Erythropoietin promotes endothelial progenitor cell proliferative and adhesive properties in a PI 3-kinase-dependent manner

OBJECTIVES: Patients with congestive heart failure (CHF) suffer considerable morbidity and mortality despite advances in therapy. Treatment with erythropoietin (Epo) has shown promise in CHF patients, yet its mechanisms of action remain elusive. Endothelial progenitor cells (EPC) contribute to postnatal angiogenesis and vasculogenesis, and Epo was shown to promote EPC mobilization. We explored the effect of chronic treatment with Epo on the numbers and functional properties of EPC in CHF patients. METHODS AND RESULTS: Twenty-eight patients with CHF treated with Epo for a mean period of 28 months were compared to a matched group (n = 28) with regard to the number of circulating hematopoietic and endothelial stem cells (either CD34+, CD34+/CD45+, CD34+/CD133+, CD34+/VEGF-R2+ or CD34+/CD133+/VEGF-R2+) as well as their proliferative and adhesive capacity. In vitro, Epo was added to cultured EPC from healthy subjects to test proliferation and adhesion. No differences were observed in circulating numbers of hematopoietic and endothelial stem cells between CHF patients chronically treated with Epo or untreated. EPC from Epo-treated patients exhibited enhanced proliferation as well as a trend towards adhesion to cultured endothelial cells prior to and following stimulation with TNF-alpha. Addition of Epo to EPC from healthy subjects dose-dependently increased their proliferation and adhesion to fibronectin, cultured endothelial cells, and cardiomyocytes. These effects were significantly reduced in the presence of phosphatidylinositol (PI) 3-kinase inhibitors. CONCLUSIONS: Chronic Epo treatment is associated with an increase in the adhesive and proliferative properties of circulating EPC in patients with CHF.     

Identification of patients with chronic obstructive pulmonary disease (COPD) by measurement of plasma biomarkers

Introduction: Inflammation is an important constituent of the pathology of chronic obstructive pulmonary disease (COPD), leading to alveolar destruction and airway remodelling. Objective: The aim of this study was to assess the difference in plasma biomarkers of inflammation between asymptomatic smokers and patients with COPD. Methods: We used commercially available enzyme‐linked immunosorbent assay kits to measure the plasma levels of tumour necrosis factor‐α (TNF‐α), interleukin‐8 (IL‐8), matrix metalloproteinase‐9 (MMP‐9), monocyte chemotactic protein‐1 (MCP‐1), tissue inhibitor of metalloproteinase‐1 (TIMP‐1) and tissue inhibitor of metalloproteinase‐2 (TIMP‐2) on two occasions with a 2‐week interval in patients with COPD (n = 20), asymptomatic smokers (n = 10) and healthy lifelong non‐smokers (n = 10). The participants were characterised clinically, physiologically and by quantitative computed tomography by measuring the relative area of emphysema below ?910 Hounsfield units (RA‐910). Results: The results of the biomarker measurements on the two occasions were highly reproducible. Patients with COPD had significantly higher plasma levels of IL‐8 (P = 0.004) and significantly lower levels of TIMP‐1 (P = 0.02) than smokers and non‐smokers. There was no statistically significant difference between the three groups in the level of TNF‐α, MMP‐9, MCP‐1 and TIMP‐2. The IL‐8/TIMP‐1 ratio correlated significantly with the degree of airway obstruction measured as forced expiratory volume in 1 second (FEV₁) % predicted (r = ?0.47, P < 0.01); with the diffusion capacity (r = ?0.41, P < 0.01); and with the grade of emphysema measured as RA‐910 (r = 0.39, P = 0.01). Conclusion: These findings suggest that the measurement of plasma biomarkers, such as IL‐8/TIMP‐1, may aid to discriminate patients with COPD from smokers at lower risk of developing COPD. Please cite this paper as: Shaker SB, von Wachenfeldt KA, Larsson S, Mile I, Persdotter S, Dahlbäck M, Broberg P, Stoel B, Bach KS, Hestad M, Fehniger TE and Dirksen A. Identification of patients with chronic obstructive pulmonary disease (COPD) by measurement of plasma biomarkers. The Clinical Respiratory Journal 2008; 2: 17–25.     

Can Lactobacillus acidophilus improve minimal hepatic encephalopathy? A neurometabolite study using magnetic resonance spectroscopy

Background and study aimsMinimal hepatic encephalopathy (MHE) is diagnosed when hepatic patients perform worse on psychometric tests compared to healthy controls. This study aimed to evaluate probiotics as alternative therapy in MHE.Patients and methodsThis is an open-label randomised controlled trial, performed in the Department of Tropical Medicine and Infectious Diseases, Tanta University Hospitals, from March 2010 to January 2012. A total of 90 patients with MHE were allocated by simple randomisation to three parallel equal groups. Group A received lactulose, group B a probiotic (Lactobacillus acidophilus) and group C served as the control. After informed consent, patients were tested for gut micrecology, fasting blood ammonia, liver functions and magnetic resonance spectroscopy (MRS) examination to study brain metabolites, mainly choline (Cho), myo-inositol (mI), glutamine + glutamate (Glx) and creatinin (Cre). Patients who developed overt encephalopathy were excluded from analysis. The whole battery of investigations was repeated in the same order after 4 weeks.ResultsThe probiotic was better tolerated than lactulose. The relative risk reduction (RRR) of developing overt encephalopathy was 60% in the case of lactulose and 80% in the case of probiotic, with a number needed to treat (NNT) of 2.4 and 2.3, respectively. The differential but not total microecology count was significantly shifted towards saccharolytic rather than proteolytic bacteria. The mI/Cre and (Cho + mI)/Glx ratios were significantly increased and the Glx/Cre ratio was significantly reduced after 1 month-follow-up in the probiotic group compared to the lactulose group and in both treatment groups compared to the control group.ConclusionBoth probiotic and lactulose therapy can improve blood ammonia and psychometric tests in MHE and reduce the risk of developing overt encephalopathy. MRS showed more improvement in the levels of brain neurometabolites in the probiotic group.     

Breaking down the barriers: a qualitative study to understand child oral health in refugee and migrant communities in Australia

Objective. Australia is an increasingly multicultural nation. Never before has the dental workforce been exposed to such language, cultural, religious and ethnic diversity. There is evidence that refugee and migrant children experience significantly poorer oral health than the nonmigrant population. However, little is known about the oral health knowledge, practices and beliefs of parents with young children from refugee and migrant backgrounds. The aim of this study was to identify the sociocultural influences on child oral health in these communities.

Design. Participatory and qualitative research methods were utilised. Partnerships were established with community agencies representing migrants from Iraq, Lebanon and Pakistan. Focus group discussions and semi-structured interviews were conducted with community members. Qualitative data were analysed thematically, combining focus group and interview data.

Results. Over 100 women participated in focus groups (n = 11) and semi-structured interviews (n = 7). Key findings included the knowledge, beliefs and practices concerning: caries risk factors, oral health practices and oral health literacy. Despite mothers' knowledge of the major causes of poor oral health – dietary changes, confusion about child oral hygiene practices and limited oral health literacy all influenced child oral health outcomes.

Conclusion. This culturally competent qualitative study explores the sociocultural factors influencing child oral health in refugee and migrant communities. Understanding and acknowledging these factors are a prerequisite to determining where and how to intervene to improve oral health. Furthermore, it has implications for both dental and non-dental health professionals working to reduce health inequalities within such communities.     

A swift all-atom energy-based computational protocol to predict DNA-ligand binding affinity and DeltaTm

A hybrid molecular mechanics-statistical mechanics-solvent accessibility-based computational protocol is developed to calculate DNA-ligand binding affinity without any database training and is validated on 50 DNA-ligand complexes. The calculated binding energies yield high correlation coefficients of 0.95 (R2 = 0.90) and 0.96 (R2 = 0.93) in linear plots against experimental binding free energies (DeltaGo) and DeltaTm, respectively. The protocol is translated into a swift, web-enabled, freely accessible computational tool, http://www.scfbio-iitd.res.in/preddicta, for DeltaGo and DeltaTm prediction for DNA-ligand complexes to aid and expedite rational drug design attempts.     

Acceptability and feasibility of infant-feeding options: experiences of HIV-infected mothers in the World Health Organization Kesho Bora mother-to-child transmission prevention (PMTCT) trial in Burkina Faso

In Burkina Faso, prolonged breastfeeding with introduction of ritual fluids from birth is a deep-seated norm. We explored HIV-infected mothers' views and experiences of the acceptability and feasibility of the World Health Organization's recommended infant-feeding options within a mother-to-child-transmission prevention trial. A qualitative study was conducted on 17 formula-feeding and 19 breastfeeding mothers, from a larger cohort of 51 eligible HIV-infected women, consenting to participate in separate focus group discussions in early post-partum. Mothers opted for breastfeeding essentially out of fear of family rejection. Most of them were afraid of denigration for disrespecting tradition if they formula-fed or being suspected of HIV infection. Achieving exclusive breastfeeding remained a difficult challenge as they engaged in a continuous struggle with close elders to avoid fluid feeding. Additional stress and fatigue were fed by their perception of a high transmission risk through breast milk. Exclusive formula-feeding seemed easier to implement, especially as formula was provided free of charge. Formula-feeding mothers more frequently had a supportive partner, a strong personality and lived in better socio-economic conditions than breastfeeding mothers (76% had education and electricity supply vs. 42%, respectively). Exclusive breastfeeding for the first 6 months remains the most appropriate option for many HIV-infected mothers in sub-Saharan Africa. Its acceptability and feasibility urgently need to be improved by promoting it as the best feeding option for all infants. Other crucial interventions are the promotion of voluntary counselling and testing for couples, and greater partner involvement in infant-feeding counselling.     

Cardiovascular, neuroendocrine, and sedative responses to four graded doses of clonidine in a placebo-controlled study.

Effects of four doses of the alpha 2-receptor agonist clonidine (CLO) (0.25, 0.5, 1, and 2 micrograms/kg IV) and placebo were studied in seven healthy men who volunteered in a double-blind randomized design in order to delineate possible presynaptic and postsynaptic components in the mechanism of action of CLO. Blood pressure, heart rate, plasma noradrenaline (NOR), plasma 3-methoxy-4-hydroxyphenylglycol (MHPG), plasma growth hormone (GH), and subjective sedation were monitored for a period of 1 hr following infusion of CLO. NOR and MHPG were also analyzed in urine, collected at 1 and 4 hr after the infusions. Dose-dependent decrements were observed in systolic and diastolic blood pressure and plasma NOR levels, and dose-dependent increases in subjective sedation and plasma GH. CLO did not influence plasma MHPG levels, whereas only urinary MHPG excretion was reduced 4 hr after infusion of 2 micrograms/kg CLO. Because no obvious differences between dose-response relations of plasma NOR (believed to be a presynaptic and peripheral effect), blood pressure (believed to be mainly a central presynaptic and postsynaptic effect), and subjective sedation (believed to be a central and probably postsynaptic effect) were observed, our results do not provide simple parameters to discern the multiple mechanisms of action of CLO. However, at a dose of 0.5 micrograms/kg CLO (a dose lower than that generally used) clear effects on plasma NOR, blood pressure, and sedation, but not on plasma GH (a central postsynaptic effect) or urinary MHPG (a presynaptic effect), were observed. When using CLO as a challenge test in psychiatric disorders, a design with 0.5 micrograms/kg CLO, in addition to the traditional 2 micrograms/kg CLO, may provide more information to characterize discrete abnormalities in the noradrenergic system at the level of the brainstem, the pituitary, or the peripheral sympathetic nervous system.     

Embolization Therapy for Traumatic Splenic Lacerations

Purpose

This study was designed to evaluate the clinical success, complications, and transfusion requirements based on the location of and agents used for splenic artery embolization in patients with splenic trauma.

Methods

A retrospective study was performed of patients with splenic trauma who underwent angiography and embolization from September 2000 to January 2010 at a level I trauma center. Electronic medical records were reviewed for demographics, imaging data, technical aspects of the procedure, and clinical outcomes.

Results

Fifty patients were identified (34 men and 16 women), with an average age of 48 (range, 16–80) years. Extravasation was seen on initial angiography in 27 (54%) and was absent in 23 (46%). All 27 patients with extravasation were embolized, and 18 of 23 (78.2%) without extravasation were embolized empirically. Primary clinical success was similar (>75%) across all embolization locations, embolic agents, and grades of laceration treated. Of 45 patients treated, 9 patients (20%) were embolized in the main splenic artery, 34 (75.6%) in the splenic hilum, and 2 (4.4%) were embolized in both locations. Partial splenic infarctions developed in 47.3% treated in the splenic hilum compared with 12.5% treated in the main splenic artery. There were four (8.9%) mortalities: two occurred in patients with multiple critical injuries and two from nonbleeding etiologies.

Conclusions

Embolization of traumatic splenic artery injuries is safe and effective, regardless of the location of treatment. Embolization in splenic hilar branches may have a higher incidence of infarction. The grade of laceration and agents used for embolotherapy did not impact the outcomes.     

Progression parameters for emphysema: a clinical investigation

In patients with airflow limitation caused by cigarette smoking, lung density measured by computed tomography is strongly correlated with quantitative pathology scores of emphysema, but the ability of lung densitometry to detect progression of emphysema is disputed. We assessed the sensitivity of lung densitometry as a parameter of disease progression of emphysema in comparison to FEV(1) and gas transfer. At study baseline and after 30 months we measured computed tomography (CT)-derived lung density, spirometry and carbon monoxide diffusion coefficient in 144 patients with chronic obstructive pulmonary disease (COPD) in five different centers. Annual change in lung density was 1.31 g/L/year (CI 95%: -2.12 to -0.50 HU, p=0.0015, 39.5 mL/year (CI 95%: -100.0-21.0 mL, p=0.2) for FEV(1) (-39.5 mL) and 24.3 micromol/min/kPa/L/year for gas transfer (CI 95%: -61.0-12.5 micromol/min/kPa/L/year, p=0.2). Signal-to-noise ratio (mean change divided by standard error of the change) for the detection of annual change was 3.2 for lung densitometry, but 1.3 for both FEV(1) and gas diffusion. We conclude that detection of progression of emphysema was found to be 2.5-fold more sensitive using lung densitometry than by using currently recommended lung function parameters. Our results support CT scan as an efficacious test for novel drugs for emphysema.