Correlation between BCG genomics and protective efficacy

Between the derivation of bacille Calmette-Guérin (BCG) vaccine in 1921 and the lyophilization of BCG daughter strains in the 1960s, a number of clinical trials were performed looking at the protective efficacy of BCG vaccination against tuberculosis. These trials differed from one another in a number of ways: they employed different methodologies for delivering the vaccine and interpreting outcomes; they were performed on populations with different genetic backgrounds and different levels of exposure to environmental Mycobacteria; and, finally, they used different BCG vaccine strains. The results of these trials were estimates of protective efficacy against pulmonary tuberculosis ranging from about 80% to nil. Because of the differences in outcomes and confounding variables, it is difficult to conclude whether differences in interventions alone may have contributed to the remarkably variable results. Analysis of BCG vaccines used in clinical trials suggests a trend towards decreasing efficacy with increased passage in the laboratory; however, trials that used relatively "older" BCG strains were generally performed at different sites than trials which used "younger" BCG strains. Genomic analysis of BCG vaccines demonstrates that during the half-century of ongoing passage of BCG vaccines in vitro there have been numerous genetic changes, comprising single nucleotide polymorphisms, duplications and deletions. The impact of these changes in the BCG genome on the protective efficacy observed in field trials remains to be determined.     

Proportion of tuberculosis transmission that takes place in households in a high-incidence area

The prevalence of infection among household contacts of people with tuberculosis is high. This information frequently guides active case finding. We analysed DNA fingerprints of Mycobacterium tuberculosis from 765 tuberculosis patients in Ravensmead and Uitsig, adjacent suburbs of Cape Town, South Africa. In 129 households in which DNA fingerprints were available for more than one patient, we identified 313 patients, of whom 145 (46%) had a fingerprint pattern matching that of another member of the household. The proportion of transmission in the community that took place in the household was 19%, and therefore, in this high-incidence area, tuberculosis transmission occurs mainly outside the household.     

Steps toward the percutaneous replacement of atrioventricular valves an experimental study

OBJECTIVES: The goal of this study was to develop a device for percutaneous replacement of the tricuspid valve in animals. BACKGROUND: Percutaneous valve replacement has recently been introduced, and early clinical experience has been reported. To date, this technique is limited to the replacement of pulmonary and aortic valves in selected patients. METHODS: A newly designed nitinol stent, forming two large disks separated by a cylinder with a diameter of 18 mm, was specially designed for the purpose of this study. An 18-mm bovine valve was mounted in the central part of the stent, and a polytetrafluoroethylene membrane was sutured onto the ventricular disk. Eight ewes were equally divided into two groups (group 1, acute study; group 2, killed at one month). RESULTS: Seven of eight devices were successfully delivered in the desired position. In one animal, the device was trapped in tricuspid cordae, leading to its incomplete opening. A significant paravalvular leak was noticed in one animal of group 2. Mean right atrial pressure increased from 5 to 7 mm Hg and did not change during the follow-up. At autopsy, examination confirmed the good position of devices in successfully implanted animals. CONCLUSIONS: Implantation of a semi-lunar valve in the tricuspid position is possible in ewes through a transcatheter approach. A disk-based nitinol stent is needed to allow valve implantation in the atrioventricular position. These studies open new perspectives into tricuspid as well as mitral valve replacement.     

Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011

In the 2009 European Guidelines on the diagnosis and treatment of pulmonary hypertension (PH), one section covers aspects of pathophysiology, diagnosis and treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The practical implementation of the guidelines for this disease is of crucial importance, because CTEPH is a subset of PH which can potentially be cured by pulmonary endarterectomy (PEA). Nowadays, CTEPH is commonly underdiagnosed and not properly managed. Any patient with unexplained PH should be evaluated for the presence of CTEPH, and a ventilation/perfusion (V/Q) lung scan is recommended as screening method of choice. If the V/Q scan or CT angiography reveals signs of CTEPH, the patient should be referred to a specialized center with expertise in the medical and surgical management of this disease. Every case has to be reviewed by an experienced PEA surgeon for the assessment of operability. In this updated recommendation, important contents of the European guidelines were commented, and more recent information regarding diagnosis and treatment was added.     

Comparison of in vitro fracture strength of metallic and tooth-coloured posts and cores

In root-treated anterior teeth a better aesthetic can be achieved by using translucent and tooth-coloured post and core restorations instead of traditional metal post systems. The aim of this in vitro study was to compare the fracture strength of tooth-coloured ceramic and fibre-reinforced posts as well as titanium posts with clinically proven gold alloy posts as a control. Two all-ceramic, one gold alloy and three combined post restoration systems (titanium and ceramic, respectively, fibre-reinforced posts with composite core) were each applied to upper incisors and after thermal cycling and mechanical loading (TCML) the fracture strength was determined. The variant providing the most reliable fracture strength values and the experimental fibre-reinforced composite (FRC) posts were - in combination with adhesively luted crowns - used to determine the fracture strength of the restoration after thermal cycling and mechanical loading. The median fracture strength of the luted posts and cores fluctuated between 114 and 546 N. Posts with composite cores demonstrate a higher fracture strength in comparison to the all-ceramic and gold alloy systems. Typical failure of metal systems was marked by loosening of the bonding and pulling out of the post in contrast to fracture of the ceramic posts. After the application of the crowns the ceramic system with composite core provided a fracture strength of 338 N and the FRC system a fracture strength of 228 N. Regarding fracture strength, the ceramic posts with composite cores are an alternative to commonly used gold posts and cores. A standardized technical manufacture of FRC posts and cores would provide better fracture strength results of this new dental material. Post and core restorations with tooth-coloured, translucent material offer an improved aesthetic especially in anterior restorations. Because of the high fracture strength prefabricated ceramic posts in combination with composite cores should prove their clinical applicability.     

Inhaled iloprost to treat severe pulmonary hypertension. An uncontrolled trial. German PPH Study Group

BACKGROUND: Inhaled aerosolized iloprost, a stable prostacyclin analogue, has been considered a selective pulmonary vasodilator in the management of pulmonary hypertension. OBJECTIVE: To assess the efficacy of inhaled iloprost in the treatment of life-threatening pulmonary hypertension. DESIGN: Open, uncontrolled, multicenter study. SETTING: Intensive care units and pulmonary hypertension clinics at six university hospitals in Germany. PATIENTS: 19 patients who had progressive right-heart failure despite receiving maximum conventional therapy (12 with primary pulmonary hypertension, 3 with pulmonary hypertension related to collagen vascular disease without lung fibrosis, and 4 with secondary pulmonary hypertension). INTERVENTION: Inhaled iloprost, 6 to 12 times daily (50 to 200 microg/d). MEASUREMENTS: Right-heart catheterization and distance walked in 6 minutes at baseline and after 3 months of therapy. RESULTS: During the first 3 months of therapy, New York Heart Association functional class improved in 8 patients and was unchanged in 7 patients. Four patients died, 3 of right-heart failure and 1 of sepsis. The acute hemodynamic response to inhaled iloprost was predominant pulmonary vasodilatation with little systemic effect at baseline and at 3 months (data available for 12 patients). Hemodynamic variables were improved at 3 months, and the distance walked in 6 minutes improved by 148 m (95% CI, 4.5 to 282 m; P = 0.048). Of the 15 patients who continued to use inhaled iloprost, 8 stopped: Four had lung transplantation, 1 switched to intravenous prostacyclin therapy, and 3 died. Seven patients are still receiving inhaled iloprost (mean +/-SD) duration of therapy, 536 +/- 309 days; mean dosage, 164 +/- 38 microg/d). CONCLUSIONS: Inhaled iloprost may offer a new therapeutic option for improvement of hemodynamics and physical function in patients with life-threatening pulmonary hypertension and progressive right-heart failure that is refractory to conventional therapy.     

Preserved pulmonary vasodilative properties of aerosolized brain natriuretic peptide

IntroductionInhalation of vasoactive substances is an effective treatment of pulmonary hypertension. The B-type natriuretic peptide (BNP) leads to relaxation of smooth muscle cells, caused by an increased formation of cyclic guanosine monophosphate (cGMP). The biologic activity of BNP using an inhalative approach has not been addressed.MethodsIn order to assess the vasorelaxing capacity of exogenous BNP in the isolated ventilated and buffer perfused rabbit lung model, a stable pulmonary vasoconstriction was established by either the application of endothelin-1 or the thromboxane A₂ mimetic U46619. This was followed by an intravascular or aerosol application of BNP. CGMP was measured in the recirculating buffer fluid using a radioimmunoassay technique.ResultsDuring a stable plateau of U46619 induced pulmonary vasoconstriction (mean pulmonary artery pressure, PAP 25.5 ± 0.23 mmHg), the intravascular administration of BNP induced a rapid vasodilation (mean PAP 18.13 ± 0.95 mmHg, p < 0.001). This vasodilation was dose dependent and was paralleled by a 6-fold increase of cGMP. When BNP was aerosolized, pulmonary vasoconstriction was also significantly alleviated in the U46619 model (mean PAP 22 ± 2.1 mmHg) and during endothelin-1 induced vasoconstriction (mean PAP 17.1 ± 2.47 mmHg). Correspondingly, inhalation caused a significant augmentation of cGMP levels was.ConclusionThe vasodilative capability of BNP as an indicator of the biologic activity of this peptide is preserved during its aerosolization. Presumably these vascular actions are caused at least in part by an increased availability of cGMP.     

Next Generation Diagnostics in Inherited Arrhythmia Syndromes

Next-generation sequencing (NGS) provides an unprecedented opportunity to assess genetic variation underlying human disease. Here, we compared two NGS approaches for diagnostic sequencing in inherited arrhythmia syndromes. We compared PCR-based target enrichment and long-read sequencing (PCR-LR) with in-solution hybridization-based enrichment and short-read sequencing (Hyb-SR). The PCR-LR assay comprehensively assessed five long-QT genes routinely sequenced in diagnostic laboratories and “hot spots” in RYR2. The Hyb-SR assay targeted 49 genes, including those in the PCR-LR assay. The sensitivity for detection of control variants did not differ between approaches. In both assays, the major limitation was upstream target capture, particular in regions of extreme GC content. These initial experiences with NGS cardiovascular diagnostics achieved up to 89 % sensitivity at a fraction of current costs. In the next iteration of these assays we anticipate sensitivity above 97 % for all LQT genes. NGS assays will soon replace conventional sequencing for LQT diagnostics and molecular pathology.