Reduction of small infrarenal abdominal aortic aneurysm expansion rate by statins.

BACKGROUND: To evaluate the effect of statins on the annual expansion rate (ER) of small infrarenal abdominal aortic aneurysms (AAA). PATIENTS AND METHODS: All patients under regular surveillance for small AAA between January 2000 and September 2007, in the Department of Angiology, Lausanne University Hospital, were included. Inclusion criteria were baseline abdominal aortic diameter between 25 and 55 mm, at least two measurements of AAA diameter and a minimum follow up of 6 months. Patients with Marfan disease, infectious or inflammatory AAA, and patients with prior AAA repair were excluded. The influence of statin use and other factors on ER were examined by bivariate and multivariate analysis. RESULTS: Among 589 patients who underwent an abdominal aorta evaluation, 94 patients (89 % men, mean age 69.1 years) were finally included in the analysis. Baseline AAA size was 39.9 ± 7.7 mm (mean±SE) and 48.7 ± 8.4 mm at end of follow-up. Patients had a regular aneurysm size assessment during 38.5 ± 27.7 months. Mean ER was 3.59 mm/y (± 2.81). The 50 patients who were treated with statin during the study period had a lower ER compared to the 44 controls (2.91 vs 4.37 mm/year, p = 0.01). CONCLUSIONS: This study confirms the considerable individual variations in the AAA expansion rate, and emphasizes the need for regular aortic diameter assessments. In this study, patients treated with statin demonstrate a significant decrease in the ER compared to controls. This finding need to be evaluated in prospective interventional studies powered to demonstrate the potential benefit of statin treatment.

A novel cyanide-inducible gene cluster helps protect Pseudomonas aeruginosa from cyanide

Pseudomonas aeruginosa produces the toxic secondary metabolite hydrogen cyanide (HCN) at high cell population densities and low aeration. Here, we investigated the impact of HCN as a signal in cell-cell communication by comparing the transcriptome of the wild-type strain PAO1 to that of an HCN-negative mutant under cyanogenic conditions. HCN repressed four genes and induced 12 genes. While the individual functions of these genes are unknown, with one exception (i.e. a ferredoxin-dependent reductase), a highly inducible six-gene cluster (PA4129-PA4134) was found to be crucial for protection of P.aeruginosa from external HCN intoxication. A double mutant deleted for PA4129-PA4134 and cioAB (encoding cyanide-insensitive oxidase) did not grow with 100M KCN, whereas the corresponding single mutants were essentially unaffected, suggesting a synergistic action of the PA4129-PA4134 gene products and cyanide-insensitive oxidase.

A Comparative Study of the Organic Acid Content of the Hemolymph of Schistosoma mansoni-Resistant and Susceptible Strains of Biomphalaria glabrata

The freshwater snail Biomphalaria glabrata is an intermediate host of the trematode Schistosoma mansoni. However, some strains of B. glabrata are resistant to successful infection by S. mansoni larvae. The present work examines the profile of organic acids present in S. mansoni-resistant and -susceptible strains of B. glabrata, in order to determine whether the type of organic acid present is related to susceptibility. The organic acids were extracted from the hemolymph of two susceptible B. glabrata strains (PR, Puerto Rico and Ba, Jacobina-Bahia from Brazil), and from the resistant strains 13-16-R1 and 10R2, using solid phase extraction procedures followed by high performance liquid chromatography. The organic acids obtained were analyzed and identified by comparison with known standards. Pyruvate, lactate, succinate, malate, fumarate, acetate, propionate, ß-hydroxybutyrate and acetoacetate were detected in all hemolymph samples. Under standard conditions, the concentration of each of these substances varied among the strains tested and appeared to be specific for each strain. An interesting variation was the low concentration of pyruvate in the hemolymph of PR-snails. Only the concentration of fumarate was consistently different (p£ 0.05) between resistant and susceptible strains

Plasmodium falciparum: nitric oxide modulates heme speciation in isolated food vacuoles.

Nitric oxide (NO) and NO-derived reactive nitrogen species (RNS) are present in the food vacuole (FV) of Plasmodium falciparum trophozoites. The product of PFL1555w, a putative cytochrome b(5), localizes in the FV membrane, similar to what was previously observed for the product of PF13_0353, a putative cytochrome b(5) reductase. These two gene products may contribute to NO generation by denitrification chemistry from nitrate and/or nitrite present in the erythrocyte cytosol. The possible coordination of NO to heme species present in the food vacuole was probed by resonance Raman spectroscopy. The spectroscopic data revealed that in situ generated NO interacts with heme inside the intact FVs to form ferrous heme nitrosyl complexes that influence intra-vacuolar heme solubility. The formation of heme nitrosyl complexes within the FV is a previously unrecognized factor that could affect the equilibrium between soluble and crystallized heme within the FV in vivo.

Pharmacological Approaches to Antitrypanosomal Chemotherapy

There is an urgent need for new drugs for the chemotherapy of human African trypanosomiasis, Chagas disease and leishmaniasis. Progress has been made in the identification and characterization of novel drug targets for rational chemotherapy and inhibitors of trypanosomatid glycosomal enzymes, trypanothione reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, cysteine proteases and of the purine and sterol biosynthetic pathways. However, less attention has been paid to the pharmacological aspects of drug design or to the use of drug delivery systems in the chemotherapy of African trypanosomiasis and Chagas disease. A review of research on pharmacology and drug delivery systems shows that there are new opportunities for improving the chemotherapy of these diseases.

Profile of organic acid concentrations in the digestive gland and hemolymph of Biomphalaria glabrata under estivation

Using high performance liquid chromatography (HPLC) analysis it was possible to determine simultaneously the concentration of organic acids (pyruvate, lactate, succinate, fumarate, malate, acetate, propionate, acetoacetate, and ß-hydroxybutyrate) in the digestive gland and the extracellular concentration of these same acids in the hemolymph of estivating Biomphalaria glabrata, the intermediate host of Schistosoma mansoni. After a 7 day period of estivation, there was a significant increase in the tissue levels of lactate, succinate, malate and acetate compared to non-estivating snails. After 14 days of estivation, the levels of lactate and acetate were also significantly elevated. The hemolymph concentrations of pyruvate and acetate increased significantly after 7 days and acetate concentrations continued to be significantly increased up to 14 days of estivation. The other organic acids studied, such as ketone body acetoacetate and ß-hydroxybutyrate or the volatile acid propionate, did not accumulate. Their tissue concentrations, however, increased on the 7th day of estivation and reached normal levels within two weeks of estivation for some of them. One should take into consideration how the reduction in metabolism can be handled under aerobic conditions, and what role anaerobic pathways may play in both energy formation and redox balance processes.

Cytotoxic effects of combination of oxidosqualene cyclase inhibitors with atorvastatin in human cancer cells.

Ten oxidosqualene cyclase inhibitors with high efficacy as cholesterol-lowering agents and of different chemical structure classes were evaluated as potential anticancer agents against human cancer cells from various tissue origins and nontumoral human-brain-derived endothelial cells. Inhibition of cancer cell growth was demonstrated at micromolar concentrations, comparable to the concentrations of statins necessary for antitumor effect. Human glioblastoma cells were among the most sensitive cells. These compounds were also able to decrease the proliferation of angiogenic brain-derived endothelial cells, as a model of tumor-induced neovasculation. Additive effects in human glioblastoma cells were also demonstrated for oxidosqualene cyclase inhibitors in combination with atorvastatin while maintaining selectivity against endothelial cells. Thus, not only statins targeting the 3-hydroxy-3-methylglutaryl coenzyme A reductase but also inhibitors of oxidosqualene cyclase decrease tumor growth, suggesting new therapeutic opportunities of combined anti-cholesterol agents for dual treatment of glioblastoma.

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

IMPORTANCE: New data and antiretroviral regimens expand treatment choices in resource-rich settings and warrant an update of recommendations to treat adults infected with human immunodeficiency virus (HIV). OBJECTIVE: To provide updated treatment recommendations for adults with HIV, emphasizing when to start treatment; what treatment to start; the use of laboratory monitoring tools; and managing treatment failure, switches, and simplification. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: An International Antiviral Society-USA panel of experts in HIV research and patient care considered previous data and reviewed new data since the 2012 update with literature searches in PubMed and EMBASE through June 2014. Recommendations and ratings were based on the quality of evidence and consensus. RESULTS: Antiretroviral therapy is recommended for all adults with HIV infection. Evidence for benefits of treatment and quality of available data increase at lower CD4 cell counts. Recommended initial regimens include 2 nucleoside reverse transcriptase inhibitors (NRTIs; abacavir/lamivudine or tenofovir disoproxil fumarate/emtricitabine) and a third single or boosted drug, which should be an integrase strand transfer inhibitor (dolutegravir, elvitegravir, or raltegravir), a nonnucleoside reverse transcriptase inhibitor (efavirenz or rilpivirine) or a boosted protease inhibitor (darunavir or atazanavir). Alternative regimens are available. Boosted protease inhibitor monotherapy is generally not recommended, but NRTI-sparing approaches may be considered. New guidance for optimal timing of monitoring of laboratory parameters is provided. Suspected treatment failure warrants rapid confirmation, performance of resistance testing while the patient is receiving the failing regimen, and evaluation of reasons for failure before consideration of switching therapy. Regimen switches for adverse effects, convenience, or to reduce costs should not jeopardize antiretroviral potency. CONCLUSIONS AND RELEVANCE: After confirmed diagnosis of HIV infection, antiretroviral therapy should be initiated in all individuals who are willing and ready to start treatment. Regimens should be selected or changed based on resistance test results with consideration of dosing frequency, pill burden, adverse toxic effect profiles, comorbidities, and drug interactions.

Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone

Chloroquine has been the mainstay of malaria chemotherapy for the past five decades, but resistance is now widespread. Pyrimethamine or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance. Both pyrimethamine and proguanil are dihydrofolate reductase (DHFR) inhibitors, the proguanil acting primarily through its major metabolite cycloguanil. Resistance to these drugs arises due to specific point mutations in the dhfr gene. Cross resistance between cycloguanil and pyrimethamine is not absolute. It is, therefore, important to investigate mutation rates in P. falciparum for pyrimethamine and proguanil so that DHFR inhibitor with less mutation rate is favored in drug combinations. Hence, we have compared mutation rates in P. falciparum genome for pyrimethamine and cycloguanil. Using erythrocytic stages of P. falciparum cultures, progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence. Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil. It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs.

Microautophagy of the nucleus coincides with a vacuolar diffusion barrier at nuclear-vacuolar junctions.

Nuclei bind yeast vacuoles via nucleus-vacuole (NV) junctions. Under nutrient restriction, NV junctions invaginate and release vesicles filled with nuclear material into vacuoles, resulting in piecemeal microautophagy of the nucleus (PMN). We show that the electrochemical gradient across the vacuolar membrane promotes invagination of NV junctions. Existing invaginations persist independently of the gradient, but final release of PMN vesicles requires again V-ATPase activity. We find that NV junctions form a diffusion barrier on the vacuolar membrane that excludes V-ATPase but is enriched in the VTC complex and accessible to other membrane-integral proteins. V-ATPase exclusion depends on the NV junction proteins Nvj1p,Vac8p, and the electrochemical gradient. It also depends on factors of lipid metabolism, such as the oxysterol binding protein Osh1p and the enoyl-CoA reductase Tsc13p, which are enriched in NV junctions, and on Lag1p and Fen1p. Our observations suggest that NV junctions form in two separable steps: Nvj1p and Vac8p suffice to establish contact between the two membranes. The electrochemical potential and lipid-modifying enzymes are needed to establish the vacuolar diffusion barrier, invaginate NV junctions, and form PMN vesicles.

Urologie [Urology in 2011].

In 2011, therapeutic acquisitions in urology allow optimizing management of acute uncomplicated cystitis and acute pyelonephritis by female patients and in men clinical implications of benign prostatic hyperplasia opposed to prostate cancer detection as well as hormonal treatment of advanced prostate cancer.

Replacement therapy for iron deficiency improves exercise capacity and quality of life in patients with cyanotic congenital heart disease and/or the Eisenmenger syndrome

La teràpia suplementària de ferro millora la capacitat d’exercici i la qualitat de vida en malalts amb una cardiopatia congènita cianòtica i/ o síndrome d’Eisenmenger El dèficit de ferro és una troballa comú en la cardiopatia congènita cianòtica, i pot ser la causa d’una reducció en la capacitat d’exercici. Actualment, està indicada la reposició dels dipòsits de ferro en aquest grup de malalts, éssent les evidències científiques escasses. En el present treball investiguem la seguretat i eficàcia del tractament amb ferro en malalts amb una cardiopatia congènita cianòtica. Per tal motiu, vint-i-cinc malalts amb una cardiopatia congenita cianòtica i dèficit de ferro van ser inclosos de forma prospectiva entre Agost del 2008 i Gener del 2009. El tractament utilitzat fou fumarat ferròs oral, fins a una dosi màxima de 200 mg tres vegades al dia. En l’anàlisi basal i als tres mesos de seguiment es va utilitzar el test de qualitat de vida “CAMPHOR”, el test de la marxa dels 6 minuts i la prova d’esforç amb consum d’oxigen. L’edat mitja fou 39.9+/-10.9 anys, 80% dones. Catorze malalts tenien la síndrome d’Eisenmenger, sis una malaltia cianòtica complexa i cinc circulació de Fontan. Cap d’ells va haver d'interrompre el tractament degut a efectes adversos. Després de tres mesos de tractament, l’hemoglobina (19.0+/-2.9g/dL a 20.4+/-2.7g/dL, p&0.001), ferritina (13.3+/-4.7mug/L a 54.1+/-24.2mug/L, p&0.001) i saturació de transferrina (17.8+/-9.6% a 34.8+/-23.4%, p&0.001) van augmentar significativament. També hi va haver una millora significativa en la puntuació del test de qualitat de vida (20.7+/-10.9 a 16.2+/-10.4, p=0.001) i el test de la marxa (371.7+/-84.7m a 402.8.0+/-74.9m, p=0.001). No es van evidenciar canvis significatius en els valors de consum d’oxigen (40.7+/-9.2% a 43.8+/-12.4%, p=0.15). En definitiva, la teràpia suplementària amb ferro en els malats amb una cardiopatia congènita cianòtica i dèficit de ferro és segura i millora la qualitat de vida i la capacitat funcional. En aquest grup de malalts, per tant, és aconsellable identificar el dèficit de ferro i restaurar-ne els seus dipòsits.

Genetic analysis of phenoxyalkanoic acid degradation in Sphingomonas herbicidovorans MH.

Phenoxyalkanoic acid degradation is well studied in Beta- and Gammaproteobacteria, but the genetic background has not been elucidated so far in Alphaproteobacteria. We report the isolation of several genes involved in dichlor- and mecoprop degradation from the alphaproteobacterium Sphingomonas herbicidovorans MH and propose that the degradation proceeds analogously to that previously reported for 2,4-dichlorophenoxyacetic acid (2,4-D). Two genes for alpha-ketoglutarate-dependent dioxygenases, sdpA(MH) and rdpA(MH), were found, both of which were adjacent to sequences with potential insertion elements. Furthermore, a gene for a dichlorophenol hydroxylase (tfdB), a putative regulatory gene (cadR), two genes for dichlorocatechol 1,2-dioxygenases (dccA(I/II)), two for dienelactone hydrolases (dccD(I/II)), part of a gene for maleylacetate reductase (dccE), and one gene for a potential phenoxyalkanoic acid permease were isolated. In contrast to other 2,4-D degraders, the sdp, rdp, and dcc genes were scattered over the genome and their expression was not tightly regulated. No coherent pattern was derived on the possible origin of the sdp, rdp, and dcc pathway genes. rdpA(MH) was 99% identical to rdpA(MC1), an (R)-dichlorprop/alpha-ketoglutarate dioxygenase from Delftia acidovorans MC1, which is evidence for a recent gene exchange between Alpha- and Betaproteobacteria. Conversely, DccA(I) and DccA(II) did not group within the known chlorocatechol 1,2-dioxygenases, but formed a separate branch in clustering analysis. This suggests a different reservoir and reduced transfer for the genes of the modified ortho-cleavage pathway in Alphaproteobacteria compared with the ones in Beta- and Gammaproteobacteria.

Sativa seeds against Schistosoma mansoni different stages

The schistosomicidal properties of Nigella sativaseeds were tested in vitro against Schistosoma mansoni miracidia, cercariae, and adult worms. Results indicate its strong biocidal effects against all stages of the parasite and also showed an inhibitory effect on egg-laying of adult female worms. In the present work we also studied the effects of crushed seeds on some antioxidant enzymes; which have a role in protection of adult worms against host oxidant killing; as well as some enzymes of glucose metabolism; which have a crucial role in the survival of adult worms inside their hosts. The data revealed that the used drug induce an oxidative stress against adult worms which indicated by a decrease in the activities of both antioxidant enzymes, superoxide dismutase, glutathione peroxidase, and glutathione reductase and enzymes of glucose metabolism, hexokinase and glucose-6-phosphate dehydrogenase. Disturbing of such enzymes of adult worms using N. sativa seeds could in turn render the parasite vulnerable to damage by the host and may play a role in the antischistosomal potency of the used drug.