Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

Treatment of the Breast’s Lateral Pole: Adjuvant Maneuver to Pitanguy’s Technique

Surgical procedures for the mammary region currently are assuming an important role in body-contouring surgery. Enhancement of results is a constant challenge to the plastic surgeon. A simple and efficient maneuver for resection of the breast’s lateral pole based on the mammoplasty technique of Professor Ivo Pitanguy is described. This study realized at the Private Clinic Sérgio Carreir?o, Rio de Janeiro, RJ, Brazil.     

Relationship Between Exhaled Carbon Monoxide and Airway Hyperresponsiveness in Asthmatic Patients

The study objectives were to analyze the changes in exhaled carbon monoxide (COex) induced by histamine provocation challenge in asthmatic patients and to evaluate the relationship between COex and airway sensitivity and reactivity. Levels of COex were measured in 105 nonsmoking mildly asthmatic subjects before and after histamine provocation challenge. Dose-response curves were characterized by their sensitivity (PD₂₀) and reactivity. Dose-response slope (DRS), continuous index of responsiveness (CIR), and bronchial reactivity index (BRI) were determined as reactivity indices. Bronchial challenge was positive for 47 subjects and negative for 58. The COex levels rose significantly after bronchial challenge in the positive response group (4.49 ± 0.4 vs. 5.74 ± 0.57 ppm, p = 0.025) and in the negative response group (2.84 ± 0.25 vs 4.00 ± 0.41 ppm, p = 0.000). An inverse relation between basal COex and PD₂₀ was found (r = - 0.318, p = 0.030). In all subjects, a proportional direct relationship between COex and DRS (r = 0.214, p = 0.015), CIR (r = 0.401, p = 0.000), and BRI (r = 0.208, p = 0.012) was observed. On stepwise multiple linear regression analysis, COex only significantly correlated with CIR (multiple r² = 0.174, p = 0.000). In conclusion, exhaled CO determination is a noninvasive inflammatory marker of the respiratory tract, which shows an acceptable association with airway hyperresponsiveness.     

Early onset Alzheimer's disease in a South American pedigree from Argentina

We report the clinical, SPET, immunohistochemical and DNA features of an early-onset familial Alzheimer's disease (FAD) in an Argentine pedigree of South American indian ethnic background. Pedigree spans 5 generations comprising more than 110 biological relatives. Clinical data supported the diagnosis of early onset FAD (mean age at onset 38.9 years) in 10 family members, including 3 with pathological confirmation (mean age at death 48.5). The pattern of transmission suggested autosomal dominant inheritance. Prominent features were mood changes, early language impairment, myoclonus, seizures and cerebellar signs. SPET displayed bilateral frontal, temporo-parietal and cerebellar hypoperfusion in early stages and in an asymptomatic member at risk, suggesting that SPET may have predictive value in this family. Immunohistochemistry showed β amyloid deposits within neuritic plaques and vessel walls and no anti-PrP immunoreactivity. DNA analysis showed no abnormalities in the β amyloid precursor protein gene. The identification of additional genetic defects in well characterized independent FAD pedigrees will contribute to the understanding of the pathogenesis of Alzheimer's disease.     

How reproducible is cutaneous electrogastrography? An in-depth evidence-based study1

AIM: To check on reproducibility of parameters of the cutaneous electrogastrogram registered at a close or a distant time span. METHODS: Twenty-two volunteers recruited by an advertisement (11 females and 11 males, median age 25 years, range: 18-35) underwent three surface electrogastrography examinations of which two were taken on consecutive days and the third one was accomplished at least 2 weeks before or after the two other sessions. The examination involved a 30-min fasted recording, followed by a 90-min postprandial registration after intake of a 394-kcal mixed solid-liquid test meal. RESULTS: Parameters of the electrogastrogram pertaining to the frequency of the gastric slow waves exhibited good to moderate reproducibility, whereas fair reproducibility characterized parameters expected to describe the power of gastric slow waves. With the exception of the difference fed minus fasted power (DeltaDP), in no instance was the medium term reproducibility any worse than the short term one. Categorical data analysis revealed that the relative time share of normogastria postprandially exhibited a better reproducibility than in the fasted period. The Cohen's kappa-value of 0.459 for the DeltaDP for the medium term reproducibility placed this parameter within the range of moderate agreement between repeat examinations. Of the two two-parameter combinations considered, the alliance of the fasted and fed normogastria performed worse than any of those parameters considered alone, whereas a combination of the DeltaDP with the fed-state normogastria revealed a kappa-value amounting to 0.510 for the medium term reproducibility. CONCLUSIONS: The feasibility of some electrogastrographic parameters to convey clinically useful information may be hampered by their fair reproducibility. Recoding of parameters of the cutaneous electrogastrogram from primary continuous to secondary categorical may help achieve a better agreement between repeat examinations.