluated the cytotoxic properties of the pH neutral salt zinc acetate on the prostate cancer cell lines PC3, DU145 and LNCaP. Zinc acetate killed prostate cancer cell lines in vitro, independent of androgen sensitivity, in a dose-dependent manner in a range between 200 and 600 μM. Cell death occurred rapidly with 50% cell death by six hours and maximal cell death by 18 hours. We next established a xenograft model of prostate cancer and tested an experimental treatment protocol of direct intra-tumoral injection of zinc acetate. We found that zinc treatments halted the growth of the prostate cancer tumors and substantially extended the survival of the animals, whilst causing no detectable cytoxicity to other tissues. Thus, our studies form a solid proof-of-concept that direct intra-tumoral injection of zinc acetate could be a safe and effective treatment strategy for prostate cancer

Psychological impact of visible differences in patients with congenital craniofacial anomalies

© 2015, Singh and Moss; licensee Springer. Background: Patients with craniofacial anomalies often have appearance concerns and related social anxiety which can affect their quality of life. This study assessed the psychological impact of facial and dental appearance in patients with craniofacial anomalies in comparison to a general population control group. Methods: The study involved 102 adult patients (51% male) with congenital craniofacial anomalies and 102 controls (49% male). Both groups completed the Nepali version of Derriford Appearance Scale (DAS) and the Psychological Impact of Dental Aesthetic Questionnaire (PIDAQ) in a clinical setting to assess appearance-related distress, avoidance, and anxiety. Results: There was a significant difference between patients and controls on both PIDAQ (mean score for patients 33.25 ± 9.45 while for controls 27.52 ± 5.67, p < 0.001) and DAS59 scores (mean score for patients 159.16 ± 31.54 while for controls 77.64 ± 6.57, p < 0.001), indicating that patients experienced greater negative psychological impact of living with their appearance (PIDAQ) and more appearance-related distress (DAS) than controls. DAS scores were not associated with gender. There was no association of the place of residence (rural vs. urban) with PIDAQ or DAS59 scores. Conclusions: There is a significant psychological impact of altered facial and dental appearance in patients with craniofacial anomalies compared to controls. There was no effect of locality (rural/urban) on the psychological impact of facial and dental appearance in patients

Comparison of cardiovascular health profiles across population surveys from five high- to low-income countries

Aims With the greatest burden of cardiovascular disease morbidity and mortality increasingly observed in lower-income countries least prepared for this epidemic, focus is widening from risk factor management alone to primordial prevention to maintain high levels of cardiovascular health (CVH) across the life course. To facilitate this, the American Heart Association (AHA) developed CVH scoring guidelines to evaluate and track CVH. We aimed to compare the prevalence and trajectories of high CVH across the life course using nationally representative adult CVH data from five diverse high- to low-income countries. Methods Surveys with CVH variables (physical activity, cigarette smoking, body mass, blood pressure, blood glucose, and total cholesterol levels) were identified in Ethiopia, Bangladesh, Brazil, England, and the United States (US). Participants were included if they were 18-69y, not pregnant, and had data for these CVH metrics. Comparable data were harmonized and each of the CVH metrics was scored using AHA guidelines as high (2), moderate (1), or low (0) to create total CVH scores with higher scores representing better CVH. High CVH prevalence by age was compared creating country CVH trajectories. Results The analysis included 28,092 adults (Ethiopia n=7686, 55.2% male; Bangladesh n=6731, 48.4% male; Brazil n=7241, 47.9 % male; England n=2691, 49.5% male, and the US n=3743, 50.3% male). As country income level increased, prevalence of high CVH decreased (>90% in Ethiopia, >68% in Bangladesh and under 65% in the remaining countries). This pattern remained using either five or all six CVH metrics and following exclusion of underweight participants. While a decline in CVH with age was observed for all countries, higher income countries showed lower prevalence of high CVH already by age 18y. Excess body weight appeared the main driver of poor CVH in higher income countries, while current smoking was highest in Bangladesh. Conclusion Harmonization of nationally representative survey data on CVH trajectories with age in 5 highly diverse countries supports our hypothesis that CVH decline with age may be universal. Interventions to promote and preserve high CVH throughout the life course are needed in all populations, tailored to country-specific time courses of the decline. In countries where CVH remains relatively high, protection of whole societies from risk factor epidemics may still be feasible.This study was funded with support from the Institute for Global Health, Northwestern University [Catalyzer Award No. 1005]; from the DSI-NRF Centre of Excellence in Human Development hosted at the University of the Witwatersrand in South Africa, and the support of the University of the Witwatersrand research office

Self-rated health in middle-aged and elderly Chinese : distribution, determinants and associations with cardio-metabolic risk factors

Background: Self-rated health (SRH) has been demonstrated to be an accurate reflection of a person's health and a valid predictor of incident mortality and chronic morbidity. We aimed to evaluate the distribution and factors associated with SRH and its association with biomarkers of cardio-metabolic diseases among middle-aged and elderly Chinese. Methods: Survey of 1,458 men and 1,831 women aged 50 to 70 years, conducted in one urban and two rural areas of Beijing and Shanghai in 2005. SRH status was measured and categorized as good (very good and good) vs. not good (fair, poor and very poor). Determinants of SRH and associations with biomarkers of cardio-metabolic diseases were evaluated using logistic regression. Results: Thirty two percent of participants reported good SRH. Males and rural residents tended to report good SRH. After adjusting for potential confounders, residence, physical activity, employment status, sleep quality and presence of diabetes, cardiovascular disease, and depression were the main determinants of SRH. Those free from cardiovascular disease (OR 3.68; 95%CI 2.39; 5.66), rural residents (OR 1.89; 95% CI 1.47; 2.43), non-depressed participants (OR 2.50; 95% CI 1.67; 3.73) and those with good sleep quality (OR 2.95; 95% CI 2.22; 3.91) had almost twice or over the chance of reporting good SRH compared to their counterparts. There were significant associations -and trend- between SRH and levels of inflammatory markers, insulin levels and insulin resistance. Conclusion: Only one third of middle-aged and elderly Chinese assessed their health status as good or very good. Although further longitudinal studies are required to confirm our findings, interventions targeting social inequalities, lifestyle patterns might not only contribute to prevent chronic morbidity but as well to improve populations' perceived health