Removing exogenous information using pedigree data

Management of certain populations requires the preservation of its pure genetic background. When, for different reasons, undesired alleles are introduced, the original genetic conformation must be recovered. The present study tested, through computer simulations, the power of recovery (the ability for removing the foreign information) from genealogical data. Simulated scenarios comprised different numbers of exogenous individuals taking partofthe founder population anddifferent numbers of unmanaged generations before the removal program started. Strategies were based on variables arising from classical pedigree analyses such as founders? contribution and partial coancestry. The ef?ciency of the different strategies was measured as the proportion of native genetic information remaining in the population. Consequences on the inbreeding and coancestry levels of the population were also evaluated. Minimisation of the exogenous founders? contributions was the most powerful method, removing the largest amount of genetic information in just one generation.However, as a side effect, it led to the highest values of inbreeding. Scenarios with a large amount of initial exogenous alleles (i.e. high percentage of non native founders), or many generations of mixing became very dif?cult to recover, pointing out the importance of being careful about introgression events in populatio

A phase II trial of bryostatin-1 administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma

Bryostatin-1 is a macrocyclic lactone whose main mechanism of action is protein kinase C modulation. We investigated its activity as a weekly 24-h infusion in recurrent ovarian carcinoma. In all, 17 patients were recruited and 11 had chemotherapy-resistant disease as defined by disease progression within 4 months of last cytotoxic therapy. All were evaluable for toxicity and 14 for response. There were no disease responses and the main toxicity was myalgia

Phase I dose escalation and pharmacokinetic study of pluronic polymer-bound doxorubicin (SP1049C) in patients with advanced cancer

SP1049C is a novel anticancer agent containing doxorubicin and two nonionic pluronic block copolymers. In preclinical studies, SP1049C demonstrated increased efficacy compared to doxorubicin. The objectives of this first phase I study were to determine the toxicity profile, dose-limiting toxicity, maximum tolerated dose and pharmacokinetic profile of SP1049C, and to document any antitumour activity. The starting dose was 5 mg m−2 (doxorubicin content) as an intravenous infusion once every 3 weeks for up to six cycles. A total of 26 patients received 78 courses at seven dose levels. The dose-limiting toxicity was myelosuppression and DLT was reached at 90 mg m−2. The maximum tolerated dose was 70 mg m−2 and is recommended for future trials. The pharmacokinetic profile of SP1049C showed a slower clearance than has been reported for conventional doxorubicin. Evidence of antitumour activity was seen in some patients with advanced resistant solid tumours. Phase II trials with this agent are now warranted to further define its antitumour activity and safety profile

Up-to-date on mortality in COPD - report from the OLIN COPD study

<p>Abstract</p> <p>Background</p> <p>The poor recognition and related underdiagnosis of COPD contributes to an underestimation of mortality in subjects with COPD. Data derived from population studies can advance our understanding of the true burden of COPD. The objective of this report was to evaluate the impact of COPD on mortality and its predictors in a cohort of subjects with and without COPD recruited during the twenty first century.</p> <p>Methods</p> <p>All subjects with COPD (n = 993) defined according to the GOLD spirometric criteria, FEV₁/FVC < 0.70, and gender- and age-matched subjects without airway obstruction, non-COPD (n = 993), were identified in a clinical follow-up survey of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies cohorts in 2002-2004. Mortality was observed until the end of year 2007. Baseline data from examination at recruitment were used in the risk factor analyses; age, smoking status, lung function (FEV₁% predicted) and reported heart disease.</p> <p>Results</p> <p>The mortality was significantly higher among subjects with COPD, 10.9%, compared to subjects without COPD, 5.8% (p < 0.001). Mortality was associated with higher age, being a current smoker, male gender, and COPD. Replacing COPD with FEV₁% predicted in the multivariate model resulted in the decreasing level of FEV₁being a significant risk factor for death, while heart disease was not a significant risk factor for death in any of the models.</p> <p>Conclusions</p> <p>In this cohort COPD and decreased FEV₁were significant risk factors for death when adjusted for age, gender, smoking habits and reported heart disease.</p

Common Gene Therapy Viral Vectors Do Not Efficiently Penetrate Sputum from Cystic Fibrosis Patients

Norwalk virus and human papilloma virus, two viruses that infect humans at mucosal surfaces, have been found capable of rapidly penetrating human mucus secretions. Viral vectors for gene therapy of Cystic Fibrosis (CF) must similarly penetrate purulent lung airway mucus (sputum) to deliver DNA to airway epithelial cells. However, surprisingly little is known about the rates at which gene delivery vehicles penetrate sputum, including viral vectors used in clinical trials for CF gene therapy. We find that sputum spontaneously expectorated by CF patients efficiently traps two viral vectors commonly used in CF gene therapy trials, adenovirus (d∼80 nm) and adeno-associated virus (AAV serotype 5; d∼20 nm), leading to average effective diffusivities that are ∼3,000-fold and 12,000-fold slower than their theoretical speeds in water, respectively. Both viral vectors are slowed by adhesion, as engineered muco-inert nanoparticles with diameters as large as 200 nm penetrate the same sputum samples at rates only ∼40-fold reduced compared to in pure water. A limited fraction of AAV exhibit sufficiently fast mobility to penetrate physiologically thick sputum layers, likely because of the lower viscous drag and smaller surface area for adhesion to sputum constituents. Nevertheless, poor penetration of CF sputum is likely a major contributor to the ineffectiveness of viral vector based gene therapy in the lungs of CF patients observed to date

The health impact of remarriage behavior on chronic obstructive pulmonary disease: findings from the US longitudinal survey

<p>Abstract</p> <p>Background</p> <p>Chronic obstructive pulmonary disease (COPD) is a major disease among adults, and its deterioration was reported to be associated with psychological imbalance. Meanwhile, bereavement and divorce have proven harmful to the health status of a surviving spouse. But few studies have been conducted to evaluate the remedial effect on survivors' health outcome by remarriage after bereavement. The present study thus examined the associations between remarriage and the onset of COPD.</p> <p>Methods</p> <p>Our cohort was drawn from Health and Retirement Study participants in the United States, and consisted of 2676 subjects who were divorced or bereaved from 1992 to 2002. We then followed them for up to 11 years and assessed the incidence rate of COPD using a Cox proportional hazard model after adjusting for marital status, age, gender, education and the number of cigarettes smoked.</p> <p>Results</p> <p>Among all subjects, 224 who remarried after bereavement or divorce tended to be younger and more male dominated. Remarriage after bereavement/divorce was associated with significantly decreased risk of COPD onset for overall subjects [hazard ratio (HR): 0.51, 95% confidence interval (95% CI): 0.28-0.94], female subjects [HR: 0.36, 95% CI: 0.13-0.98], and for those under 70 years old [HR: 0.36, 95% CI: 0.17-0.79].</p> <p>Conclusion</p> <p>This study investigates the impact of remarriage on health outcome based on a large-scale population survey and indicates that remarriage significantly correlates with reduced risk of COPD incidence, even after adjusting smoking habit.</p

A randomised trial of a 5 week, manual based, self-management programme for hypertension delivered in a cardiac patient club in Shanghai

<p>Abstract</p> <p>Background</p> <p>In Shanghai there are 1.2 million people with hypertension, many of whom have difficulty in affording medical treatment. Community based, anti-hypertensive clubs have been created to provide health education but education alone is often ineffective. Lifestyle change programmes have shown some potential for reducing blood pressure but in previous trials have required specialist staff and extensive contact. We have previously demonstrated that self-management programmes delivered by health professionals, such as a nurse who has had short training in self-management techniques can change health behaviour and reduce symptoms. This study was designed to evaluate the benefits of a simple, cognitive-behavioural, self-management programme for hypertension based around a hypertension manual and delivered in the setting of a community anti-hypertensive club in Shanghai.</p> <p>Method</p> <p>The method was a pragmatic randomised controlled trial with an intention-to-treat analysis. Adult patients with mild-to-moderate primary hypertension, waiting to join a neighbourhood anti-hypertension club, were randomised to the self-management programme or to an information only control procedure. They attended the group treatment sessions on 4 occasions over 5 weeks for education combined with goal setting for lifestyle change and an introduction to exercise. The main outcome measures were: changes in blood pressure; blood total cholesterol; diet; activity level and health related quality of life 1 month and 4 months after the end of treatment.</p> <p>Results</p> <p>A total of 140 adults with mild-to-moderate primary hypertension took part. All of the main outcomes showed beneficial changes. Four months after the end of treatment the mean blood pressure differences between groups were systolic 10.15 mm Hg (P < 0.001, 95% CI 7.25–13.05), and diastolic 8.29 mmHg (P < 0.001, 95% CI 6.71–9.88). Patients in the intervention group also had significantly reduced weight, lowered blood total cholesterol, increased physical activity and improved quality of life.</p> <p>Conclusion</p> <p>Patients with mild-to-moderate primary hypertension attending a 5 week, group and manual based, cognitive-behavioural self-management programme, delivered through a voluntary club in Shanghai experienced a significant reduction in blood pressure.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN73114566</p

Is it possible to diagnose the therapeutic adherence of patients with COPD in clinical practice? A cohort study

<p>Abstract</p> <p>Background</p> <p>Therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is poor. It is therefore necessary to determine the magnitude of non-adherence to develop strategies to correct this behaviour. The purpose of this study was to analyse the diagnostic validity of indirect adherence methods.</p> <p>Methods</p> <p>Sample: 195 COPD patients undergoing scheduled inhaled treatment attending 5 Primary Care Centres of Malaga, Spain. Variables: Sociodemographic profile, illness data, spirometry, quality of life (St. George Respiratory Questionnaire: SGRQ), and inhaled medication counting (count of dose/pill or electronic monitoring) were collected. The patient's knowledge of COPD (Batalla test:BT),their attitude towards treatment (Morisky-Green test: MGT) and their self-reported therapeutic adherence (Haynes-Sackett test: HST) were used as methods of evaluating adherence. The follow-up consisted four visits over one year (the recruitment visit: V0; and after 1 month:V1; 6 months:V2; and 1 year:V3).</p> <p>Results</p> <p>The mean age was 69.59 (95% CI, 68.29-70.89) years old and 93.8% were male. Other findings included: 85.4% had a low educational level, 23.6% were smokers, 71.5% mild-moderate COPD stage with a FEV1 = 56.86 (SD = 18.85); exacerbations per year = 1.41(95% CI, 1-1.8). The total SGRQ score was 44.96 (95% CI, 42.46-47.46), showing a mild self-perceived impairment in health. The prevalence of adherence (dose/pill count) was 68.1% (95% CI, 60.9-75.3) at V1, 80% (95% CI, 73-87) at V2 and 84% (95% CI, 77.9) at V3. The MGT showed a specificity of 67.34% at V1, 76.19% at V2 and 69.62% at V3. The sensitivity was 53.33% at V1, 66.66% at V2 and 33.33% at V3.The BT showed a specificity of 55.1% at V1, 70.23% at V2 and 67.09% at V3. The sensitivity was 68.88% at V1, 71.43% at V2 and 46.66% at V3. Considering both tests together, the specificity was 86.73% at V1, 94.04% at V2 and 92.49% at V3 and the sensitivity was 37.77% at V1, 47.62% at V2 and 13.3% at V3.</p> <p>Conclusions</p> <p>The prevalence of treatment adherence changes over time. Indirect methods (dose/pill count and self-reported) can be useful to detect non-adherence in COPD patients. The combination of MGT and BT is the best approach to test self-reported adherence.</p

Mutations in STK11 gene in Czech Peutz-Jeghers patients

<p>Abstract</p> <p>Background</p> <p>Peutz-Jeghers syndrome (PJS) is an autosomal dominant hereditary disease characterized by mucocutaneous pigmentation and gastrointestinal hamartomatous polyposis. The germline mutations in the serine/threonine kinase 11 (<it>STK11</it>) gene have been shown to be associated with the disease. Individuals with PJS are at increased risk for development of various neoplasms. The aim of the present study was to characterize the genotype and phenotype of Czech patients with PJS.</p> <p>Methods</p> <p>We examined genomic DNA of 8 individuals from five Czech families by sequencing analysis of <it>STK11 </it>gene, covering its promotor region, the entire coding region and the splice-site boundaries, and by multiplex ligation-dependent probe amplification (MLPA) assay designed for the identification of large exonic deletions or duplications of <it>STK11 </it>gene.</p> <p>Results</p> <p>We found pathogenic mutations in <it>STK11 </it>gene in two families fulfilling the diagnostic criteria of PJS and in one of three sporadic cases not complying with the criteria. The patient with the frameshift mutation in <it>STK11 </it>gene developed aggressive gastric cancer. No other studied proband has developed a carcinoma so far.</p> <p>Conclusion</p> <p>Our results showed that a germline mutation of <it>STK11 </it>gene can be found not only in probands fulfilling the PJS diagnostic criteria, but also in some sporadic cases not complying with the criteria. Moreover, we observed a new case of aggressive gastric cancer in a young patient with a frameshift mutation of <it>STK11 </it>gene.</p