Hereditary systemic immunoglobulin light-chain amyloidosis

Several members of a family died from renal failure as a result of systemic amyloidosis. Extensive studies to detect previously documented gene mutations associated with amyloidosis failed to identify a causative factor. In search of the genetic basis for this syndrome, amyloid fibrils were isolated from renal tissue of a member of the kin who died while on renal dialysis. Amino acid sequencing of isolated amyloid protein identified sequences compatible with the constant region of the immunoglobulin κ light-chain. Isolation and characterization of κ light-chain protein from serum of an affected member of the kindred revealed mutation in the constant region of κ light-chain, with cysteine replacing serine at amino acid residue 131. This mutation (Ser131Cys) was confirmed by DNA analysis, which identified a single-base change of cytosine to guanine at the second position of codon 131 of the κ light-chain gene (TCT131TGT). DNA analysis of members of the extended family revealed transmission of the Ser131Cys mutation and association with systemic amyloidosis. This amyloid light-chain (AL) amyloidosis, which is a hereditary type of amyloidosis and not the result of a monoclonal plasma cell dyscrasia, may be misdiagnosed and lead to inappropriate chemotherapy

The Ile-84-->Ser amino acid substitution in transthyretin interferes with the interaction with plasma retinol-binding protein.

In plasma the thyroid hormone-binding protein transthyretin (TTR) forms a tight complex with the specific retinol carrier retinol-binding protein (RBP). The Ile-84–>Ser mutation and several other point mutations in TTR are associated with familial amyloidotic polyneuropathy, which is characterized by extracellular depositions of amyloid fibrils mainly consisting of mutated TTRs. The interactions with human RBP of recombinant human normal and Ser-84 TTRs were investigated by monitoring the fluorescence anisotropy of RBP-bound retinol. A nearly negligible affinity of the recombinant Ser-84 TTR for RBP was found. This result indicates the participation of a region on the outer surface of TTR that comprises Ile-84 in the recognition of RBP. In preliminary studies the Ser-84 TTR was the only one among several amyloidogenic variant TTRs to display negligible interaction with RBP. Therefore, in general a substantially altered binding of TTR to RBP is not associated with familial amyloidotic polyneuropathy. Instead, the altered binding of Ser-84 TTR to RBP appears to be responsible for an abnormal plasma transport of RBP. The recombinant normal TTR exhibits binding properties, in its interaction with human RBP, approximately similar to those of TTR purified from human plasma. Two independent and equivalent RBP binding sites on recombinant normal TTR are characterized by a dissociation constant of about 0.4 microM

Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant TTR gene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR

St George's Respiratory Questionnaire Score Predicts Outcomes in Patients with COPD: Analysis of Individual Patient Data in the COPD Biomarkers Qualification Consortium Database.

Background: We aimed to estimate the usefulness of a disease specific health status measure, the St George's Respiratory Questionnaire (SGRQ), to predict outcomes in patients with chronic obstructive pulmonary disease (COPD). Methods: Individual patient-data of 12043 patients from long-term randomized clinical trials (2-4 years' duration) in the COPD Biomarkers Qualification Consortium database were analyzed. The adverse COPD outcomes were: exacerbations of COPD, hospital admissions due to exacerbation and all-cause mortality. Cox proportional hazards regression was used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CIs) for quartiles of SGRQ scores at baseline and time to first event, and time from first to second event, where appropriate. Results: The risk of adverse COPD outcomes increased with each increasing quartile of SGRQ score for all time to first event analyses. When comparing the lowest versus the highest quartile, the event risk (HRs [95% CIs]) increased by 40% for exacerbations (1.40 [1.29, 1.51]); 2-fold for hospital admissions (2.01 [1.78, 2.28]) and more than 2-fold for all-cause mortality (2.30 [1.91, 2.78]). For second event analyses in a subset of eligible patients, these trends persisted albeit with reduced risk estimates for exacerbations. Conclusions: Among patients with COPD, health status measured by a SGRQ score predicted exacerbations of COPD, hospital admissions due to exacerbations and their recurrence and death after adjustment. These data support the rationale for a health status measure use as a drug development tool and suggest that a health status measure may also have a role in risk assessment for COPD patients in routine medical care

Socioeconomic Status as a Determinant of Health Status Treatment Response in COPD Trials.

Background: Randomized controlled trials (RCTs) often recruit patients from low and high socioeconomic status (SES) countries, but little is known about the effect of SES on clinical outcomes, particularly patient-centered measures of symptomatic benefit. Methods: Combined individual chronic obstructive pulmonary disease (COPD) patient data from the placebo and long-acting bronchodilator arms of 17 RCTs (from the COPD Biomarkers Qualification Consortium database) were analyzed. Health status was measured using the St George's Respiratory Questionnaire (SGRQ) (minimum clinically important difference [MCID]: 4 units). Trials were grouped into short-term (≤12 months) and medium-term (>12 months to 48 months). A participant's country of residence was categorized into Low/Medium or High SES using World Health Organization criteria. Results: Data from 19765 individuals (6109 Low/Medium SES) were available. Patients in Low/Medium SES countries had more severe disease at baseline. Improvement in SGRQ score with placebo was ≈2 units greater in Low/Medium than in High SES countries; at its greatest, the improvement from baseline exceeded the MCID in Low/Medium countries. This difference was maintained for at least 1 year. Improvement with bronchodilator was also greater in Low/Medium versus High SES countries; overall there was no evidence that the treatment effect versus placebo was different between countries of different SES status. Conclusions: Participants in Low/Medium SES countries experienced significantly larger treatment effects, irrespective of treatment group (placebo and bronchodilator). Despite this, COPD patients in Low/Medium SES countries experienced a health status gain from long-acting bronchodilator treatment that is similar to that seen in High SES countries

The COPD Biomarkers Qualification Consortium Database: Baseline Characteristics of the St George's Respiratory Questionnaire Dataset.

The COPD Biomarkers Qualification Consortium (CBQC) is a public-private partnership formed in 2010 with a goal of qualifying biomarkers and clinical assessment tools for use in clinical or nonclinical decision-making and particularly within the regulatory context. The St George's Respiratory Questionnaire (SGRQ) is a measure of health-related quality of life widely used in clinical research. The aim of the CBQC working group on SGRQ was to construct an individual patient level database of clinical trial data that included the SGRQ, to use this to confirm the reliability and validity of the SGRQ as an outcome measure of health status, and investigate its use as a predictor of future events (exacerbations and mortality). This manuscript describes the formulation of the CBQC database and presents the baseline demographic and clinical characteristics of the integrated SGRQ database overall, and by study type (short-term [≤1 year], medium-term [2-4 years] and observational studies). Distribution of baseline SGRQ scores varied little by demographic determinants except for income region in the observational data set (low-middle income countries +10 units compared with high income, p<0.0001) and this observation held across studies. SGRQ scores increased with increasing modified Medical Research Council dyspnea scores (mean differences ranged 6.9-17.9 units) and with increasing airflow limitations (Global initiative for chronic Obstructive Lung Disease grades 1 to 4; differences ranged 4.5-16.1 units), consistent across study types. As a method of cross-sectional comparison, the SGRQ appears to be relatively free of bias from demographic factors although care should be taken when making cross sectional comparisons of scores between patients in countries at different levels of socio-economic development/

4mu spectra of AGB stars I: Observations

We present times series of high resolution spectra of AGB variables at 4mu. Line profiles from the major contributors to the spectra of oxygen rich stars at 4mu, OH, H$_2$O, HCl and SiO, are examined. The velocity as well as shape variations of these profiles with time are discussed. The line profiles investigated frequently have emission and multiple absorption components. The changes with time of the 4mu region lines do not always follow the cyclic variability seen in NIR spectra and in the photometric light curve. We interpret and discuss the results qualitatively considering comparing the spectral variability with that of the well behaved 1.6mu region and of dynamical model atmospheres. Miras and semiregular variables are compared. The origins of non-periodic behavior are discussed, including the role of spatial inhomogeneities in the stellar atmosphere.Comment: 14 pages, 12 figures, accepted for publication in A&