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1.
Nature ; 620(7973): 374-380, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37532932

RESUMO

Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA3, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.


Assuntos
Envelhecimento , Encéfalo , Disfunção Cognitiva , Inflamação , Proteínas de Membrana , Doenças Neurodegenerativas , Nucleotidiltransferases , Animais , Humanos , Camundongos , Envelhecimento/metabolismo , Envelhecimento/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Efeito Espectador , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , DNA/imunologia , Inflamação/enzimologia , Inflamação/metabolismo , Proteínas de Membrana/metabolismo , Transtornos da Memória/enzimologia , Transtornos da Memória/metabolismo , Microglia/metabolismo , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/metabolismo , Nucleotidiltransferases/metabolismo , Especificidade de Órgãos , Transdução de Sinais , Hipocampo/metabolismo , Hipocampo/patologia
2.
Rev Med Suisse ; 20(866): 570-574, 2024 Mar 20.
Artigo em Francês | MEDLINE | ID: mdl-38506456

RESUMO

The management of obesity is changing dramatically with the emergence of new drug treatments. Glucagon-like peptide-1 (GLP-1) receptor agonists are approved for this indication in Switzerland, and approval is currently being sought for a GLP-1 and glucose-dependent insulinotropic polypetide (GIP) co-agonist. Reimbursement conditions are restrictive, and patients are given only one opportunity to achieve the weight loss required for continued reimbursement. The popularity of these treatments has led to worldwide stock-outs for several months now, and it is essential that prescribers respect the indications so as not to prejudice obese patients. This article provides a review of the treatments available and the conditions under which they are reimbursed, as well as those that should be reimbursed soon.


La prise en charge de l'obésité est profondément modifiée par l'essor de nouveaux traitements médicamenteux. Les agonistes du récepteur du glucagon-like peptide-1 (GLP-1) sont approuvés dans cette indication en Suisse et une approbation est en cours d'analyse pour un coagoniste du GLP-1 et du glucose-dependent insulinotropic polypetide (GIP). Les conditions de remboursement sont cependant strictes et les patients ne bénéficient que d'une seule opportunité pour obtenir les pertes pondérales qui autorisent la poursuite du remboursement. La popularité de ces traitements occasionne des ruptures de stocks depuis plusieurs mois au niveau mondial et il est essentiel que les prescripteurs respectent les indications afin de ne pas prétériter les patients en situation d'obésité. Cet article propose un rappel des traitements disponibles et les conditions encadrant leur remboursement, ainsi que ceux qui le seront prochainement.


Assuntos
Glicemia , Diabetes Mellitus Tipo 2 , Humanos , Polipeptídeo Inibidor Gástrico , Obesidade/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon , Glucose , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas
3.
Rev Med Suisse ; 20(866): 575-579, 2024 Mar 20.
Artigo em Francês | MEDLINE | ID: mdl-38506457

RESUMO

Bariatric surgery is regularly offered to women of childbearing age. Pregnancy after such surgery should be planned and requires special attention. Some complications associated with obesity during pregnancy are reduced after bariatric surgery, but reduced dietary intake and malabsorption can cause nutritional deficiencies, that need to be carefully screened for and supplemented. Dietary management is recommended, and any unusual abdominal pain should be referred to a bariatric surgeon. We offer a summary of recommendations for appropriate follow-up of these pregnancies.


La chirurgie bariatrique est régulièrement proposée à des femmes en âge de procréer. Une grossesse après une telle chirurgie devrait être planifiée et demande une attention particulière. Certaines complications liées à l'obésité durant la grossesse sont réduites après une chirurgie bariatrique mais une diminution des apports alimentaires et la malabsorption peuvent engendrer des carences nutritionnelles qui doivent être attentivement dépistées et supplémentées. Une prise en charge diététique est recommandée et toute douleur abdominale inhabituelle doit faire demander l'avis d'un chirurgien bariatrique. Nous proposons une synthèse des recommandations pour un suivi adéquat de ces grossesses.


Assuntos
Cirurgia Bariátrica , Desnutrição , Complicações na Gravidez , Gravidez , Feminino , Humanos , Cirurgia Bariátrica/efeitos adversos , Obesidade/complicações , Desnutrição/etiologia , Período Pós-Parto , Suplementos Nutricionais , Complicações na Gravidez/etiologia , Resultado da Gravidez
4.
Rev Med Suisse ; 19(819): 555-561, 2023 Mar 22.
Artigo em Francês | MEDLINE | ID: mdl-36950785

RESUMO

Obesity is a chronic and recurrent metabolic disease associated with serious complications and increased mortality. Bariatric surgery was until recently the only intervention that could lead to significant and sustained weight loss. A better understanding of the endocrine regulation of appetite has allowed the development of new treatments. GLP-1 analogues are already available and a dual treatment of GLP-1 analogue and GIP has recently shown even greater efficacy in terms of weight loss. We present a summary of the known mechanisms of action and clinical data that support the use of these molecules in the treatment of obesity.


L'obésité est une maladie métabolique chronique et récidivante associée à de graves complications et à une mortalité accrue. La chirurgie bariatrique était jusqu'à récemment la seule intervention permettant d'obtenir une perte de poids significative et son maintien. Une meilleure compréhension de la régulation endocrinienne de l'appétit a permis le développement de nouveaux traitements. Les analogues du GLP-1 sont déjà disponibles et une double activation des récepteurs du GLP-1 et du GIP (double agoniste) a récemment montré une efficacité encore plus importante en termes de perte pondérale. Nous proposons une synthèse des mécanismes d'action connus et des données cliniques qui soutiennent l'utilisation de ces molécules dans le traitement de l'obésité.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Humanos , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Hipoglicemiantes/uso terapêutico , Redução de Peso , Receptor do Peptídeo Semelhante ao Glucagon 1 , Diabetes Mellitus Tipo 2/tratamento farmacológico
5.
Rev Med Suisse ; 19(819): 546-551, 2023 Mar 22.
Artigo em Francês | MEDLINE | ID: mdl-36950783

RESUMO

Obesity (BMI ≥ 30 kg/m2) has been officially classified as a disease by the WHO since 2008, yet individuals affected by obesity often face blame and negative stereotypes from society and healthcare providers. This stigmatization can lead to negative impacts on both mental and physical health. This phenomenon can also lead the stigmatized person to internalize the prejudice, considering their fate as deserved. This article aims to provide healthcare professionals with the tools to better understand and care for patients with obesity.


L'OMS reconnaît officiellement l'obésité (IMC ≥ 30 kg/m2) comme une maladie depuis 2008. Pourtant, les personnes touchées par l'obésité font souvent l'objet de reproches et de stéréotypes négatifs de la part de la société et des prestataires de soins de santé. Cette stigmatisation peut avoir des répercussions négatives sur la santé mentale comme physique. Ce phénomène peut aussi conduire le stigmatisé à intérioriser le préjudice, considérant son sort comme normal. Cet article vise à fournir aux professionnels de santé les outils nécessaires pour comprendre et aborder cette question, afin de mieux soigner les patients touchés par l'obésité.


Assuntos
Obesidade , Estereotipagem , Humanos , Preconceito , Pessoal de Saúde , Atitude do Pessoal de Saúde
6.
Rev Med Suisse ; 19(819): 567-571, 2023 Mar 22.
Artigo em Francês | MEDLINE | ID: mdl-36950787

RESUMO

Obesity is a chronic disease that seriously affects physical and psychological health. However, its management is insufficiently coordinated. The lack of defined therapeutic strategies is particularly evident since the arrival of new drug treatments. Coordination between the professionals involved- obesity specialists, general practitioners and other caregivers - and the involvement of the patient are all issues at the heart of an evaluation necessary for the construction of a personalized care project. Interdisciplinary centers must guarantee access to information and offer the full range of therapies currently available. An early psychological evaluation allows for the orientation of care, taking into account the vulnerability and resources of patients.


L'obésité est une maladie chronique qui affecte gravement la santé physique et psychologique, mais sa prise en charge est insuffisamment coordonnée. L'absence de stratégies thérapeutiques définies est particulièrement évidente depuis l'arrivée de nouveaux traitements médicamenteux. La coordination entre les professionnels impliqués (spécialistes de l'obésité, médecins généralistes et autres soignants) et l'implication du patient sont autant d'enjeux au cœur d'une évaluation nécessaire pour la construction d'un projet de soins personnalisés. Les centres interdisciplinaires doivent garantir un accès à l'information et offrir l'ensemble des thérapies actuellement disponibles. Une évaluation psychologique précoce permet d'orienter la prise en charge en tenant compte de la vulnérabilité et des ressources des patients.


Assuntos
Clínicos Gerais , Obesidade , Humanos , Doença Crônica , Obesidade/terapia
7.
J Physiol ; 600(4): 979-996, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34505286

RESUMO

Understanding the mechanisms involved in the higher energy cost of walking (NCw : the energy expenditure above resting per unit distance) in adults with obesity is pivotal to optimizing the use of walking in weight management programmes. Therefore, this study aimed to investigate the mechanics, energetics and mechanical efficiency of walking after a large body mass loss induced by bariatric surgery in individuals with obesity. Nine adults (39.5 ± 8.6 year; BMI: 42.7 ± 4.6 kg m-2 ) walked at five fixed speeds before (baseline) and after the bariatric surgery (post 1 and post 2). Gas exchanges were measured to obtain NCw . A motion analysis system and instrumented treadmill were combined to assess total mechanical work (Wtot ). Mechanical efficiency (Wtot NCw-1 ) was also calculated. Participants lost 25.7 ± 3.4% of their body mass at post 1 (6.6 months; P < 0.001) and 6.1 ± 4.9% more at post 2 (12 months; P = 0.014). Mass-normalized NCw was similar between baseline and post 1 and decreased at post 2 compared to that at baseline (-6.2 ± 2.7%) and post 1 (-8.1 ± 1.9%; P ≤ 0.007). No difference was found in mass-normalized Wtot during follow-up (P = 0.36). Mechanical efficiency was similar at post 1 and post 2 when compared to that at baseline (P ≥ 0.19), but it was higher (+14.1 ± 4.6%) at post 2 than at post 1 (P = 0.013). These findings showed that after a very large body mass loss, individuals with obesity may reorganize their walking pattern into a gait more similar to that of lean adults, thus decreasing their NCw by making their muscles work more efficiently. KEY POINTS: A higher net (above resting) energy cost of walking (lower gait economy) is observed in adults with obesity compared to lean individuals. Understanding the mechanisms (i.e. mass driven, gait pattern and behavioural changes) involved in this extra cost of walking in adults with obesity is pivotal to optimizing the use of walking to promote daily physical activity and improve health in these individuals. We found that very large weight loss induced by bariatric surgery significantly decreased the energy cost of walking per kg of body mass after 1 year with similar total mechanical work per kg of body mass, resulting in an increased mechanical efficiency of walking. Individuals with obesity may reorganize their walking pattern into a gait more similar to that of adults of normal body mass, thus decreasing their energy cost of walking by making their muscles work more efficiently.


Assuntos
Adaptação Fisiológica , Caminhada , Adulto , Fenômenos Biomecânicos , Metabolismo Energético/fisiologia , Marcha/fisiologia , Humanos , Obesidade , Caminhada/fisiologia
8.
Microvasc Res ; 140: 104298, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34896377

RESUMO

OBJECTIVE: Lipedema is a chronic and progressive disease associated with lymphatic impairment at later stages. The aim of our study was to describe the functional status and anatomy of lower limb superficial lymphatic system using indocyanine green (ICG) lymphography in patients with lipedema. METHODS: Following ICG injection at the dorsum of the foot, distance (cm) covered by the dye at 10 (T10') and 25 min (T25') was measured and normalized for limb length. If the dye did not reach the groin within 25 min, patients were classified as "drainage-needing" group (DNG). Values of fat and lean distribution assessed by dual-energy X-ray absorptiometry were extracted, and correlation analysis was performed. Furthermore, anatomical patterns of superficial lymphatics were assessed. RESULTS: Overall, 45 women were included, 25 (56%) of whom were classified as DNG. Symptoms duration was significantly associated with DNG status at multivariate analysis (odds ratio 1.07; 95% CI 1.01-1.14; p = 0.047). Moreover, Spearman's analysis showed a negative correlation between symptoms duration and T25' dye migration (r = -0.469; p = 0.037). Overall, no major anatomical lymphatic changes were found. CONCLUSIONS: Present study suggests that lymphatic functioning in patients with lipedema correlates with symptoms duration. Further research on larger cohorts should verify our findings and clarify their potential therapeutic implications. Overall, ICG lymphography may be promising technique to assess both lymphatic anatomy and functioning in patients with lipedema.


Assuntos
Corantes Fluorescentes , Verde de Indocianina , Lipedema/diagnóstico por imagem , Vasos Linfáticos/diagnóstico por imagem , Linfografia/métodos , Imagem Óptica , Absorciometria de Fóton , Adiposidade , Adulto , Diagnóstico Precoce , Feminino , Humanos , Lipedema/fisiopatologia , Extremidade Inferior , Vasos Linfáticos/fisiopatologia , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos
9.
Rev Med Suisse ; 18(774): 522-526, 2022 Mar 23.
Artigo em Francês | MEDLINE | ID: mdl-35343120

RESUMO

The relative risk of developing MetS is higher in patients with severe mental illness (SMI) than in the general population. Similarly, the risk of developing obesity or type 2 diabetes (T2DM) is also higher in patients with SMI. GLP-1 receptor agonists, such as liraglutide, have been shown to be effective in the treatment of T2DM and, more recently, in obesity or overweight associated with at least one metabolic disease. Their psychiatric adverse effect profiles seem to be reassuring, thus not represent a limitation for prescribing in psy chiatry. We aimed to explore the therapeutic usefulness of liraglutide in patients with psychiatric disorders associated with somatic comorbidities such as obesity, T2DM or MetS.


Le risque relatif de développer un syndrome métabolique (SMet) est plus élevé chez les patients connus pour une maladie psychiatrique sévère (MPS) que dans la population générale. De même, le risque de développer une obésité ou un diabète de type 2 (DT2) est également plus important chez les patients souffrant de MPS. Les analogues du GLP-1 (Glucagon-Like Peptide 1), tels que le liraglutide, ont fait leurs preuves pour le traitement du DT2 et, plus récemment, de l'obésité ou de la surcharge pondérale associée à une maladie métabolique. Leurs profils d'effets indésirables sur la santé mentale semblent rassurants, ne représentant ainsi pas de limitation à leur prescription en psychiatrie. Nous questionnons ici l'intérêt du liraglutide chez les patients souffrant de troubles psychiques associés à des comorbidités somatiques telles que l'obésité, le DT2 ou le SMet.


Assuntos
Diabetes Mellitus Tipo 2 , Transtornos Mentais , Psiquiatria , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Liraglutida/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Obesidade/complicações , Obesidade/tratamento farmacológico
10.
Rev Med Suisse ; 18(774): 516-521, 2022 Mar 23.
Artigo em Francês | MEDLINE | ID: mdl-35343119

RESUMO

Liraglutide, which has been prescribed for several years for the treatment of type 2 diabetes, is now proposed for the management of patients with BMI between 28 and 35 kg/m2 in the presence of metabolic comorbidity or BMI ≥ 35 kg/m2. Its reimbursement by the health insurance is conditioned on weight loss results and time limited. Careful preparation of the patient and his commitment to lifestyle changes are essential for the success and good tolerance of the treatment. The introduction of this treatment requires a multidisciplinary follow-up to ensure optimal results. The place of liraglutide in the pharmacopeia of obesity, a chronic disease that requires long-term treatment, should be clarified.


Le liraglutide, un analogue du GLP-1 (Glucagon-Like Peptide-1) prescrit depuis plusieurs années dans le traitement du diabète de type 2, est désormais proposé dans la prise en charge des patients avec un IMC entre 28 et 35 kg/m2 en présence d'une comorbidité métabolique ou avec un IMC ≥ 35 kg/m2. Son remboursement par l'assurance obligatoire des soins est conditionné par des résultats de perte pondérale et limité dans le temps. Une préparation attentive du patient et son engagement dans des modifications de l'hygiène de vie sont indispensables au succès et à la bonne tolérance du traitement. L'instauration de celui-ci nécessite un suivi pluridisciplinaire pour permettre un résultat optimal. La place du liraglutide dans la pharmacopée de l'obésité, maladie chronique qui nécessite un traitement de longue durée, devra être précisée.


Assuntos
Fármacos Antiobesidade , Diabetes Mellitus Tipo 2 , Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Liraglutida/uso terapêutico , Obesidade/tratamento farmacológico , Redução de Peso
11.
Blood Press ; 30(1): 67-74, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33073631

RESUMO

PURPOSE: Sodium and water handling by the kidney and the sympathetic nervous system have been implicated in the development of obesity-related hypertension and kidney disease. They have seldom been studied together during stress conditions. The objective of this study was to compare the systemic, renal and hormonal responses to lower body negative pressure (LBNP) in adult healthy participants (H), obese normotensive (OBN) and obese hypertensive patients (OBH). MATERIALS AND METHODS: This was a prospective case-control study. Participants from the three groups were exposed to one hour of LBNP. Systemic and renal haemodynamics, sodium and water excretion and hormones were measured before and after LBNP. Intergroup LBNP responses were tested using a Student t-test or a Wilcoxon rank-sum test. An extension of the Wilcoxon rank-sum test was used to test for a trend across the three groups. RESULTS: The study included 54 participants (H: 25, OBN: 16, OBH: 13). LBNP induced a stepwise increase in systolic blood pressure (+2.7 ± 4.7 mmHg (H) vs. +4.7 ± 8.8 mmHg (OBN) vs. +8.0 ± 8.6 mmHg (OBH, p = .028)) and heart rate (-1.3 ± 4.9 bpm (H) vs. 2.2 ± 6.1 bpm (OBN) vs. 1.9 ± 4.1 bpm (OBH, p = .041). Urinary output (-2.8 ± 2.1 ml/min vs. -1.4 ± 1.7 ml/min, p = .028) and free water clearance (-1.9 ± 1.7 mOsm/kg vs. -0.7 ± 1.3 mOsm/kg, p = .016) responses were more marked in OBN compared to H. CONCLUSIONS: These results show that the systemic and the renal response to LBNP differ according to weight and to BP categories. Systolic BP and heart show a progressive increased response form healthy volunteers to OBN and then to obese hypertensive participants while urinary output and free water clearance responses are increased in OBN only, suggesting that the occurrence of hypertension in obese individuals modifies the early kidney responses to stress. CLINICALTRIAL.GOV IDENTIFIER: NCT01734096.


Assuntos
Hemodinâmica , Hipertensão/complicações , Rim/fisiopatologia , Obesidade/complicações , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Taxa de Filtração Glomerular , Frequência Cardíaca , Humanos , Hipertensão/sangue , Hipertensão/fisiopatologia , Pressão Negativa da Região Corporal Inferior , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , Estudos Prospectivos , Adulto Jovem
12.
Rev Med Suisse ; 17(731): 558-563, 2021 Mar 24.
Artigo em Francês | MEDLINE | ID: mdl-33760416

RESUMO

The COVID-19 pandemic has become a major public health crisis and increasing evidence demonstrates a strong correlation between obesity and severe forms of SARS-CoV-2 infections. Several mechanisms are advanced to explain this collusion. Obesity leads to an altered and delayed initial immune response, a chronic low-grade inflammation that promotes cytokine storm and a hypercoagulable state. Diagnosis is sometimes delayed by a tendency for these patients to avoid medical consultations and care complicated by weight and ventilation difficulties. In this article, we propose to review the mechanisms potentially involved in the collusion of these two pandemics.


La pandémie de Covid-19 est devenue une crise majeure de santé publique et les données épidémiologiques ont démontré que l'obésité augmentait considérablement les risques d'issues défavorables chez les patients atteints d'infection sévère à SARS-CoV-2. Plusieurs mécanismes sont avancés pour expliquer cette collusion néfaste. L'obésité entraîne une réponse immunitaire initiale altérée et retardée, une inflammation chronique de bas grade qui favorise la tempête de cytokines et un état hypercoagulable. Le diagnostic est parfois retardé par une tendance de ces patients à éviter les consultations médicales et les soins compliqués par le poids ainsi que les difficultés de ventilation. Nous proposons dans cet article de passer en revue les mécanismes potentiellement impliqués dans la collusion de ces deux pandémies.


Assuntos
COVID-19 , Pandemias , Síndrome da Liberação de Citocina , Humanos , Obesidade/complicações , Obesidade/epidemiologia , SARS-CoV-2
13.
Rev Med Suisse ; 17(731): 582-587, 2021 Mar 24.
Artigo em Francês | MEDLINE | ID: mdl-33760421

RESUMO

Vitamin B12 deficiency is common in outpatients and inpatient populations, with potentially severe neuropsychiatric and hematological impact, which requires timely diagnosis and treatment. The different diagnostic tests all have their limitations but can be combined, sequentially. We propose to review the treatment options according to the different etiologies of the deficiency, highlighting the costs of the therapies and their coverage by the health insurance.


La carence en vitamine B12 est fréquente en médecine ambulatoire et hospitalière, avec des conséquences neuropsychiatriques et hématologiques potentiellement sévères, nécessitant un diagnostic et un traitement adéquat. Les différents tests diagnostiques ont tous leurs limitations mais peuvent être utilisés de manière complémentaire. Nous proposons de refaire un point sur les possibilités de traitement en fonction des différentes étiologies de la carence, en mettant notamment en exergue les différents coûts des thérapies et leur prise en charge par l'assurance de base.


Assuntos
Deficiência de Vitamina B 12 , Vitamina B 12 , Humanos , Seguro Saúde , Deficiência de Vitamina B 12/diagnóstico , Deficiência de Vitamina B 12/tratamento farmacológico
14.
Hum Mol Genet ; 27(2): 359-372, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29202173

RESUMO

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by absent puberty and infertility due to GnRH deficiency, and is often associated with anosmia [Kallmann syndrome (KS)]. The genetic etiology of CHH is heterogeneous, and more than 30 genes have been implicated in approximately 50% of patients with CHH. We hypothesized that genes encoding axon-guidance proteins containing fibronectin type-III (FN3) domains (similar to ANOS1, the first gene associated with KS), are mutated in CHH. We performed whole-exome sequencing in a cohort of 133 CHH probands to test this hypothesis, and identified rare sequence variants (RSVs) in genes encoding for the FN3-domain encoding protein deleted in colorectal cancer (DCC) and its ligand Netrin-1 (NTN1). In vitro studies of these RSVs revealed altered intracellular signaling associated with defects in cell morphology, and confirmed five heterozygous DCC mutations in 6 probands-5 of which presented as KS. Two KS probands carry heterozygous mutations in both DCC and NTN1 consistent with oligogenic inheritance. Further, we show that Netrin-1 promotes migration in immortalized GnRH neurons (GN11 cells). This study implicates DCC and NTN1 mutations in the pathophysiology of CHH consistent with the role of these two genes in the ontogeny of GnRH neurons in mice.


Assuntos
Receptor DCC/genética , Hipogonadismo/genética , Netrina-1/genética , Adulto , Estudos de Coortes , Receptor DCC/metabolismo , Feminino , Domínio de Fibronectina Tipo III , Hormônio Liberador de Gonadotropina/deficiência , Humanos , Hipogonadismo/metabolismo , Hipogonadismo/patologia , Masculino , Mutação , Netrina-1/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Linhagem , Sequenciamento do Exoma
15.
J Transl Med ; 18(1): 472, 2020 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-33298113

RESUMO

Aberrant metabolism is the root cause of several serious health issues, creating a huge burden to health and leading to diminished life expectancy. A dysregulated metabolism induces the secretion of several molecules which in turn trigger the inflammatory pathway. Inflammation is the natural reaction of the immune system to a variety of stimuli, such as pathogens, damaged cells, and harmful substances. Metabolically triggered inflammation, also called metaflammation or low-grade chronic inflammation, is the consequence of a synergic interaction between the host and the exposome-a combination of environmental drivers, including diet, lifestyle, pollutants and other factors throughout the life span of an individual. Various levels of chronic inflammation are associated with several lifestyle-related diseases such as diabetes, obesity, metabolic associated fatty liver disease (MAFLD), cancers, cardiovascular disorders (CVDs), autoimmune diseases, and chronic lung diseases. Chronic diseases are a growing concern worldwide, placing a heavy burden on individuals, families, governments, and health-care systems. New strategies are needed to empower communities worldwide to prevent and treat these diseases. Precision medicine provides a model for the next generation of lifestyle modification. This will capitalize on the dynamic interaction between an individual's biology, lifestyle, behavior, and environment. The aim of precision medicine is to design and improve diagnosis, therapeutics and prognostication through the use of large complex datasets that incorporate individual gene, function, and environmental variations. The implementation of high-performance computing (HPC) and artificial intelligence (AI) can predict risks with greater accuracy based on available multidimensional clinical and biological datasets. AI-powered precision medicine provides clinicians with an opportunity to specifically tailor early interventions to each individual. In this article, we discuss the strengths and limitations of existing and evolving recent, data-driven technologies, such as AI, in preventing, treating and reversing lifestyle-related diseases.


Assuntos
Inteligência Artificial , Diabetes Mellitus , Doença Crônica , Diabetes Mellitus/terapia , Gerenciamento Clínico , Humanos , Medicina de Precisão
16.
Rev Med Suisse ; 16(687): 592-595, 2020 Mar 25.
Artigo em Francês | MEDLINE | ID: mdl-32216183

RESUMO

The occurrence of hypophosphatemia after iron infusion has been known for a long time but has only recently led to clinical concerns. It was considered to be of low clinical importance. The elucidation of the physiological mechanisms responsible for this effect, involving FGF23 and the ever-increasing number of cases with regard to the potentially very serious consequences on bone metabolism have recently raised probably justified concerns. In this article, we summarize the mechanisms of phosphate homeostasis, how intravenous iron can induce a phosphate deficiency and what precautions and treatments needs to be undertaken to prevent it.


La survenue d'une hypophosphatémie après une perfusion de fer est connue de longue date mais n'a que depuis peu suscité des inquiétudes cliniques. L'élucidation des mécanismes physiologiques à l'origine de cet effet indésirable, impliquant le facteur de croissance des fibroblastes 23 (FGF23), et les rapports de cas toujours plus nombreux quant aux conséquences potentiellement graves sur le métabolisme osseux ont récemment soulevé des préoccupations probablement justifiées. Dans cet article, nous résumons les mécanismes de régulation du phosphate et la manière dont le fer par voie intraveineuse peut induire un déficit en phosphate, ainsi que les précautions et traitements à mettre en œuvre pour le prévenir.


Assuntos
Hipofosfatemia/induzido quimicamente , Hipofosfatemia/prevenção & controle , Ferro/administração & dosagem , Ferro/efeitos adversos , Administração Intravenosa , Fator de Crescimento de Fibroblastos 23 , Humanos , Fosfatos/metabolismo
17.
Rev Med Suisse ; 16(687): 582-585, 2020 Mar 25.
Artigo em Francês | MEDLINE | ID: mdl-32216181

RESUMO

Metabolic surgery is becoming increasingly important in the treatment of obese and diabetic patients. Its impact is major on immediate post-operative glycemic control and adaptation of anti-diabetic treatments is necessary. Over time, a recurrence of diabetes may be observed and the choice of treatments to be reintroduced must take into account the surgery performed. By discussing pharmacological options during the preoperative, peri-operative and post-operative periods, this article provides a review of the literature on a subject for which few guidelines are currently proposed.


La chirurgie métabolique prend une place toujours plus importante dans l'offre de traitement des patients obèses et diabétiques. Son impact est radical sur l'équilibre glycémique postopératoire immédiat et une adaptation rapide des traitements antidiabétiques est nécessaire. Au fil du temps, une récidive du diabète peut être observée et le choix des traitements à réintroduire doit tenir compte de l'intervention chirurgicale effectuée. En discutant les options pharmacologiques durant les périodes préopératoire, périopératoire et postopératoire, cet article propose une revue de la littérature sur un sujet pour lequel peu de directives sont actuellement proposées.


Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Obesidade/complicações , Obesidade/cirurgia , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Humanos , Obesidade/sangue
18.
Rev Med Suisse ; 16(687): 586-591, 2020 Mar 25.
Artigo em Francês | MEDLINE | ID: mdl-32216182

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases with an epidemiology correlated to obesity and metabolic syndrome. The last decade was rich of significant advances in understanding the pathophysiology of the disease, linking environmental elements, genetic factors and microbiota modifications, as well as in staging, screening and therapeutic development. The purpose of this article is to summarize recent advances in the field of NAFLD, on her way to become the first cause of cirrhosis and liver transplantation worldwide.


La maladie stéatosique non alcoolique du foie (NAFLD) est l'une des atteintes hépatiques les plus prévalentes dans le monde avec une épidémiologie corrélée à celles de l'obésité et du syndrome métabolique. La dernière décennie a connu des avancées importantes dans la compréhension de la physiopathologie en mettant en lien des facteurs environnementaux, génétiques et microbiotiques, ainsi que dans la terminologie de la maladie, ses classifications et ses moyens diagnostiques et thérapeutiques. Le but de cet article est de résumer les avancées récentes dans le domaine de la NAFLD, sur le point de devenir la première cause de cirrhose et de transplantation hépatique dans le monde.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Cirrose Hepática/etiologia , Transplante de Fígado , Síndrome Metabólica/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicações
19.
Ther Umsch ; 76(3): 143-149, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31498052

RESUMO

Long-term results after Roux-en-Y gastric bypass for severe obesity Abstract. Roux-en-Y gastric bypass (RYGB) has been performed for almost 50 years, yet long-term results have only been scarcely reported. In this paper, we report results up to 15 years after gastric bypass and review the relevant literature on long-term results after this operation. MATERIAL AND METHODS: Our prospective database has been reviewed for this study. A literature search via Pubmed was done, and articles reporting on 10-year results after RYGB in at least 50 patients were retrieved and analyzed. RESULTS: A total of 822 patients underwent primary RYGB in our institutions between 1999 and 2007. All are eligible for 10-year analysis, and 186 operated before 2003 for 15-year analysis. Follow-up rates after 10 and 15 years are 76 and 55 % respectively. Patients loose a mean of 12,9 BMI units after 10 years, a figure that remains unchanged after 15 years. 80 %, respectively 72 % of patients maintain a %total body weight loss of at least 20 % after 10 and 15 years. Comorbidities are markedly improved, as well as quality of life. These results compare well with those reported in the literature after this length of time. Studies from the literature also show a preventive effect of RYGB in the development of metabolic comorbidities in obese individuals submitted to RYGB. CONCLUSIONS: RYGB provides good to excellent long-term weight loss which persists up to 15 years after surgery. This is associated with markedly improved comorbidities and reduced cardiovascular risk, improved quality-of-life and reduced mortality. RYGB represents a good option for most patients who seek surgery for severe obesity.


Assuntos
Derivação Gástrica/métodos , Obesidade Mórbida , Índice de Massa Corporal , Humanos , Obesidade Mórbida/cirurgia , Estudos Prospectivos , Qualidade de Vida , Resultado do Tratamento
20.
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