Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Comparison of five bacterial strains producing siderophores with ability to chelate iron under alkaline conditions

Iron deficiency is one of the main causes of chlorosis in plants, which leads to losses in field crops quality and yield. The use of synthetic chelates to prevent or correct iron-deficiency is not satisfactory mainly due to their poor biodegradability. The present work aimed to search suitable microorganisms to produce alternative, environment-friendly iron-chelating agents (siderophores). For this purpose, the performance of five bacteria (Azotobacter vinelandii, Bacillus megaterium, Bacillus subtilis, Pantoea allii and Rhizobium radiobacter) was evaluated, regarding siderophore production kinetics, level of siderophore production (determined by chrome azurol S, CAS method), type of siderophore produced (using Arnow and Csaky's tests) and iron-chelating capacity at pH 9.0. All bacteria were in stationary phase at 24 h, except A. vinelandii (at 72 h) and produced the maximum siderophore amount (80--140 \textmumol L?1) between 24 and 48 h, with the exception of A. vinelandii (at 72 h). The analysis of culture filtrates revealed the presence of catechol-type siderophores for B. subtilis and R. radiobacter and hydroxamate-type siderophores for B. megaterium and P. allii. In the case of A. vinelandii, both siderophore-types (catechol and hydroxamates) were detected. The highest iron-chelating capacity, at pH 9.0, was obtained by B. megaterium followed by B. subtilis and A. vinelandii. Therefore, these three bacteria strains are the most promising bacteria for siderophore production and chlorosis correction under alkaline conditions.This work is financed by the FEDER funds through the Operational Competitiveness Factors Program—COMPETE and by national funds through FCT—Foundation for Science and Technology within the scope of the project PTDC‑AGR‑TEC/0458/2014—POCI‑01‑0145‑FEDER‑016681.info:eu-repo/semantics/publishedVersio

Altered composition and functional profile of high-density lipoprotein in leprosy patients.

The changes in host lipid metabolism during leprosy have been correlated to fatty acid alterations in serum and with high-density lipoprotein (HDL) dysfunctionality. This is most evident in multibacillary leprosy patients (Mb), who present an accumulation of host lipids in Schwann cells and macrophages. This accumulation in host peripheral tissues should be withdrawn by HDL, but it is unclear why this lipoprotein from Mb patients loses this function. To investigate HDL metabolism changes during the course of leprosy, HDL composition and functionality of Mb, Pb patients (paucibacillary) pre- or post-multidrug therapy (MDT) and HC (healthy controls) were analyzed. Mb pre-MDT patients presented lower levels of HDL-cholesterol compared to HC. Moreover, Ultra Performance Liquid Chromatography-Mass Spectrometry lipidomics of HDL showed an altered lipid profile of Mb pre-MDT compared to HC and Pb patients. In functional tests, HDL from Mb pre-MDT patients showed impaired anti-inflammatory and anti-oxidative stress activities and a lower cholesterol acceptor capacity compared to other groups. Mb pre-MDT showed lower concentrations of ApoA-I (apolipoprotein A-I), the major HDL protein, when compared to HC, with a post-MDT recovery. Changes in ApoA-I expression could also be observed in M. leprae-infected hepatic cells. The presence of bacilli in the liver of a Mb patient, along with cell damage, indicated hepatic involvement during leprosy, which may reflect on ApoA-I expression. Together, altered compositional and functional profiles observed on HDL of Mb patients can explain metabolic and physiological changes observed in Mb leprosy, contributing to a better understanding of its pathogenesis

Poesia e infância: o corpo em viva voz Poetry and childhood: the body in live voice

Neste artigo busco problematizar a possibilidade desafiadora, colocada à escola da infância, de perceber o vínculo da leitura de poemas com sua potência enquanto experiência poética que pode ser conquistada em viva voz por um corpo que sente. No momento em que, no cenário educacional brasileiro, discute-se o currículo das escolas de Educação Infantil, o texto defende, a partir dos aportes teóricos da imaginação criadora em Gaston Bachelard; da pedagogia poética em Georges Jean; da performance vocal em Paul Zumthor; e da experiência em Walter Benjamin, a abordagem da literatura não como área do conhecimento ou campo disciplinar, mas como linguagem que emerge da corporeidade.<br>This article seeks to discuss the challenging possibility, placed to the childhood school, of perceiving the bond of the poems reading with its strength as a poetic experience that can be conquered in live voice by a body that feels. At the moment in which, at the Brazilian educational scenario, the organization of the elementary schools curriculum has been discussed, the text defends, based onthe theoretical framework of Gaston Bachelard's creative imagination; on the poetic pedagogy in Georges Jean; on Paul Zumthor's vocal performance and on Walter Benjamin's experience, the approach to literature not as a knowledge area or a subject matter, but as language that emerges from corporeality

TNF-α production by DCs challenged with Pb18 or Pb265 or activated by LPS for 48 h, and measured by ELISA.

<p>The results are expressed as mean ± SD of independent experiments performed with cells obtained from 4 subjects. Statistically significant differences between groups are indicated: *p< 0.05.</p

Involvement of MR, TLR2, Dectin-1 and DC-SIGN on PGE₂ production inhibition induced by <i>P</i>. <i>brasiliensis</i> in human DCs.

<p>Cells were incubated with anti-MR, anti-TLR2, anti-Dectin-1 and/or anti-DC-SIGN monoclonal antibodies for 1 h, challenged with Pb18 or Pb265 (DCs/yeast ratio 5:1) for 4 and 24 h, and evaluated for PGE₂ production by ELISA. The results are expressed in mean ± SD of independent experiments performed with cells obtained from 4 subjects. Statistically significant differences between groups are indicated: *p< 0.05 versus control DCs and other available receptors.</p

Effect of exogenous PGE₂ on percentage of cells, mean of fluorescence intensity (MFI) relative to the expression of CD40, CD80 (A) CD83, CD86 (B), HLA-DR, CXCR4 (C) CCR5, and CCR7 (D) by DCs after challenge or not with Pb18 and Pb265.

<p>The results are expressed in mean ± SD of experiments performed with cells obtained from 4 subjects. Statistically significant differences between groups are indicated: *p< 0.05 versus without PGE₂.</p