Assessment of Right Ventricular Afterload in COPD

Background: We aimed to study whether pulmonary hypertension (PH) and elevated pulmonary vascular resistance (PVR) could be predicted by conventional echo Doppler and novel tissue Doppler imaging (TDI) in a population of chronic obstructive pulmonary disease (COPD) free of LV disease and co-morbidities.Methods: Echocardiography and right heart catheterization was performed in 100 outpatients with COPD. By echocardiography the time-integral of the TDI index, right ventricular systolic velocity (RVSmVTI) and pulmonary acceleration-time (PAAcT) were measured and adjusted for heart rate. The COPD patients were randomly divided in a derivation (n = 50) and a validation cohort (n = 50). Results: PH (mean pulmonary artery pressure (mPAP) ≥ 25mmHg) and elevated PVR ≥ 2Wood unit (WU) were predicted by satisfactory area under the curve for RVSmVTI of 0.93 and 0.93 and for PAAcT of 0.96 and 0.96, respectively. Both echo indices were 100% feasible, contrasting 84% feasibility for parameters relying on contrast enhanced tricuspid-regurgitation. RVSmVTI and PAAcT showed best correlations to invasive measured mPAP, but less so to PVR. PAAcT was accurate in 90- and 78% and RVSmVTI in 90- and 84% in the calculation of mPAP and PVR, respectively. Conclusions: Heart rate adjusted-PAAcT and RVSmVTI are simple and reproducible methods that correlate well with pulmonary artery pressure and PVR and showed high accuracy in detecting PH and increased PVR in patients with COPD. Taken into account the high feasibility of these two echo indices, they should be considered in the echocardiographic assessment of COPD patients.     

Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin‐Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3) Trial

Statins are the accepted standard for lowering low‐density lipoprotein cholesterol (LDL‐C). However, 5% to 10% of statin‐treated patients report intolerance, mostly due to muscle‐related adverse effects. Challenges exist to objective identification of statin‐intolerant patients. Evolocumab is a monoclonal antibody that binds proprotein convertase subtilisin/kexin type 9 (PCSK9), resulting in marked LDL‐C reduction. We report the design of Goal Achievement After Utilizing an Anti‐PCSK9 Antibody in Statin‐Intolerant Subjects 3 (GAUSS‐3), a phase 3, multicenter, randomized, double‐blind, ezetimibe‐controlled study to compare effectiveness of 24 weeks of evolocumab 420 mg monthly vs ezetimibe 10 mg daily in hypercholesterolemic patients unable to tolerate an effective statin dose. The study incorporates a novel atorvastatin‐controlled, double‐blind, crossover phase to objectively identify statin intolerance. Eligible patients had LDL‐C above the National Cholesterol Education Project Adult Treatment Panel III target level for the appropriate coronary heart disease risk category and were unable to tolerate ≥3 statins or 2 statins (one of which was atorvastatin ≤10 mg/d) or had a history of marked creatine kinase elevation accompanied by muscle symptoms while on 1 statin. This trial has 2 co‐primary endpoints: mean percent change from baseline in LDL‐C at weeks 22 and 24 and percent change from baseline in LDL‐C at week 24. Key secondary efficacy endpoints include change from baseline in LDL‐C, percent of patients attaining LDL‐C <70 mg/dL (1.81 mmol/L), and percent change from baseline in total cholesterol, non–high‐density lipoprotein cholesterol, and apolipoprotein B. Recruitment of 511 patients was completed on November 28, 2014.     

Investigation of platelet function and platelet disorders using flow cytometry

Patients with thrombocytopenia or platelet disorders are at risk of severe bleeding. We report the development and validation of flow cytometry assays to diagnose platelet disorders and to assess platelet function independently of platelet count. The assays were developed to measure glycoprotein levels (panel 1) and platelet function (panel 2) in sodium citrated blood. Twenty healthy volunteers and five patients diagnosed with different platelet disorders were included. Glycoprotein expression levels of the receptors Ia, Ib, IIb, IIIa and IX were measured and normalised with forward scatter (FS) as a measurement of platelet size. Platelet function was assessed by CD63, P-selectin and bound fibrinogen in response to arachidonic acid, adenosine diphosphate (ADP), collagen-related peptide, ristocetin and thrombin receptor-activation peptide-6. All patients except one with suspected δ-granule defect showed aberrant levels of glycoproteins in panel 1. Glanzmann's thrombasthenia and genetically verified Bernard–Soulier syndrome could be diagnosed using panel 1. All patients showed reduced platelet function according to at least one agonist. Using panel 2 it was possible to diagnose Bernard–Soulier syndrome, δ-granule defect and GPVI disorder. By combining the two assays, we were able to diagnose different platelet disorders and investigate platelet function independent of platelet count.     

Animal models of pancreatitis: Can it be translated to human pain study?

Chronic pancreatitis affects many individuals around the world,and the study of the underlying mechanisms leading to better treatment possibilities are important tasks.Therefore,animal models are needed to illustrate the basic study of pancreatitis.Recently,animal models of acute and chronic pancreatitis have been thoroughly reviewed,but few reviews address the important aspect on the translation of animal studies to human studies.It is well known that pancreatitis is associated with epigastric pain,but the understanding regarding to mechanisms and appropriate treatment of this pain is still unclear.Using animal models to study pancreatitis associated visceral pain is difficult,however,these types of models are a unique way to reveal the mechanisms behind pancreatitis associated visceral pain.In this review,the animal models of acute,chronic and un-common pancreatitis are briefly outlined and animal models related to pancreatitis associated visceral pain are also addressed.     

Craniofacial and dental findings in cystinosis

Oral Diseases (2010) 16 , 488–495 Objectives: Cystinosis is a rare autosomal recessive lysosomal storage disorder with developmental and mineralization anomalies as part of its clinical presentation. The objective of this study was to provide the first systematic assessment of the craniofacial and dental characteristics associated with cystinosis. Study Design: Oral and radiographic evaluations were performed on 73 patients with cystinosis. Analyses of cephalometry (n = 20), taurodontism (n = 47), caries (n = 47), enamel defects (n = 48), soft tissue anomalies (n = 48), and dental age (n = 41) were performed on the cystinosis group, and compared with age‐ and sex‐comparable controls or standards. Results: Cystinosis patients manifested relative mandibular deficiency, an increased facial height, and a reduced airway space. Taurodontism and enamel defects were significantly more prevalent in cystinosis patients compared with controls (P < 0.0001 and P = 0.027, respectively). Children (aged <15 years) with cystinosis also demonstrated a significant delay, of almost 9 months, of their dental development (P < 0.001). Conclusion: Novel craniofacial and dental features are associated with cystinosis. Craniofacial deficiencies may influence the swallowing and respiratory complications seen in cystinosis. Renal pathology and associated mineral imbalance may explain the dental root and enamel anomalies found in cystinosis patients; the developmental delays in cystinosis include delayed dental formation.     

Five-year effect of community-based intervention Hartslag Limburg on quality of life: A longitudinal cohort study

Background  

During the past decade, quality of life (QoL) has become an accepted measure of disease impact, therapeutic outcome, and evaluation of interventions. So far, very little is known about the effects of community-based interventions on people's QoL. Therefore, the effect of an integrative cardiovascular diseases community-based intervention programme 'Hartslag Limburg' on QoL after 5-years of intervention is studied.     

The cost-effectiveness of a treatment-based classification system for low back pain: design of a randomised controlled trial and economic evaluation

Background

Systematic reviews have shown that exercise therapy and spinal manipulation are both more effective for low back pain (LBP) than no treatment at all. However, the effects are at best modest. To enhance the clinical outcomes, recommendations are to improve the patient selection process, and to identify relevant subgroups to guide clinical decision-making. One of the systems that has potentials to improve clinical decision-making is a treatment-based classification system that is intended to identify those patients who are most likely to respond to direction-specific exercises, manipulation, or stabilisation exercises.

Methods/Design

The primary aim of this randomised controlled trial will be to assess the effectiveness of a classification-based system. A sample of 150 patients with subacute and chronic LBP who attend a private physical therapy clinic for treatment will be recruited. At baseline, all participants will undergo a standard evaluation by trained research physical therapists and will be classified into one of the following subgroups: direction-specific exercises, manipulation, or stabilisation. The patient will not be informed about the results of the examination. Patients will be randomly assigned to classification-based treatment or usual care according to the Dutch LBP guidelines, and will complete questionnaires at baseline, and 8, 26, and 52 weeks after the start of the treatment. The primary outcomes will be general perceived recovery, functional status, and pain intensity. Alongside this trial, an economic evaluation of cost-effectiveness and cost-utility will be conducted from a societal perspective.

Discussion

The present study will contribute to our knowledge about the effectiveness and cost-effectiveness of classification-based treatment in patients with LBP.

Trial registration

Trial registration number: NTR1176     

Ribosome-induced changes in elongation factor Tu conformation control GTP hydrolysis

In translation, elongation factor Tu (EF-Tu) molecules deliver aminoacyl-tRNAs to the mRNA-programmed ribosome. The GTPase activity of EF-Tu is triggered by ribosome-induced conformational changes of the factor that play a pivotal role in the selection of the cognate aminoacyl-tRNAs. We present a 6.7-Å cryo-electron microscopy map of the aminoacyl-tRNA·EF-Tu·GDP·kirromycin-bound Escherichia coli ribosome, together with an atomic model of the complex obtained through molecular dynamics flexible fitting. The model reveals the conformational changes in the conserved GTPase switch regions of EF-Tu that trigger hydrolysis of GTP, along with key interactions, including those between the sarcin-ricin loop and the P loop of EF-Tu, and between the effector loop of EF-Tu and a conserved region of the 16S rRNA. Our data suggest that GTP hydrolysis on EF-Tu is controlled through a hydrophobic gate mechanism.