Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells.

The HOX genes encode a family of transcription factors that are dysregulated in several malignancies and have been implicated in oncogenesis and cancer cell survival. Disruption of HOX protein function using the peptide HXR9 has shown anti-tumor effects against melanoma, lung cancer and renal cancer. In this report, we evaluated the expression of all 39 HOX genes in a panel of six malignant B-cell lines, including multiple myeloma cells and found different levels of expression of HOX family members suggesting that they also have a role in malignant B-cell survival. We show that disrupting HOX function using the peptide HXR9 induces significant cytotoxicity in the entire panel of cell lines. Importantly, we found that the cytotoxic effects of HXR9 can be enhanced by combining it with ch128.1Av, an antibody-avidin fusion protein specific for the human transferrin receptor 1 (CD71). Iron starvation induced by the fusion protein contributes to the enhanced effect and involves, at least in part, the induction of a caspase-independent pathway. These results show the relevance of HOX proteins in malignant B-cell survival and suggest that our therapeutic strategy may be effective in the treatment of incurable B-cell malignancies such as multiple myeloma

Can "presumed consent" justify the duty to treat infectious diseases? An analysis

<p>Abstract</p> <p>Background</p> <p>AIDS, SARS, and the recent epidemics of the avian-flu have all served to remind us the debate over the limits of the moral duty to care. It is important to first consider the question of whether or not the "duty to treat" might be subject to contextual constraints. The purpose of this study was to investigate the opinions and beliefs held by both physicians and dentists regarding the occupational risks of infectious diseases, and to analyze the argument that the notion of "presumed consent" on the part of professionals may be grounds for supporting the duty to treat.</p> <p>Methods</p> <p>For this cross-sectional survey, the study population was selected from among physicians and dentists in Ankara. All of the 373 participants were given a self-administered questionnaire.</p> <p>Results</p> <p>In total, 79.6% of the participants said that they either had some degree of knowledge about the risks when they chose their profession or that they learned of the risks later during their education and training. Of the participants, 5.2% said that they would not have chosen this profession if they had been informed of the risks. It was found that 57% of the participants believed that there is a standard level of risk, and 52% of the participants stated that certain diseases would exceed the level of acceptable risk unless specific protective measures were implemented.</p> <p>Conclusion</p> <p>If we use the presumed consent argument to establish the duty of the HCW to provide care, we are confronted with problems ranging over the difficulty of choosing a profession autonomously, the constant level of uncertainty present in the medical profession, the near-impossibility of being able to evaluate retrospectively whether every individual was informed, and the seemingly inescapable problem that this practice would legitimize, and perhaps even foster, discrimination against patients with certain diseases. Our findings suggest that another problem can be added to the list: one-fifth of the participants in this study either lacked adequate knowledge of the occupational risks when they chose the medical profession or were not sufficiently informed of these risks during their faculty education and training. Furthermore, in terms of the moral duty to provide care, it seems that most HCWs are more concerned about the availability of protective measures than about whether they had been informed of a particular risk beforehand. For all these reasons, the presumed consent argument is not persuasive enough, and cannot be used to justify the duty to provide care. It is therefore more useful to emphasize justifications other than presumed consent when defining the duty of HCWs to provide care, such as the social contract between society and the medical profession and the fact that HCWs have a greater ability to provide medical aid.</p

Regression of target organ damage in children and adolescents with primary hypertension

We assessed the effects of 12 months of non-pharmacological and pharmacological therapy on 24-h ambulatory blood pressure, regression of target organ damage (TOD) and metabolic abnormalities in 86 children (14.1 ± 2.4 years) with primary hypertension. Twenty-four hour systolic and diastolic blood pressure (BP) decreased (130 ± 8 vs 126 ± 8, 73 ± 7 vs 70 ± 7, p = 0.0001 and 0.004 respectively). Body mass index (BMI) did not change, but waist-to-hip (0.85 ± 0.07 vs 0.83 ± 0.05, p = 0.01) and waist-to-height ratio (WHtR; 0.49 ± 0.07 vs 0.48 ± 0.05, p = 0.008) decreased. Left ventricular mass index (LVMi; 38.5 ± 10.7 vs 35.2 ± 7.5 g/m2.7, p = 0.0001), prevalence of left ventricular hypertrophy (46.5% vs 31.4%; p = 0.0001), carotid intima-media thickness (cIMT; 0.44 ± 0.05 vs 0.42 ± 0.04 mm, p = 0.0001), wall cross sectional area (WCSA; 7.5 ± 1.3 vs 6.9 ± 1.2 mm2, p = 0.002), hsCRP (1.1 ± 1.0 vs 0.7 ± 0.7 mg/l, p = 0.002), and LDL-cholesterol (115 ± 33 vs 107 ± 26 mg/dl, p = 0.001) decreased. Patients who had lowered BP had a lower cIMT at the second examination (0.41 ± 0.04 vs 0.43 ± 0.04 mm, p = 0.04) and lower initial hsCRP values (0.9 ± 0.7 vs 1.5 ± 1.3 mg/l, p = 0.04) in comparison to non-responders. Regression analysis revealed that the main predictor of LVMi decrease was a decrease in abdominal fat expressed as a decrease in waist circumference (WC) (R2 = 0.280, β = 0.558, p = 0.005), for WCSA-SDS a decrease in WC (R2 = 0.332, β = 0.611, p = 0.009) and for a cIMT-SDS decrease the main predictor was a decrease in hsCRP concentrations (R2 = 0.137, β = 0.412, p = 0.03). Standard antihypertensive treatment lowered BP and led to regression of TOD in hypertensive children. Lean body mass increase and decrease in abdominal obesity correlated with TOD regression

Geographical ecology of dry forest tree communities in the West Indies

© 2018 The Authors. Journal of Biogeography Published by John Wiley & Sons Ltd Aim: Seasonally dry tropical forest (SDTF) of the Caribbean Islands (primarily West Indies) is floristically distinct from Neotropical SDTF in Central and South America. We evaluate whether tree species composition was associated with climatic gradients or geographical distance. Turnover (dissimilarity) in species composition of different islands or among more distant sites would suggest communities structured by speciation and dispersal limitations. A nested pattern would be consistent with a steep resource gradient. Correlation of species composition with climatic variation would suggest communities structured by broad-scale environmental filtering. Location: The West Indies (The Bahamas, Cuba, Hispaniola, Jamaica, Puerto Rico, US Virgin Islands, Guadeloupe, Martinique, St. Lucia), Providencia (Colombia), south Florida (USA) and Florida Keys (USA). Taxon: Seed plants—woody taxa (primarily trees). Methods: We compiled 572 plots from 23 surveys conducted between 1969 and 2016. Hierarchical clustering of species in plots, and indicator species analysis for the resulting groups of sites, identified geographical patterns of turnover in species composition. Nonparametric analysis of variance, applied to principal components of bioclimatic variables, determined the degree of covariation in climate with location. Nestedness versus turnover in species composition was evaluated using beta diversity partitioning. Generalized dissimilarity modelling partitioned the effect of climate versus geographical distance on species composition. Results: Despite a set of commonly occurring species, SDTF tree community composition was distinct among islands and was characterized by spatial turnover on climatic gradients that covaried with geographical gradients. Greater Antillean islands were characterized by endemic indicator species. Northern subtropical areas supported distinct, rather than nested, SDTF communities in spite of low levels of endemism. Main conclusions: The SDTF species composition was correlated with climatic variation. SDTF on large Greater Antillean islands (Hispaniola, Jamaica and Cuba) was characterized by endemic species, consistent with their geological history and the biogeography of plant lineages. These results suggest that both environmental filtering and speciation shape Caribbean SDTF tree communities

Tactile thermal oral stimulation increases the cortical representation of swallowing

<p>Abstract</p> <p>Background</p> <p>Dysphagia is a leading complication in stroke patients causing aspiration pneumonia, malnutrition and increased mortality. Current strategies of swallowing therapy involve on the one hand modification of eating behaviour or swallowing technique and on the other hand facilitation of swallowing with the use of pharyngeal sensory stimulation. Thermal tactile oral stimulation (TTOS) is an established method to treat patients with neurogenic dysphagia especially if caused by sensory deficits. Little is known about the possible mechanisms by which this interventional therapy may work. We employed whole-head MEG to study changes in cortical activation during self-paced volitional swallowing in fifteen healthy subjects with and without TTOS. Data were analyzed by means of synthetic aperture magnetometry (SAM) and the group analysis of individual SAM data was performed using a permutation test.</p> <p>Results</p> <p>Compared to the normal swallowing task a significantly increased bilateral cortical activation was seen after oropharyngeal stimulation. Analysis of the chronological changes during swallowing suggests facilitation of both the oral and the pharyngeal phase of deglutition.</p> <p>Conclusion</p> <p>In the present study functional cortical changes elicited by oral sensory stimulation could be demonstrated. We suggest that these results reflect short-term cortical plasticity of sensory swallowing areas. These findings facilitate our understanding of the role of cortical reorganization in dysphagia treatment and recovery.</p

Acid Stability of the Hemagglutinin Protein Regulates H5N1 Influenza Virus Pathogenicity

Highly pathogenic avian influenza viruses of the H5N1 subtype continue to threaten agriculture and human health. Here, we use biochemistry and x-ray crystallography to reveal how amino-acid variations in the hemagglutinin (HA) protein contribute to the pathogenicity of H5N1 influenza virus in chickens. HA proteins from highly pathogenic (HP) A/chicken/Hong Kong/YU562/2001 and moderately pathogenic (MP) A/goose/Hong Kong/437-10/1999 isolates of H5N1 were found to be expressed and cleaved in similar amounts, and both proteins had similar receptor-binding properties. However, amino-acid variations at positions 104 and 115 in the vestigial esterase sub-domain of the HA1 receptor-binding domain (RBD) were found to modulate the pH of HA activation such that the HP and MP HA proteins are activated for membrane fusion at pH 5.7 and 5.3, respectively. In general, an increase in H5N1 pathogenicity in chickens was found to correlate with an increase in the pH of HA activation for mutant and chimeric HA proteins in the observed range of pH 5.2 to 6.0. We determined a crystal structure of the MP HA protein at 2.50 Å resolution and two structures of HP HA at 2.95 and 3.10 Å resolution. Residues 104 and 115 that modulate the acid stability of the HA protein are situated at the N- and C-termini of the 110-helix in the vestigial esterase sub-domain, which interacts with the B loop of the HA2 stalk domain. Interactions between the 110-helix and the stalk domain appear to be important in regulating HA protein acid stability, which in turn modulates influenza virus replication and pathogenesis. Overall, an optimal activation pH of the HA protein is found to be necessary for high pathogenicity by H5N1 influenza virus in avian species

Adoption of an innovation to repair aortic aneurysms at a Canadian hospital: a qualitative case study and evaluation

<p>Abstract</p> <p>Background</p> <p>Priority setting in health care is a challenge because demand for services exceeds available resources. The increasing demand for less invasive surgical procedures by patients, health care institutions and industry, places added pressure on surgeons to acquire the appropriate skills to adopt innovative procedures. Such innovations are often initiated and introduced by surgeons in the hospital setting. Decision-making processes for the adoption of surgical innovations in hospitals have not been well studied and a standard process for their introduction does not exist. The purpose of this study is to describe and evaluate the decision-making process for the adoption of a new technology for repair of abdominal aortic aneurysms (endovascular aneurysm repair [EVAR]) in an academic health sciences centre to better understand how decisions are made for the introduction of surgical innovations at the hospital level.</p> <p>Methods</p> <p>A qualitative case study of the decision to adopt EVAR was conducted using a modified thematic analysis of documents and semi-structured interviews. Accountability for Reasonableness was used as a conceptual framework for fairness in priority setting processes in health care organizations.</p> <p>Results</p> <p>There were two key decisions regarding EVAR: the decision to adopt the new technology in the hospital and the decision to stop hospital funding. The decision to adopt EVAR was based on perceived improved patient outcomes, safety, and the surgeons' desire to innovate. This decision involved very few stakeholders. The decision to stop funding of EVAR involved all key players and was based on criteria apparent to all those involved, including cost, evidence and hospital priorities. Limited internal communications were made prior to adopting the technology. There was no formal means to appeal the decisions made.</p> <p>Conclusion</p> <p>The analysis yielded recommendations for improving future decisions about the adoption of surgical innovations. ese empirical findings will be used with other case studies to help develop guidelines to help decision-makers adopt surgical innovations in Canadian hospitals.</p

A systematic review of frameworks for the interrelationships of mental health evidence and policy in low- and middle-income countries

Background: The interrelationships between research evidence and policy-making are complex. Different theoretical frameworks exist to explain general evidence–policy interactions. One largely unexplored element of these interrelationships is how evidence interrelates with, and influences, policy/political agenda-setting. This review aims to identify the elements and processes of theories, frameworks and models on interrelationships of research evidence and health policy-making, with a focus on actionability and agenda-setting in the context of mental health in low- and middle-income countries (LMICs). Methods: A systematic review of theories was conducted based on the BeHeMOTh search method, using a tested and refined search strategy. Nine electronic databases and other relevant sources were searched for peer-reviewed and grey literature. Two reviewers screened the abstracts, reviewed full-text articles, extracted data and performed quality assessments. Analysis was based on a thematic analysis. The included papers had to present an actionable theoretical framework/model on evidence and policy interrelationships, such as knowledge translation or evidence-based policy, specifically target the agenda-setting process, focus on mental health, be from LMICs and published in English. Results: From 236 publications included in the full text analysis, no studies fully complied with our inclusion criteria. Widening the focus by leaving out ‘agenda-setting’, we included ten studies, four of which had unique conceptual frameworks focusing on mental health and LMICs but not agenda-setting. The four analysed frameworks confirmed research gaps from LMICs and mental health, and a lack of focus on agenda-setting. Frameworks and models from other health and policy areas provide interesting conceptual approaches and lessons with regards to agenda-setting. Conclusion: Our systematic review identified frameworks on evidence and policy interrelations that differ in their elements and processes. No framework fulfilled all inclusion criteria. Four actionable frameworks are applicable to mental health and LMICs, but none specifically target agenda-setting. We have identified agenda-setting as a research theory gap in the context of mental health knowledge translation in LMICs. Frameworks from other health/policy areas could offer lessons on agenda-setting and new approaches for creating policy impact for mental health and to tackle the translational gap in LMICs

A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy

Prostate cancer (PCa) is the second leading cause of cancer deaths in men in the United States. The prostate-specific antigen (PSA), often found at high levels in the serum of PCa patients, has been used as a marker for PCa detection and as a target of immunotherapy. The murine IgG1 monoclonal antibody AR47.47, specific for human PSA, has been shown to enhance antigen presentation by human dendritic cells and induce both CD4 andCD8 T-cell activation when complexed with PSA. In this study, we explored the properties of a novel mouse/human chimeric anti-PSA IgE containing the variable regions of AR47.47 as a potential therapy for PCa. Our goal was to take advantage of the unique properties of IgE in order to trigger immune activation against PCa.Fil: Daniels-Wells, Tracy R. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Helguera, Gustavo Fernando. Universidad de Buenos Aires. Facultad de Farmacia y Bioquimica. Departamento de Tecnologia Farmaceutica; Argentina; University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Leuchter, Richard K. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Quintero, Rafael. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Kozman, Maggie. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Rodríguez, José A.. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América;Fil: Ortiz-Sánchez, E. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; Biomedical Research in Cancer. Basic Research Division. National Institute of Cancerology; Mexico.;Fil: Martínez-Maza, Otonel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América;Fil: Schultes, Brigit C.. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Nicodemus Christopher. Advanced Immune Therapeutics; Estados Unidos de América;Fil: Penichet, Manuel. University of California. David Geffen School of Medicine. Department of Surgery. Division of Surgical Oncology; Estados Unidos de América; University of California. The Molecular Biology Institute; Estados Unidos de América

A qualitative study into the perceived barriers of accessing healthcare among a vulnerable population involved with a community centre in Romania

(1) Interview guide for family members, and (2) Interview guide for staff members. (DOCX 103 kb