Quantified planar collagen distribution in healthy and degenerative mitral valve: biomechanical and clinical implications.

Degenerative mitral valve disease is a common valvular disease with two arguably distinct phenotypes: fibroelastic deficiency and Barlow's disease. These phenotypes significantly alter the microstructures of the leaflets, particularly the collagen fibers, which are the main mechanical load carriers. The predominant method of investigation is histological sections.

The importance of concomitant mitral regurgitation for estimates of mitral valve area by pressure half time in patients with chronic rheumatic heart disease.

Aims: Aim was to study how concomitant mitral regurgitation (MR) assessed by qualitative and quantitative methods influence mitral valve area (MVA) calculations by the pressure half time method (MVA) compared to reference MVA (planimetry) in patients with rheumatic heart disease.

Methods And Results: In 72 patients with chronic rheumatic heart disease, MVA was calculated as 220 divided by the pressure half time of the mitral early inflow Doppler spectrum. Direct measurement by planimetry was used as reference MVA and was mean (SD) 0.

In silico analysis provides insights for patient-specific annuloplasty in Barlow's disease.

Objective: To predict the required mitral annular area reduction in patients with Barlow's disease to obtain a predefined leaflet area index by a novel in silico modeling method.

Methods: Three-dimensional echocardiography was used to create patient-specific mitral valve models of 8 patients diagnosed with Barlow's disease and bileaflet prolapse preoperatively. Six patients were also studied postoperatively in a finite element framework, to quantify the optimal coaptation area index.

Mitral annular dynamics are influenced by left ventricular load and contractility in an acute animal model.

The purpose of this study was to investigate the effects of loading conditions and left ventricular (LV) contractility on mitral annular dynamics. In 10 anesthetized pigs, eight piezoelectric transducers were implanted equidistantly around the mitral annulus. High-fidelity catheters measured left ventricular pressures and the slope of the end-systolic pressure-volume relationship (E ) determined LV contractility.

Mechanical behavior and collagen structure of degenerative mitral valve leaflets and a finite element model of primary mitral regurgitation.

Degenerative mitral valve disease is the main cause of primary mitral regurgitation with two phenotypes: fibroelastic deficiency (FED) often with localized myxomatous degeneration and diffuse myxomatous degeneration or Barlow's disease. Myxomatous degeneration disrupts the microstructure of the mitral valve leaflets, particularly the collagen fibers, which affects the mechanical behavior of the leaflets. The present study uses biaxial mechanical tests and second harmonic generation microscopy to examine the mechanical behavior of Barlow and FED tissue.

Sympathetic and vagal interaction in the control of cardiac pacemaker rhythm in the guinea-pig heart: Importance of expressing heart rhythm using an appropriate metric.

There are many reports that, through pre- and post-junctional mechanisms, sympathetic and parasympathetic (vagal) nerves can interact in the control of heart rate. The predominant interaction is accentuated antagonism (AA), where the bradycardia produced by vagal stimulation (VNS) is amplified when heart rate has been increased by sympathetic stimulation (SNS) or beta-adrenergic agonists. The acetylcholine-activated potassium current (I), is the primary driver of vagal bradycardia.

Finite element analysis of mitral valve annuloplasty in Barlow's disease.

Barlow's Disease affects the entire mitral valve apparatus causing mitral regurgitation. Standard annuloplasty procedures lead to an average of 55% annular area reduction of the end diastolic pre-operative annular area in Barlow's diseased valves. Following annular reduction, mitral valvuloplasty may be needed, usually with special focus on the posterior leaflet.

Mitral Annular Elasticity Determines Severity of Regurgitation in Barlow's Mitral Valve Disease.

Objectives: Barlow's mitral valve disease with late systolic mitral regurgitation provides diagnostic and therapeutic challenges. The mechanisms of the regurgitation are still unclear. We hypothesized that the onset and the severity of late systolic regurgitation are determined by annulus dynamics and the mechanical stresses imposed by the left ventricle.

Short-term outcome after open-heart surgery for severe chronic rheumatic heart disease in a low-income country, with comparison with an historical control group: an observational study.

Objectives: Rheumatic heart disease (RHD) is a major burden in low-income and middle-income countries (LMICs). Cardiac surgery is the only curative treatment. Little is known about patients with severe chronic RHD operated in LMICs, and challenges regarding postoperative follow-up are an important issue.

A novel case of impaired C-reactive protein response following open-heart surgery: A case report and review of the literature.

Background: C-reactive protein (CRP) is expected to increase in response to a range of inflammatory stimuli such as infections or extensive tissue trauma.

Case Report: We present a novel case of severely impaired CRP response following NSTEMI, influenza A infection and open-heart surgery in which serum CRP concentrations remained < 1 mg/L during an observational period of 28 days.

Conclusion: To our knowledge, no previous publications exists describing patients with a lack of CRP response following cardiothoracic surgery.

Liver-Targeted Anti-HBV Single-Stranded Oligonucleotides with Locked Nucleic Acid Potently Reduce HBV Gene Expression In Vivo.

Chronic hepatitis B infection (CHB) is an area of high unmet medical need. Current standard-of-care therapies only rarely lead to a functional cure, defined as durable hepatitis B surface antigen (HBsAg) loss following treatment. The goal for next generation CHB therapies is to achieve a higher rate of functional cure with finite treatment duration.

Locked nucleic acid: modality, diversity, and drug discovery.

Over the past 20 years, the field of RNA-targeted therapeutics has advanced based on discoveries of modified oligonucleotide chemistries, and an ever-increasing understanding of how to apply cellular assays to identify oligonucleotides with improved pharmacological properties in vivo. Locked nucleic acid (LNA), which exhibits high binding affinity and potency, is widely used for this purpose. Our understanding of RNA biology has also expanded tremendously, resulting in new approaches to engage RNA as a therapeutic target.

From the Cover: The Minipig is a Suitable Non-Rodent Model in the Safety Assessment of Single Stranded Oligonucleotides.

Non-human primates (NHPs) are currently considered to be the non-rodent species of choice for the preclinical safety assessment of single-stranded oligonucleotide (SSO) drugs. We evaluated minipigs as a potential alternative to NHPs to test the safety of this class of compounds. Four different phosphorothioated locked nucleic acid-based SSOs (3 antisense and 1 anti-miR), all with known safety profiles, were administered to minipigs using similar study designs and read-outs as in earlier NHP studies with the same compounds.

The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection.

Background: To investigate in a cohort with previous gastrointestinal infection and a control group the prevalence of overactive bladder syndrome (OAB), and how it was associated with three other functional disorders; irritable bowel syndrome (IBS), functional dyspepsia (FD) and chronic fatigue (CF).

Methods: Controlled historic cohort study including 724 individuals with laboratory confirmed giardiasis six years earlier, and 847 controls matched by gender and age. Prevalence and odds ratios (OR) with 95 % confidence intervals (CI) were calculated.

Biological activity and biotechnological aspects of locked nucleic acids.

Locked nucleic acid (LNA) is one of the most promising new nucleic acid analogues that has been produced under the past two decades. In this chapter, we have tried to cover many of the different areas, where this molecule has been used to improve the function of synthetic oligonucleotides (ONs). The use of LNA in antisense ONs, including gapmers, splice-switching ONs, and siLNA, as well as antigene ONs, is reviewed.

Treatment of HCV infection by targeting microRNA.

Background: The stability and propagation of hepatitis C virus (HCV) is dependent on a functional interaction between the HCV genome and liver-expressed microRNA-122 (miR-122). Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function.

Methods: In this phase 2a study at seven international sites, we evaluated the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection.

A locked nucleic acid oligonucleotide targeting microRNA 122 is well-tolerated in cynomolgus monkeys.

MicroRNA 122 (miR-122) is liver specific, fine-tunes lipid metabolism, and is required for hepatitis C virus (HCV) abundance. Miravirsen, an oligonucleotide with locked nucleic acid, binds to miR-122, potently inhibiting its activity. We aimed at determining the safety of the miR-122 antagonism in vivo in 6 to 10 cynomolgus monkeys/group intravenously treated with a range of dose levels twice weekly for 4 weeks.

PCSK9 LNA antisense oligonucleotides induce sustained reduction of LDL cholesterol in nonhuman primates.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for the reduction of low-density lipoprotein cholesterol (LDL-C). PCSK9 increases the degradation of the LDL receptor, resulting in high LDL-C in individuals with high PCSK9 activity. Here, we show that two locked nucleic acid (LNA) antisense oligonucleotides targeting PCSK9 produce sustained reduction of LDL-C in nonhuman primates after a loading dose (20 mg/kg) and four weekly maintenance doses (5 mg/kg).

Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection.

The liver-expressed microRNA-122 (miR-122) is essential for hepatitis C virus (HCV) RNA accumulation in cultured liver cells, but its potential as a target for antiviral intervention has not been assessed. We found that treatment of chronically infected chimpanzees with a locked nucleic acid (LNA)-modified oligonucleotide (SPC3649) complementary to miR-122 leads to long-lasting suppression of HCV viremia, with no evidence of viral resistance or side effects in the treated animals. Furthermore, transcriptome and histological analyses of liver biopsies demonstrated derepression of target mRNAs with miR-122 seed sites, down-regulation of interferon-regulated genes, and improvement of HCV-induced liver pathology.

High blood pressure despite treatment: results from a cross-sectional primary healthcare-based study in southern Sweden.

Objective: To study degree of blood pressure (BP) control in primary healthcare (PHC) treated hypertensive patients in relation to sex, age, drug treatment, and concomitant diseases.

Design: Random sample of patients with hypertension.

Setting: Ten PHC centres in the Region of Skåne, Sweden.

Cytochrome P450 3A4 is the major enzyme responsible for the metabolism of laquinimod, a novel immunomodulator.

In the present study, the involvement of cytochrome P450 enzyme(s) in the primary metabolism of laquinimod, a new orally active immunomodulator, has been investigated in human liver microsomes. Hydroxylated and dealkylated metabolites were formed. The metabolite formation exhibited single enzyme Michaelis-Menten kinetics with apparent KM in the range of 0.

A new screening model for safety evaluation of superantigen-antibody recombinant fusion proteins (mAb Fab-SEA/E) using telemetric monitoring in conscious rabbits.

Introduction: Carcinoma recognising monoclonal antibodies (mAb) and mutated forms of the T-cell-activating bacterial staphylococcal enterotoxin A/E (SEA/E) have been combined in single hybrid constructs (mAb Fab-SEA/E). By introducing substitutions in an MHC class II binding site, these harmful toxins can be converted into tolerable immunotoxins. Rabbits and humans are sensitive to SE toxins, and cardiovascular effects in rabbits are similar to those seen in septic shock in man.