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1.
Hepatology ; 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38809154

RESUMO

BACKGROUND AND AIMS: NASH confers an increased liver-related and kidney morbidity. Phospholipid curcumin (Meriva) is a phospholipid formulation with ameliorated systemic curcumin absorption and delivery. We assessed the safety and efficacy of Meriva in NASH. APPROACH AND RESULTS: In this double-blind trial, 52 patients with biopsy-proven NASH (71% with stage ≥F2 fibrosis, 58% with stage A2-G2/A2-G3a chronic kidney disease) were randomized 1:1 to receive Meriva 2 g/d or placebo for 72 weeks. The primary endpoint was NASH resolution with no worsening of fibrosis. The secondary endpoints included a ≥1 stage liver fibrosis improvement with no NASH worsening; regression of significant (ie, stage ≥F2) fibrosis and CKD; and improvement in renal, glucose, lipid, and inflammatory parameters. We also explored the treatment effect on hepatic activation of NF-kB, a key proinflammatory transcription factor and a major target of curcumin. Fifty-one patients (26 on Meriva and 25 on placebo) completed the trial. Sixteen (62%) patients on Meriva versus 3 (12%) patients on placebo had NASH resolution (RR = 5.33 [95% CI = 1.76-12.13]; p = 0.003). Thirteen (50%) patients on Meriva versus 2 (8%) patients on placebo had ≥1 stage fibrosis improvement (RR = 6.50 [1.63-21.20]; p = 0.008). Eleven (42%) patients on Meriva versus 0 (0%) on placebo had regression of significant liver fibrosis (RR = 18.01 [1.43-36.07]; p = 0.02). Hepatic NF-kB inhibition predicted NASH resolution (AUC = 0.90, 95% CI = 0.84-0.95) and fibrosis improvement (AUC = 0.89, 95% CI = 0.82-0.96). Thirteen (50%) patients on Meriva versus 0 (0%) on placebo had chronic kidney disease regression (RR = 10.71 [1.94-17.99)]; p = 0.004). Compared with placebo, Meriva improved eGFR (difference in adjusted eGFR change: +3.59 [2.96-4.11] mL/min/1.73 m 2 /y, p = 0.009), fasting glucose(-17 mg/dL; 95% CI = -22, -12), HbA1c (-0.62%; 95% CI = -0.87%, -0.37%), LDL-C (-39 mg/dL; 95% CI = -45, -33), triglycerides (-36 mg/dL, 95% CI = -46, -26), HDL-C (+10 mg/dL; 95% CI = +8, +11), and inflammatory markers. Adverse events were rare, mild, and evenly distributed. CONCLUSIONS: In patients with NASH, Meriva administration for 72 weeks was safe, well-tolerated, and improved liver histology, possibly through NF-kB inhibition, kidney disease, and metabolic profile.

2.
Crit Care Med ; 51(9): 1185-1200, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37232709

RESUMO

OBJECTIVES: To study: 1) the effect of prone position (PP) on noninvasive ventilation (NIV)-delivered mechanical power (MP) and 2) the impact of MP on physio-anatomical and clinical responses to early versus late PP in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. DESIGN: Nonrandomized trial with inverse probability of treatment weighted-matched groups. SETTING: HUMANITAS Gradenigo Sub-ICU. PATIENTS: One hundred thirty-eight SARS-CoV-2 pneumonia patients with moderate-to-severe acute hypoxemic respiratory failure (Pa o2 /F io2 ratio < 200 mm Hg) receiving NIV from September 1, 2020, to February 28, 2021 (Ethics approval: ISRCTN23016116). INTERVENTIONS: Early PP or late PP or supine position. MEASUREMENTS AND MAIN RESULTS: Respiratory parameters were hourly recorded. Time-weighted average MP values were calculated for each ventilatory session. Gas exchange parameters and ventilatory ratio (VR) were measured 1 hour after each postural change. Lung ultrasonographic scores and circulating biomarkers were assessed daily. MP delivered during the initial 24 hours of NIV (MP [first 24 hr]) was the primary exposure variable. Primary outcomes: 28-day endotracheal intubation and death. Secondary outcomes: oxygen-response, C o2 -response, ultrasonographic, and systemic inflammatory biomarker responses after 24 hours of NIV. Fifty-eight patients received early PP + NIV, 26 late PP + NIV, and 54 supine NIV. Early PP group had lower 28-day intubation and death than late PP (hazard ratio [HR], 0.35; 95% CI, 0.19-0.69 and HR, 0.26; 95% CI, 0.07-0.67, respectively) and supine group. In Cox multivariate analysis, (MP [first 24 hr]) predicted 28-day intubation (HR, 1.70; 95% CI, 1.25-2.09; p = 0.009) and death (HR, 1.51; 95% CI, 1.19-1.91; p = 0.007). Compared with supine position, PP was associated with a 35% MP reduction. VR, ultrasonographic scores, and inflammatory biomarkers improved after 24 hours of NIV in the early PP, but not in late PP or supine group. A MP (first 24 hr) greater than or equal to 17.9 J/min was associated with 28-day death (area under the curve, 0.92; 95% CI, 0.88-0.96; p < 0.001); cumulative hours of MP greater than or equal to 17.9 J/min delivered before PP initiation attenuated VR, ultrasonographic, and biomarker responses to PP. CONCLUSIONS: MP delivered by NIV during initial 24 hours predicts clinical outcomes. PP curtails MP, but cumulative hours of NIV with MP greater than or equal to 17.9 J/min delivered before PP initiation attenuate the benefits of PP.


Assuntos
COVID-19 , Ventilação não Invasiva , Insuficiência Respiratória , Humanos , COVID-19/terapia , Pulmão , Respiração Artificial , Insuficiência Respiratória/terapia , SARS-CoV-2
3.
Crit Care ; 26(1): 118, 2022 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-35488356

RESUMO

BACKGROUND: Whether prone position (PP) improves clinical outcomes in COVID-19 pneumonia treated with noninvasive ventilation (NIV) is unknown. We evaluated the effect of early PP on 28-day NIV failure, intubation and death in noninvasively ventilated patients with moderate-to-severe acute hypoxemic respiratory failure due to COVID-19 pneumonia and explored physiological mechanisms underlying treatment response. METHODS: In this controlled non-randomized trial, 81 consecutive prospectively enrolled patients with COVID-19 pneumonia and moderate-to-severe (paO2/FiO2 ratio < 200) acute hypoxemic respiratory failure treated with early PP + NIV during Dec 2020-May 2021were compared with 162 consecutive patients with COVID-19 pneumonia matched for age, mortality risk, severity of illness and paO2/FiO2 ratio at admission, treated with conventional (supine) NIV during Apr 2020-Dec 2020 at HUMANITAS Gradenigo Subintensive Care Unit, after propensity score adjustment for multiple baseline and treatment-related variables to limit confounding. Lung ultrasonography (LUS) was performed at baseline and at day 5. Ventilatory parameters, physiological dead space indices (DSIs) and circulating inflammatory and procoagulative biomarkers were monitored during the initial 7 days. RESULTS: In the intention-to-treat analysis. NIV failure occurred in 14 (17%) of PP patients versus 70 (43%) of controls [HR = 0.32, 95% CI 0.21-0.50; p < 0.0001]; intubation in 8 (11%) of PP patients versus 44 (30%) of controls [HR = 0.31, 95% CI 0.18-0.55; p = 0.0012], death in 10 (12%) of PP patients versus 59 (36%) of controls [HR = 0.27, 95% CI 0.17-0.44; p < 0.0001]. The effect remained significant within different categories of severity of hypoxemia (paO2/FiO2 < 100 or paO2/FiO2 100-199 at admission). Adverse events were rare and evenly distributed. Compared with controls, PP therapy was associated with improved oxygenation and DSIs, reduced global LUS severity indices largely through enhanced reaeration of dorso-lateral lung regions, and an earlier decline in inflammatory markers and D-dimer. In multivariate analysis, day 1 CO2 response outperformed O2 response as a predictor of LUS changes, NIV failure, intubation and death. CONCLUSION: Early prolonged PP is safe and is associated with lower NIV failure, intubation and death rates in noninvasively ventilated patients with COVID-19-related moderate-to-severe hypoxemic respiratory failure. Early dead space reduction and reaeration of dorso-lateral lung regions predicted clinical outcomes in our study population. CLINICAL TRIAL REGISTRATION: ISRCTN23016116 . Retrospectively registered on May 1, 2021.


Assuntos
COVID-19 , Ventilação não Invasiva , Síndrome do Desconforto Respiratório , Insuficiência Respiratória , COVID-19/complicações , COVID-19/terapia , Humanos , Ventilação não Invasiva/efeitos adversos , Decúbito Ventral , Estudos Prospectivos , Respiração Artificial , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , SARS-CoV-2
4.
Arch Womens Ment Health ; 25(2): 257-266, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35237876

RESUMO

Several lines of research suggest that reproductive-related hormonal events may affect the course of bipolar disorder in some women. However, data on associations between bipolar disorder and menarche, menstrual cycle, and menopause are mixed. This article reviews the literature on the potential effects of menarche, menstrual cycle, and menopause on bipolar disorder.A narrative review of published articles on bipolar disorder and menstrual cycle events was conducted. The primary outcome assessed was the impact of menarche, menstrual cycle and menopause on the course of bipolar illness. Databases searched were PubMed, Ovid, Scopus, PsycINFO, Medline, and Cochrane Libraries from inception to August 2021.Twenty-two studies were identified and included in the narrative synthesis. Research suggested that a subset of women with bipolar disorder are vulnerable to the impact of menstrual cycle events. Menarche seems to be associated with age at onset of bipolar illness especially in case of bipolar disorder type I and the specific age at menarche may predict some clinical features of the disorder. Menstrual cycle likely affects the course of bipolar disorder but the pattern of mood variability is not clear. Menopause appears to be not only a period of vulnerability to mood alteration, especially depressive episodes, and impairment of quality of life, but also a potential trigger of bipolar illness onset.The impact of menarche, menstrual cycle, and menopause on bipolar disorder is largely understudied. Preliminary evidence suggests that a subset of women with bipolar disorder may have their mood shifts affected by menstrual cycle events, with different patterns depending on the type of bipolar disorder also. Further researches are needed to deep the impact of menarche, menstrual cycle, and menopause on bipolar illness.


Assuntos
Transtorno Bipolar , Transtorno Bipolar/complicações , Transtorno Bipolar/epidemiologia , Feminino , Humanos , Menarca , Menopausa , Ciclo Menstrual , Distúrbios Menstruais , Qualidade de Vida
5.
Hum Mol Genet ; 26(9): 1747-1758, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28334911

RESUMO

The loss-of-function rs4374383 G > A variant in Myeloid-epithelial-reproductive Tyrosine Kinase (MERTK) gene has been linked to hepatic fibrosis in chronic liver diseases. MERTK is expressed by immune and non-immune cells involved in inflammation, metabolism and vascular homeostasis. We assessed the impact of MERTK rs4374383 G > A variant on nonalcoholic fatty liver disease (NAFLD) incidence and severity and on glucose and lipid metabolism. We followed-up 305 healthy nonobese nondiabetic, metabolic syndrome-free insulin sensitive participants in a population-based study, characterized for MERTK G > A polymorphism, adipokine profile and inflammatory markers.An independent cohort of 69 biopsy-proven nondiabetic NAFLD patients and 69 healthy controls underwent indirect calorimetry, an OGTT with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, and of Nuclear Factor (NF)-κB activation in circulating mononuclear cells (MNCs). In the longitudinal cohort, MERTK G > A polymorphism protected against 9-year incident NAFLD (OR:0.48,95%CI:0.26-0.79) and diabetes (OR: 0.47, 95% CI: 0.19-0.87).In the cross-sectional cohort, MERTK A-allele carriers had higher fat oxidation rates and tissue insulin sensitivity. Despite comparable fastign and postprandial lipid profiles, MERTK A-allele carriers showed lower resistin and MCP-1 responses, milder MNC NF-κB activation, and a higher postprandial adiponectin response to fat, which predicted tissue insulin resistance hepatocyte apoptosis and liver histology. MERTK G > A variant affects liver disease, nutrient oxidation and glucose metabolism in NAFLD. The modulation of adipokine, chemokine and pro-inflammatory MNC activation in response to fat ingestion may contribute to the observed effects on liver and metabolic disease.


Assuntos
Diabetes Mellitus/genética , Hepatopatia Gordurosa não Alcoólica/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Adipocinas/metabolismo , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus/metabolismo , Gorduras na Dieta/metabolismo , Feminino , Predisposição Genética para Doença , Variação Genética , Glucose/metabolismo , Humanos , Resistência à Insulina/genética , Leucócitos Mononucleares/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas/genética , Cirrose Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polimorfismo de Nucleotídeo Único , c-Mer Tirosina Quinase
6.
Gastroenterology ; 155(2): 282-302.e8, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29906416

RESUMO

The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis.


Assuntos
Fármacos Gastrointestinais/uso terapêutico , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Progressão da Doença , Eicosanoides/metabolismo , Eicosanoides/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Fármacos Gastrointestinais/farmacologia , Humanos , Fígado/citologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Prevalência , Esfingolipídeos/metabolismo , Esfingolipídeos/uso terapêutico
7.
Am J Gastroenterol ; 114(4): 607-619, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30920415

RESUMO

OBJECTIVES: Hypertension has been linked to the presence and severity of nonalcoholic fatty liver disease (NAFLD) through unclear mechanisms. The gain-of-function rs5186 A1166C variant in angtiotensin receptor type 1 (AGTR1) gene has been linked to hypertension, cardiovascular disease and metabolic syndrome. We assessed the impact of AGTR1 A1166C variant on NAFLD incidence and severity and on glucose and lipid metabolism and explored the underlying mechanisms. METHODS: We followed up 314 healthy nonobese, nondiabetic, nonhypertensive, insulin-sensitive participants in a population-based study, characterized for AGTR1 rs5186 A1166C variant, adipokine profile, inflammatory and endothelial dysfunction markers. An independent cohort of 78 biopsy-proven nondiabetic NAFLD patients and controls underwent an oral glucose tolerance test with Minimal Model analysis of glucose homeostasis, and an oral fat tolerance test with measurement of plasma lipoproteins, adipokines, MCP-1, calprotectin, and nuclear factor-κB activation in circulating mononuclear cells. RESULTS: AGTR1 A1166C polymorphism predicted 9.8-year incident NAFLD (odds ratio: 1.67, 95% CI: 1.26-2.21) and hypertension (odds ratio: 1.49, 95% CI: 1.12-2.63) and 9-year increase in cardiovascular disease risk and endothelial dysfunction markers. In the cross-sectional cohort, AGTR1 C allele carriers had higher insulin resistance. Despite comparable fasting lipid profiles, AGTR1 C allele carriers showed postprandial triglyceride-rich and cholesterol-rich VLDL lipoprotein accumulation, higher resistin, MCP-1 and calprotectin responses and nuclear factor-κB activation in mononuclear cells, and a blunted postprandial adiponectin response to fat, which predicted liver histology, hepatocyte apoptosis activation, insulin resistance, and endothelial dysfunction. DISCUSSION: AGTR1 A1166C variant affects liver disease, insulin resistance, and endothelial dysfunction in NAFLD, at least in part by modulating adipokine, chemokine, and pro-inflammatory cell activation in response to fat ingestion.


Assuntos
Gorduras na Dieta/metabolismo , Hipertensão/genética , Hepatopatia Gordurosa não Alcoólica/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Angiotensina/genética , Biomarcadores/metabolismo , Estudos Transversais , Feminino , Genótipo , Glucose/metabolismo , Humanos , Hipertensão/metabolismo , Metabolismo dos Lipídeos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Fatores de Risco , Índice de Gravidade de Doença
8.
Pharmacol Res ; 144: 390-408, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-29378252

RESUMO

A large number of different microbial species populates intestine. Extensive research has studied the entire microbial population and their genes (microbiome) by using metagenomics, metatranscriptomics and metabolomic analysis. Studies suggest that the imbalances of the microbial community causes alterations in the intestinal homeostasis, leading to repercussions on other systems: metabolic, nervous, cardiovascular, immune. These studies have also shown that alterations in the structure and function of the gut microbiota play a key role in the pathogenesis and complications of Hypertension (HTN) and Chronic Kidney Disease (CKD). Increased blood pressure (BP) and CKD are two leading risk factors for cardiovascular disease and their treatment represents a challenge for the clinicians. In this Review, we discuss mechanisms whereby gut microbiota (GM) and its metabolites act on downstream cellular targets to contribute to the pathogenesis of HTN and CKD, and potential therapeutic implications.


Assuntos
Microbioma Gastrointestinal , Hipertensão/microbiologia , Insuficiência Renal Crônica/microbiologia , Animais , Humanos , Hipertensão/metabolismo , Hipertensão/patologia , Hipertensão/terapia , Probióticos/uso terapêutico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/terapia
9.
Int J Mol Sci ; 20(7)2019 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-30970564

RESUMO

Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.


Assuntos
Carcinoma Hepatocelular/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Carcinoma Hepatocelular/etiologia , Hipóxia Celular , Progressão da Doença , Proteínas Hedgehog/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Humanos , Integrinas/metabolismo , Cirrose Hepática/complicações , Neoplasias Hepáticas/etiologia , Hepatopatia Gordurosa não Alcoólica/complicações , Transdução de Sinais
10.
Curr Diab Rep ; 18(10): 98, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30215149

RESUMO

PURPOSE OF REVIEW: In the last decade many studies have suggested an association between the altered gut microbiota and multiple systemic diseases including diabetes. In this review, we will discuss potential pathophysiological mechanisms, the latest findings regarding the mechanisms linking gut dysbiosis and type 2 diabetes (T2D), and the results obtained with experimental modulation of microbiota. RECENT FINDINGS: In T2D, gut dysbiosis contributes to onset and maintenance of insulin resistance. Different strategies that reduce dysbiosis can improve glycemic control. Evidence in animals and humans reveals differences between the gut microbial composition in healthy individuals and those with T2D. Changes in the intestinal ecosystem could cause inflammation, alter intestinal permeability, and modulate metabolism of bile acids, short-chain fatty acids and metabolites that act synergistically on metabolic regulation systems contributing to insulin resistance. Interventions that restore equilibrium in the gut appear to have beneficial effects and improve glycemic control. Future research should examine in detail and in larger studies other possible pathophysiological mechanisms to identify specific pathways modulated by microbiota modulation and identify new potential therapeutic targets.


Assuntos
Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal , Animais , Diabetes Mellitus Tipo 2/terapia , Transplante de Microbiota Fecal , Interações Hospedeiro-Patógeno , Humanos , Inflamação/patologia , Metaboloma
11.
J Lipid Res ; 58(6): 1221-1229, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28242789

RESUMO

Mechanisms underlying the opposite effects of transmembrane 6 superfamily member 2 (TM6SF2) rs58542926 C>T polymorphism on liver injury and cardiometabolic risk in nonalcoholic fatty liver disease (NAFLD) are unclear. We assessed the impact of this polymorphism on postprandial lipoprotein metabolism, glucose homeostasis, and nutrient oxidation in NAFLD. Sixty nonobese nondiabetic normolipidemic biopsy-proven NAFLD patients and 60 matched controls genotyped for TM6SF2 C>T polymorphism underwent: indirect calorimetry; an oral fat tolerance test with measurement of plasma lipoprotein subfractions, adipokines, and incretin glucose-dependent insulinotropic polypeptide (GIP); and an oral glucose tolerance test with minimal model analysis of glucose homeostasis. The TM6SF2 T-allele was associated with higher hepatic and adipose insulin resistance, impaired pancreatic ß-cell function and incretin effect, and higher muscle insulin sensitivity and whole-body fat oxidation rate. Compared with the TM6SF2 C-allele, the T-allele entailed lower postprandial lipemia and nefaemia, a less atherogenic lipoprotein profile, and a postprandial cholesterol (Chol) redistribution from smaller atherogenic lipoprotein subfractions to larger intestinal and hepatic VLDL1 subfractions. Postprandial plasma VLDL1-Chol response independently predicted the severity of liver histology. In conclusion, the TM6SF2 C>T polymorphism affects nutrient oxidation, glucose homeostasis, and postprandial lipoprotein, adipokine, and GIP responses to fat ingestion independently of fasting values. These differences may contribute to the dual and opposite effect of this polymorphism on liver injury and cardiometabolic risk in NAFLD.


Assuntos
Glucose/metabolismo , Homeostase/genética , Lipoproteínas/metabolismo , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Polimorfismo de Nucleotídeo Único , Período Pós-Prandial , Adulto , Feminino , Humanos , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/fisiopatologia
12.
Clin Gastroenterol Hepatol ; 15(7): 972-985, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27521506

RESUMO

Epidemiologic data show an association between the prevalence and severity of nonalcoholic fatty liver disease and the incidence and stage of chronic kidney disease (CKD); furthermore, nonalcoholic steatohepatitis (NASH)-related cirrhosis has a higher risk of renal failure, a greater necessity for simultaneous liver-kidney transplantation, and a poorer renal outcome than cirrhosis of other etiologies even after simultaneous liver-kidney transplantation. These data suggest that NASH and CKD share common proinflammatory and profibrotic mechanisms of progression, which are targeted incompletely by current treatments. We reviewed therapeutic approaches to late preclinical/early clinical stage of development in NASH and/or CKD, focusing on anti-inflammatory and antifibrotic treatments, which could slow the progression of both disease conditions. Renin inhibitors and angiotensin-converting enzyme-2 activators are new renin-angiotensin axis modulators that showed incremental advantages over angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers in preclinical models. Novel, potent, and selective agonists of peroxisome proliferator-activated receptors and of farnesoid X receptor, designed to overcome limitations of older compounds, showed promising results in clinical trials. Epigenetics, heat stress response, and common effectors of redox regulation also were subjected to intensive research, and the gut was targeted by several approaches, including synbiotics, antilipopolysaccharide antibodies, Toll-like receptor-4 antagonists, incretin mimetics, and fibroblast growth factor 19 analogs. Promising anti-inflammatory therapies include inhibitors of NOD-like receptor family, pyrin domain containing 3 inflammasome, of nuclear factor-κB, and of vascular adhesion protein-1, chemokine antagonists, and solithromycin, and approaches targeting common profibrogenic pathways operating in the liver and the kidney include galectin-3 antagonists, and inhibitors of rho-associated protein kinase and of epidermal growth factor activation. The evidence, merits, and limitations of each approach for the treatment of NASH and CKD are discussed.


Assuntos
Descoberta de Drogas/tendências , Fibrose/tratamento farmacológico , Inflamação/tratamento farmacológico , Nefropatias/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/complicações , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos
13.
Acta Obstet Gynecol Scand ; 94(2): 165-74, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25421298

RESUMO

OBJECTIVE: To explore the views of a multidisciplinary group of experts and achieve consensus on the importance of perineal support in preventing obstetric anal sphincter injuries (OASIS). DESIGN: A three-generational Delphi survey. SETTING: A UK-wide survey of experts. POPULATION: A panel of 20 members consisting of obstetricians, midwives and urogynecologists recommended by UK professional bodies. METHODS: A 58-item web-based questionnaire was sent to all participants who were asked to anonymously rate the importance of each item on a six-point Likert scale. They were asked to rate their level of agreement on statements related to hands-on/hands-poised techniques, the association of hands-poised/hands-off approach with OASIS, the need to implement perineal support and the need to improve the evidence to support it. Systematic feedback of responses from previous rounds was provided to participants. MAIN OUTCOME MEASURES: To achieve consensus on key areas related to perineal support. RESULTS: The response rate was 100% in all three iterations. There was consensus that current UK practice regarding perineal protection was not based on robust evidence. The respondents agreed that hands-poised/hands-off and OASIS are causally related and that hands-poised was misinterpreted by clinicians as hands-off. Although 90% of experts agreed that some form of randomized trial was required and that all would be prepared to take part, there was also consensus (75%) that in the meantime, hands-on should be the recommended technique. CONCLUSIONS: Our results highlight the current lack of evidence to support policies of perineal support at time of birth and the need to address this controversial issue.


Assuntos
Canal Anal/lesões , Parto Obstétrico/efeitos adversos , Adulto , Parto Obstétrico/métodos , Técnica Delphi , Feminino , Humanos , Padrões de Prática Médica , Gravidez
14.
Mediators Inflamm ; 2015: 815721, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25873773

RESUMO

Obstructive sleep apnoea syndrome (OSAS) is a common sleep disorder, affecting over 4% of the general population, and is associated with metabolic syndrome and cardiovascular disease, independent of obesity and traditional risk factors. OSAS has been recently connected to nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the world, which can be found in 30% of the general adult population. Several studies suggest that the chronic intermittent hypoxia (CIH) of OSAS patients may per se trigger liver injury, inflammation, and fibrogenesis, promoting NAFLD development and the progression from steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In NAFLD patients, liver disease may be caused by hypoxia both indirectly by promoting inflammation and insulin resistance and directly by enhancing proinflammatory cytokine production and metabolic dysregulation in liver cells. In this review, we focus on molecular mechanisms linking OSAS to NAFLD, including hypoxia inducible factor (HIF), nuclear factor kappa B (NF-κB), YKL-40, unfolded protein response, and hypoxic adipose tissue inflammation, which all could provide novel potential therapeutic approaches for the management of NAFLD patients with OSAS.


Assuntos
Inflamação/etiologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Apneia Obstrutiva do Sono/complicações , Adipocinas/sangue , Proteína 1 Semelhante à Quitinase-3 , Humanos , Hipóxia/complicações , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Resistência à Insulina , Lectinas/sangue , NF-kappa B/fisiologia , Fator de Necrose Tumoral alfa/sangue , Resposta a Proteínas não Dobradas
16.
Am J Obstet Gynecol ; 210(6): 501-509.e6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24113256

RESUMO

Perinatal mental illness has a significant implication on maternal health, birth outcomes, and the offspring's development. Prevalence estimates of perinatal psychiatric illnesses range widely, with substantial heterogeneity in different population studies, with a lower prevalence rate in high- rather than low- or middle-income countries. Because of the potential negative impact on maternal and child outcomes and the potential lability of these disorders, the perinatal period is a critical time to identify psychiatric illnesses. Thus, obstetricians and midwives play a crucial role in assessing women's mental health needs and to refer identified women promptly for multidisciplinary specialist assessment. However, there is still limited evidence on best practice assessment and management policies during pregnancy and postpartum. This review focuses on the prevalence of common perinatal mental disorders and antenatal screening policies to identify women at risk. The effect of these conditions and their management on pregnancy, fetal outcomes, and child development are discussed.


Assuntos
Transtornos Mentais , Complicações na Gravidez , Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Transtornos Mentais/terapia , Gravidez , Complicações na Gravidez/diagnóstico , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/terapia , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Prevalência
18.
Dig Dis Sci ; 58(2): 344-8, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23086110

RESUMO

The headword "overlap syndromes" of liver diseases includes the coexistence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. These syndromes often represent a diagnostic and therapeutic challenge for hepatologists; it remains unclear whether these overlap syndromes form distinct entities or they are only variants of the major autoimmune liver diseases. The most frequent reported association occurs between autoimmune hepatitis and primary biliary cirrhosis, whereas the overlap between autoimmune hepatitis and primary sclerosing cholangitis is less frequent, typically at young age and often attendant with an inflammatory bowel disease. The choice therapy is based on ursodeoxycholic acid and immunosuppressive drugs, used at the same time or consecutively, according to the course of disease. The diagnostic scores for autoimmune hepatitis can help for diagnosis, even though their definitive soundness is lacking.


Assuntos
Colangite Esclerosante/complicações , Colangite Esclerosante/diagnóstico , Hepatite Autoimune/complicações , Hepatite Autoimune/diagnóstico , Cirrose Hepática Biliar/complicações , Cirrose Hepática Biliar/diagnóstico , Humanos , Síndrome
19.
Arch Womens Ment Health ; 16(3): 197-201, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23292120

RESUMO

The purpose of this study was to classify the clinical subtypes of core premenstrual disorders during the International Society for Premenstrual Disorders' second consensus meeting. Multiple iterations were used to achieve consensus between a group of experts; these iterations included a two-generational Delphi technique that was preceded and followed by open group discussions. The first round was to generate a list of all potential clinical subtypes, which were subsequently prioritized using a Delphi methodology and then finalised in a final round of open discussion. On a six-point scale, 4 of the 12 potential clinical subtypes had a mean score of ≥5.0 following the second iteration and only 3 of the 4 still had a mean score of ≥5.0 after the third iteration. The final list consisted of these three subtypes and an additional subtype, which was introduced and agreed upon, in the final iteration. There is consensus amongst experts that core premenstrual disorder is divided into three symptom-based subtypes: predominantly physical, predominantly psychological and mixed. A proportion of psychological and mixed subtypes may meet the DSM-IV diagnostic criteria for premenstrual dysphoric disorder.


Assuntos
Consenso , Técnica Delphi , Síndrome Pré-Menstrual/classificação , Síndrome Pré-Menstrual/diagnóstico , Conferências de Consenso como Assunto , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Pesquisa sobre Serviços de Saúde , Humanos , Síndrome Pré-Menstrual/psicologia
20.
EPMA J ; : 1-39, 2023 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-37359998

RESUMO

Background: Concern exists that noninvasive ventilation (NIV) may promote ventilation-induced lung injury(VILI) and worsen outcome in acute hypoxemic respiratory failure (AHRF). Different individual ventilatory variables have been proposed to predict clinical outcomes, with inconsistent results.Mechanical power (MP), a measure of the energy transfer rate from the ventilator to the respiratory system during mechanical ventilation, might provide solutions for this issue in the framework of predictive, preventive and personalized medicine (PPPM). We explored (1) the impact of ventilator-delivered MP normalized to well-aerated lung (MPWAL) on physio-anatomical and clinical responses to NIV in COVID-19-related AHRF and (2) the effect of prone position(PP) on MPWAL. Methods: We analyzed 216 noninvasively ventilated COVID-19 patients (108 patients receiving PP + NIV and 108 propensity score-matched patients receiving supine NIV) with moderate-to-severe(paO2/FiO2 ratio < 200) AHRF enrolled in the PRO-NIV controlled non-randomized study (ISRCTN23016116).Quantification of differentially aerated lung volumes by lung ultrasonography (LUS) was validated against CT scans. Respiratory parameters were hourly recorded, ABG were performed 1 h after each postural change. Time-weighed average values of ventilatory variables, including MPWAL, and gas exchange parameters (paO2/FiO2 ratio, dead space indices) were calculated for each ventilatory session. LUS and circulating biomarkers were assessed daily. Results: Compared with supine position, PP was associated with a 34% MPWAL reduction, attributable largely to an absolute MP reduction and secondly to an enhanced lung reaeration.Patients receiving a high MPWAL during the 1st 24 h of NIV [MPWAL(day 1)] had higher 28-d NIV failure (HR = 4.33,95%CI:3.09 - 5.98) and death (HR = 5.17,95%CI: 3.01 - 7.35) risks than those receiving a low MPWAL(day 1).In Cox multivariate analyses, MPWAL(day 1) remained independently associated with 28-d NIV failure (HR = 1.68,95%CI:1.15-2.41) and death (HR = 1.69,95%CI:1.22-2.32).MPWAL(day 1) outperformed other power measures and ventilatory variables as predictor of 28-d NIV failure (AUROC = 0.89;95%CI:0.85-0.93) and death (AUROC = 0.89;95%CI:0.85-0.94).MPWAL(day 1) predicted also gas exchange, ultrasonographic and inflammatory biomarker responses, as markers of VILI, on linear multivariate analysis. Conclusions: In the framework of PPPM, early bedside MPWAL calculation may provide added value to predict response to NIV and guide subsequent therapeutic choices i.e. prone position adoption during NIV or upgrading to invasive ventilation, to reduce hazardous MPWAL delivery, prevent VILI progression and improve clinical outcomes in COVID-19-related AHRF. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00325-5.

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