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INTRODUCTION: In patients with traumatic intracranial haemorrhage (tICH) there is significant risk of both venous thromboembolism (VTE) and haemorrhage progression. There is a paucity of literature to inform the timing of pharmacological thromboprophylaxis (PTP) initiation. AIM: This meta-analysis aims to summarise the current literature on the timing of PTP initiation in tICH. METHODS: This meta-analysis followed the Methodological Expectations of Cochrane Intervention Reviews checklist and the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Following the literature search, studies were matched against the criteria for inclusion. Data from included studies was pooled, analysed using random-effect analysis and presented as forest plots of risk ratios, except one result reported as difference of means. The ROBINS-I tool was used to assess the risk of bias in the studies. The GRADE approach was taken to assess the quality of included studies. Heterogeneity of studies was assessed using Tauâ§2. Funnel plots were generated and used in conjunction with Harbord's test and Rucker's arcsine to assess for small-study effect including publication bias. RESULTS: A total of 9927 ICH patients who received PTP were included from 15 retrospective observational cohort studies, 4807 patients received early PTP, the remaining 5120 received late PTP. The definition of early was dependent on the study but no more than 72-hours after admission. The mean age of the included cohort was 45.3 (std dev ±9.5) years, and the proportion of males was 71%. Meta-analysis indicated that there was a significant difference between early and late groups for the rate of VTE (RR, 0.544; p = 0.000), pulmonary embolus (RR, 0.538; p = 0.004), deep vein thrombosis (RR, 0.484; p = 0.000) and the intensive care unit length of stay (difference of means, -2.021; 95% CI, -2.250, -1.792; p = 0.000; Tauâ§2 = 0.000), favouring the early group. However, the meta-analysis showed no significant difference between the groups for the rate of mortality (RR, 1.008; p = 0.936), tICH progression (RR, 0.853; p = 0.157), and neurosurgical intervention (RR, 0.870; p = 0.480). CONCLUSION: These findings indicated that early PTP appears to be safe and effective in patients with tICH.
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Hypertension is a major risk factor for kidney and cardiovascular disease. The treatment of hypertensive individuals by selected ACE inhibitors and certain di-and tripeptides halts the progression of renal deterioration and extends life-span. Renal reabsorption of these low molecular weight substrates are mediated by the PEPT1 and PEPT2 cotransporters. This study aims to investigate whether hypertension and ageing affects renal PEPT cotransporters at gene, protein expression and distribution as well as function in the superficial cortex and the outer medulla of the kidney. Membrane vesicles from the brush border (BBMV) and outer medulla (OMMV) were isolated from the kidneys of young Wistar Kyoto (Y-WKY), young spontaneously hypertensive (Y-SHR), and middle aged SHR (M-SHR) rats. Transport activity was measured using the substrate, ß-Ala-Lys (AMCA). Gene expression levels of PEPT genes were assessed with qRT-PCR while renal localisation of PEPT cotransporters was examined by immunohistochemistry with Western Blot validation. The Km and Vmax of renal PEPT1 were decreased significantly in SHR compared to WKY BBMV, whilst the Vmax of PEPT2 showed differences between SHR and WKY. By contrast to the reported cortical distribution of PEPT1, PEPT1-staining was detected in the outer medulla, whilst PEPT2 was expressed primarily in the cortex of all SHR; PEPT1 was significantly upregulated in the cortex of Y-SHR. These outcomes are indicative of a redistribution of PEPT1 and PEPT2 in the kidney proximal tubule under hypertensive conditions that has potential repercussions for nutrient handling and the therapeutic use of ACE inhibitors in hypertensive individuals.
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Hipertensão , Simportadores , Inibidores da Enzima Conversora de Angiotensina , Animais , Hipertensão/genética , Hipertensão/metabolismo , Rim/metabolismo , Transportador 1 de Peptídeos/genética , Transportador 1 de Peptídeos/metabolismo , Peptídeos/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Roedores/metabolismo , Simportadores/genética , Simportadores/metabolismoRESUMO
Some dipeptides have been implicated in myocardial protection, but little is known about their membrane transporter PEPT2. The aim of this study was to determine whether the expression and activity of the cardiac-type PEPT2 cotransporter could be affected by ageing and/or hypertension. Sarcolemmal vesicles (SV) were isolated from the hearts of all rat groups using a standard procedure to investigate the transport activity and protein abundance by fluorescence spectroscopy and Western blot, respectively. SLC15A2 "PEPT2" gene expression was relatively quantified by RT-qPCR. In the Wistar rat groups, the protein and gene expression of PEPT2 were upregulated with ageing. These changes were accompanied by corresponding increases in the competitive inhibition and the transport rate (Vmax) of ß-Ala-Lys (AMCA) into SV isolated from middle-aged hearts. Although, the transport rate of ß-Ala-Lys (AMCA) into SV isolated from old hearts was significantly the lowest compared to middle-aged and young adult hearts, the inhibition percentage of ß-Ala-Lys (AMCA) transport by Gly-Gln was the highest. In the WKY and SHR rat groups, Y-SHR hypertrophied hearts showed an increase in PEPT2 gene expression accompanied by a significant decrease in protein expression and activity. With advanced age, however, M-SHR hypertrophied hearts revealed significantly lower gene expression, but higher protein expression and activity than Y-SHR hearts. These findings suggest that increased expression of PEPT2 cotransporter in all types of middle-aged hearts could be exploited to facilitate di-and tripeptide transport by PEPT2 in these hearts, which subsequently could result in improved myocardial protection in these populations.
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Envelhecimento/metabolismo , Cardiomegalia/metabolismo , Hipertensão/metabolismo , Simportadores/metabolismo , Animais , Transporte Biológico , Cardiomegalia/genética , Dipeptídeos/metabolismo , Hipertensão/genética , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Simportadores/genéticaRESUMO
Homocysteine (Hcy) is a breakdown product of methionine metabolism. The risk of cardiovascular disease (CVD) correlates with an increase in plasma Hcy levels. The aim of this study was to investigate whether 1% methionine supplementation of adult rats altered intracellular reactive oxygen species (ROS) generation, intracellular Ca2+ content, and contractile activity in freshly isolated cardiomyocytes. This was measured under normal conditions and during oxidative stress in freshly isolated cardiomyocytes. Single rat cardiomyocytes from both sexes were isolated by enzymatic and mechanical dispersion techniques. Fluorescence microscopy was used to measure ROS production and intracellular Ca2+ concentration. Cell contraction was measured using a video camera. During exposure to 200 µM, H2O2 female cardiomyocytes produced significantly fewer ROS and had a higher intracellular Ca2+ concentration compared to male cardiomyocytes in control and methionine-fed conditions. The contractility of cardiomyocytes isolated from male rats was insignificantly decreased after methionine feeding compared to control, while the contractility of cardiomyocytes from female rats insignificantly reduced after methionine feeding and acute exposure to oxidative stress. These findings provide evidence that during exposure to 200 µM H2O2, cardiomyocytes from female rats produce less ROS and have higher intracellular Ca2+ levels. There were no significant effects on contractility in cardiomyocytes from either gender and under any of the different conditions.
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Cálcio/metabolismo , Metionina/farmacologia , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ração Animal , Animais , Células Cultivadas , Feminino , Masculino , Ratos , Ratos WistarRESUMO
BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) cardioplegia for myocardial protection obviates the need for maintenance cardioplegia doses, and thus allows for greater focus on procedure accuracy. The aim of this meta-analysis is to evaluate the safety and efficacy of HTK versus multidose cardioplegias during cardiac surgery in an adult population. METHODS: Electronic searches were performed using PubMed, Science Direct, and Google Scholar databases. The key search terms included HTK cardioplegia AND cardiac surgery AND adult. This was followed by a meta-analysis investigating cardiopulmonary bypass (CPB) duration, cross-clamp duration, spontaneous defibrillation, inotropic support, mortality, atrial fibrillation, creatine kinase muscle brain band (CK-MB) and troponin I (TnI). RESULTS: Seven randomized controlled trials (n = 804) were analyzed. Spontaneous defibrillation following aortic cross-clamp removal significantly favored HTK (odds ratio [OR], 2.809; 95% confidence interval [CI], 1.574 to 5.012; I2 = 0%; p < .01). There were no other notable significant differences between HTK and multidose cardioplegia in any of the parameters measured. In particular, the OR for mortality was 1.237 (95% CI, 0.385 to 3.978; I2 = 0%; p = .721) and the mean difference for CPB duration overall was 2.072 min (95% CI, -2.405 to 6.548; I2 = 74%; p = .364). CONCLUSION: HTK is safe and effective during adult cardiac surgery when compared with multidose cardioplegias for myocardial protection during surgical correction of acquired pathology in the adult population. HTK may, therefore, be suitable for complex cases or those of extensive duration, without the prospect of increased postoperative morbidity or mortality.
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Procedimentos Cirúrgicos Cardíacos , Histidina , Adulto , Soluções Cardioplégicas , Parada Cardíaca Induzida , Humanos , TriptofanoRESUMO
BACKGROUND: Consensus on the optimum choice of cardioplegia remains elusive. One possibility that has been suggested to have beneficial properties is microplegia, a cardioplegia of reduced crystalloid volume. The aim of this meta-analysis is to comprehensively investigate microplegia against a range of clinical outcomes. METHODS: To identify potential studies, systematic searches were carried out in four databases (eg, Pubmed, EMBASE). The search strategy included the key concepts of "microplegia" OR "mini-cardioplegia" OR "miniplegia" AND "cardiac surgery." This was followed by a meta-analysis investigating: mortality, crystalloid volume; cardiopulmonary bypass time; cross-clamp time; intra-aortic balloon pump use; spontaneous heartbeat recovery; inotropic support; low cardiac output syndrome; myocardial infarction; acute renal failure; atrial fibrillation, reoperation for bleeding; creatine kinase myocardial band (CK-MB); intensive care unit (ICU) time and hospital stay. RESULTS: Eleven studies comprising 5798 participants were analyzed. Microplegia used a lower volume of crystalloids and led to a higher spontaneous return of heartbeat, odds ratio (OR) 4.271 (95% confidence intervals [CIs]: 1.935, 9.423; I2 = 76.57%; P < .001) and a lower requirement for inotropic support, OR: 0.665 (95% CI: 0.47, 0.941; I2 = 3.53%; P = .021). Microplegia was also associated with a lower CK-MB release, mean difference (MD) -6.448 ng/mL (95% CI: -9.386, -3.511; I2 = 0%; P < .001) and a shorter ICU stay, MD: -0.411 days (95% CI: -0.812, -0.009; I2 = 17.65%; P = .045). All other comparisons were nonsignificant. CONCLUSIONS: Microplegia has similar effects to other types of cardioplegia and is beneficial with regard to spontaneous return of heartbeat, inotropic support, ICU stay, and CK-MB release.
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Procedimentos Cirúrgicos Cardíacos , Soluções Cardioplégicas/administração & dosagem , Parada Cardíaca Induzida/métodos , Injúria Renal Aguda , Baixo Débito Cardíaco , Ponte Cardiopulmonar , Creatina Quinase Forma MB/metabolismo , Frequência Cardíaca , Humanos , Tempo de Internação , Infarto do Miocárdio , Duração da Cirurgia , Complicações Pós-Operatórias , Recuperação de Função Fisiológica , Resultado do TratamentoRESUMO
Renal PEPT1 and PEPT2 cotransporters play an important role in the balance of circulating body oligopeptides and selected peptidomimetic drugs. We aim to comprehensively characterise age-related changes of the renal PEPT cotransporters at the gene, protein, and functional level. Brush border membrane vesicles (BBMV) and outer medulla membrane vesicles (OMMV) were isolated from the kidneys of young, middle-aged and old rats. The protein expression of PEPT1 was not only increased in BBMV from old rats, but PEPT1 also appeared in OMMV from middle-aged and old rats. SLC15A1 gene expression in the renal cortex increased in middle-aged group. PEPT2 protein expression was not only increased with ageing, but PEPT2 also was found in BBMV from middle-aged and old groups. SLC15A2 gene expression in the renal outer medulla increased in the old group. These changes in the expressions and localisations of PEPT1 and PEPT2 could explain the changes to transport activity in BBMV and OMMV. These findings provide novel insights that would be useful for maintaining protein nutrition and optimising the delivery of some peptidomimetic drugs in elderly individuals.
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Envelhecimento/patologia , Rim/patologia , Transportador 1 de Peptídeos/metabolismo , Simportadores/metabolismo , Envelhecimento/metabolismo , Animais , Transporte Biológico , Rim/metabolismo , Masculino , Microvilosidades/metabolismo , Microvilosidades/patologia , Transportador 1 de Peptídeos/genética , Ratos , Ratos Wistar , Simportadores/genéticaRESUMO
BACKGROUND AND AIMS: Atherogenesis and endothelial dysfunction contribute to cardiovascular risk and vitamin D has been implemented in endothelial repair. This systematic review, meta-analysis and meta-regression aims to establish the effect of vitamin D supplementation on endothelial function. METHODS AND RESULTS: To conduct the systematic review we searched the Cochrane Library of Controlled Trials, PubMed, ProQuest and EMBASE for randomized controlled trials that investigated the effects of vitamin D supplementation on flow-mediated dilation (FMD%), pulse wave velocity (PWV), and central augmentation index (AIx). Meta-analysis was based on a random effects model and inverse-variance methods to calculate either mean difference (MD) or standardized mean difference (SMD) as effects sizes. This was followed by meta-regression investigating the effect of baseline vitamin D concentrations, vitamin D dosing and study duration. Risk of bias was assessed using the JADAD scale and funnel plots. We identified 1056 studies of which 26 studies met inclusion criteria for quantitative analysis. Forty-two percent of the 2808 participants had either deficient or insufficient levels of vitamin D. FMD% (MD 1.17% (95% CI -0.20, 2.54), p = 0.095), PWV (SMD -0.09 m/s (95% CI -0.24, 0.07), p = 0.275) and AIx (SMD 0.05% (95% CI -0.1, 0.19), p = 0.52) showed no improvement with vitamin D supplementation. Sub-analysis and meta-regression revealed a tendency for AIx and FMD% to increase as weekly vitamin doses increased; no other significant relationships were identified. CONCLUSIONS: Vitamin D supplementation showed no improvement in endothelial function. More evidence is required before recommendations for management of endothelial dysfunction can be made.
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Aterosclerose/tratamento farmacológico , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Deficiência de Vitamina D/tratamento farmacológico , Vitamina D/uso terapêutico , Adulto , Idoso , Aterosclerose/epidemiologia , Aterosclerose/fisiopatologia , Suplementos Nutricionais/efeitos adversos , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do Tratamento , Vitamina D/efeitos adversos , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/fisiopatologiaRESUMO
Integral membrane proteins PEPT1 and PEPT2 are essential for reabsorbing almost all hydrolysed or filtered di- and tripeptides alongside a wide range of peptidomimetic drugs in the kidney. The aim of this study was to investigate the potential use of the fluorophore-conjugated dipeptide ß-Ala-Lys (AMCA) as a biosensor for measuring peptide transport activity in brush border membrane vesicles isolated from the outer cortex (BBMV-OC) and outer medulla (BBMV-OM) (representing PEPT1 and PEPT2 respectively). The vesicles were isolated using a dual magnesium precipitation and centrifugation technique. Intravesicular fluorescence accumulation was measured after incubating extra-vesicular media at pH6.6 and different concentrations of ß-Ala-Lys (AMCA) with vesicles pre-equilibrated at pH7.4. Both BBMV-OC and BMMV-OM showed accumulation of an intravesicular fluorescence signal after 20min incubation. Changing the extra-vesicular pH to 7.4 caused a significant reduction in the ß-Ala-Lys (AMCA) uptake into BBMV-OC at concentrations >100µM. When different concentrations of dipeptide, Gly-Gln was added, there was a significant inhibition of 100µM ß-Ala-Lys (AMCA) uptake into BBMV-OC and BMMV-OM, reaching 69% and 80%, respectively. Kinetic analysis of ß-Ala-Lys (AMCA) at 20min showed that the Km and Vmax were 783.7±115.7µM and 2191.2±133.9ΔF/min/mg for BBMV-OC, while BMMV-OM showed significantly higher affinity, but lower capacity at Km=93.6±21.9µM and Vmax=935.8±50.2ΔF/min/mg. These findings demonstrate the applicability of ß-Ala-Lys (AMCA) as a biosensor to measure the transport activity of the renal-type PEPT1 and PEPT2 in BBMV-OC and BMMV-OM respectively.
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Cumarínicos/farmacocinética , Córtex Renal/metabolismo , Medula Renal/metabolismo , Microvilosidades/metabolismo , Oligopeptídeos/farmacocinética , Transportador 1 de Peptídeos/metabolismo , Simportadores/metabolismo , Animais , Transporte Biológico , Corantes Fluorescentes/farmacocinética , Rim/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
Tri- and dipeptides are transported in the kidney by PEPT1 and PEPT2 isoforms. The aim of this study was to investigate differences in transport kinetics between renal brush border (BBMV) and outer medulla (OMMV) membrane vesicles (where PEPT1 and PEPT2 are sequentially available) for a range of di- and tripeptides and peptidomimetic drugs. This was accomplished through the use of the potential-sensitive fluorescent dye 3,3'-dipropylthiacarbocyanine iodide [DiS-C3-(3)]. BBMV and OMMV were prepared from the rat kidney using standard techniques. The presence of PEPT1 in BBMV and PEPT2 in OMMV was confirmed using Western blotting. Fluorescence changes were measured when extravesicular medium at pH 6.6 containing 0-1 mM substrates was added to a cuvette containing vesicles pre-equilibrated at pH 7.4 and 2.71 µM DiS-C3-(3). An increase in fluorescence intensity occurred upon substrate addition reflecting the expected positive change in membrane potential difference. Of the range of substrates studied, OMMV manifested the highest affinity to cefadroxil and valacyclovir (K m 4.3 ± 1.2 and 11.7 ± 3.2 µM, respectively) compared to other substrates, whilst the BBMV showed a higher affinity to Gly-His (K m 15.4 ± 3.1 µM) compared to other substrates. In addition, OMMV showed higher affinity and capacity to Gly-Gln (K m 47.1 ± 9.8 µM, 55.5 ± 2.8 ΔF/s/mg protein) than BBMV (K m 78.1 ± 13.3 µM and 35.5 ± 1.7 ΔF/s/mg protein, respectively). In conclusion, this study successfully separated the expression of PEPT1 and PEPT2 into different vesicle preparations inferring their activity in different regions of the renal proximal tubule.
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Peptidomiméticos , Animais , Transporte Biológico , Rim/metabolismo , Cinética , Potenciais da Membrana/fisiologia , RatosRESUMO
BACKGROUND/AIMS: Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. METHODS: Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H2O2) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes ± 0.1 mM L-homocysteine. RESULTS: During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 ± 749 vs. 5955 ± 567 mmHg bpm, p < 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the amplitude of the calcium transient and slowed the time to half relaxation. CONCLUSIONS: These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined.
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Homocisteína/administração & dosagem , Isquemia Miocárdica/fisiopatologia , Estresse Oxidativo , Traumatismo por Reperfusão/metabolismo , Animais , Células Cultivadas , Técnicas In Vitro , Masculino , Miócitos Cardíacos/metabolismo , Ratos , Ratos WistarRESUMO
The amino acids glycine and glutamine have been implicated in myocardial protection of the much studied young adult heart. This study aimed to determine whether such protection could be enhanced using the dipeptide, L-glycyl-L-glutamine (gly-gln) in both young hearts and in middle-aged hearts representative of a more clinically relevant age group. Hearts from 8-week-old and 36-week-old rats were perfused in the Langendorff mode for 20 min, before 40 min global normothermic ischaemia and 30 min reperfusion. Where present, 0.5, 2, or 5 mM gly-gln was added 10 min into baseline perfusion, was present throughout ischaemia and was washed out after 10 min reperfusion. Reperfusion damage was assessed from the release of lactate dehydrogenase. Metabolic fitness was assessed from the time to ischaemic contracture and the accumulation of lactate and thiobarbituric acid reactive substances during ischaemia. The presence of 5 mM gly-gln significantly improved the post-ischaemic rate pressure product (RPP) and decreased reperfusion damage in both the 8 (RPP in control on reperfusion 5527 ± 957 vs. 10,320 ± 795 mmHg beat min(-1) in 5 mM gly-gln, n = 6 ± SE, p < 0.05) and 36-week-old (RPP in control on reperfusion 1964.33 ± 876.3 vs. 4008 ± 675 mmHg beat min(-1), n = 6 ± SE, p < 0.01) hearts. Five mM gly-gln also increased the time to ischaemic contracture and was able to protect against the rise in lactate that occurred in the controls during ischaemia. These results suggest that gly-gln has good potential as a combatant against ischaemia-reperfusion injury in both the young adult and middle-aged populations.
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Dipeptídeos/farmacologia , Isquemia Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Fatores Etários , Animais , Preparação de Coração Isolado/métodos , Ácido Láctico/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miocárdio/metabolismo , Ratos , Ratos WistarRESUMO
Oxidative stress has been implicated in ageing and the pathogenesis of chronic kidney disease. We examined levels of antioxidant enzymes glutathione peroxidase, glutathione reductase, glutathione S-transferase, catalase and superoxide dismutase as modulated by age and oxidative stress in different regions of the kidney. Antioxidant enzymes were examined in different regions of the kidney in male Wistar rats. Kidneys from rats of different ages (5, 12, 36 and 60 weeks) were dissected into cortex, outer medulla and inner medulla. Tissues were incubated for 30 min with or without 0.2 mM H2O2 to induce oxidative stress. Antioxidant enzyme activities progressively decreased with age under both control and stress conditions (P < 0.05) after peaking at 12 weeks. Antioxidant enzyme activities were greater in the cortex (P < 0.05) by comparison with the outer and inner medulla, respectively.
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Antioxidantes/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Glutationa Transferase/metabolismo , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Fatores Etários , Animais , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Rim/efeitos dos fármacos , Rim/enzimologia , Masculino , Ratos , Ratos WistarRESUMO
Metabolic and oxidative stresses have been implicated in ageing and the pathogenesis of chronic kidney disease. In this study, we investigated the glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and lactate concentrations in different kidney regions under control conditions and after exposure to oxidative stress invoked by 0.2 mM H2O2. Slices of superficial cortex, outer or inner medulla were dissected from kidneys of male Wistar rats of 5-, 12-, 36- and 60-week old. Samples were incubated for 30 min ± 0.2 mM H2O2 prior to homogenisation and centrifugation. The concentrations of GSH, TBARS and lactate were measured by colorimetry. Each metabolite showed a distinctive pattern. For GSH, this was 12 weeks > 36 weeks > 60 weeks and 5 weeks with the highest concentration measured in the superficial cortex at 12 weeks. For TBARS and lactate, the pattern was for the lowest concentration at 12 weeks and the highest at 60 and 5 weeks. The highest lactate and TBARS concentrations were measured under oxidative stress conditions, particularly at 5 and 60 weeks. These results suggest that GSH in different kidney regions peaks at maturity and then reduces with increasing age.
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Glutationa/análise , Rim/química , Ácido Láctico/análise , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Fatores Etários , Animais , Peróxido de Hidrogênio/farmacologia , Rim/fisiologia , Masculino , Ratos , Ratos Wistar , Estresse FisiológicoRESUMO
This meta-analysis aimed to compare the midterm clinical outcomes of reimplantation versus remodeling techniques for valve-sparing aortic root replacement (VSARR) in patients with connective tissue disorders (CTDs). Studies were screened and identified after the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines from the PubMed, Web of Science, and Embase databases. Forest plots were produced using Review Manager 5.3 (Cochrane, UK). Studies comparing early and midterm clinical outcomes of reimplantation versus remodeling VSARR in patients with CTD with a mean age ≥18 years were included. The sensitivity analysis excluded studies and subgroups of patients that received ring or suture annuloplasty in addition to remodeling surgery. The study selection identified 9 eligible studies. After analysis of the study period and location for patient crossover, 7 retrospective studies consisting of 597 patients (301 reimplantation and 296 remodeling) were pooled. The pooling revealed no significant difference in postoperative mortality (estimated mean follow-up of 10.5 years) (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.30 to 1.48, I2 = 30%, p = 0.32), reoperation (OR 0.35, CI 0.04 to 3.30, I2 = 81%, p = 0.36), or occurrence of postoperative aortic regurgitation of ≥2 (OR 0.56, CI 0.31 to 1.02, I2 = 47%, p = 0.06). The sensitivity analysis excluding annuloplasty demonstrated improved mortality (OR 0.19, CI 0.06 to 0.64, I2 = 0%, p = 0.007) and decreased aortic regurgitation of ≥2 (OR 0.23, CI 0.10 to 0.53, I2 = 47%, p = 0.0005) in reimplantation VSARR. The rates of reoperation remained insignificant in the sensitivity analysis (OR 0.43, CI 0.05 to 3.53, I2 = 71%, p = 0.43). In conclusion, this meta-analysis has demonstrated no significant difference in the midterm clinical outcomes of reimplantation versus remodeling techniques of VSARR. The sensitivity analysis excluding studies and patient subgroups that received remodeling and annuloplasty suggests remodeling alone to be inferior to reimplantation in patients with CTDs. Further research is required to assess remodeling and annuloplasty against reimplantation in patients of this demographic because the current body of knowledge does not allow sufficient analysis.
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Insuficiência da Valva Aórtica , Doenças do Tecido Conjuntivo , Adolescente , Humanos , Valva Aórtica/cirurgia , Insuficiência da Valva Aórtica/cirurgia , Tecido Conjuntivo , Doenças do Tecido Conjuntivo/complicações , Reoperação , Reimplante , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVES: This meta-analysis aims to compare the clinical outcomes of transcatheter aortic valve implantation (TAVI) versus aortic valve replacement (AVR) for aortic stenosis in dialysis-dependent patients. METHODS: Literature searches employed PubMed, Web of Science, Google Scholar and Embase to identify relevant studies. Bias-treated data were prioritized, isolated and pooled for analysis; raw data were utilized where bias-treated data were unavailable. Outcomes were analysed to assess for study data crossover. RESULTS: Literature search identified 10 retrospective studies; following data source analysis, five studies were included. Upon pooling of bias-treated data, TAVI was significantly favoured in early mortality [odds ratio (OR), 0.42; 95% confidence interval (95% CI), 0.19-0.92; I2 â=â92%; P â=â0.03], 1-year mortality (OR, 0.88; 95% CI 0.80-0.97; I2 â=â0%; P â=â0.01), rates of stroke/cerebrovascular events (OR, 0.71; 95% CI 0.55-0.93; I2 â=â0%; P â=â0.01) and blood transfusions (OR, 0.36; 95% CI 0.21-0.62; I2 â=â86%; P â=â0.0002). Pooling demonstrated fewer new pacemaker implantations in the AVR group (OR, 3.33; 95% CI 1.94-5.73; I2 â=â74%; P â≤â0.0001) and no difference in the rate of vascular complications (OR, 2.27; 95% CI 0.60-8.59; I2 â=â83%; P â=â0.23). Analysis including raw data revealed the length of hospital stay to favour TAVI with a mean difference of -9.20âdays (95% CI -15.58 to -2.82; I2 â=â97%; P â=â0.005). CONCLUSION: Bias-treated meta-analysis comparing surgical AVR and TAVI favoured TAVI in early mortality, 1-year mortality, rates of stroke/cerebrovascular events and blood transfusions. There was no difference in the rates of vascular complications; however, TAVI required more pacemaker implantations. Data pooling including raw data revealed that the length of hospital admission favours TAVI.
Assuntos
Estenose da Valva Aórtica , Implante de Prótese de Valva Cardíaca , Acidente Vascular Cerebral , Substituição da Valva Aórtica Transcateter , Humanos , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Substituição da Valva Aórtica Transcateter/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Diálise Renal/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Acidente Vascular Cerebral/cirurgia , Resultado do TratamentoRESUMO
The general anaesthetic propofol shows promise in protecting normal hearts against various cardiac insults, but little is known about its cardioprotective potential in hypertrophic hearts. This study tested the hypothesis that propofol at a clinically relevant dose would enhance functional recovery in hypertrophic hearts following ischaemia. Hypertrophic hearts from spontaneously hypertensive rats and hearts from their normotensive controls, Wistar Kyoto Rats, were equilibrated in the working mode prior to global normothermic ischaemia. Reperfusion commenced with 10 min in Langendorff mode, followed by 30-min working reperfusion. Functional performance was measured throughout the working mode, whilst reperfusion damage was assessed from myocardial troponin I release during Langendorff reperfusion. Where used, 4 µg/ml propofol was added 10 min before ischaemia and was washed out 10 min into working reperfusion. An additional protocol investigated recovery of hearts protected by normothermic hyperkalaemic cardioplegic arrest. Following 20-min ischaemia, reperfusion damage was significantly worse in hypertrophic hearts compared to normal hearts, whilst addition of propofol to hypertrophic hearts significantly improved the aortic flow (31 ± 5.8 vs. 11.6 ± 2.0 ml/min, n = 6-7 ± SE, p < 0.05). Propofol also conferred significant protection following 30-min ischaemia where the recovery of cardiac output and stroke volume was similar to that for cardioplegia alone. Incubation with propofol improved the NADH/NAD(+) ratio in freshly isolated cardiomyocytes from hypertrophic hearts, suggesting possible improvements in metabolic flux. These findings suggest that propofol at the clinically relevant dose of 4 µg/ml is as effective as cardioplegic arrest in protecting hypertrophic hearts against ischaemia-reperfusion.
Assuntos
Cardiomegalia/fisiopatologia , Propofol/farmacologia , Animais , Débito Cardíaco/efeitos dos fármacos , Técnicas In Vitro , Reperfusão Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , NAD/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Volume Sistólico/efeitos dos fármacosRESUMO
Shiga toxin-producing Escherichia coli (STEC) is a zoonotic pathogen that causes diarrheal disease in humans and is of public health concern because of its ability to cause outbreaks and severe disease such as hemorrhagic colitis or hemolytic-uremic syndrome. More than 400 serotypes of STEC have been implicated in outbreaks and sporadic human disease. The aim of this study was to develop a PCR binary typing (P-BIT) system that could be used to aid in risk assessment and epidemiological studies of STEC by using gene targets that would represent a broad range of STEC virulence genes. We investigated the distribution of 41 gene targets in 75 O157 and non-O157 STEC isolates and found that P-BIT provided 100% typeability for isolates, gave a diversity index of 97.33% (compared with 99.28% for XbaI pulsed-field gel electrophoresis [PFGE] typing), and produced 100% discrimination for non-O157 STEC isolates. We identified 24 gene targets that conferred the same level of discrimination and produced the same cluster dendrogram as the 41 gene targets initially examined. P-BIT clustering identified O157 from non-O157 isolates and identified seropathotypes associated with outbreaks and severe disease. Numerical analysis of the P-BIT data identified several genes associated with human or nonhuman sources as well as high-risk seropathotypes. We conclude that P-BIT is a useful approach for subtyping, offering the advantage of speed, low cost, and potential for strain risk assessment that can be used in tandem with current molecular typing schema for STEC.
Assuntos
Técnicas de Tipagem Bacteriana/métodos , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , Reação em Cadeia da Polimerase/métodos , Escherichia coli Shiga Toxigênica/classificação , Escherichia coli Shiga Toxigênica/genética , Fatores de Virulência/genética , Genótipo , Humanos , Escherichia coli Shiga Toxigênica/patogenicidadeRESUMO
Intracellular cysteine availability is an important rate-limiting factor governing glutathione synthesis in the heart. This is also dependent on the magnitude and rate of cysteine uptake into cardiomyocytes, which has been little studied. This study investigated the hypothesis that changes to cysteine transporter expression and activity during oxidative stress influence cardiomyocyte glutathione levels. The uptake of 0-3 mM L-[(35)S]cysteine into ventricular cardiomyocytes isolated from adult male Wistar rats was measured using oil filtration. Cysteine transporter expression was investigated by conventional and real-time quantitative reverse-transcription polymerase chain reaction and Western blotting. Glutathione levels were measured enzymatically. Oxidative stress was induced via 0-6 h incubation with 0.05 mM H(2)O(2). Cysteine uptake was greatest in sodium-containing media and was inhibited by glutamine, 2-(methylamino)-isobutyric acid (αMeAIB), serine or alanine. The K(m) and V(max) of the αMeAIB insensitive and sensitive portions were 0.133 ± 0.01 mM and 468.11 ± 9.04 pmol/µl cell vol/min, and 0.557 ± 0.096 mM and 279.87 ± 16.06 pmol/µl cell vol/min, respectively. Cardiomyocytes expressed ASCT2, SNAT1 and SNAT2 but not ASCT1. Oxidative stress significantly enhanced cysteine uptake, which was attenuated by αMeAIB. This was accompanied by significantly enhanced SNAT1 expression, whilst SNAT2 and ASCT2 were unaffected. Incubation with cysteine significantly reduced the oxidative-stress-induced decline in cardiomyocyte glutathione as compared to cells incubated without cysteine or cells incubated with cysteine and αMeAIB. In conclusion, under control conditions SNAT transporters aid in the delivery of cysteine for cardiomyocyte GSH synthesis, whilst oxidative stress increases cardiomyocyte cysteine uptake and stimulates cardiomyocyte SNAT1 expression.
Assuntos
Sistema A de Transporte de Aminoácidos/genética , Cisteína/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Regulação para Cima , Sistema A de Transporte de Aminoácidos/metabolismo , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Sistemas de Transporte de Aminoácidos/metabolismo , Animais , Transporte Biológico , Células Cultivadas , Cisteína/química , Peróxido de Hidrogênio/metabolismo , Cinética , Masculino , Antígenos de Histocompatibilidade Menor , Miócitos Cardíacos/química , Ratos , Ratos WistarRESUMO
BACKGROUND: Electronic prescriptions are often created and delivered electronically to the pharmacy while paper-based/handwritten prescriptions may be delivered to the pharmacy by the patients. These differences in the mode of creation and transmission of the two types of prescription could influence the rate at which outpatients fill new prescriptions of previously untried medications. OBJECTIVES: This study aimed to evaluate literatures to determine the impact of electronic prescribing compared with paper-based/handwritten prescribing on primary medication adherence in an outpatient setting. METHODS: The keywords and phrases "outpatients," "e-prescriptions," "paper-based prescriptions," and "primary medication adherence" were combined with their relevant synonyms and medical subject headings. A comprehensive literature search was conducted on EMBASE, CINAHL, and MEDLINE databases, and Google Scholar. The results of the search were screened and selected using predefined inclusion and exclusion criteria. The Critical Appraisal Skills Program (CASP) was used for quality appraisal of included studies. Data relevant to the objective of the review were extracted and analyzed through narrative synthesis. RESULTS: A total of 10 original studies were included in the final review, including 1 prospective randomized study and 9 observational studies. Nine of the 10 studies were performed in the United States. Four of the studies indicated that electronic prescribing significantly increases initial medication adherence, while four of the studies suggested the opposite. The remaining two studies found no significant difference in primary medication adherence between the two methods of prescribing. The variations in the studies did not allow the homogeneity required for meta-analysis to be achieved. CONCLUSION: The conflicting findings relating to the efficacy of primary medication adherence across both systems demonstrate the need for a standardized measure of medication adherence. This would help further determine the respective benefits of both approaches. Future research should also be conducted in different countries to give a more accurate representation of adherence.