Quantitative proteomics study of carnosine effect in an animal model of Western diet-induced nonalcoholic fatty liver disease.

The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver.

The nuclear factor E2-related factor 2 and age-related macular degeneration / O fator 2 relacionado a NF-E2 e a degeneração macular relacionada à idade

ABSTRACT After the discovery of anti-vascular endothelial growth factor agents as treatment of wet age-related macular degeneration, the number of studies with the objective to understand the molecular mechanisms involved in the age-re lated macular degeneration genesis has increased. The importance of the nuclear factor e2-related factor 2 lies in its activation-derived proteins being involved in the maintenance of the redox balance and consequent prevention of degenerative macular disease. This article aims to present the characteristics of nuclear factor e2-related factor 2 and describe the main nuclear factor e2-related factor 2-activated antioxidant enzymes that contribute to the preservation of vision.

RESUMO Após a descoberta do anti fator de crescimento en dotelial vascular no tratamento da degeneração macular relacionada à idade úmida, muitas pesquisas têm sido realizadas com o intuito de elucidar os mecanismos moleculares envolvidos na gênese da degeneração macular relacionada à idade. O fator nuclear eritroide 2 relacionado ao fator 2 destaca-se pelo fato de diversas proteínas, oriundas de sua ativação, estarem envolvidas na manutenção do equilíbrio do estado redox e consequente prevenção da doença macular degenerativa. Este artigo mostra as características do fator nuclear eritroide 2 relacionado ao fator 2 e descreve as principais enzimas antioxidantes originadas da ativação que contribuem para a preservação da visão.

The nuclear factor E2-related factor 2 and age-related macular degeneration.

After the discovery of anti-vascular endothelial growth factor agents as treatment of wet age-related macular degeneration, the number of studies with the objective to understand the molecular mechanisms involved in the age-re lated macular degeneration genesis has increased. The importance of the nuclear factor e2-related factor 2 lies in its activation-derived proteins being involved in the maintenance of the redox balance and consequent prevention of degenerative macular disease. This article aims to present the characteristics of nuclear factor e2-related factor 2 and describe the main nuclear factor e2-related factor 2-activated antioxidant enzymes that contribute to the preservation of vision.

Age-related macular degeneration: an overview / Degeneração macular relacionada à idade: um panorama geral

ABSTRACT Age-related macular degeneration is the most important cause of irreversible vision loss in the elderly and has been considered a severe public health problem. Current treatments have only been successful in delaying the loss of central vision. Due to increased life expectancy, governments and researchers have been challenged to seek more efficient and successful treatments for age-related macular degeneration. Considering its relevance for public health and the need of further research, this article aims to address age-related macular degeneration objectively, tackling on the current knowledge about its pathophysiology, potential molecular biomarkers, main prevention procedures and treatments, as well as introducing possible molecules that may be a therapeutic target in this disease.

RESUMO Degeneração macular relacionada à idade é a causa mais importante de perda irreversível da visão em idosos, e é considerada um sério problema de saúde pública. Os tratamentos atuais são bem-sucedidos apenas ao postergar a perda da visão central. Devido à maior expectativa de vida, os governos e pesquisadores têm dificuldade de encontrar tratamentos mais eficientes e exitosos para degeneração macular relacionada à idade. Considerando sua relevância para saúde pública e a necessidade de mais pesquisas, este artigo procura abordar a degeneração macular relacionada à idade de forma objetiva, abordando os conhecimentos atuais sobre sua fisiopatologia, potenciais biomarcadores moleculares, principais procedimentos de prevenção e tratamentos, e apresentar possíveis moléculas que podem ser alvo terapêutico nessa doença.

Intra-abdominal pressure as a predictor of acute kidney injury in postoperative abdominal surgery.

OBJECTIVES: The purpose of this study was to determine if intra-abdominal pressure (IAP) could predict acute renal injury (AKI) in the postoperative period of abdominal surgeries, and which would be its cutoff value. PATIENTS AND METHODS: A prospective observational study was conducted in the period from January 2010 to March 2011 in the Intensive Care Units (ICUs) of the University Hospital of Botucatu Medical School, UNESP. Consecutive patients undergoing abdominal surgery were included in the study. Initial evaluation, at admission in ICU, was performed in order to obtain demographic, clinical surgical and therapeutic data. Evaluation of IAP was obtained by the intravesical method, four times per day, and renal function was evaluated during the patient's stay in the ICU until discharge, death or occurrence of AKI. RESULTS: A total of 60 patients were evaluated, 16 patients developed intra-abdominal hypertension (IAH), 45 developed an abnormal IAP (>7 mmHg) and 26 developed AKI. The first IAP at the time of admission to the ICU was able to predict the occurrence of AKI (area under the receiver-operating characteristic curve was 0.669; p=0.029) with the best cutoff point (by Youden index method) ≥ 7.68 mmHg, sensitivity of 87%, specificity of 46% at this point. The serial assessment of this parameter did not added prognostic value to initial evaluation. CONCLUSION: IAH was frequent in patients undergoing abdominal surgeries during ICU stay, and it predicted the occurrence of AKI. Serial assessments of IAP did not provided better discriminatory power than initial evaluation.

Predictors of beta-blocker intolerance and mortality in patients after acute coronary syndrome.

PURPOSE: To investigate the predictors of intolerance to beta-blockers treatment and the 6-month mortality in hospitalized patients with acute coronary syndrome (ACS). METHODS: This was a single-center, prospective, and longitudinal study including 370 consecutive ACS patients in Killip class I or II. BBs were prescribed according to international guidelines and withdrawn if intolerance occurred. The study was approved by the institutional ethics committee of our university. STATISTICS: the clinical parameters evaluated at admission, and the related intolerance to BBs and death at 6 months were analyzed using logistic regression (p<0.05)in PATIENTS. RESULTS: BB intolerance was observed in 84 patients and was associated with no prior use of statins (OR: 2.16, 95%CI: 1.26-3.69, p= 0.005) and Killip class II (OR: 2.5, 95%CI: 1.30-4.75, p=0.004) in the model adjusted for age, sex, blood pressure, and renal function. There was no association with ST-segment alteration or left anterior descending coronary artery plaque. Intolerance to BB was associated with the greatest risk of death (OR: 4.5, 95%CI: 2.15-9.40, p<0.001). CONCLUSIONS: After ACS, intolerance to BBs in the first 48 h of admission was associated to non previous use of statin and Killip class II and had a high risk of death within 6 months.

A comparative genotoxicity study of a supraphysiological dose of triiodothyronine (T3) in obese rats subjected to either calorie-restricted diet or hyperthyroidism.

This study was designed to determine the genotoxicity of a supraphysiological dose of triiodothyronine (T3) in both obese and calorie-restricted obese animals. Fifty male Wistar rats were randomly assigned to one of the two following groups: control (C; n = 10) and obese (OB; n = 40). The C group received standard food, whereas the OB group was fed a hypercaloric diet for 20 weeks. After this period, half of the OB animals (n = 20) were subjected to a 25%-calorie restriction of standard diet for 8 weeks forming thus a new group (OR), whereas the remaining OB animals were kept on the initial hypercaloric diet. During the following two weeks, 10 OR animals continued on the calorie restriction diet, whereas the remaining 10 rats of this group formed a new group (ORS) given a supraphysiological dose of T3 (25 µg/100 g body weight) along with the calorie restriction diet. Similarly, the remaining OB animals were divided into two groups, one that continued on the hypercaloric diet (OB, n = 10), and one that received the supraphysiological dose of T3 (25 µg/100 g body weight) along with the hypercaloric diet (OS, n = 10) for two weeks. The OB group showed weight gain, increased adiposity, insulin resistance, increased leptin levels and genotoxicity; T3 administration in OS animals led to an increase in genotoxicity and oxidative stress when compared with the OB group. The OR group showed weight loss and normalized levels of adiposity, insulin resistance, serum leptin and genotoxicity, thus having features similar to those of the C group. On the other hand, the ORS group, compared to OR animals, showed higher genotoxicity. Our results indicate that regardless of diet, a supraphysiological dose of T3 causes genotoxicity and potentiates oxidative stress.

Evaluation of the diagnostic performance and cut-off value for the rapid shallow breathing index in predicting extubation failure.

OBJECTIVE: To evaluate the diagnostic performance of the rapid shallow breathing index (RSBI) in predicting extubation failure among adult patients in the intensive care unit and to determine the appropriateness of the classical RSBI cut-off value. METHODS: This was a prospective study conducted in the adult intensive care unit of the Botucatu School of Medicine Hospital das Clínicas. The RSBI was evaluated in 73 consecutive patients considered clinically ready for extubation. RESULTS: The classical RSBI cut-off value (105 breaths/min/L) presented a sensitivity of 20% and a specificity of 95% (sum = 115%). Analysis of the receiver operator characteristic (ROC) curve revealed a better cut-off value (76.5 breaths/min/L), which presented a sensitivity of 66% and a specificity of 74% (sum = 140%). The area under the ROC curve for the RSBI was 0.78. CONCLUSIONS: The classical RSBI cut-off value proved inappropriate, predicting only 20% of the cases of extubation failure in our sample. The new cut-off value provided substantial improvement in sensitivity, with an acceptable loss of specificity. The area under the ROC curve indicated that the discriminative power of the RSBI is satisfactory, which justifies the validation of this index for use.

Avaliação do desempenho diagnóstico e do valor de corte para o índice de respiração rápida e superficial na predição do insucesso da extubação / Evaluation of the diagnostic performance and cut-off value for the rapid shallow breathing index in predicting extubation failure

OBJETIVO: Avaliar o desempenho diagnóstico do índice de respiração rápida e superficial (IRRS) na predição do insucesso da extubação de pacientes adultos em terapia intensiva e verificar a adequação do valor de corte clássico para esse índice. MÉTODOS: Estudo prospectivo realizado na unidade de terapia intensiva de adultos do Hospital das Clínicas da Faculdade de Medicina de Botucatu, através da avaliação do IRRS em 73 pacientes consecutivos considerados clinicamente prontos para extubação. RESULTADOS: O IRRS com valor de corte clássico (105 ciclos/min/L) apresentou sensibilidade de 20 por cento e especificidade de 95 por cento (soma = 115 por cento). A análise da curva receiver operator characteristic (ROC) demonstrou melhor valor de corte (76,5 ciclos/min/L), o qual forneceu sensibilidade de 66 por cento e especificidade de 74 por cento (soma = 140 por cento), e a área sob a curva ROC para o IRRS foi de 0,78. CONCLUSÕES: O valor de corte clássico do IRRS se mostrou inadequado nesta casuística, prevendo apenas 20 por cento dos pacientes com falha na extubação. A obtenção do novo valor de corte permitiu um acréscimo substancial de sensibilidade, com aceitável redução da especificidade. O valor da área sob a curva ROC indicou satisfatório poder discriminativo do índice, justificando a validação de sua aplicação.

OBJECTIVE: To evaluate the diagnostic performance of the rapid shallow breathing index (RSBI) in predicting extubation failure among adult patients in the intensive care unit and to determine the appropriateness of the classical RSBI cut-off value. METHODS: This was a prospective study conducted in the adult intensive care unit of the Botucatu School of Medicine Hospital das Clínicas. The RSBI was evaluated in 73 consecutive patients considered clinically ready for extubation. RESULTS: The classical RSBI cut-off value (105 breaths/min/L) presented a sensitivity of 20 percent and a specificity of 95 percent (sum = 115 percent). Analysis of the receiver operator characteristic (ROC) curve revealed a better cut-off value (76.5 breaths/min/L), which presented a sensitivity of 66 percent and a specificity of 74 percent (sum = 140 percent). The area under the ROC curve for the RSBI was 0.78. CONCLUSIONS: The classical RSBI cut-off value proved inappropriate, predicting only 20 percent of the cases of extubation failure in our sample. The new cut-off value provided substantial improvement in sensitivity, with an acceptable loss of specificity. The area under the ROC curve indicated that the discriminative power of the RSBI is satisfactory, which justifies the validation of this index for use.

[Infection in elderly interned in long-term care facilities]. / Infecção em idosos internados em instituição de longa permanência.

OBJECTIVE: To evaluate the occurrence of infection in elderly interned in long-term care facilities (LTCF) during 13 consecutive months. METHODS: Fifty five elderly were evaluated according to infection and, reporting was standardized. RESULTS: The median age was 75 (66 81) years. The data set consisted of 20,896 patients-day (PD) of care during the period, with a total of 76 infections for a pooled mean rate of infections 3.20 per 1,000 PD of care. Patient infection rate was 63.6%. Prevalent topographies of infection were respiratory (50%), urinary tract (32%), skin and soft tissue (12%) and gastroenteritis (7%), with an infection rate for specific categories/1000 PD of 1.60, 1.01, 0.38, 0.21, respectively. Mortality infection rate was 5%. Microbiological agents were isolated in 30.5% of the infection episodes. Escherichia coli and Staphylococcus aureus were prevalent. CONCLUSION: Infection presented an elevated incidence in the elderly interned, but no unusual problem with infections was disclosed.

Infecção em idosos internados em instituição de longa permanência / Infection in elderly interned in long-term care facilities

OBJETIVO: Avaliar ocorrência de infecção em idosos de instituição de longa permanência (ILP) durante 13 meses consecutivos. MÉTODOS: Cinqüenta e cinco idosos foram avaliados segundo critérios de infecção e de comunicação padronizada. RESULTADOS: A idade mediana foi de 75 (66-81) anos. O conjunto de dados constituiu-se de 20.896 pacientes-dia (PD) durante o período, com um total de 76 infecções para uma taxa média de infecção de 3,2 por 1000 PD. A taxa de pacientes com infecção foi de 63,6 por cento. As topografias prevalentes foram respiratória (50 por cento), trato urinário (32 por cento), pele e partes moles (12 por cento) e gastrintestinal (7 por cento), com taxa de infecção/1000 PD de 1,60; 1,01; 0,38; e 0,2, respectivamente. A taxa de mortalidade por infecção foi de 5 por cento. Agentes microbiológicos foram isolados em 30,5 por cento dos episódios infecciosos e Escherichia coli e Staphylococcus aureus foram os mais freqüentes. CONCLUSÃO: Infecção apresentou elevada incidência nos idosos institucionalizados, porém nenhum evento extraordinário foi observado.

OBJECTIVE: To evaluate the occurrence of infection in elderly interned in long-term care facilities (LTCF) during 13 consecutive months. METHODS: Fifty five elderly were evaluated according to infection and, reporting was standardized. RESULTS: The median age was 75 (66 81) years. The data set consisted of 20,896 patients-day (PD) of care during the period, with a total of 76 infections for a pooled mean rate of infections 3.20 per 1,000 PD of care. Patient infection rate was 63.6 percent. Prevalent topographies of infection were respiratory (50 percent), urinary tract (32 percent), skin and soft tissue (12 percent) and gastroenteritis (7 percent), with an infection rate for specific categories/1000 PD of 1.60, 1.01, 0.38, 0.21, respectively. Mortality infection rate was 5 percent. Microbiological agents were isolated in 30.5 percent of the infection episodes. Escherichia coli and Staphylococcus aureus were prevalent. CONCLUSION: Infection presented an elevated incidence in the elderly interned, but no unusual problem with infections was disclosed.

[Myocardial remodeling in chronic pressure or volume overload in the rat heart]. / Remodelação miocárdica na sobrecarga crônica de pressão ou de volume no coração de ratos.

OBJECTIVE: To compare cardiac structural changes in experimental pressure and volume overload models. METHODS: The study analysis included renovascular hypertensive rats (RVH, n = 8), normotensive rats with volume overload caused by an aortocaval fistula (ACF, n = 10) and control rats (CONT, n = 8). After four weeks, tail cuff blood pressure (SBP) was recorded. Rats were killed, the hearts were excised and the right and left ventricles (RV&LV) were weighed (RVW&LVW). Using histological sections, myocyte cross sectional areas (MA). LV wall thickness (LVWT) LV cavity diameter (LVD), normalized LVWT (LVWT/LVD) and collagen volume fraction (CVF) were measured. The comparisons were made using the ANOVA and Tukey test for a significance level of 5%. RESULTS: Tail cuff blood pressure (mmHg) was higher in the RVH group (RVH = 187 +/- 22; CONT = 125 +/- 10; ACF = 122 +/- 6, p < 0.05). LV hypertrophy was observed in the RVH and ACF groups. The ACF group presented a significant increase in size of LVD, compared to CONT and RVH. The absolute and normalized ventricular wall thickness were similar among the groups. The RVH group presented a significant increase in CVF compared to CONT group and ACF group. CONCLUSION: Cardiac remodeling patterns following volume or pressure overload are distinct, suggesting that their implications on ventricular dysfunction are not interchangeable.

Remodelação miocárdica na sobrecarga crônica de pressão ou de volume no coração de ratos / Myocardial remodeling in chronic pressure or volume overload in the rat heart

OBJETIVO: Comparar as alterações estruturais cardíacas em modelos experimentais de sobrecarga de pressão e de volume. MÉTODOS: Foram analisados ratos com hipertensão renovascular (HRV, n = 8), normotensos com sobrecarga de volume por fístula aortocava (FAV, n = 10) e animais controles (CONT, n = 8). Após quatro semanas, registrou-se a pressão arterial caudal (PAS) e obtiveram-se os pesos dos ventrículos direito (PVD) e esquerdo (PVE). Em cortes histológicos, foram medidas as áreas seccionais dos miócitos (AM), a espessura da parede do VE (E), o diâmetro da cavidade (DVE), a relação E/DVE, e a fração de colágeno (CVF). As comparações foram feitas pela ANOVA e teste de Tukey para nível de significância de 5 por cento. RESULTADOS: A PAS (mmHg) foi maior no grupo HRV (HRV = 187 ± 22; CONT = 125 ± 10; FAV = 122 ± 6, p < 0,05). A hipertrofia do VE foi observada nos grupos HRV e FAV. O grupo FAV apresentou aumento significante do DVE, comparado ao CONT e HRV. As espessuras absoluta e normalizada da parede ventricular foram semelhantes entre os grupos. Houve aumento significante do CVF no grupo HRV em relação aos grupos CONT e FAV. CONCLUSÃO: A sobrecarga de volume causa padrão distinto de remodelação cardíaca, quando comparada com aquela decorrente da hipertensão arterial, sugerindo que as implicações funcionais de cada padrão não são intercambiáveis.

Enzymatic and oxidative metabolites of lycopene.

Using the post-mitochondrial fraction of rat intestinal mucosa, we have investigated lycopene metabolism. The incubation media was composed of NAD(+), KCl, and DTT with or without added lipoxygenase. The addition of lipoxygenase into the incubation significantly increased the production of lycopene metabolites. The enzymatic incubation products of (2)H(10) lycopene were separated using high-performance liquid chromatography and analyzed by UV/Vis spectrophotometer and atmospheric pressure chemical ionization-mass spectroscopy. We have identified two types of products: cleavage products and oxidation products. The cleavage products are likely: (1) 3-keto-apo-13-lycopenone (C(18)H(24)O(2) or 6,10,14-trimethyl-12-one-3,5,7,9,13-pentadecapentaen-2-one) with lambdamax = 365 nm and m/z = 272 and (2) 3,4-dehydro-5,6-dihydro-15,15'-apo-lycopenal (C(20)H(28)O or 3,7,11,15-tetramethyl-2,4,6,8,12,14-hexadecahexaen-1-al) with lambdamax = 380 nm and m/z = 284. The oxidative metabolites are likely: (3) 2-apo-5,8-lycopenal-furanoxide (C(37)H(50)O) with lambdamax = 415 nm, 435 nm, and 470 nm, and m/z = 510; (4) lycopene-5, 6, 5', 6'-diepoxide (C(40)H(56)O(2)) with lambdamax = 415 nm, 440 nm, and 470 nm, and m/z = 568; (5) lycopene-5,8-furanoxide isomer (I) (C(40)H(56)O) with lambdamax = 410 nm, 440nm, and 470 nm, and m/z = 552; (6) lycopene-5,8-epoxide isomer (II) (C(40)H(56)O) with lambdamax = 410, 440, 470 nm, and m/z = 552; and (7) 3-keto-lycopene-5',8'-furanoxide (C(40)H(54)O(2)) with lambdamax = 400 nm, 420 nm, and 450 nm, and m/z = 566. These results demonstrate that both central and excentric cleavage of lycopene occurs in the rat intestinal mucosa in the presence of soy lipoxygenase.

Aspectos anatomopatológicos da disfunção ventricular / Histopathological aspects of ventricular dysfunction

A disfunção ventricular está associada a um conjunto de alterações envolvendo miócitos, vasos coronários e interstício, que caracterizam a remodelação miocárdica. Esse processo não ocorre de maneira uniforme e depende de vários fatores, associados à agressão cardíaca e à resposta individual. Esta revisão inclui alguns aspectos anatomopatológicos da remodelação miocárdica, ao mesmotempo que discute os aspectos fisiopatológicos das lesões miocárdicas...

Curso: Tópicos de Medicina Interna: Aula 1: Glutationa: o antioxidante: síntese, metabolismo e degradação / Course: Internal Medicine Topics: Class 1: Glutathione: the antioxidant: synthesis, metabolism and degradation

Existem várias evidências de que a glutationa reduzida (GSH)atua na destruição de intermediários reativos de oxigênio e de outros radicais livres que são constantemente formados sob condições normais ou após administração de certas drogas, raios X e oxigênio. O nível celular da GSH é regulado por processos que compreendem o sistema de captação de aminoácidos através da membrana, o grupo de enzimas intracelulares envolvidas na síntese e regulação por feedback e o processo de exportação do tripeptídeo. A regulação da GSH intracelular pode ocorrer pela glutationa oxidada (GSSG) indesejável. São de grande interesse terapêutico os estudos com agentes que, de alguma forma, aumentam ou diminuem o nível da GSH. Em geral, o aumento da GSH é prejudicial ao tratamento químio ou radioterápico do câncer e o tratamento com butionina sulfoximina (BSO), promovendo o decréscimo do nível celular da GSH, pode aumentar a sensibilidade tumoral a drogas anti-câncer e à radioterapia. Por outro lado, os estudos com agentes que aumentam o nível de GSH podem contribuir para o aumento da proteção contra o estresse oxidativo.