Sneh Arora

Delayed resolution of inflammatory response compared with clinical recovery in patients with acute exacerbations of chronic obstructive pulmonary disease

Background and objective:  The temporal profile of inflammatory markers during acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and their relationship to clinical response are not well characterized. The aim was to assess the changes in levels of inflammatory markers in AECOPD and correlate these with clinical and laboratory indices of recovery.

THE DESIGN OF AN INHIBITOR USING ALPHA ,BETA -DEHYDRO RESIDUES

X-ray crystallography and NMR spectroscopic studies on peptides containing alpha, beta-unsaturated (dehydro) residues have indicated that the steric effects caused by the dehydro residue are strong and predictable, and such residues can be used to generate specific peptide structures. In particular, dehydro-Alanine (delta Ala) is found to adopt an extended conformation and also induces a definite conformation in the neighboring saturated residue. In order to design a sequence that would fold into a known three-dimensional structure, we have undertaken a systematic theoretical study of the preferred conformations of tetrapeptide sequences of the type N-Ac-delta Ala-X-delta Ala-NHCH3 (x = Gly, L-Ala, L-Val, L-Leu, L-Lys, L-Arg, L-Phe). The methodology and parameters used have been standardized against sequences with known crystal structures. In all the sequences a consistent folding pattern is observed in which the delta Ala residues are in an extended conformation with phi approximately 140 degrees and psi approximately -40 degrees. The results are used to predict a sequence which has a structure very similar to that of the binding loop region of the bovine pancreatic trypsin inhibitor (BPTI).

A proteinase K inhibitor using alpha,beta-unsaturated (dehydro) residues: a presumptive model.

Enzymes of the subtilisin family, of which proteinase K is a member, have been studied extensively on account of their numerous biological applications. Specific inhibitors of the proteinases are of immense importance in regulating their activity so as to protect the cells against uncontrolled proteolysis. Using the specific design principles of peptides containing dehydro-Alanine (deltaAla), generated by our theoretical calculations, we present here the design of an inhibitor of proteinase K. Energy minimization and molecular modeling of the interaction of the designed tetrapeptide with the recognition site of proteinase K indicate that it is an effective inhibitor.

Evaluation of plasma leptin, tumor necrosis factor-α, and prealbumin as prognostic biomarkers during clinical recovery from acute exacerbations of chronic obstructive pulmonary disease

Background: Inflammatory and nutritional biomarkers have an important bearing on outcomes of acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but the temporal profile of these compounds during an acute episode is unclear. Patients and Methods: Plasma leptin, prealbumin, and tumor necrosis factor-alpha (TNF-α) were estimated at baseline and before hospital discharge in patients with AECOPD. Results: A total of 82 patients were evaluated (66 males; mean (standard deviation) age, 61.6 (10.1) years. Of these, 74 subjects (90.2%) were current or former smokers, with median (range) pack-years of 15 (0–96), duration of COPD of 8 years (range, 2–25 years) and duration of current symptoms being 5 days (range, 1–30 days). Majority (41.5%) had type I (severe) exacerbation. During the current episode, 46 patients (58.9%) required mechanical ventilation for a median of 6 days (range, 1–34). The median duration of hospital stay was 13 days, (range, 1–110). At discharge, significant reduction was observed in dyspnea, total leukocyte count, erythrocyte sedimentation rate (ESR), partial pressure of carbon dioxide, hemoglobin, urea, creatinine, potassium, aspartate transferase, and TNF-α levels compared to baseline, whereas arterial pH, PO2, serum albumin, prealbumin, and leptin significantly improved. No difference was seen in leptin, prealbumin, and TNF-α between patients with mild/moderate and severe exacerbation, or between patients who required or did not require mechanical ventilation. Change in leptin correlated with body mass index and change in ESR; no associations were observed between leptin, prealbumin, and TNF-α with other clinico-laboratory variables. Conclusion: Plasma levels of novel inflammatory and nutritional biomarkers, i.e., leptin, TNF-α, and prealbumin are altered in AECOPD episodes and lag behind other parameters during recovery. These biomarkers are not reliable predictors of clinical outcomes in these patients.