Uncontrolled pilot studies demonstrated promising results of endoscopic lung volume reduction using emphysematous lung sealant (ELS) in patients with advanced, upper lobe predominant emphysema. We ...aimed to evaluate the safety and efficacy of ELS in a randomised controlled setting.Patients were randomised to ELS plus medical treatment or medical treatment alone. Despite early termination for business reasons and inability to assess the primary 12-month end-point, 95 out of 300 patients were successfully randomised, providing sufficient data for 3- and 6-month analysis.57 patients (34 treatment and 23 control) had efficacy results at 3 months; 34 (21 treatment and 13 control) at 6 months. In the treatment group, 3-month lung function, dyspnoea, and quality of life improved significantly from baseline when compared to control. Improvements persisted at 6 months with >50% of treated patients experiencing clinically important improvements, including some whose lung function improved by >100%. 44% of treated patients experienced adverse events requiring hospitalisation (2.5-fold more than control, p=0.01), with two deaths in the treated cohort. Treatment responders tended to be those experiencing respiratory adverse events.Despite early termination, results show that minimally invasive ELS may be efficacious, yet significant risks (probably inflammatory) limit its current utility.
Objective: To characterize by molecular methods a multidrug-resistant Salmonella enterica serovar Agona (S. enterica Agona) isolated from a hospitalized patient in Rio de Janeiro, Brazil. Methods: ...The S. enterica Agona strain was screened by PCR and DNA sequencing for TEM, SHV and CTX-M-type ²-lactamase genes, tet(A), (B), (C) and (D) tetracycline resistance genes, chloramphenicol resistance genes and class 1 integrons. Plasmid characterization was carried out by PCR and Southern hybridization analysis. PCR and PFGE were used to characterize nine other S. enterica Agona strains collected from hospitals in Rio de Janeiro. Results: The study strain was found to harbour a 105 kb plasmid, which contained catA1, bla TEM-1 , a class 1 integron with two novel genes labelled bla OXA-53 and aac(6')-I30, respectively, and an additional unidentified aminoglycoside resistance gene. A second 53 kb plasmid from the same strain contained tet(D) and bla SHV-5 . OXA-53 was shown to provide reduced susceptibility to ceftazidime, and its activity was inhibited in the presence of clavulanic acid. PFGE analysis of the nine other S. enterica Agona strains revealed two clusters of related strains (78% similarity), and PCR analysis showed that all strains contained the novel integron. Conclusion: An S. enterica Agona strain was found to harbour three plasmid-encoded ²-lactamases, one (OXA-53) on a novel class 1 integron that also contains a new aminoglycoside resistance gene, aac(6')-I30. The multidrug resistance plasmids appear to have disseminated to other city hospitals via other S. enterica Agona strains.
Flavin-containing monooxygenases (FMO) catalyze the oxidation of certain xenobiotics and drugs which contain a nucleophilic heteroatom. Here we report the first assessment of human brain ...flavin-containing monooxygenase from tissues obtained at autopsy from seven traffic accident victims. Human brain microsomes catalyzed the
S-oxidation or
N-oxidation of model substrates methimazole and
N,N-dimethylaniline, respectively. The psychoactive drugs chlorpromazine, imipramine and fluoxetine, were also metabolized by human brain FMO. ‘Western’ immunoblot analyses revealed immunological cross-reactivity of the human brain FMO with rabbit pulmonary FMO. Immunocytochemistry further revealed the localization of the FMO predominantly in the neuronal cell bodies in the magnocellular reticular nuclei, colliculi and substantia nigra. Human brain clearly contains an active FMO system, and it is conceivable that such enzyme(s) are significantly involved in the local metabolism and modulation of pharmacological effects of psychoactive drugs.
Members of a domestic cat colony with chylomicronemia share many phenotypic features with human lipoprotein lipase (LPL) deficiency. Biochemical analysis reveals that these cats do have defective LPL ...catalytic activity and have a clinical phenotype very similar to human LPL deficiency. To determine the molecular basis underlying this biochemical phenotype, we have cloned the normal and affected cat LPL cDNAs and shown that the affected cat has a nucleotide change resulting in a substitution of arginine for glycine at residue 412 in exon 8. In vitro mutagenesis and expression studies, in addition to segregation analysis, have shown that this DNA change is the cause of LPL deficiency in this cat colony. Reduced body mass, growth rates, and increased stillbirth rates are observed in cats homozygous for this mutation. These findings show that this LPL deficient cat can serve as an animal model of human LPL deficiency and will be useful for in vivo investigation of the relationship between triglyceride rich lipoproteins and atherogenic risk and for the assessment of new approaches for treatment of LPL deficiency, including gene therapy.
Like a star chart this volume orientates the reader to the key issues and debates in Pacific and Australasian biogeography, palaeoecology and human ecology. A feature of this collection is the ...diversity of approaches ranging from interpretation of the biogeographic significance of plant and animal distributional patterns, pollen analysis from peats and lake sediments to discern Quaternary climate change, explanation of the patterns of faunal extinction events, the interplay of fire on landscape evolution, and models of the environmental consequences of human settlement patterns. The diversity of approaches, geographic scope and academic rigor are a fitting tribute to the enormous contributions of Geoff Hope. As made apparent in this volume, Hope pioneered multidisciplinary understanding of the history and impacts of human cultures in the Australia- Pacific region, arguably the globe's premier model systems for understanding the consequences of human colonization on ecological systems. The distinguished scholars who have contributed to this volume also demonstrate Hope's enduring contribution as an inspirational research leader, collaborator and mentor. Terra Australis leave no doubt that history matters, not only for land management, but more importantly, in alerting settler and indigenous societies alike to their past ecological impacts and future environmental trajectories.
Ebola virus (Ebo) causes severe hemorrhagic fever and high mortality in humans. There are currently no effective therapies. Here, we have explored potential anti-Ebo activity of the human ...immunodeficiency virus (HIV)-inactivating protein cyanovirin-N (CV-N). CV-N is known to potently inhibit the infectivity of a broad spectrum of HIV strains at the level of viral entry. This involves CV-N binding to N-linked high-mannose oligossacharides on the viral glycoprotein gp120. The Ebola envelope contains somewhat similar oligosaccharide constituents, suggesting possible susceptibility to inhibition by CV-N. Our initial results revealed that CV-N had both in vitro and in vivo antiviral activity against the Zaire strain of the Ebola virus (Ebo-Z). Addition of CV-N to the cell culture medium at the time of Ebo-Z infection inhibited the development of viral cytopathic effects (CPEs). CV-N also delayed the death of Ebo-Z-infected mice, both when given as a series of daily subcutaneous injections and when the virus was incubated ex vivo together with CV-N before inoculation into the mice. Furthermore, similar to earlier results with HIV gp120, CV-N bound with considerable affinity to the Ebola surface envelope glycoprotein, GP
1,2. Competition experiments with free oligosaccharides were consistent with the view that carbohydrate-mediated CV-N/GP
1,2 interactions involve oligosaccharides residing on the Ebola viral envelope. Overall, these studies broaden the range of viruses known to be inhibited by CV-N, and further implicate carbohydrate moieties on viral surface proteins as common viral molecular targets for this novel protein.
The total synthesis of both michellamine A (1a) and B (1b), by consecutive construction first of the inner (non-stereogenic) axis and subsequently the two outer (stereogenic) axes in a highly ...convergent manner, is described. The michellamines are of considerable interest due to their pronounced anti-HIV activity.
During a survey of latex samples of Calophyllum teysmannii for anti-HIV coumarins (calanolide A, costatolide), calanone, an unprecedented benzoyl substituted coumarin, was isolated and its structure ...determined by spectroscopic analyses. The known soulattrolide, and the related ketone 4 were also isolated. Soulattrolide inhibited the cytopathic effect of in vitro HIV-1 infection, while calanone and the ketone 4 were inactive.
Electron bifurcation is the coupling of exergonic and endergonic redox reactions to simultaneously generate (or utilize) low- and high-potential electrons. It is the third recognized form of energy ...conservation in biology and was recently described for select electron-transferring flavoproteins (Etfs). Etfs are flavin-containing heterodimers best known for donating electrons derived from fatty acid and amino acid oxidation to an electron transfer respiratory chain via Etf-quinone oxidoreductase. Canonical examples contain a flavin adenine dinucleotide (FAD) that is involved in electron transfer, as well as a non-redox-active AMP. However, Etfs demonstrated to bifurcate electrons contain a second FAD in place of the AMP. To expand our understanding of the functional variety and metabolic significance of Etfs and to identify amino acid sequence motifs that potentially enable electron bifurcation, we compiled 1,314 Etf protein sequences from genome sequence databases and subjected them to informatic and structural analyses. Etfs were identified in diverse archaea and bacteria, and they clustered into five distinct well-supported groups, based on their amino acid sequences. Gene neighborhood analyses indicated that these Etf group designations largely correspond to putative differences in functionality. Etfs with the demonstrated ability to bifurcate were found to form one group, suggesting that distinct conserved amino acid sequence motifs enable this capability. Indeed, structural modeling and sequence alignments revealed that identifying residues occur in the NADH- and FAD-binding regions of bifurcating Etfs. Collectively, a new classification scheme for Etf proteins that delineates putative bifurcating versus nonbifurcating members is presented and suggests that Etf-mediated bifurcation is associated with surprisingly diverse enzymes.
Electron bifurcation has recently been recognized as an electron transfer mechanism used by microorganisms to maximize energy conservation. Bifurcating enzymes couple thermodynamically unfavorable reactions with thermodynamically favorable reactions in an overall spontaneous process. Here we show that the electron-transferring flavoprotein (Etf) enzyme family exhibits far greater diversity than previously recognized, and we provide a phylogenetic analysis that clearly delineates bifurcating versus nonbifurcating members of this family. Structural modeling of proteins within these groups reveals key differences between the bifurcating and nonbifurcating Etfs.
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