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

Development of a scale to measure stigma related to podoconiosis in Southern Ethiopia

Background: Health-related stigma adds to the physical and economic burdens experienced by people suffering from neglected tropical diseases (NTDs). Previous research into the NTD podoconiosis showed significant stigma towards those with the disease, yet no formal instrument exists by which to assess stigma or interventions to reduce stigma. We aimed to develop, pilot and validate scales to measure the extent of stigma towards podoconiosis among patients and in podoconiosis-endemic communities. Methods: Indicators of stigma were drawn from existing qualitative podoconiosis research and a literature review on measuring leprosy stigma. These were then formulated into items for questioning and evaluated through a Delphi process in which irrelevant items were discounted. The final items formed four scales measuring two distinct forms of stigma (felt stigma and enacted stigma) for those with podoconiosis and those without the disease. The scales were formatted as two questionnaires, one for podoconiosis patients and one for unaffected community members. 150 podoconiosis patients and 500 unaffected community members from Wolaita zone, Southern Ethiopia were selected through multistage random sampling to complete the questionnaires which were interview-administered. The scales were evaluated through reliability assessment, content and construct validity analysis of the items, factor analysis and internal consistency analysis. Results: All scales had Cronbach’s alpha over 0.7, indicating good consistency. The content and construct validity of the scales were satisfactory with modest correlation between items. There was significant correlation between the felt and enacted stigma scales among patients (Spearman’s r = 0.892; p < 0.001) and within the community (Spearman’s r = 0.794; p < 0.001). Conclusion: We report the development and testing of the first standardised measures of podoconiosis stigma. Although further research is needed to validate the scales in other contexts, we anticipate they will be useful in situational analysis and in designing, monitoring and evaluating interventions. The scales will enable an evidencebased approach to mitigating stigma which will enable implementation of more effective disease control and help break the cycle of poverty and NTDs

The impact of different DNA extraction kits and laboratories upon the assessment of human gut microbiota composition by 16S rRNA gene sequencing

Peer reviewedPublisher PD

Treatment adherence with the easypod™ growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents

<p>Abstract</p> <p>Background</p> <p>Accurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypod™, automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device.</p> <p>Methods</p> <p>A multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing ≤2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naïve and treatment-experienced children.</p> <p>Results</p> <p>Of 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment-naïve (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; <it>p </it>= 0.0062]. According to self-reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed ≥1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device.</p> <p>Conclusions</p> <p>easypod™ provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypod™, short-term adherence is good, and significantly higher in treatment-naïve children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey.</p

Reliability and Validity of the Ethiopian Version of the Hospital Anxiety and Depression Scale (HADS) in HIV Infected Patients

The hospital anxiety and depression scale (HADS) is a widely used instrument for evaluating psychological distress from anxiety and depression. HADS has not yet been validated in Ethiopia. The aim of this study was to evaluate the reliability and validity of the Amharic (Ethiopian language) version of HADs among HIV infected patients.The translated scale was administered to 302 HIV/AIDS patients on follow up for and taking anti-retroviral treatment. Consistency assessment was conducted using Cronbach's alpha, test-retest reliability using intra-class correlation coefficients (ICC). Construct validity was examined using principal components analysis (PCA). Parallel analysis, Kaiser's criterion and the scree test were used for factor extraction.The internal consistency was 0.78 for the anxiety, 0.76 for depression subscales and 0.87 for the full scale of HADS. The intra-class correlation coefficient (ICC) was 80%, 86%, and 84% for the anxiety and depression subscales, and total score respectively. PCA revealed a one dimensional scale.This preliminary validation study of the Ethiopian version of the HADs indicates that it has promising acceptability, reliability and validity. The adopted scale has a single underlying dimension as indicated by Razavi's model. The HADS can be used to examine psychological distress in HIV infected patients. Findings are discussed and recommendations made

Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma

Background: Preclinical studies suggest that chemotherapy may enhance the immune response against pancreatic cancer. Methods: The levels of granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) and the associated inflammatory marker C-reactive protein (CRP) were assessed in 38 patients receiving gemcitabine and capecitabine combination chemotherapy for advanced pancreatic cancer within the TeloVac trial. Apoptosis (M30) and total immune response (delayed-type hypersensitivity and/or T-cell response) were also assessed and levels of apoptosis induction correlated with immune response. The telomerase GV1001 vaccine was given either sequentially (n=18) or concomitantly (n=24) with the combination chemotherapy. Results: There were no differences between baseline and post-treatment levels of CRP (P=0.19), IL-6 (P=0.19) and GM-CSF (P=0.71). There was a positive correlation between post-chemotherapy CRP and IL-6 levels (r=0.45, P=0.005) and between CRP with carbohydrate antigen-19-9 (CA19-9) levels at baseline (r=0.45, P=0.015) and post treatment (r=0.40, P=0.015). The change in CRP and IL-6 levels was positively correlated (r=0.40, P=0.012). Hazard ratios (95% CI) for baseline CA19-9 (1.30 (1.07–1.59), P=0.009) and CRP (1.55 (1.00–2.39), P=0.049) levels were each independently predictive of survival. The M30 mean matched differences between pre- and post-chemotherapy showed evidence of apoptosis in both the sequential (P=0.058) and concurrent (P=0.0018) chemoimmunotherapy arms. Respectively, 5 of 10 and 9 of 20 patients had a positive immune response but there was no association with apoptosis. Conclusions: Combination gemcitabine and capecitabine chemotherapy did not affect circulating levels of GM-CSF, IL-6 and CRP. Chemotherapy-induced apoptosis was not associated with the immunogenicity induced by the GV1001 vaccine in advanced pancreatic cancer

Diagnostic accuracy of plasma NT-proBNP levels for excluding cardiac abnormalities in the very elderly

<p>Abstract</p> <p>Background</p> <p>In the elderly the diagnosis of chronic heart failure is often challenging and the availability of echocardiography can be limited. Plasma levels of NT-proBNP are valuable tools to diagnose patients with heart failure. However, the performance of this biomarker to detect cardiac abnormalities in the very elderly remains unclear. The aims of this study were to investigate the relation between NT-proBNP and cardiac abnormalities and to evaluate the use of NT-proBNP to exclude structural and functional cardiac abnormalities in a community-based sample of "well-functioning" nonagenarians.</p> <p>Methods</p> <p>A diagnostic cross-sectional study embedded within the Leiden 85-plus Study in the municipality of Leiden, the Netherlands. Plasma NT-proBNP levels were measured and 2-dimensional echocardiography was performed in a subgroup of 80 well-functioning nonagenarians. Linear regression analysis was used to explore the relation between NT-proBNP and cardiac abnormalities and ROC curve analysis was used to assess the performance of NT-proBNP to exclude cardiac abnormalities. The upper limit of the lowest tertile of NT-proBNP was used as a cut-off value.</p> <p>Results</p> <p>NT-proBNP levels were associated with abnormal left ventricular (LV) dimensions, LV systolic and diastolic function, left atrial enlargement and valvular heart disease. LV mass, E/A ratio and degree of aortic regurgitation were identified as independent predictors of NT-proBNP. NT-proBNP levels were higher with greater number of echocardiographic abnormalities (P < 0.001). A cut-off level of 269.5 pg/mL identified patients with abnormal LV dimensions or depressed LV systolic function (sensitivity 85%, negative predictive value (NPV) 77%, area under the curve 0.75 (95% CI 0.64-0.85)). In addition, high NPV were found for LV systolic dysfunction, left atrial enlargement, severe valvular heart disease and pulmonary hypertension. The test performance of NT-proBNP to exclude any echocardiographic abnormality showed a sensitivity of 82% and a NPV of 65%.</p> <p>Conclusions</p> <p>In this convenience sample of well-functioning nonagenarians NT-proBNP was related to a wide variety of functional and structural echocardiographic abnormalities. Moreover, NT-proBNP could be used to exclude echocardiographic abnormalities in well-functioning nonagenarians and might be used to indicate who needs to be referred for further cardiovascular examination.</p

The development and psychometric properties of a measure of clinicians’ attitudes to depression: the revised Depression Attitude Questionnaire (R-DAQ)

Background: Depression is a common mental disorder associated with substantial disability. It is inadequately recognised and managed, and clinicians’ attitudes to this condition and its treatment may play a part in this. Most research in this area has used the Depression Attitude Questionnaire (DAQ), but analyses have shown this measure to exhibit problems in psychometric properties and suitability for the health professionals and settings where depression recognition may occur. Methods: We revised the DAQ using a pooled review of findings from studies using this measure, together with a Delphi study which sought the opinions of a panel of relevant experts based in the UK, USA, Australia, and European countries (n = 24) using 3 rounds of questioning to consider attitude dimensions, content, and item wording. After item generation, revision and consensus (agreement >70%) using the Delphi panel, the revised DAQ (R-DAQ) was tested with 1193 health care providers to determine its psychometric properties. Finally the test-retest reliability of the R-DAQ was examined with 38 participants. Results: The 22-item R-DAQ scale showed good internal consistency: Cronbach’s alpha coefficient was 0.84; and satisfactory test-retest reliability: intraclass correlation coefficient was 0.62 (95% C.I. 0.37 to 0.78). Exploratory factor analysis favoured a three-factor structure (professional confidence, therapeutic optimism/pessimism, and a generalist perspective), which accounted for 45.3% of the variance. Conclusions: The R-DAQ provides a revised tool for examining clinicians’ views and understanding of depression. It addresses important weaknesses in the original measure whilst retaining items and dimensions that appeared valid. This revised scale is likely to be useful in examining attitudes across the health professional workforce and beyond the confines of the UK, and may be valuable for the purpose of evaluating training that aims to address clinicians’ attitudes to depression. It incorporates key dimensions of attitudes with a modest number of items making it applicable to use in busy clinical settings

Prognostic impact of peritumoral lymphocyte infiltration in soft tissue sarcomas

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to clarify the prognostic significance of peritumoral lymphocyte infiltration in the capsule of soft tissue sarcomas (STS). Multiple observations in preclinical and clinical studies have shown that the immune system has a role in controlling tumor growth and progression. Prognostic markers in potentially curable STS should guide therapy after surgical resection. The immune status at the time of resection may be important, but the prognostic significance of peritumoral lymphocytes is unknown.</p> <p>Methods</p> <p>Tissue microarrays from 80 patients with STS were constructed from duplicate cores of tissue from the tumor and the peritumoral capsule. Immunohistochemistry was used to evaluate the CD3+, CD4+, CD8+ and CD20+ lymphocytes in the tumor and the peritumoral capsule.</p> <p>Results</p> <p>In univariate analyses, increasing numbers of CD20+ (<it>P </it>= 0.032) peritumoral lymphocytes were associated with a reduced disease free survival (DSS). In multivariate analyses, a high number of CD20+ peritumoral lymphocytes (<it>P </it>= 0.030) in the capsule was an independent negative prognostic factor for DSS. There were no such associations of lymphocyte infiltration in the tumor.</p> <p>Conclusions</p> <p>A high density of CD20+ peritumoral lymphocytes is an independent negative prognostic indicator for patients with STS. Further research is needed to determine whether CD20 cells in the peritumoral capsule of STS may promote tumor invasion in the surrounding tissue and increase the metastatic potential.</p