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BACKGROUND: Reports of DILI due to herbal and dietary supplements have been increasing over time. AIMS: To characterise clinical, laboratory and histopathological phenotypes and outcomes of drug-induced liver injury (DILI) due to anabolic-androgenic steroids (AAS), selective androgen receptor modulators (SARMs), and bodybuilding supplements (BBS) in Australia. METHODS: Retrospective case series. Patients presented to nine Australian tertiary hospitals, 2017-2023. DILI was defined biochemically and patients were included if their treating physician attributed DILI to preceding use of AAS, SARMs or BBS. Primary endpoint was time to normalisation of liver biochemistry. Secondary endpoints were hospitalisation for investigation or management of DILI, death attributable to liver injury, and liver transplantation. RESULTS: Twenty-three cases of DILI were identified, involving 40 drugs: 18 AAS, 14 SARMs and eight BBS. Patients were predominantly male (22/23), with median age 30 years (IQR 26-42). Most were symptomatic (21/23). Median latency of onset was 58 days (IQR 28-112 days) from drug commencement. Most patients (17/23) were admitted to hospital. Based on updated Roussel Uclaf Causality Assessment Method, DILI was possible in 17/23, probable in 2/23 and unlikely in 4/23. Median time to normalisation of liver biochemistry was 175 days (IQR 70-292 days) from presentation. Three (3/23) were treated with corticosteroids, 14/23 were treated for itch, and one (1/23) underwent liver transplantation. There were no deaths. CONCLUSIONS: The prognosis of DILI from AAS, SARMs and BBS is good although liver transplantation may rarely be required. A detailed drug history is important in uncovering DILI due to these supplements.
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Doença Hepática Induzida por Substâncias e Drogas , Receptores Androgênicos , Humanos , Masculino , Adulto , Feminino , Esteróides Androgênicos Anabolizantes , Estudos Retrospectivos , Austrália/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Suplementos Nutricionais/efeitos adversos , EsteroidesRESUMO
BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.
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Hepatite C Crônica , Hepatite C , Adulto , Humanos , Masculino , Idoso , Adolescente , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Programas Nacionais de Saúde , Hepatite C/tratamento farmacológico , Hepacivirus , Resposta Viral Sustentada , Assistência ao Paciente , Continuidade da Assistência ao PacienteRESUMO
Artificial sensory feedback via electrocutaneous stimulation can be used to assist or rehabilitate stroke survivors with sensory deficits. Conveying the magnitude of tactile stimuli is an important aspect of artificial sensory feedback. Here, we explore how stroke-related sensory deficits impact the ability of electrocutaneous stimulation to convey the magnitude of tactile stimuli. Using classical psychophysical methods, we quantified the threshold of detection and the just-noticeable difference of electrocutaneous stimulation current in five stroke survivors with unilateral sensory deficits. We show significantly greater (40%) stimulation currents are needed for initial perception on the paretic hand compared to the non-paretic hand. We also show significantly greater percent changes in stimulation current (140%) are needed for reliable incremental perception on the paretic hand compared to the non-paretic hand. Lastly, we show little correlation between electrocutaneous discrimination performance and clinical sensory assessments of light-touch and spatial mechanoperception. These findings can help guide the implementation of artificial sensory feedback as an assistive or rehabilitative intervention for individuals experiencing sensory loss after a stroke.Clinical Relevance- Our results can help guide the implementation of electrical stimulation as an assistive or rehabilitative intervention for individuals with sensory loss after stroke.
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Terapia por Estimulação Elétrica , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral , Humanos , Mãos , Acidente Vascular Cerebral/complicações , Tato/fisiologiaRESUMO
Asian-Pacific nations are home to more than half the world's population and similar to other global super regions, metabolic dysfunction associated fatty liver disease (MAFLD) is the principal cause for chronic liver disease. To address the challenges ahead for tackling the disease at-scale, the Asian Pacific Association for the Study of the Liver (APASL) was the first pan-national society to endorse and lead the process for redefining the disease and adopting the more appropriate term "MAFLD" with its accompanying set of positive diagnostic criteria. As with this initiative, APASL and Hepatology International will continue to strive to lead the field and work with sister societies towards full adoption of MAFLD. This will advance the science and practice of Hepatology and help incorporate MAFLD within multidisciplinary care teams. Ultimately, it will lead to more cogent clinical trials built on innovative design platforms that include patients with any disease related to metabolic dysfunction. For our patients, an outcome of these endeavours will be the provision of holistic person-centred care for this disease that is so common in our region.
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Hepatopatias , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatias/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/terapia , Assistência Centrada no PacienteRESUMO
BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.
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Hepatite C Crônica , Hepatite C , Adulto , Idoso , Antivirais/uso terapêutico , Austrália/epidemiologia , Seguimentos , Hepacivirus , Hepatite C/tratamento farmacológico , Hepatite C Crônica/tratamento farmacológico , Humanos , Programas Nacionais de Saúde , Estudos Prospectivos , Resposta Viral SustentadaAssuntos
Biomarcadores Tumorais , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , RNA Longo não Codificante , Sorafenibe/farmacologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Análise de Célula Única , Sorafenibe/uso terapêutico , TranscriptomaRESUMO
With the global epidemics of obesity and associated conditions, including type 2 diabetes, metabolic dysfunction-associated fatty liver disease, chronic kidney disease, hypertension, stroke, cardiovascular disease, osteoporosis, cancer, and cognitive changes, the prevalence of multimorbidity is rapidly increasing worldwide. In this Review, a panel of international experts from across the spectrum of metabolic diseases come together to identify the challenges and provide perspectives on building a framework for a virtual primary care-driven, patient-centred, multidisciplinary model to deliver holistic care for patients with metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. We focus on clinical care and innovative trial design for metabolic dysfunction-associated fatty liver disease and associated metabolic diseases. This work represents a call to action to promote collaboration and partnerships between stakeholders for improving the lives of people with, or at risk of, metabolic dysfunction-associated fatty liver disease and associated metabolic diseases.
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Ensaios Clínicos como Assunto/métodos , Doenças Metabólicas/complicações , Hepatopatia Gordurosa não Alcoólica/terapia , Saúde Global , Humanos , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/terapia , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Fatores de RiscoRESUMO
Idiosyncratic drug-induced liver injury mimics acute and chronic liver disease. It is under recognized and underrecognised because of the lack of pathognomonic diagnostic serological markers. Its consequences may vary from being asymptomatic to self-limiting illness to severe liver injury leading to acute liver failure. Its incidence is likely to be more common in Asia than other parts of the world, mainly because of hepatotoxicity resulting from the treatment of tuberculosis disease and the ubiquitous use of traditional and complimentary medicines in Asian countries. This APASL consensus guidelines on DILI is a concise account of the various aspects including current evidence-based information on DILI with special emphasis on DILI due to antituberculosis agents and traditional and complementary medicine use in Asia.
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Doença Hepática Induzida por Substâncias e Drogas , Ásia/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Humanos , Incidência , Falência Hepática AgudaRESUMO
Gastrointestinal (GI) cancers constitute the largest portion of all human cancers and represent a significant health burden on modern society. Conventional therapeutic approaches such as chemotherapy and surgical resections often fail due to poor treatment response or tumour relapse. Unfortunately, drug discovery for GI cancers has stalled as current cancer models fail to recapitulate critical features of the parent tumour, leading to poor translation from bench to bedside. Recent advances in three-dimensional (3D) cell culturing techniques have driven the surge of interest in stem cell-derived organoid models, a promising platform with a plethora of potential applications due to its ability to retain crucial architectural, genomic and transcriptional properties of the native tissue. In this review article, we discuss current applications and advantages of organoid models in the translational research of GI cancers with a particular focus on primary liver cancer that currently lack effective curative treatments.
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Técnicas de Cultura de Células/métodos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Organoides , Antineoplásicos , Bancos de Espécimes Biológicos , Diferenciação Celular , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Neoplasias Gastrointestinais/patologia , Humanos , Fígado/citologia , Neoplasias Hepáticas/patologia , Células-Tronco Pluripotentes/fisiologiaRESUMO
Maternal smoking leads to glucose and lipid metabolic disorders and hepatic damage in the offspring, potentially due to mitochondrial oxidative stress. Mitoquinone mesylate (MitoQ) is a mitochondrial targeted antioxidant with high bioavailability. This study aimed to examine the impact of maternal cigarette smoke exposure (SE) on offspring's metabolic profile and hepatic damage, and whether maternal MitoQ supplementation during gestation can affect these changes. Female Balb/c mice (eight weeks) were either exposed to air or SE for six weeks prior to mating and throughout gestation and lactation. A subset of the SE dams were supplied with MitoQ in the drinking water (500 µmol/L) during gestation and lactation. Intraperitoneal glucose tolerance test was performed in the male offspring at 12 weeks and the livers and plasma were collected at 13 weeks. Maternal SE induced glucose intolerance, hepatic steatosis, mitochondrial oxidative stress and related damage in the adult offspring. Maternal MitoQ supplementation reduced hepatic mitochondrial oxidative stress and improved markers of mitophagy and mitochondrial biogenesis. This may restore hepatic mitochondrial health and was associated with an amelioration of glucose intolerance, hepatic steatosis and pathological changes induced by maternal SE. MitoQ supplementation may potentially prevent metabolic dysfunction and hepatic pathology induced by intrauterine SE.
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Fígado Gorduroso/induzido quimicamente , Exposição Materna , Síndrome Metabólica/induzido quimicamente , Compostos Organofosforados/farmacologia , Poluição por Fumaça de Tabaco/efeitos adversos , Ubiquinona/análogos & derivados , Animais , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Feminino , Lactação , Lipidômica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias Hepáticas/fisiologia , Compostos Organofosforados/administração & dosagem , Estresse Oxidativo , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ubiquinona/administração & dosagem , Ubiquinona/farmacologiaRESUMO
Although recent advances in neuroprostheses offer opportunities for improved and intuitive control of advanced motorized and sensorized robotic arms, practical complications associated with such hardware can impede the research necessary for clinical translation. These hurdles potentially can be reduced with virtual reality environments (VREs) with embedded physics engines using virtual models of physical robotic hands. These software suites offer several advantages over physical prototypes, including high repeatability, reduced human error, elimination of many secondary sensory cues, and others. There are limited demonstrations of closed-loop prostheses in the VRE, and it is unclear whether VRE performance translates to the physical world. Here we describe how two trans-radial amputees with neural and intramuscular implants identified objects and performed activities of daily living with closed-loop control of prostheses in the VRE. Our initial evidence further suggests that capabilities with virtual prostheses may be predictors of physical prosthesis performance, demonstrating the utility of VREs for neuroprosthetic research.
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Eletromiografia/métodos , Próteses Neurais , Realidade Virtual , Atividades Cotidianas , Amputados , Biorretroalimentação Psicológica , Sinais (Psicologia) , Eletrodos Implantados , Mãos/fisiologia , Humanos , Desenho de Prótese , Robótica , Sensação/fisiologia , SoftwareRESUMO
Being overweight increases the risk of the development of metabolic conditions such as non-alcoholic fatty liver disease (NAFLD), which is itself an independent predictor of cardiovascular disease. Omega-3 polyunsaturated fatty acid (PUFA) supplementation is recommended for prevention of chronic disease, and is thought to reduce raised liver fat, yet there have been few randomized controlled trials with accurate measurement of liver fat. We assessed the effect of 12 weeks of supplementation with omega-3 PUFA from fish oil versus placebo on quantified liver fat, liver tests, and body composition including visceral adipose tissue (VAT) in a double-blind randomized controlled trial. Fifty apparently healthy overweight men (BMI 25.0â»29.9 kg/m²; waist > 94 cm) were randomly allocated to consume fish oil (total daily dose: 1728 mg marine triglycerides, of which 588 mg EPA and 412 mg DHA, combined with 200 mg antioxidant, coenzyme Q10) or placebo (olive oil capsules) daily for 12 weeks. Liver fat was assessed using proton magnetic resonance spectroscopy. All outcomes were assessed at baseline and following 6 and 12 weeks of supplementation. Baseline liver fat was 4.6 ± 0.5% (range: 0.6 to 18.2%); 16 (32%) participants met the criteria for NAFLD (>5.5% liver fat). Repeated measures ANOVA revealed no significant time or group × time effect for fish oil versus placebo for liver fat, liver enzymes, anthropometry, or body composition including VAT (p > 0.05 for all), with similar finding for sub-analysis of participants with NAFLD. Omega-3 PUFA did not appear to be an effective agent for reducing liver fat in overweight men. The factors determining the health benefits of omega-3 PUFA supplementation on an individual level need to be clarified.
Assuntos
Óleos de Peixe/administração & dosagem , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Sobrepeso , Adulto , Composição Corporal , Suplementos Nutricionais , Ácidos Graxos Ômega-3/metabolismo , Humanos , Fígado/fisiologia , MasculinoRESUMO
This Review presents current epidemiological trends of the most common liver diseases in Asia-Pacific countries. Hepatitis B virus (HBV) remains the primary cause of cirrhosis; despite declining prevalence in most Asian nations, this virus still poses a severe threat in some territories and regions. Mortality resulting from HBV infection is declining as a result of preventive measures and antiviral treatments. The epidemiological transition of hepatitis C virus (HCV) infection has varied in the region in the past few decades, but the medical burden of infection and the prevalence of its related cancers are increasing. The lack of licensed HCV vaccines highlights the need for novel treatment strategies. The prevalence of nonalcoholic fatty liver disease (NAFLD) has risen in the past decade, mostly owing to increasingly urbanized lifestyles and dietary changes. Alternative herbal medicine and dietary supplements are major causes of drug-induced liver injury (DILI) in some countries. Complications arising from these chronic liver diseases, including cirrhosis and liver cancer, are therefore emerging threats in the Asia-Pacific region. Key strategies to control these liver diseases include monitoring of at-risk populations, implementation of national guidelines and increasing public and physician awareness, in concert with improving access to health care.
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Hepatopatias/epidemiologia , Ásia/epidemiologia , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , Coinfecção/epidemiologia , Coinfecção/virologia , Ásia Oriental/epidemiologia , Hepatite B/epidemiologia , Hepatite C/epidemiologia , Humanos , Hepatopatias Alcoólicas/epidemiologia , Hepatopatia Gordurosa não Alcoólica/epidemiologiaRESUMO
Allopurinol and its active metabolite, oxypurinol are widely used in the treatment of gout and hyperuricemia. They inhibit xanthine oxidase (XO) an enzyme in the purine degradation pathway that converts xanthine to uric acid. This investigation examined the effect of allopurinol and oxypurinol on bone formation, cell number and viability, gene expression and enzyme activity in differentiating and mature, bone-forming osteoblasts. Although mRNA expression remained relatively constant, XO activity decreased over time with mature osteoblasts displaying reduced levels of uric acid (20% decrease). Treatment with allopurinol and oxypurinol (0.1-1 µM) reduced XO activity by up to 30%. At these concentrations, allopurinol and oxypurinol increased bone formation by osteoblasts ~4-fold and ~3-fold, respectively. Cell number and viability were unaffected. Both drugs increased tissue non-specific alkaline phosphatase (TNAP) activity up to 65%. Osteocalcin and TNAP mRNA expression was increased, 5-fold and 2-fold, respectively. Expression of NPP1, the enzyme responsible for generating the mineralisation inhibitor, pyrophosphate, was decreased 5-fold. Col1α1 mRNA expression and soluble collagen levels were unchanged. Osteoclast formation and resorptive activity were not affected by treatment with allopurinol or oxypurinol. Our data suggest that inhibition of XO activity promotes osteoblast differentiation, leading to increased bone formation in vitro.
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Alopurinol/farmacologia , Conservadores da Densidade Óssea/farmacologia , Diferenciação Celular/efeitos dos fármacos , Osteoblastos/fisiologia , Animais , Sobrevivência Celular , Células Cultivadas , Colágeno/metabolismo , Avaliação Pré-Clínica de Medicamentos , Expressão Gênica , Camundongos , Osteoblastos/efeitos dos fármacos , Osteogênese , Oxipurinol/farmacologia , Ratos , Ratos Sprague-Dawley , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/genética , Xantina Oxidase/metabolismoRESUMO
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of abnormalities that can range from bland liver fat (steatosis), to hepatic inflammation and liver injury (steatohepatitis). It is estimated that NAFLD will become the principal cause of liver disease in Western nations and the leading indication for liver transplantation. Advancements in disease recognition and management are therefore paramount. Although the development of new, reliable drug therapies is vital, lifestyle interventions remain the most effective treatment modality. In addition to weight loss as a primary measure of treatment success, there is growing recognition that other endpoints, including the prevention or delay of diabetes onset, reduced cardiovascular events, prevention of cancer, and improved overall mortality, are equally important outcomes that can be independently modified by lifestyle change. Moreover, NAFLD is inextricably part of a complex, systemic disease process that is linked with deeply entrenched maladaptive lifestyle behaviors. Thus, a holistic, multidisciplinary, and individualized approach to disease management will be the key to achieving any realistic population-level change.
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Terapia Cognitivo-Comportamental , Dieta , Exercício Físico , Estilo de Vida , Hepatopatia Gordurosa não Alcoólica/terapia , Comportamento de Redução do Risco , Dieta/efeitos adversos , Progressão da Doença , Ingestão de Energia , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/psicologia , Estado Nutricional , Medição de Risco , Fatores de Risco , Comportamento Sedentário , Resultado do Tratamento , Redução de PesoRESUMO
Non-alcoholic fatty liver disease (NAFLD) is an independent predictor of CVD in otherwise healthy individuals. Low n-3 PUFA intake has been associated with the presence of NAFLD; however, the relationship between a biomarker of n-3 status - the Omega-3 Index - and liver fat is yet to be elucidated. A total of eighty overweight adults (fifty-six men) completed the anthropometric and biochemical measurements, including the Omega-3 Index, and underwent proton magnetic resonance spectroscopy assessment of liver fat. Bivariate correlations and multiple regression analyses were performed with reference to prediction of liver fat percentage. The mean Omega-3 Index was high in both NAFLD (intrahepatic lipid concentration≥5·5 %) and non-NAFLD groups. The Omega-3 Index, BMI, waist circumference, glucose, insulin, TAG, high-sensitive C-reactive protein (hsCRP) and alanine aminotransferase (ALT) were positively correlated, and HDL and erythrocyte n-6:n-3 ratio negatively correlated with liver fat concentration. Regression analysis found that simple anthropometric and demographic variables (waist, age) accounted for 31 % of the variance in liver fat and the addition of traditional cardiometabolic blood markers (TAG, HDL, hsCRP and ALT) increased the predictive power to 43 %. The addition of the novel erythrocyte fatty acid variable (Omega-3 Index) to the model only accounted for a further 3 % of the variance (P=0·049). In conclusion, the Omega-3 Index was associated with liver fat concentration but did not improve the overall capacity of demographic, anthropometric and blood markers to predict NAFLD.
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Membrana Eritrocítica/metabolismo , Ácidos Graxos Ômega-3/sangue , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/metabolismo , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/etiologia , Estado Nutricional , Obesidade/sangue , Obesidade/complicações , Projetos Piloto , Adulto JovemRESUMO
Allopurinol, an inhibitor of xanthine oxidase, has been used in clinical trials of patients with cardiovascular and chronic kidney disease. These are two pathologies with extensive links to hypoxia and activation of the transcription factor hypoxia inducible factor (HIF) family. Here we analysed the effects of allopurinol treatment in two different cellular models, and their response to hypoxia. We explored the dose-dependent effect of allopurinol on Human Foreskin Fibroblasts (HFF) and Human Umbilical Vein Endothelial Cells (HUVEC) under hypoxia and normoxia. Under normoxia and hypoxia, high dose allopurinol reduced the accumulation of HIF-1α protein in HFF and HUVEC cells. Allopurinol had only marginal effects on HIF-1α mRNA level in both cellular systems. Interestingly, allopurinol effects over the HIF system were independent of prolyl-hydroxylase activity. Finally, allopurinol treatment reduced angiogenesis traits in HUVEC cells in an in vitro model. Taken together these results indicate that high doses of allopurinol inhibits the HIF system and pro-angiogenic traits in cells.
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Alopurinol/farmacologia , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia Celular , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Prepúcio do Pênis/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Neovascularização Fisiológica/efeitos dos fármacosRESUMO
OBJECTIVES: To demonstrate reduction in detrusor overactivity using surface electrical stimulation of posterior tibial nerve (PTN) or dorsal penile nerve (DPN) in patients with spinal cord injury (SCI). DESIGN: Patients with SCI with symptoms of urinary urgency/leaks, with cystometrogram (CMG) proven detrusor overactivity were recruited in this study. Ten persons with observable F-wave from tibial nerve were included in the PTN group. Five persons who had F-wave absent but preserved bulbocavernosus reflex were included in the DPN group. Stimulation was given at 20 Hz, 10-40 mA for 20 minutes/session/day for 14 consecutive days. Detrusor overactivity was recorded using CMG on days 1 and 15. SETTINGS: Rehabilitation Institute, Department of Physical Medicine and Rehabilitation, Christian Medical College and Hospital, Vellore, TN, India. PARTICIPANTS: Patients with SCI. INTERVENTIONS: Surface stimulation of peripheral nerves for reduction of detrusor overactivity. OUTCOME MEASURES: Qualitative analysis using voiding diary data and quantitative analysis using CMG data comparing pre- and post-intervention. RESULTS: P value obtained from voiding chart was 0.021 for PTN and 0.062 for DPN. P value obtained from CMG data was not significant in both groups. In one subject, treatment was extended to 4 weeks and further improvement in voiding diary was seen. CONCLUSIONS: In this pilot study of 15 patients, voiding chart data showed statistically significant improvement following PTN stimulation and trend of improvement following DPN stimulation. However, the CMG data were not statistically significant in this sample population. Further studies with larger, appropriately powered sample size would be helpful to demonstrate the associations of symptoms with CMG data. Trial registration CTRI no.; CTRI/2012/12/003234; CMCH Approval no.: CMC/IRB/6735/2008/12/18.
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Traumatismos da Medula Espinal/complicações , Estimulação Elétrica Nervosa Transcutânea , Bexiga Urinária Hiperativa/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismos da Medula Espinal/reabilitação , Nervo Tibial/fisiologia , Bexiga Urinária Hiperativa/etiologiaRESUMO
OBJECTIVES: This study sought to ascertain whether high-dose allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients' high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether allopurinol causes regression of LVH in patients with T2DM. METHODS: We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months' follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. RESULTS: Allopurinol significantly reduced absolute LVM (-2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (-1.32 ± 2.84 g/m(2) vs. placebo group +0.65 ± 3.07 g/m(2) [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. CONCLUSIONS: Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766).
Assuntos
Alopurinol/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Idoso , Análise de Variância , Método Duplo-Cego , Feminino , Ventrículos do Coração/patologia , Humanos , Hipertrofia Ventricular Esquerda/complicações , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Ácido Úrico/sangueRESUMO
Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are an increasingly common cause of chronic liver disease in the developed world, with NASH projected to be the leading cause of liver transplantation in the United States by 2020. This review of NASH management addresses current data from the perspective of levels of evidence for therapeutic options in NASH, including lifestyle modification, drug therapies, and bariatric surgery. In particular, behavioral therapies to assist patients in adopting lifestyle changes are highlighted and a research agenda for future NASH management is presented.