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2.
Adv Exp Med Biol ; 1274: 55-69, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894507

RESUMO

Leukotrienes (LTs) are potent lipid mediators that exert a variety of functions, ranging from maintaining the tone of the homeostatic immune response to exerting potent proinflammatory effects. Therefore, LTs are essential elements in the development and maintenance of different chronic diseases, such as asthma, arthritis, and atherosclerosis. Due to the pleiotropic effects of LTs in the pathogenesis of inflammatory diseases, studies are needed to discover potent and specific LT synthesis inhibitors and LT receptor antagonists. Even though most clinical trials using LT inhibitors or antagonists have failed due to low efficacy and/or toxicity, new drug development strategies are driving the discovery for LT inhibitors to prevent inflammatory diseases. A newly important detrimental role for LTs in comorbidities associated with metabolic stress has emerged in the last few years and managing LT production and/or actions could represent an exciting new strategy to prevent or treat inflammatory diseases associated with metabolic disorders. This review is intended to shed light on the synthesis and actions of leukotrienes, the most common drugs used in clinical trials, and discuss the therapeutic potential of preventing LT function in obesity, diabetes, and hyperlipidemia.


Assuntos
Comorbidade , Antagonistas de Leucotrienos/uso terapêutico , Leucotrienos/metabolismo , Doenças Metabólicas/complicações , Doenças Metabólicas/prevenção & controle , Estresse Fisiológico , Asma , Aterosclerose , Humanos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32531935

RESUMO

The lifestyle adopted by most people in Western societies has an important impact on the propensity to metabolic disorders (e.g., diabetes, cancer, cardiovascular disease, neurodegenerative diseases). This is often accompanied by chronic low-grade inflammation, driven by the activation of various molecular pathways such as STAT3 (signal transducer and activator of transcription 3), IKK (IκB kinase), MMP9 (matrix metallopeptidase 9), MAPK (mitogen-activated protein kinases), COX2 (cyclooxigenase 2), and NF-Kß (nuclear factor kappa-light-chain-enhancer of activated B cells). Multiple intervention studies have demonstrated that lifestyle changes can lead to reduced inflammation and improved health. This can be linked to the concept of real-life risk simulation, since humans are continuously exposed to dietary factors in small doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, etc.). Inflammation biomarkers improve in patients who consume a certain amount of fiber per day; some even losing weight. Fasting in combination with calorie restriction modulates molecular mechanisms such as m-TOR, FOXO, NRF2, AMPK, and sirtuins, ultimately leads to significantly reduced inflammatory marker levels, as well as improved metabolic markers. Moving toward healthier dietary habits at the individual level and in publicly-funded institutions, such as schools or hospitals, could help improving public health, reducing healthcare costs and improving community resilience to epidemics (such as COVID-19), which predominantly affects individuals with metabolic diseases.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Dieta , Inflamação/imunologia , Doenças Metabólicas/imunologia , Pneumonia Viral/imunologia , Comportamento de Redução do Risco , Infecções por Coronavirus/dietoterapia , Infecções por Coronavirus/prevenção & controle , Humanos , Inflamação/dietoterapia , Inflamação/prevenção & controle , Doenças Metabólicas/dietoterapia , Doenças Metabólicas/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/dietoterapia , Pneumonia Viral/prevenção & controle , Prevenção Primária
4.
Life Sci ; 256: 117853, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470452

RESUMO

AIMS: To investigate the diabetes-protective effect and weight-lowering potential of a novel long-acting triagonist at three metabolically related hormone receptors including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon receptors. MAIN METHODS: Triagonist were designed in an iterative manner from native GLP-1, GIP and Glucogan. Main peptide chain (termed TG peptides) and subsequently modified LTG peptides were synthesized via solid phase synthesis. In vitro receptor activity assay was performed to screen the TG peptide with most balanced potency on all three receptors. The in vitro biological activities of modified TG peptides were further investigated by albumin-binding measurement and proteolytic cleavage test. Subsequently, oral glucose tolerance test (OGTT), pharmacokinetic test and chronic study were subjected to the acute and long-term efficacy evaluation of selected fusion peptide, LTG-6. KEY FINDINGS: TG-8 exhibited equally aligned constituent efficacy and supraphysiological potency on corresponding receptor without cross-reactivity. Modified TG-8, termed LTG-6, exerted the great binding affinity for human serum albumin and the enhanced rational controlled-release of TG-8 in vitro. Further OGTT in different gene knockout mice and diabetic mice demonstrated the promising hypoglycemic and insulinotropic abilities of LTG-6. After long-term treatment for 8 weeks, LTG-6 was proved superior to co-agonists to decrease the body weight and %HbA1c, improve reverse dyslipidemia and glycemic control in the DIO models. SIGNIFICANCE: LTG-6, as a newly designed long-acting triagonist, holds potential to correct the obesity related metabolic disorders.


Assuntos
Diabetes Mellitus Experimental/prevenção & controle , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Glucagon/agonistas , Animais , Peso Corporal/efeitos dos fármacos , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/prevenção & controle , Camundongos , Camundongos Knockout , Obesidade/complicações , Obesidade/tratamento farmacológico , Peptídeos/química , Ratos , Ratos Sprague-Dawley , Trombina/química
5.
Cell ; 181(6): 1189-1193, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32442404
6.
J Sport Health Sci ; 9(3): 211-227, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32444146

RESUMO

BACKGROUND: Exercise is considered as an important intervention for treatment and prevention of several diseases, such as osteoarthritis, obesity, hypertension, and Alzheimer's disease. This review summarizes decadal exercise intervention studies with various rat models across 6 major systems to provide a better understanding of the mechanisms behind the effects that exercise brought. METHODS: PubMed was utilized as the data source. To collect research articles, we used the following terms to create the search: (exercise [Title] OR physical activity [Title] OR training [Title]) AND (rats [Title/Abstract] OR rat [Title/Abstract] OR rattus [Title/Abstract]). To best cover targeted studies, publication dates were limited to "within 11 years." The exercise intervention methods used for different diseases were sorted according to the mode, frequency, and intensity of exercise. RESULTS: The collected articles were categorized into studies related to 6 systems or disease types: motor system (17 articles), metabolic system (110 articles), cardiocerebral vascular system (171 articles), nervous system (71 articles), urinary system (2 articles), and cancer (21 articles). Our review found that, for different diseases, exercise intervention mostly had a positive effect. However, the most powerful effect was achieved by using a specific mode of exercise that addressed the characteristics of the disease. CONCLUSION: As a model animal, rats not only provide a convenient resource for studying human diseases but also provide the possibility for exploring the molecular mechanisms of exercise intervention on diseases. This review also aims to provide exercise intervention frameworks and optimal exercise dose recommendations for further human exercise intervention research.


Assuntos
Modelos Animais de Doenças , Terapia por Exercício , Prevenção Primária/métodos , Animais , Doenças Cardiovasculares/prevenção & controle , Terapia por Exercício/métodos , Doenças Metabólicas/prevenção & controle , Doenças Musculoesqueléticas/prevenção & controle , Neoplasias/prevenção & controle , Doenças do Sistema Nervoso/prevenção & controle , Ratos , Doenças Urológicas/prevenção & controle
7.
Nutr Metab Cardiovasc Dis ; 30(5): 810-821, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32143895

RESUMO

BACKGROUND AND AIMS: Atherosclerosis begins early in life, thus optimal cardiovascular health needs to be promoted early. We investigated whether appetitive behaviors among 7 year olds are associated with their cardiometabolic health years later. METHODS AND RESULTS: A sample of 2951 children from a Portuguese birth cohort was analyzed. The Children's Eating Behavior Questionnaire assessed eating behaviors, and a measure of cardiometabolic risk (higher risk group: those in the upper quartile of triglycerides, homeostatic model assessment-insulin resistance, waist circumference and systolic blood pressure and in the lower quartile of high-density lipoprotein cholesterol z-scores) was created. Linear and logistic regressions were run. Children with more food avoidant behaviors had lower cardiometabolic risk (Satiety Responsiveness - boys: OR = 0.39, 95% CI 0.16; 0.93, girls: OR=0.37, 95% CI 0.17; 0.82 and Slowness in eating - boys: OR = 0.49, 95% CI 0.25; 0.95, girls: OR = 0.49, 95% CI 0.27; 0.91). Food approach behaviors (Food responsiveness (CEBQ-FR), Enjoyment of food (CEBQ-EF) and Emotional overeating (CEBQ-EOE)) increased cardiometabolic risks (e.g. CEBQ-FR: boys: OR = 2.50, 95% CI 1.45; 4.32, girls: OR = 2.33, 95% CI 1.46; 3.71). CEBQ-EF had stronger effects in boys, while CEBQ-EOE was positively associated with cardiometabolic risk among girls. When adjusting for BMIz at 7y, associations did not remain significant. Appetitive behaviors were also associated with isolated cardiometabolic parameters; the strongest association being with waist circumference. CONCLUSIONS: Appetitive behaviors at 7-years are associated with cardiometabolic risk at age 10. While 'food avoidant' behaviors protect against cardiometabolic risk and 'food approach' behaviors increase cardiometabolic risk, these associations are largely dependent of child's adiposity.


Assuntos
Regulação do Apetite , Doenças Cardiovasculares/epidemiologia , Comportamento Infantil , Comportamento Alimentar , Doenças Metabólicas/epidemiologia , Obesidade Pediátrica/epidemiologia , Fatores Etários , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Criança , Emoções , Feminino , Seletividade Alimentar , Preferências Alimentares , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/prevenção & controle , Obesidade Pediátrica/diagnóstico , Obesidade Pediátrica/prevenção & controle , Portugal/epidemiologia , Estudos Prospectivos , Fatores de Proteção , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Fatores Sexuais
8.
PLoS One ; 15(2): e0228932, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040532

RESUMO

Although the beneficial effects of probiotics in the prevention or treatment of metabolic disorders have been extensively researched, the precise mechanisms by which probiotics improve metabolic homeostasis are still not clear. Given that probiotics usually exert a comprehensive effect on multiple metabolic disorders, defining a concurrent mechanism underlying the multiple effects is critical to understand the function of probiotics. In this study, we identified the SIRT1-dependent or independent PGC-1α pathways in multiple organs that mediate the protective effects of a strain of Lactobacillus plantarum against high-fat diet-induced adiposity, glucose intolerance, and dyslipidemia. L. plantarum treatment significantly enhanced the expression of SIRT1, PPARα, and PGC-1α in the liver and adipose tissues under HFD-fed condition. L. plantarum treated mice also exhibited significantly increased expressions of genes involved in bile acid synthesis and reverse cholesterol transport in the liver, browning and thermogenesis of adipose tissue, and fatty acid oxidation in the liver and adipose tissue. Additionally, L. plantarum treatment significantly upregulated the expressions of adiponectin in adipose tissue, irisin in skeletal muscle and subcutaneous adipose tissue (SAT), and FGF21 in SAT. These beneficial changes were associated with a significantly improved HFD-induced alteration of gut microbiota. Our findings suggest that the PGC-1α-mediated pathway could be regarded as a potential target in the development of probiotics-based therapies for the prevention and treatment of metabolic disorders.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Doenças Metabólicas/prevenção & controle , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Probióticos/uso terapêutico , Tecido Adiposo/metabolismo , Adiposidade , Animais , Ácidos e Sais Biliares/biossíntese , Colesterol/metabolismo , Dislipidemias/metabolismo , Dislipidemias/prevenção & controle , Dislipidemias/terapia , Microbioma Gastrointestinal , Intolerância à Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Intolerância à Glucose/terapia , Lactobacillus plantarum/fisiologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/terapia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Sirtuína 1/metabolismo
9.
Prog Cardiovasc Dis ; 63(2): 170-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32059838

RESUMO

Despite its potential to improve metabolic health outcomes, longitudinal physical activity (PA) patterns and their association with cardiometabolic disease among people living with HIV (PLWH) have not been well characterized. We investigated this relationship among PLWH in the Centers for AIDS Research Network of Integrated Clinical Systems with at least one PA self-report between 2008 and 2015. The 4-item Lipid Research Clinics PA instrument was used to categorize habitual PA levels as: Very Low, Low, Moderate, or High. We analyzed demographic differences in PA patterns. Multivariable generalized estimating equation regression models were fit to assess longitudinal associations of PA with blood pressure, lipid, and glucose levels. Logistic regression modeling was used to assess the odds of being diagnosed with obesity, cardiovascular disease (CVD), cerebrovascular disease, hypertension, diabetes, or multimorbidity. A total of 40,462 unique PA assessments were provided by 11,719 participants. Only 13% of PLWH reported High PA, while 68% reported Very Low/Low PA at baseline and did not increase PA levels during the study period. Compared to those reporting High PA, participants with Very Low PA had almost 2-fold increased risk for CVD. Very Low PA was also associated with several risk factors associated with CVD, most notably elevated triglycerides (odds ratio 25.4), obesity (odds ratio 1.9), hypertension (odds ratio 1.4), and diabetes (odds ratio 2.3; all p < 0.01). Low levels of PA over time among PLWH are associated with increased cardiometabolic disease risk.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Doenças Cardiovasculares/epidemiologia , Metabolismo Energético , Exercício Físico , Infecções por HIV/tratamento farmacológico , Sobreviventes de Longo Prazo ao HIV , Doenças Metabólicas/epidemiologia , Fármacos Anti-HIV/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Nível de Saúde , Humanos , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/fisiopatologia , Doenças Metabólicas/prevenção & controle , Fatores de Proteção , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Comportamento Sedentário , Fatores de Tempo , Estados Unidos/epidemiologia , Carga Viral
10.
Lancet Diabetes Endocrinol ; 8(4): 278-291, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32109422

RESUMO

BACKGROUND: An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids. METHODS: We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994. FINDINGS: Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01). INTERPRETATION: No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation. FUNDING: Barts Charity and Merck Serono.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Glucocorticoides/uso terapêutico , Hipoglicemiantes/uso terapêutico , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Metformina/uso terapêutico , Adulto , Idoso , Doenças Autoimunes/imunologia , Doenças Autoimunes/fisiopatologia , Método Duplo-Cego , Feminino , Glucocorticoides/efeitos adversos , Humanos , Inflamação/prevenção & controle , Masculino , Doenças Metabólicas/prevenção & controle , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Resultado do Tratamento , Adulto Jovem
11.
Sci Rep ; 10(1): 387, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941967

RESUMO

Nutrition during early childhood is linked to metabolic programming. We hypothesized that breastfeeding has long-term consequences on the energy metabolism exemplified by mitochondrial DNA (mtDNA). As part of the third cycle of the Flemish Environment and Health Study (FLEHSIII) cohort, 303 adolescents aged 14-15 years were included. We associated breastfeeding and blood mtDNA content 14-15 years later while adjusting for confounding variables. Compared with non-breastfed adolescents, mtDNA content was 23.1% (95%CI: 4.4-45.2; p = 0.013) higher in breastfed adolescents. Being breastfed for 1-10 weeks, 11-20 weeks, and >20 weeks, was associated with a higher mtDNA content of respectively 16.0% (95%CI: -7.1-44.9; p = 0.191), 23.5% (95%CI: 0.8-51.3; p = 0.042), and 31.5% (95%CI: 4.3-65.7; p = 0.021). Our study showed a positive association between breastfeeding and mtDNA content in adolescents which gradually increased with longer periods of breastfeeding. Higher mtDNA content may be an underlying mechanism of the beneficial effects of breastfeeding on children's metabolism.


Assuntos
Aleitamento Materno/métodos , DNA Mitocondrial/sangue , Doenças Metabólicas/prevenção & controle , Mitocôndrias/metabolismo , Adolescente , Adulto , Estudos de Coortes , Feminino , Humanos , Masculino
12.
J Am Soc Nephrol ; 31(3): 560-577, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31996409

RESUMO

BACKGROUND: Prolyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected to have other effects in addition to erythropoiesis, such as protection against metabolic disorders. However, whether such beneficial effects would extend to metabolic disorder-related kidney disease is largely unknown. METHODS: We administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR) ob/ob mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and in vitro experiments using murine mesangial cells. RESULTS: Compared with BTBR ob/ob mice that received only vehicle, BTBR ob/ob mice treated with enarodustat displayed lower body weight, reduced blood glucose levels with improved insulin sensitivity, lower total cholesterol levels, higher adiponectin levels, and less adipose tissue, as well as a tendency for lower macrophage infiltration. Enarodustat-treated mice also exhibited reduced albuminuria and amelioration of glomerular epithelial and endothelial damage. Transcriptome analysis of isolated glomeruli revealed reduced expression of C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) in enarodustat-treated mice compared with the vehicle-only group, accompanied by reduced glomerular macrophage infiltration. In vitro experiments demonstrated that both local HIF-1 activation and restoration of adiponectin by enarodustat contributed to CCL2/MCP-1 reduction in mesangial cells. CONCLUSIONS: These results indicate that the PHD inhibitor enarodustat has potential renoprotective effects in addition to its potential to protect against metabolic disorders.


Assuntos
Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores de Prolil-Hidrolase/farmacologia , Animais , Quimiocina CCL2/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Resistência à Insulina , Doenças Metabólicas/etiologia , Doenças Metabólicas/prevenção & controle , Camundongos , Camundongos Obesos , Glicinas N-Substituídas/farmacologia , Prolil Hidroxilases/metabolismo , Piridinas/farmacologia , Distribuição Aleatória , Valores de Referência , Resultado do Tratamento , Triazóis/farmacologia
13.
Dan Med J ; 67(1)2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31908255

RESUMO

INTRODUCTION: Newborn screening is a public health programme for early diagnosis of treatable diseases. METHODS: The subjects included were newborns born 2002-2019. Expanded newborn screening (eNBS) for metabolic diseases was introduced as a pilot project from 2002 to 2009, followed by routine screening with informed dissent. A total of 967,780 newborns were screened; 82,930 were unscreened. Furthermore, a historic cohort of clinically diagnosed children born in the 1992-2001 period was included. Children in the unscreened and historic cohorts were evaluated for the same diseases as were the screened children. Dried blood spot samples were collected locally and sent for screening analyses. We recorded newborns with true and false positive results as well as false negative results and their clinical signs at screening and at the last follow-up. RESULTS: A total of 603 samples were screen positive: 354 false positives and 249 true positives (222 newborns and 27 mothers). The positive predictive value (PPV) was 41% for the entire screening period; 62% for 2018. The false positive rate (FPR) was 0.036% overall; 0.024% for 2018. The overall prevalence of diseases was 1:3,900; in the historic cohort, the prevalence of the same diseases was 1:8,300; 7.3% had symptoms at the time of screening. At follow-up, 93% of the children had no clinically significant sequelae. Among 82,930 unscreened newborns, 27 (1:3,000) had eNBS panel diseases, some with severe manifestations. CONCLUSIONS: This update of eNBS in Denmark confirms that eNBS is a successful preventive public health programme. Early treatment in a latent phase of disease is effective and screening should be extended to other diseases not currently in the programme. FUNDING: The work was supported by grants from The Ronald McDonald Børnefond, Danmarks Sundhedsfond, Direktør Ib Henriksens Fond, Ragnhild Ibsens Legat til Medicinsk Forskning, Gerda og Aage Haenschs Fond, Dronning Louises Børnehospitals Forskningsfond, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis's Legat, Aase and Ejnar Danielsens Fond, Oda og Hans Svenningsens Fond, Fonden af 1870, Vanførefonden, Fonden til Lægevidenskabens Fremme and Danish Medical Research Council. TRIAL REGISTRATION: not relevant.


Assuntos
Doenças Metabólicas/prevenção & controle , Triagem Neonatal , Serviços Preventivos de Saúde/estatística & dados numéricos , Dinamarca/epidemiologia , Diagnóstico Precoce , Feminino , Humanos , Recém-Nascido , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Projetos Piloto , Serviços Preventivos de Saúde/métodos , Avaliação de Programas e Projetos de Saúde
14.
J Strength Cond Res ; 34(3): 866-877, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30741856

RESUMO

Hunter, JR, Gordon, BA, Bird, SR, and Benson, AC. Exercise supervision is important for cardiometabolic health improvements: a 16-week randomized controlled trial. J Strength Cond Res 34(3): 866-877, 2020-Exercise supervision enhances health and fitness improvements in clinical populations compared with unsupervised or home-based exercise, but effects of supervision type are unknown in healthy employees. Eighty-five Australian university employees (62 females; mean ± SD 43.2 ± 9.8 years) were randomized to personal (1:1; SUP, n = 28), nonpersonal (typical gym-based; NPS, n = 28) supervision or unsupervised control (CON, n = 29) exercise groups. Subjects received a 16-week individually tailored, moderate-to-high intensity aerobic and resistance exercise program completed at an onsite exercise facility (SUP and NPS) or without access to a specific exercise facility (CON). Repeated-measures ANOVA analyzed changes to cardiometabolic outcomes. Mean ± SD increases to V[Combining Dot Above]O2 peak were greater (p < 0.01) with SUP (+10.4 ± 11.1%) vs. CON (+3.8 ± 8.9%) but not different to NPS (+8.6 ± 8.2%). Compared to CON (+1.7 ± 7.7%), upper-body strength increases were greater with SUP (+12.8 ± 8.4%; p < 0.001) and NPS (+8.4 ± 7.3%; p < 0.05). Lower-body strength increases were greater with SUP (+26.3 ± 12.7%) vs. NPS (+15.0 ± 14.6%; p < 0.05) and CON (+4.1 ± 12.4%; p < 0.001), and NPS vs. CON (p < 0.01). Body fat reductions were greater with SUP (-2.2 ± 2.2%) vs. NPS (-0.6 ± 1.9%; p < 0.05) and CON (-0.7 ± 1.9%; p < 0.05). Access to an onsite exercise facility with personal or nonpersonal exercise supervision was important for improving several cardiometabolic outcomes, with greater improvements to lower-body strength and body composition from personal 1:1 exercise supervision.


Assuntos
Composição Corporal/fisiologia , Doenças Cardiovasculares/prevenção & controle , Exercício Físico/fisiologia , Doenças Metabólicas/prevenção & controle , Adulto , Austrália , Doenças Cardiovasculares/fisiopatologia , Feminino , Humanos , Masculino , Doenças Metabólicas/fisiopatologia , Pessoa de Meia-Idade , Força Muscular/fisiologia , Músculo Esquelético/fisiologia
15.
Biochem Pharmacol ; 171: 113693, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31706843

RESUMO

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.


Assuntos
Adiposidade/efeitos dos fármacos , Dronabinol/análogos & derivados , Doenças Metabólicas/prevenção & controle , Obesidade/prevenção & controle , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Dronabinol/metabolismo , Dronabinol/farmacologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Células HEK293 , Humanos , Masculino , Doenças Metabólicas/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , PPAR gama/agonistas , PPAR gama/metabolismo , Rosiglitazona/metabolismo , Rosiglitazona/farmacologia
16.
J Clin Pathol ; 73(7): 384-390, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31757783

RESUMO

Monogenic dyslipidaemia is a diverse group of multisystem disorders. Patients may present to various specialities from early childhood to late in adult life, and it usually takes longer before the diagnosis is established. Increased awareness of these disorders among clinicians is imperative for early diagnosis. This best practice review provides an overview of primary dyslipidaemias, highlighting their clinical presentation, relevant biochemical and molecular tests. It also addresses the emerging role of genetics in the early diagnosis and prevention of these disorders.


Assuntos
Dislipidemias/diagnóstico , Doenças Metabólicas/diagnóstico , Algoritmos , Dislipidemias/genética , Dislipidemias/patologia , Dislipidemias/prevenção & controle , Diagnóstico Precoce , Humanos , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Prognóstico
17.
Nutr Rev ; 78(6): 486-497, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31841152

RESUMO

The world's population is expanding, leading to an increased global requirement for dietary protein to support health and adaptation in various populations. Though a strong evidence base supports the nutritional value of animal-derived dietary proteins, mounting challenges associated with sustainability of these proteins have led to calls for the investigation of alternative, non-animal-derived dietary protein sources. Mycoprotein is a sustainably produced, protein-rich, high-fiber, whole food source derived from the fermentation of fungus. Initial investigations in humans demonstrated that mycoprotein consumption can lower circulating cholesterol concentrations. Recent data also report improved acute postprandial glycemic control and a potent satiety effect following mycoprotein ingestion. It is possible that these beneficial effects are attributable to the amount and type of dietary fiber present in mycoprotein. Emerging data suggest that the amino acid composition and bioavailability of mycoprotein may also position it as a promising dietary protein source to support skeletal muscle protein metabolism. Mycoprotein may be a viable dietary protein source to promote training adaptations in athletes and the maintenance of muscle mass to support healthy aging. Herein, current evidence underlying the metabolic effects of mycoprotein is reviewed, and the key questions to be addressed are highlighted.


Assuntos
Fibras na Dieta/farmacologia , Proteínas na Dieta/farmacologia , Proteínas Fúngicas/farmacologia , Músculo Esquelético/efeitos dos fármacos , Peso Corporal , Humanos , Doenças Metabólicas/prevenção & controle , Sarcopenia/prevenção & controle
18.
Nutr Rev ; 78(6): 459-464, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31774508

RESUMO

Factors such as shift work, poor diet, lack of physical activity, and irregular sleep patterns put men and women employed in high-stress occupations (e.g., firefighters, police officers) at risk for cardiometabolic diseases. Time-restricted feeding (TRF) is a new approach to combatting many of these diseases; it places an emphasis on when meals are consumed, rather than calorie content. By only manipulating the eating "window," and without changing the food composition of the diet, research in rodent models has shown promising results that have health implications in people, such as obesity prevention, improved insulin sensitivity, and decreased oxidative stress, inflammation, and cholesterol synthesis. Human trials remain limited and the current data are mixed with regard to TRF and improving health. Present findings suggest the timing of the feeding-fasting window, with feeding taking place in the waking hours and fasting in the evening hours, might offer the greatest benefit for improving cardiometabolic markers. Although additional human trials are needed, TRF might reset and synchronize metabolic "clocks" found throughout the body that are disturbed with obesity, shift work, and frequent eating. Therefore, TRF might offer an effective feeding-fasting paradigm with significant clinical implications for the management and treatment of cardiometabolic diseases observed in individuals in high-stress occupations in the United States and in the US population in general. This review outlines the current rodent and human evidence in these areas and the efficacy of TRF for improving human health.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Jejum , Doenças Metabólicas/prevenção & controle , Estresse Ocupacional/dietoterapia , Animais , Ritmo Circadiano , Humanos , Ocupações
20.
Artigo em Inglês | MEDLINE | ID: mdl-31798971

RESUMO

This perspective advocates for the adoption of recently published clinical practice guidelines on identifying and managing cardiometabolic risk after spinal cord injury (SCI). It makes the case for acting now, with the knowledge that we currently have, while continuing to address knowledge gaps with high-quality research studies in this area. Cardiovascular disease is a leading cause of death in people with SCI. Cardiometabolic disease (CMD) and risks are more likely to be overlooked after SCI. Unique SCI-related considerations impact both assessment and management of cardiometabolic risk. Risk factors and components of CMD including obesity, impaired glucose tolerance/insulin resistance, dyslipidemia, and hypertension should be evaluated and managed to optimize the cardiometabolic health of this population. While it would be optimal to base all care on high-quality evidence-based research, its absence should not be an excuse for inaction. Applying what is currently known and filling the research gaps with empirical recommendations based on clinical rationale and expert consensus is both appropriate and necessary till more definitive SCI-specific evidence becomes available.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Conhecimentos, Atitudes e Prática em Saúde , Doenças Metabólicas/prevenção & controle , Guias de Prática Clínica como Assunto/normas , Traumatismos da Medula Espinal/terapia , Adulto , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/metabolismo , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Fatores de Risco , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/metabolismo
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