Biomedical subjects
Pasupathy Sivasothy
Publications and source records attributed to Pasupathy Sivasothy.
The outcomes of lung transplantation in patients with bronchiectasis and antibody deficiency.
BACKGROUND: Lung transplantation is an established treatment for end-stage bronchiectasis. A proportion of patients with bronchiectasis have an associated antibody deficiency. This group benefits from immunoglobulin replacement therapy, but the outcome of lung transplantation is not known. METHODS: We conducted a retrospective observational study of all who received a transplant for bronchiectasis at our unit. We compared the survival after transplant, number of infective and rejection episodes, and the change in forced expiratory volume in 1 second (FEV1). RESULTS: Five of the 37 patients identified with bronchiectasis had an antibody deficiency that required immunoglobulin replacement therapy. Actuarial survival was similar in the 2 groups, being 81% at 12 months in the Bronchiectasis Group and 80% in the Antibody Deficiency Group. The FEV1 at 12 months after transplantation was similar in each group, with a predicted mean +/- SD FEV1 of 83.7% +/- 24.2% in those with bronchiectasis and 83.0% +/- 30.4% in those with antibody deficiency as well. The infection and rejection rates in the first year after transplantation were lower in the Antibody Deficiency Group. Infection episodes per 100 patient-days for bronchiectasis alone were 0.90 vs 0.53 and rejection episodes per 100 patient-days were 0.59 vs 0.24. CONCLUSIONS: There was no evidence that transplant recipients with bronchiectasis and antibody deficiency have a worse prognosis than those with bronchiectasis alone.
How small peptides block and reverse serpin polymerisation.
Many of the late-onset dementias, including Alzheimer's disease and the prion encephalopathies, arise from the aberrant aggregation of individual proteins. The serpin family of serine protease inhibitors provides a well-defined structural example of such pathological aggregation, as its mutant variants readily form long-chain polymers, resulting in diseases ranging from thrombosis to dementia. The intermolecular linkages result from the insertion of the reactive site loop of one serpin molecule into the middle strand (s4A) position of the A beta-sheet of another molecule. We define here the structural requirements for small peptides to competitively bind to and block the s4A position to prevent this intermolecular linkage and polymerisation. The entry and anchoring of blocking-peptides is facilitated by the presence of a threonine which inserts into the site equivalent to P8 of s4A. But the critical requirement for small blocking-peptides is demonstrated in crystallographic structures of the complexes formed with selected tri- and tetrapeptides. These structures indicate that the binding is primarily due to the insertion of peptide hydrophobic side-chains into the P4 and P6 sites of s4A. The findings allow the rational design of synthetic blocking-peptides small enough to be suitable for mimetic design. This is demonstrated here with a tetrapeptide that preferentially blocks the polymerisation of a pathologically unstable serpin commonly present in people of European descent.