Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population.

Lung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated proteolytic activity, mainly by neutrophil elastase (HNE), in the lung parenchyma. This is the result of a substantial reduction of circulating alpha-1-antitrypsin (AAT) and the presence in the plasma of inactive polymers of AAT. Moreover, some AAT mutants have reduced intrinsic activity toward HNE, as demonstrated for the common Z mutant, as well as for other rarer variants.

Peripheral fixation of meniscal allograft does not reduce coronal extrusion under physiological load.

Purpose: Meniscal graft extrusion is a concern following meniscal allograft transplantation (MAT). MAT surgical techniques continue to evolve in an effort to reduce extrusion; however, improvements remain difficult to measure in vivo. A novel MRI-compatible in vitro loading device capable of applying physiologically relevant loads has been developed, allowing for the measurement of extrusion under a variety of controllable conditions.

3D strain in native medial meniscus is comparable to medial meniscus allograft transplant.

Purpose: Injury or degeneration of the meniscus has been associated with the development of osteoarthritis of the knee joint. Meniscal allograft transplant (MAT) has been shown to reduce pain and restore function in patients who remain symptomatic following meniscectomy. The purpose of this study is to evaluate and compare the three-dimensional (3D) strain in native medial menisci compared to allograft-transplanted medial menisci in both the loaded and unloaded states.

Real-world clinical applicability of pathogenicity predictors assessed on SERPINA1 mutations in alpha-1-antitrypsin deficiency.

The growth of publicly available data informing upon genetic variations, mechanisms of disease, and disease subphenotypes offers great potential for personalized medicine. Computational approaches are likely required to assess a large number of novel genetic variants. However, the integration of genetic, structural, and pathophysiological data still represents a challenge for computational predictions and their clinical use.

Heteropolymerization of α-1-antitrypsin mutants in cell models mimicking heterozygosity.

The most common genotype associated with severe α-1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α-1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema.