Body weight, metabolism and clock genes

Biological rhythms are present in the lives of almost all organisms ranging from plants to more evolved creatures. These oscillations allow the anticipation of many physiological and behavioral mechanisms thus enabling coordination of rhythms in a timely manner, adaption to environmental changes and more efficient organization of the cellular processes responsible for survival of both the individual and the species. Many components of energy homeostasis exhibit circadian rhythms, which are regulated by central (suprachiasmatic nucleus) and peripheral (located in other tissues) circadian clocks. Adipocyte plays an important role in the regulation of energy homeostasis, the signaling of satiety and cellular differentiation and proliferation. Also, the adipocyte circadian clock is probably involved in the control of many of these functions. Thus, circadian clocks are implicated in the control of energy balance, feeding behavior and consequently in the regulation of body weight. In this regard, alterations in clock genes and rhythms can interfere with the complex mechanism of metabolic and hormonal anticipation, contributing to multifactorial diseases such as obesity and diabetes. The aim of this review was to define circadian clocks by describing their functioning and role in the whole body and in adipocyte metabolism, as well as their influence on body weight control and the development of obesity

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

BTCI enhances guanylin-induced natriuresis and promotes renal glomerular and tubular

Abstract Guanylin and uroguanylin are small cysteine-rich peptides involved in the regulation of fluid and electrolyte homeostasis through binding and activation of guanylyl cyclases signaling molecules expressed in intestine and kidney. Guanylin is less potent than uroguanylin as a natriuretic agent and is degraded in vitro by chymotrypsin due to unique structural features in the bioactive moiety of the peptide. Thus, the aim of this study was to verify whether or not guanylin is degraded by chymotrypsin-like proteases present in the kidney brush-border membranes. The isolated perfused rat kidney assay was used in this regard. Guanylin (0.2 µM) induced no changes in kidney function. However, when pretreated by the black-eyed pea trypsin and chymotrypsin inhibitor (BTCI -1.0 µM; guanylin -0.2 µM) it promoted increases in urine flow (ΔUF of 0.25 ± 0.09 mL.g -1 /min, P &lt; 0.05) and Na + excretion (% Δ ENa + of 18.20 ± 2.17, P &lt; 0.05). BTCI (1.0 µM) also increased %ENa + (from 22.8 ± 1.30 to 34.4 ± 3.48, P &lt; 0.05, 90 minutes). Furthermore, BTCI (3.0 µM) induced increases in glomerular filtration rate (GFR; from 0.96 ± 0.02 to 1.28 ± 0.02 mL.g -1 /min, P &lt; 0.05, 60 minutes). The present paper strongly suggests that chymotrypsin-like proteases play a role in renal metabolism of guanylin and describes for the first time renal effects induced by a member of the Bowman-Birk family of protease inhibitors. Keywords: natriuresis, kidney, Bowman-Birk protease inhibitors, BTCI, cyclic GMP, Vignia unguiculata. BTCI aumenta a natirurese induzida por guanilina e promove efeitos renais glomerulares e tubulares Resumo Guanilina e uroguanilina são peptídeos pequenos, ricos em cisteína, envolvidos na regulação da homeostase de fluidos e eletrólitos através da ligação e ativação da guanilato ciclase expressa no intestino e nos rins. A guanilina é menos potente do que a uroguanilina como agente natriurético e é degradada in vitro pela quimiotripsina devido a caracterís-ticas estruturais únicas no domínio bioativo do peptídeo. Portanto o objetivo deste trabalho foi verificar se a guanilina é degradada por proteases tipo quimiotripsina, presentes na membrana da borda em escova dos rins. Para esta investigação, foi usado o modelo do rim isolado de rato perfundido. A Guanilina (0,2 µM) não induziu mudanças na função renal. Entretanto, quando pré-tratada com inibidor de tripsina e de quimiotripsina de black-eyed pea (BTCI -1,0 µM; guanilina -0,2 µM) promoveu um aumento no fluxo urinário (ΔUF de 0,25 ± 0,09 mL.g -1 /min, P &lt; 0,05) e na excreção de Na + (%ΔENa + de 18,20 ± 2,17, P &lt; 0,05). BTCI (1,0 µM) também aumenta %ENa + (de 22,8 ± 1,30 a 34,4 ± 3,48, P &lt; 0,0590 minutos). Além disto, BTCI (3,0 µM) induziu um aumento da taxa de filtração glomerular (GFR; de 0,96 ± 0,02 para 1,28 ± 0,02 mL.g -1 /min, P &lt; 0,05, 60 minutos). O presente trabalho sugere fortemente que proteases semelhantes à quimiotripsina desempenham um papel no metabolismo renal de guanilinas e descreve, pela primeira vez, os efeitos renais induzidos por um membro da família de inibidores de proteases do tipo Bowman-Birk. Palavras-chave: natriurese, rim, Inibidores de proteases tipo Bowman-Birk, BTCI, GMP cíclico, Vignia unguiculata. Carvalho, AF. et al

Significados e usos de materiais educativos sobre hanseníase segundo profissionais de saúde pública do Município do Rio de Janeiro, Brasil Meanings and use of educational materials on Hansen disease according to public health officials in the Municipality of Rio de Janeiro, Brazil

O artigo objetiva refletir sobre os processos comunicativos de Programas de Controle de Hanseníase (PCH) do Sistema Único de Saúde (SUS), por meio da análise da recepção de materiais educativos por profissionais de dois serviços de saúde pública no Rio de Janeiro, Brasil. O trabalho discute em que medida a análise de impressos favorece a negociação dos sentidos e das práticas sobre hanseníase vigentes nos PCH. Foram analisados 38 materiais produzidos entre 1993 a 2005, por instituições governamentais e não-governamentais e realizados dois grupos focais com profissionais atuantes no PCH. Durante os grupos focais 6 materiais foram examinados. Os resultados revelaram a verticalidade e fragmentação nos processos comunicativos, expressas pela: ênfase em campanhas, produção centralizada, homogeneização dos públicos e conteúdos e privilégio dado ao saber biomédico. As atividades horizontais e participativas não eram comuns. Foi identificada uma lacuna entre a institucionalização do discurso da hanseníase, como alternativa à terminologia da lepra, e a sua circulação e consumo entre os diferentes atores sociais.<br>This article reflects on the communications processes in the Hansen Disease Control Programs under the Unified National Health System (SUS) in Brazil, analyzing how professionals at two public health services in Rio de Janeiro perceive the educational materials on the disease. The article discusses how analysis of printed materials favors negotiation of prevailing meanings and practices on Hansen disease in the programs. Thirty-eight different educational materials were analyzed (produced from 1993 to 2005 by governmental and nongovernmental institutions) through two focus groups with program staff. Six materials were examined during the focus groups. The findings showed the communications processes are vertical and fragmented, with an emphasis on campaigns, centralized production of materials, homogenization of target publics, and a focus on biomedical knowledge. Horizontal and participatory activities were uncommon. A gap was identified between the institutionalization of the discourse on Hansen disease as an alternative to leprosy terminology and its circulation and uptake among different social actors