On the role of specific drug binding in modelling arterial eluting stents

In this paper we consider drug binding in the arterial wall following delivery by a drug-eluting stent. Whilst it is now generally accepted that a non-linear saturable reversible binding model is required to properly describe the binding process, the precise form of the binding model varies between authors. Our particular interest in this manuscript is in assessing to what extent modelling specific and non-specific binding in the arterial wall as separate phases is important. We study this issue by extending a recently developed coupled model of drug release and arterial tissue distribution, and comparing simulated profiles of drug concentration and drug mass in each phase within the arterial tissue

Impaired mitochondrial biogenesis is a common feature to myocardial hypertrophy and end-stage ischemic heart failure

Mitochondrial (mt) DNA depletion and oxidative mtDNA damage have been implicated in the process of pathological cardiac remodeling. Whether these features are present in the early phase of maladaptive cardiac remodeling, that is, during compensated cardiac hypertrophy, is still unknown. We compared the morphologic and molecular features of mt biogenesis and markers of oxidative stress in human heart from adult subjects with compensated hypertrophic cardiomyopathy and heart failure. We have shown that mtDNA depletion is a constant feature of both conditions. A quantitative loss of mtDNA content was associated with significant down-regulation of selected modulators of mt biogenesis and decreased expression of proteins involved in mtDNA maintenance. Interestingly, mtDNA depletion characterized also the end-stage phase of cardiomyopathies due to a primary mtDNA defect. Oxidative stress damage was detected only in failing myocardium

Which factors predict candidate outcome in advanced life support courses? A preliminary observational study

PURPOSE: To identify factors associated with candidate outcome in the European Resuscitation Council (ERC) advanced life support (ALS) provider courses. METHODS: Medical doctors participating as candidates to consecutive ALS courses organised by an ERC training centre in Italy were enrolled in this prospective cohort study. The association between the ALS course outcome and candidate demographics, professional background and pre-course knowledge measured by using the pre-course multiple choice quiz (MCQ) was investigated by using logistic regression. RESULTS: A total of 283 candidates, median age 31 years, were evaluated. Among them, 269 (95.1%) passed the final evaluation and 14 (4.9%) failed. Candidates who passed were younger (median age 31 vs. 37.5 years; p = 0.006) and attained a higher pre-course MCQ score (median 84 vs. 72.5%; p < 0.0001). On multivariate analysis, a higher pre-course MCQ score (OR 1.18 [95%CI 1.09-1.28]) and a basic life support (BLS) certification (OR 5.00 [95%CI 1.12-22.42]) were independent predictors of candidate success, while older age was associated with a significantly higher risk of failing (OR 0.90 [95%CI 0.83-0.97]). Female candidates had higher pass rates (97.2 vs. 91.2%; p = 0.048); however, after correction for confounders gender was not significantly associated with candidate outcome. Neither candidate specialty nor site of work was a predictor of candidate success. CONCLUSIONS: On ALS courses, younger age and a higher level of specific pre-course knowledge, as measured by both the pre-course MCQ and the presence of BLS certification, are the most important predictors of success. Candidate gender and professional background did not show a significant correlation with course outcom

Role of chronic exsposure to cigarette smoke on endoglin/CD105 expression in airway epithelium.

Dysregulation of airway epithelial cell function related to cigarette smoke exposure plays an important role in the pathophysiology of COPD and is associated to tissue damage and disease severity. CD105 is a component of the receptor complex of TGF-β, a pleiotropic cytokine involved in cellular proliferation, differentiation and migration. CD105 regulates the expression of different components of the extracellular matrix suggesting a role of CD105 in cellular transmigration and remodeling processes. The aim of the present study was to investigate the expression of endoglin/CD105 in airway epithelium of COPD patients and its involvement in tissue remodeling and progression of COPD. We evaluated the immunoreactivity for CD105 expression in bronchial biopsies isolated from COPD patients and healthy controls (HC). The analysis of metaplastic epithelium was performed in bronchial biopsies by Image Analysis software (Leica Quantimet system). Finally, we investigated the expression of CD105 protein receptor in human bronchial epithelial cells (16HBE cells) exposed to 5% Cigarette Smoke Extract (CSE) for 12 days by western blot. We found that the CD105 immunoreactivity was significantly higher in bronchial epithelium of COPD than HC. Morphometric analysis of bioptic samples of COPD showed an increase of the immunoreactivity for CD105 in the area of metaplastic than in not metaplastic epithelium. Long term exposure to CSE significantly up-regulated CD105 expression in 16HBE. Chronic inflammation due to cigarette smoke might play a critic role on the alteration of CD105 protein expression in COPD, promoting tissue remodeling, angiogenesis and dysregulation of physiological reparative mechanisms, leading to squamous metaplasia

The management of cancer in the elderly: targeted therapies in oncology

Cancer is universally considered a disease of ageing. Today the management of elderly cancer patients poses many specific problems and it should be revisited in the light of the most recent advances in both diagnosis and treatment of human malignancies. In particular, the potential use of novel therapeutic options, based on therapeutic agents raised against molecular targets (the so called targeted therapy), appears to be promising in this clinical settings especially in view of the limited side-effects. The mainstays of cancer treatment during the twentieth century were surgery, radiation and chemotherapy. However, surgery is not curative in metastatic disease, radiation and chemotherapy are limited by side effects because they can't discriminate between healthy and cancerous cells. When key molecular changes responsible for malignant transformation were identified (e.g. growth factors and their receptors), it was hoped that new targeted agents, by inhibiting cancer-specific pathways, would spare normal cells and thereby offer improved safety benefits and a higher therapeutic index over standard chemotherapeutics. The most common targeted therapies used in clinical practice, i.e. monoclonal antibodies and small molecules, are described

How to Obtain NNT from Cohen's d: Comparison of Two Methods

Background: In the literature we find many indices of size of treatment effect (effect size: ES). The preferred index of treatment effect in evidence-based medicine is the number needed to treat (NNT), while the most common one in the medical literature is Cohen’s d when the outcome is continuous. There is confusion about how to convert Cohen’s d into NNT. Methods: We conducted meta-analyses of individual patient data from 10 randomized controlled trials of second generation antipsychotics for schizophrenia (n = 4278) to produce Cohen’s d and NNTs for various definitions of response, using cutoffs of 10 % through 90 % reduction on the symptom severity scale. These actual NNTs were compared with NNTs calculated from Cohen’s d according to two proposed methods in the literature (Kraemer, et al., Biological Psychiatry, 2006; Furukawa, Lancet, 1999). Results: NNTs from Kraemer’s method overlapped with the actual NNTs in 56%, while those based on Furukawa’s method fell within the observed ranges of NNTs in 97 % of the examined instances. For various definitions of response corresponding with 10 % through 70 % symptom reduction where we observed a non-small number of responders, the degree of agreement for the former method was at a chance level (ANOVA ICC of 0.12, p = 0.22) but that for the latter method was ANOVA ICC of 0.86 (95%CI: 0.55 to 0.95, p,0.01)

Alcohol Consumption, Genetic Variants in Alcohol Deydrogenases, and Risk of Cardiovascular Diseases: A Prospective Study and Meta-Analysis

OBJECTIVE: First, to investigate and compare associations between alcohol consumption and variants in alcohol dehydrogenase (ADH) genes with incidence of cardiovascular diseases (CVD) in a large German cohort. Second, to quantitatively summarize available evidence of prospective studies on polymorphisms in ADH1B and ADH1C and CVD-risk. METHODS: We conducted a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort including a randomly drawn subcohort (n = 2175) and incident cases of myocardial infarction (MI; n = 230) or stroke (n = 208). Mean follow-up time was 8.2±2.2 years. The association between alcohol consumption, ADH1B or ADH1C genotypes, and CVD-risk was assessed using Cox proportional hazards regression. Additionally, we report results on associations of variants in ADH1B and ADH1C with ischemic heart disease and stroke in the context of a meta-analysis of previously published prospective studies published up to November 2011. RESULTS: Compared to individuals who drank >0 to 6 g alcohol/d, we observed a reduced risk of MI among females consuming >12 g alcohol/d (HR = 0.31; 95% CI: 0.10-0.97) and among males consuming >24 to 60 g/d (HR = 0.57; 95% CI: 0.33-0.98) or >60 g alcohol/d (HR = 0.30; 95% CI: 0.12-0.78). Stroke risk was not significantly related to alcohol consumption >6 g/d, but we observed an increased risk of stroke in men reporting no alcohol consumption. Individuals with the slow-coding ADH1B*1/1 genotype reported higher median alcohol consumption. Yet, polymorphisms in ADH1B or ADH1C were not significantly associated with risk of CVD in our data and after pooling results of eligible prospective studies [ADH1B*1/1: RR = 1.35 (95% CI: 0.98-1.88; p for heterogeneity: 0.364); ADH1C*2/2: RR = 1.07 (95% CI: 0.90-1.27; p for heterogeneity: 0.098)]. CONCLUSION: The well described association between alcohol consumption and CVD-risk is not reflected by ADH polymorphisms, which modify the rate of ethanol oxidation

Drivers and barriers to acceptance of human-papillomavirus vaccination among young women: a qualitative and quantitative study

<p>Abstract</p> <p>Background</p> <p>Human papillomavirus (HPV) is a necessary cause of cervical dysplasia and cancer, and of genital warts. Few studies have examined attitudes to HPV vaccination since the introduction of HPV vaccines. We aimed to investigate the reasons for young women's acceptance or rejection of the quadrivalent HPV vaccine after its general availability in Denmark.</p> <p>Method</p> <p>A literature review assessed attitudes towards HPV vaccination and the information was used to identify relevant questions for telephone and focus group interviews with women aged 16-26 who had decided to receive or reject HPV vaccination. 435 women across Denmark were interviewed by telephone. Qualitative interviews were undertaken in focus groups with 33 women living in Odense who had completed the telephone survey. Four focus groups were set up according to age (16-20 and 21-26 years of age) and acceptance/rejection of the vaccine.</p> <p>Results</p> <p>Of 839 women initially contacted by telephone, 794 were included, 411 (49%) said they accepted vaccination but only 201 (24%) had actually received the vaccine and these latter were interviewed. 242 women said they refused vaccination of which 234 were interviewed. Women who were undecided were excluded from the study. Prevention of cervical cancer was the main driver for acceptance of the vaccine, followed by parental encouragement and financial support, personal experience of someone with cancer and recommendation by health-care professionals. The greatest barrier to vaccination was its cost. A lack of information about the benefits of vaccination for sexually active women was also an important barrier and the older participants in particular considered that they were too old to be vaccinated. Knowledge about HPV and its role in the development of cervical cancer and genital warts was poor.</p> <p>Conclusions</p> <p>The difference between intention to be vaccinated and starting vaccination was considerable, and a large proportion of women aged 16-26 did not wish to be vaccinated. If the most important barriers to vaccination were addressed (cost and a lack of information about vaccination benefits), it is likely that the uptake of vaccination in Denmark would increase substantially.</p

Risk Factors for Chronic Cerebrospinal Venous Insufficiency (CCSVI) in a Large Cohort of Volunteers

BACKGROUND: The role of intra- and extra-cranial venous system impairment in the pathogenesis of various vascular, inflammatory and neurodegenerative neurological disorders, as well as in aging, has not been studied in detail. Nor have risk factors been determined for increased susceptibility of venous pathology in the intra-cranial and extra-cranial veins. The aim of this study was to investigate the association between presence of a newly proposed vascular condition called chronic cerebrospinal venous insufficiency (CCSVI) and environmental factors in a large volunteer control group without known central nervous system pathology. METHODS AND FINDINGS: The data were collected in a prospective study from 252 subjects who were screened for medical history as part of the entry criteria and participated in the case-control study of CCSVI prevalence in multiple sclerosis (MS) patients, and then were analyzed post-hoc. All participants underwent physical and Doppler sonography examinations, and were assessed with a structured environmental questionnaire. Fullfilment of ≥ 2 positive venous hemodynamic (VH) criteria on Doppler sonography was considered indicative of CCSVI diagnosis. Risk and protective factors associated with CCSVI were analyzed using logistic regression analysis. Seventy (27.8%) subjects presented with CCSVI diagnosis and 153 (60.7%) presented with one or more VH criteria. The presence of heart disease (p = .001), especially heart murmurs (p = .007), a history of infectious mononucleosis (p = .002), and irritable bowel syndrome (p = .005) were associated with more frequent CCSVI diagnosis. Current or previous smoking (p = .029) showed a trend for association with more frequent CCSVI diagnosis, while use of dietary supplements (p = .018) showed a trend for association with less frequent CCSVI diagnosis. CONCLUSIONS: Risk factors for CCSVI differ from established risk factors for peripheral venous diseases. Vascular, infectious and inflammatory factors were associated with higher CCSVI frequency

Cardiovascular and renal outcomes of renin-angiotensin system blockade in adult patients with diabetes mellitus: a systematic review with network meta-analyses

Medications aimed at inhibiting the renin-angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes