Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 132
Filtrar
1.
Hypertension ; 80(12): 2495-2500, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37800386

RESUMO

There are mounting data that at least 30% of hypertensives who are appropriately screened have primary aldosteronism (PA), rather than the commonly reported figure of 5% to 10%. Second, there are similar data that undertreated patients with PA have a 3-fold higher risk profile than essential hypertensives with the same blood pressure levels. Third, clinicians managing hypertension measure success as sustainable lowering of blood pressure; untreated hypertensive patients with PA are thus in double jeopardy. Finally, and crucially, fewer than 1% of patients with hypertension are ever screened-let alone investigated-for PA. Accordingly, for "Who should we screen?" the answer is simple-all patients with hypertension. For "How they should be screened?" the answer is also simple-add spironolactone 25 mg/day for 4 weeks and measure the blood pressure response. In established hypertension, a fall of <10 mm Hg means PA is unlikely; above 12 mm Hg PA, it is probable. Newly presenting hypertension is much the same-hold off on first-order antihypertensive(s) and prescribe spironolactone 25 mg/day for 4 weeks. If blood pressure falls into the normal range, continue; if it does not, prescribe a standard antihypertensive. It is likely that the above protocols-a first start, amenable to refinement-will find additional hypertensives with unilateral PA; it is probable that the overwhelming majority will have bilateral disease. What this means is that we have a major public health issue on our hands: how can this be the case?


Assuntos
Hiperaldosteronismo , Hipertensão , Humanos , Espironolactona/uso terapêutico , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Pressão Sanguínea , Aldosterona , Renina
4.
Hypertension ; 79(4): 726-735, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35067069

RESUMO

Primary aldosteronism, the most common secondary form of hypertension, is thought to be present in ≈5% to 10% of hypertensive adults. However, recent studies indicate that its prevalence may be at least 3-fold higher based on the identification of renin-independent (autonomous) aldosterone production that is not suppressible with dietary sodium loading in a large fraction of adults with primary hypertension. Currently, the screening rate for primary aldosteronism in adults with primary hypertension is <1%. This review summarizes current thinking about primary aldosteronism from the standpoint of 3 key questions: Where are we now? Where to from here? So how do we get there?


Assuntos
Hiperaldosteronismo , Hipertensão , Sódio na Dieta , Adulto , Aldosterona , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiologia , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/etiologia , Renina
7.
Breast Cancer Res ; 22(1): 122, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33148314

RESUMO

BACKGROUND: The role of nuclear receptors in both the aetiology and treatment of breast cancer is exemplified by the use of the oestrogen receptor (ER) as a prognostic marker and treatment target. Treatments targeting the oestrogen signalling pathway are initially highly effective for most patients. However, for the breast cancers that fail to respond, or become resistant, to current endocrine treatments, the long-term outlook is poor. ER is a member of the nuclear receptor superfamily, comprising 48 members in the human, many of which are expressed in the breast and could be used as alternative targets in cases where current treatments are ineffective. METHODS: We used sparse canonical correlation analysis to interrogate potential novel nuclear receptor expression relationships in normal breast and breast cancer. These were further explored using whole transcriptome profiling in breast cancer cells after combinations of ligand treatments. RESULTS: Using this approach, we discovered a tumour suppressive relationship between the mineralocorticoid receptor (MR) and retinoic acid receptors (RAR), in particular RARß. Expression profiling of MR expressing breast cancer cells revealed that mineralocorticoid and retinoid co-treatment activated an expression program consistent with a reverse Warburg effect and growth inhibition, which was not observed with either ligand alone. Moreover, high expression of both MR and RARB was associated with improved breast cancer-specific survival. CONCLUSION: Our study reveals a previously unknown relationship between MR and RAR in the breast, which is dependent on menopausal state and altered in malignancy. This finding identifies potential new targets for the treatment of breast cancers that are refractory to existing therapeutic options.


Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Receptores de Mineralocorticoides/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Efeito Warburg em Oncologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Biologia Computacional , Feminino , Humanos , Receptores de Estrogênio/metabolismo , Receptores de Mineralocorticoides/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
15.
Vitam Horm ; 109: 1-15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678851

RESUMO

Aldosterone was characterized as the major mineralocorticoid hormone 65 years ago, and since then its physiologic role in epidural electrolyte homeostasis the province of nephrologists. In epithelia it acts via the mineralocorticoid receptor (MR) to retain Na+ and excrete K+; MRs, however, are widely expressed in organs not known to be aldosterone target tissues. MRs are not merely "aldosterone receptors," as they have equivalently high affinity for the physiologic glucocorticoids, and for progesterone. In epithelia (plus in the blood vessel wall and in the nucleus tractus solitarius of the brain) MRs are "protected" by coexpression of the enzyme 11ß-hydroxysteroid dehydrogenase. This enzyme converts cortisol-which circulates at much higher concentrations than aldosterone-to receptor-inactive cortisone, thus allowing aldosterone selectively to activate "protected" MR. In tissues which do not express 11ß-hydroxysteroid dehydrogenase, the default MR ligand is cortisol, which circulates at ≥100-fold higher plasma free concentrations than aldosterone. In such tissues there is as yet scant evidence for the physiologic role of cortisol-occupied MR: over the past decade, however, it has become clear that in damaged tissues cortisol can act as an MR-agonist, mimicking the effects seen with aldosterone under experimental conditions, in vitro and in vivo. Many pathophysiologic roles have been attributed to aldosterone: on the current evidence there are none outside its long established epithelial actions, those on the blood vessel wall and on the nucleus tractus solitarius.


Assuntos
Aldosterona/metabolismo , Pesquisa Biomédica/história , Animais , Regulação da Expressão Gênica , História do Século XX , História do Século XXI , Humanos
16.
Vitam Horm ; 109: 285-302, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30678860

RESUMO

Primary aldosteronism (PA), currently recognized to be 5-10% of hypertension, has a cardiovascular risk profile double that in age-, sex-, and blood pressure-matched essential hypertensives. Screening for PA is by determining the plasma aldosterone to renin ratio (ARR), followed by one of half a dozen confirmatory/exclusion tests. Unilateral hyperaldosteronism normally reflects an aldosterone producing adenoma; bilateral disease is the more common form, and termed idiopathic hyperaldosteronism (IHA). Subjects confirmed undergo imaging, followed by adrenal venous sampling (AVS) for lateralization. Unilateral lesions undergo laparoscopic adrenalectomy, to normalize aldosterone levels, and in approximately half reduction of BP/antihypertensive use. Bilateral hyperaldosteronism is treated by low dose mineralocorticoid receptor antagonists MRAs, plus amiloride/conventional antihypertensives, if/as indicated.In the future, what is needed is recognition that inappropriate aldosterone levels for sodium status (i.e., PA) represents up to 50% of "essential" hypertensives; all hypertensive should thus be screened by a modified ARR, using 24-h urinary aldosterone rather than a single plasma aldosterone. The current reluctance to do so reflects the costs of AVS if PA is confirmed-optimally by a standard seated saline suppression test-followed by surgery or life-long MRAs. Increasingly AVS will be replaced by plasma steroid assays capable of discriminating APA from the far more common IAH. Third generation MRAs (as selective as eplerenone, as potent as spironolactone, non-steroidal) are in development; in the interim, to minimize side effects and maximize compliance, spironolactone dosage should be set at 12.5-25 mg/day.


Assuntos
Hiperaldosteronismo/patologia , Hipertensão/etiologia , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia , Anti-Hipertensivos/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/genética , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/patologia , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Mutação , Guias de Prática Clínica como Assunto
17.
Hypertension ; 72(4): 839-840, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354730
20.
Proc Natl Acad Sci U S A ; 114(52): E11248-E11256, 2017 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-29229831

RESUMO

Mutations in 11ß-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) cause an extraordinarily rare autosomal recessive disorder, apparent mineralocorticoid excess (AME). AME is a form of low renin hypertension that is potentially fatal if untreated. Mutations in the HSD11B2 gene result either in severe AME or a milder phenotype (type 2 AME). To date, ∼40 causative mutations have been identified. As part of the International Consortium for Rare Steroid Disorders, we have diagnosed and followed the largest single worldwide cohort of 36 AME patients. Here, we present the genotype and clinical phenotype of these patients, prominently from consanguineous marriages in the Middle East, who display profound hypertension and hypokalemic alkalosis. To correlate mutations with phenotypic severity, we constructed a computational model of the HSD11B2 protein. Having used a similar strategy for the in silico evaluation of 150 mutations of CYP21A2, the disease-causing gene in congenital adrenal hyperplasia, we now provide a full structural explanation for the clinical severity of AME resulting from each known HSD11B2 missense mutation. We find that mutations that allow the formation of an inactive dimer, alter substrate/coenzyme binding, or impair structural stability of HSD11B2 yield severe AME. In contrast, mutations that cause an indirect disruption of substrate binding or mildly alter intramolecular interactions result in type 2 AME. A simple in silico evaluation of novel missense mutations could help predict the often-diverse phenotypes of an extremely rare monogenic disorder.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , Genótipo , Síndrome de Excesso Aparente de Minerolocorticoides , Mutação de Sentido Incorreto , Multimerização Proteica/genética , Adolescente , Criança , Pré-Escolar , Simulação por Computador , Estabilidade Enzimática , Feminino , Humanos , Lactente , Masculino , Síndrome de Excesso Aparente de Minerolocorticoides/enzimologia , Síndrome de Excesso Aparente de Minerolocorticoides/genética , Síndrome de Excesso Aparente de Minerolocorticoides/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...