Multidrug-resistant tuberculosis (MDRTB) has emerged as a major public health problem worldwide. To determine the incidence and risk factors associated with tuberculosis among contacts of MDRTB index cases, we studied human immunodeficiency virus-seronegative close contacts of 64 culture-confirmed MDRTB patients in Rio de Janeiro, Brazil. Between March 1988 and July 1992, tuberculosis developed in 17 (7.8%) of 218 previously healthy close contacts of 64 MDRTB index cases (1.6 cases per 1,000-person-months of contact). Among strains of Mycobacterium tuberculosis isolated from 13 contacts of 12 index cases, six (46%) had susceptibility patterns identical to those of their index cases, four (31%) had different patterns of resistance, and three (23%) were susceptible to all drugs. Tuberculosis developed more frequently in male contacts (p < 0.05), persons > or = 15 yr of age (p < 0.05), nonwhites (p < 0.001), and persons not previously vaccinated with bacillus Calmette-Guerin (BCG) (p < 0.05). The association of BCG vaccination with decreased risk of disease was significant even when this variable was controlled (by Cox's regression analysis) for age, sex, race, purified protein derivative (PPD) status, and isoniazid prophylaxis. BCG vaccination appears to offer protection against tuberculosis during prolonged exposures to persons with MDRTB, which identifies a novel and specific indication of BCG use.
Activation of the enzyme indoleamine 2,3-dioxygenase 1 (IDO1) underlies the course of several human pathological conditions and, to date, no efficacious therapeutic IDO inhibitors are available. We proposed to develop a robust screening system based on the use of yeast cells to identify new lead compounds for the pharmacological inhibition of IDO-the BLOCKADE platform. Yeast combines the advantages of a relevant surrogate model for eukaryotic cell processes with the amenity to miniaturization and automation. We brought added value to the system by increasing the stringency of our assay, as the BLOCKADE strain was not deleted for any efflux pump, thus creating additional challenges for test compounds to be identified as hits. Screening of a library of 50 080 small molecules led to the identification of 101 potential IDO inhibitors, a low hit rate of 0.2%, reflecting the stringent assay conditions imposed. Most important, secondary pharmacology assays in mammalian cells confirmed activity for 76% of the hits, whereas hepatotoxicity testing indicated that 87% of them displayed a safe profile. The high predictivity rates obtained using the BLOCKADE platform clearly validate our system as a powerful tool for drug discovery.
Interesting biological activities have been found for numerous marine compounds. In fact, screening of phylogenetically diverse marine microorganisms from extreme environments revealed to be a rational approach for the discovery of novel molecules with relevant bioactivities for industries such as pharmaceutical and cosmeceutical. Nevertheless, marine sources deliverables are still far from the expectations and new extreme sources of microbes should be explored. In this work, a marine prokaryotic collection from four Mid-Atlantic Ridge (MAR) deep sea hydrothermal vents near the Azores Islands, Portugal, was created, characterized and tested for its photoprotective capacity. Within 246 isolates, a polyphasic approach, using chemotaxonomic and molecular typing methods, identified 23-related clusters of phenetically similar isolates with high indexes of diversity. Interestingly, 16S rRNA gene sequencing suggested the presence of 43% new prokaryotic species. A sub-set of 139 isolates of the prokaryotic collection was selected for biotechnological exploitation with 484 bacterial extracts prepared in a sustainable upscalling manner. 22% of the extracts showed an industrially relevant photoprotective activity, with two extracts, belonging to new strains of the species Shewanella algae and Vibrio fluvialis, uniquely showing UV-A, UV-B and UV-C protective capacity. This clearly demonstrates the high potential of the bacteria MAR vents collection in natural product synthesis with market applications.
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