Prevalence of severe-to-Profound hearing loss in the adult Swedish population and comparison with cochlear implantation rate.

Background: The prevalence of disabling hearing loss is increasing worldwide. However, previous studies on hearing loss prevalence have enrolled small populations or only provided estimates.

Aim: To establish the prevalence of severe-to-profound hearing loss (STPHL) in the adult Swedish population and compare it with the cochlear implantation rate in Sweden.

Atrial high-rate episodes predict clinical outcome in patients with cardiac resynchronization therapy.

Objectives: Up to 50% of patients qualified for cardiac resynchronization therapy (CRT) have documented atrial fibrillation (AF) prior to CRT-implantation. This finding is associated with worse prognosis but few studies have evaluated the importance of post-implant device-detected AF. This study aimed to assess the prognostic impact of device-detected atrial high-rate episodes (AHRE), as a surrogate for AF.

Immunoseq: the identification of functionally relevant variants through targeted capture and sequencing of active regulatory regions in human immune cells.

Background: The observation that the genetic variants identified in genome-wide association studies (GWAS) frequently lie in non-coding regions of the genome that contain cis-regulatory elements suggests that altered gene expression underlies the development of many complex traits. In order to efficiently make a comprehensive assessment of the impact of non-coding genetic variation in immune related diseases we emulated the whole-exome sequencing paradigm and developed a custom capture panel for the known DNase I hypersensitive site (DHS) in immune cells - "Immunoseq".

Results: We performed Immunoseq in 30 healthy individuals where we had existing transcriptome data from T cells.

Autonomic influence on atrial fibrillatory process: head-up and head-down tilting.

Background: Changes in the autonomic nervous system (ANS) tone are present before, during, and after episodes of atrial fibrillation (AF). Atrial fibrillatory rate (AFR, the inverse of the atrial cycle length) has been used as a surrogate marker for local refractoriness and is a key characteristic of the fibrillatory process in patients with AF. Aim of this study is to assess changes in AFR, as an effect of autonomic balance change.

Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding.

The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein.

Investigating protein variants using structural calculation techniques.

Structure calculation techniques can be very useful to bridge the gap between available sequence information and structural knowledge. In order to understand the molecular mechanisms behind diseases caused by residue exchanges, knowledge about the modified structure is needed. In this chapter, we describe how energy minimizations and molecular dynamics can be useful tools in order to study the structural effects of sequence variation.

Structural and biochemical investigation of two Arabidopsis shikimate kinases: the heat-inducible isoform is thermostable.

The expression of plant shikimate kinase (SK; EC 2.7.1.

Polypeptide conjugate binders that discriminate between two isoforms of human carbonic anhydrase in human blood.

Two binder candidates 4-C37L34-B and 3-C15L8-B from a 16-membered set of 42-residue polypeptide conjugates designed to bind human carbonic anhydrase II (HCAII), were shown to bind HCAII with high affinity in a fluorescence-based screening assay. Two carbonic anhydrase isoforms with 60 % homology exist in human blood with HCAI being present in five- to sevenfold excess over HCAII. The ability of the binders to discriminate between HCAI and HCAII was evaluated with regard to what selectivity could be achieved by the conjugation of polypeptides from a 16-membered set to a small organic molecule that binds both isoforms with similar affinities.

Functionally important amino acids in the Arabidopsis thylakoid phosphate transporter: homology modeling and site-directed mutagenesis.

The anion transporter 1 (ANTR1) from Arabidopsis thaliana, homologous to the mammalian members of the solute carrier 17 (SLC17) family, is located in the chloroplast thylakoid membrane. When expressed heterologously in Escherichia coli, ANTR1 mediates a Na(+)-dependent active transport of inorganic phosphate (P(i)). The aim of this study was to identify amino acid residues involved in P(i) binding and translocation by ANTR1 and in the Na(+) dependence of its activity.

Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3.

Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3.

Validity and reliability of a new, short symptom rating scale in patients with persistent atrial fibrillation.

Background: Symptoms related to atrial fibrillation and their impact on health-related quality of life (HRQoL) are often evaluated in clinical trials. However, there remains a need for a properly validated instrument. We aimed to develop and validate a short symptoms scale for patients with AF.

Investigation and prediction of the severity of p53 mutants using parameters from structural calculations.

A method has been developed to predict the effects of mutations in the p53 cancer suppressor gene. The new method uses novel parameters combined with previously established parameters. The most important parameter is the stability measure of the mutated structure calculated using molecular modelling.

Usefulness of N-terminal pro-brain natriuretic Peptide and brain natriuretic peptide to predict cardiovascular outcomes in patients with heart failure and preserved left ventricular ejection fraction.

More than 40% of patients hospitalized with heart failure have preserved left ventricular ejection fraction (HF-PLVEF) and are at high risk for cardiovascular (CV) events. The purpose of this study was to determine the value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in predicting CV outcomes in patients with HF-PLVEF. Participants with an ejection fraction >40% in the prospective CHARM Echocardiographic Substudy were included in this analysis.

The hemoglobin A1c level as a progressive risk factor for cardiovascular death, hospitalization for heart failure, or death in patients with chronic heart failure: an analysis of the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program.

Background: A progressive relationship between hemoglobin A(1c) (HbA(1c)) levels and cardiovascular (CV) events has been observed in persons with and without diabetes. To our knowledge, the nature of such a relationship in patients with symptomatic chronic heart failure (HF) has not been studied.

Methods: A total of 2412 participants (907 with prior diabetes) in the Candesartan in Heart failure: Assessment of Reduction in Mortality and Morbidity (CHARM) program with at least 1 HbA(1c) level were followed up for a median of 34 months.

An international comparison of the burden of illness in patients with dyspepsia.

Background/aims: This study investigates the symptoms and the impact of symptoms on health-related quality of life (HRQL) in patients consulting with dyspepsia.

Methods: Consecutive patients with a diagnosis of dyspepsia were recruited from primary and secondary care in Germany, Hungary, Italy, Poland, South Africa and Spain. Investigators assessed symptom frequency and severity, and subjects completed the following questionnaires: the Gastrointestinal Symptom Rating Scale (GSRS), the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire, the Hospital Anxiety and Depression (HAD) scale and the Short Form 36 (SF-36).

A multinational investigation of time and traveling costs in attending anticoagulation clinics.

Objectives: Anticoagulation is used in patients with atrial fibrillation to reduce the risk of ischemic stroke. The therapy requires regular monitoring and, frequently, dose adjustment. This study aimed to determine the time and traveling costs that patients incur to themselves and society in attending anticoagulation clinics.

BNP and NT-proBNP predict echocardiographic severity of diastolic dysfunction.

Aims: To evaluate the best combination of clinical parameters and brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), to predict diastolic dysfunction (DD) in heart failure with preserved left ventricular ejection fraction (HF-PLEF) as determined by Doppler-echocardiography.

Methods And Results: HF patients with EF >40% in the CHARM Echocardiographic Substudy were included and classified to have normal diastolic function, or mild, moderate or severe diastolic dysfunction. Plasma BNP and NT-proBNP levels were measured and relevant clinical characteristics recorded.

Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: a six-country study.

Background: Symptoms of dyspepsia significantly disrupt patients' lives and reliable methods of assessing symptom status are important for patient management. The aim of the current study was to document the psychometric characteristics of the Gastrointestinal Symptom Rating Scale (GSRS) and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) in Afrikaans, German, Hungarian, Italian, Polish and Spanish patients with dyspepsia.

Methods: 853 patients with symptoms of dyspepsia completed the GSRS, the QOLRAD, the 36-item Short-Form Health Survey (SF-36) and the Hospital Anxiety and Depression scale.

Three novel CYP21A2 mutations and their protein modelling in patients with classical 21-hydroxylase deficiency from northeastern Iran.

Objective: Congenital adrenal hyperplasia (CAH) refers to a group of autosomal recessive disorders frequently caused by mutations in the steroid 21-hydroxylase gene (CYP21A2). We describe three novel CYP21A2 mutations in CAH patients.

Design And Methods: Sequence analysis of the entire CYP21A2 gene followed by molecular modelling was performed in three unrelated classical CAH patients of northeastern Iranian origin.

Psychometric validation of the italian translation of the gastrointestinal symptom-rating scale and quality of life in reflux and dyspepsia questionnaire in patients with gastro-oesophageal reflux disease.

Background: Symptoms of heartburn and their impact on health-related quality of life (HR-QOL) are often evaluated in clinical trials. When a questionnaire is translated into a new language, a linguistic validation is necessary but not sufficient unless the psychometric characteristics have been verified.

Objective: To document the psychometric characteristics of the Italian translation of the Gastrointestinal Symptom-Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire.

Disruption of the GDNF binding site in NCAM dissociates ligand binding and homophilic cell adhesion.

Most plasma membrane proteins are capable of sensing multiple cell-cell and cell-ligand interactions, but the extent to which this functional versatility is founded on their modular design is less clear. We have identified the third immunoglobulin domain of the Neural Cell Adhesion Molecule (NCAM) as the necessary and sufficient determinant for its interaction with Glial Cell Line-derived Neurotrophic Factor (GDNF). Four charged contacts were identified by molecular modeling as the main contributors to binding energy.

A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer.

In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17beta-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression.

Characterization of health-related quality of life in heart failure patients with preserved versus low ejection fraction in CHARM.

Background: Limited comparative studies assessing the health-related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate.

Aims: The aims of this study were a) to characterize HRQL in a large population of HF patients with preserved and low LVEF and b) to determine the factors associated with worse HRQL.

Molecular model of human CYP21 based on mammalian CYP2C5: structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia.

Enhanced understanding of structure-function relationships of human 21-hydroxylase, CYP21, is required to better understand the molecular causes of congenital adrenal hyperplasia. To this end, a structural model of human CYP21 was calculated based on the crystal structure of rabbit CYP2C5. All but two known allelic variants of missense type, a total of 60 disease-causing mutations and six normal variants, were analyzed using this model.