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1.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157

RESUMO

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31735971

RESUMO

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n=30, eight patients had two and one had three pituitary operations), surgery+radiotherapy+adrenalectomy (n=17, two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n=2) and adrenalectomy (n=19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (HR 4.6; 95% CI, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31606735

RESUMO

OBJECTIVE: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013. PARTICIPANTS: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration. EVIDENCE: This evidence-based Consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities. CONSENSUS PROCESS: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system. CONCLUSIONS: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.

4.
Hypertension ; 74(5): 1152-1159, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564164

RESUMO

Microarray comparison of the transcriptomes of human adrenal zona glomerulosa (ZG) and zona fasciculata found several ZG-specific genes that negatively regulate aldosterone secretion. The third and most significantly upregulated ZG-gene (19.9-fold compared with zona fasciculata, P=6.58×10-24) was ANO4, a putative Ca2+-activated chloride channel. We have investigated the role of ANO4 in human adrenal, and whether it functions like the prototype anoctamin, ANO1. We evaluated ANO4 mRNA and protein expression in human adrenal by qPCR and immunohistochemistry, compared the effects of ANO4 and ANO1 overexpression on baseline and stimulated aldosterone secretion and cell proliferation in H295R cells, and analyzed ANO4 activity as a Ca2+-activated chloride channel in comparison with other anoctamins by a fluorescence-based functional assay. The expression of ANO4 in ZG was confirmed by qPCR as 23.21-fold upregulated compared with zona fasciculata (n=18; P=4.93×10-7). Immunohistochemistry found cytoplasmic, ZG-selective expression of ANO4 (anoctamin 4) protein. ANO4 overexpression in H295R cells attenuated calcium-mediated aldosterone secretion and cell proliferation in comparison to controls. The latter effects were in a different direction to those of ANO1. The functional assay showed that, in contrast to ANO1, ANO4 expression results in low levels of calcium-dependent anion transport. In conclusion, ANO4 is one of the most highly expressed genes in ZG. It attenuates stimulated aldosterone secretion and cell proliferation. Although belonging to a family of Ca2+-activated chloride channels, it does not generate significant plasma membrane chloride channel activity.


Assuntos
Aldosterona/biossíntese , Anoctaminas/genética , Regulação da Expressão Gênica , Hiperaldosteronismo/genética , Hipertensão/fisiopatologia , Transdução de Sinais/genética , Zona Glomerulosa/metabolismo , Córtex Suprarrenal/citologia , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/patologia , Análise de Variância , Comunicação Celular/genética , Proliferação de Células , Células Cultivadas , Imunofluorescência , Humanos , Hiperaldosteronismo/patologia , Hipertensão/etiologia , Reação em Cadeia da Polimerase em Tempo Real/métodos , Análise Serial de Tecidos , Técnicas de Cultura de Tecidos , Transcriptoma/genética , Regulação para Cima , Zona Fasciculada/metabolismo , Zona Fasciculada/patologia , Zona Glomerulosa/patologia
5.
ERJ Open Res ; 5(3)2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31579676

RESUMO

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody approved in several countries for the add-on maintenance treatment of patients with severe eosinophilic asthma aged 12 years and older. In the 28-week Phase III ZONDA trial (ClinicalTrials.gov identifier: NCT02075255), benralizumab produced a median 75% reduction from baseline in oral corticosteroid (OCS) dosage (versus 25% for placebo) while maintaining asthma control for patients with OCS-dependent severe asthma. This manuscript presents the detailed protocol for the Phase IIIb PONENTE (ClinicalTrials.gov identifier: NCT03557307), a study that will build on the findings from ZONDA. As the largest steroid-sparing study undertaken in severe asthma, PONENTE has a faster steroid tapering schedule for prednisone dosages ≥7.5 mg·day-1 than previous studies, and it includes an evaluation of adrenal insufficiency and an algorithm to taper OCS dosage when prednisone dosage is ≤5 mg·day-1. It also has a longer maintenance phase to assess asthma control for up to 6 months after completion of OCS tapering. The two primary endpoints are whether patients achieve 100% reduction in daily OCS use and whether patients achieve 100% reduction in daily OCS or achieve OCS dosage ≤5 mg·day-1, if adrenal insufficiency prevented further reduction, both sustained over ≥4 weeks without worsening of asthma. Safety and change from baseline in health-related quality of life will also be assessed. PONENTE should provide valuable guidance for clinicians on tapering OCS dosage, including the management of adrenal insufficiency, following benralizumab initiation for the treatment of patients who are OCS-dependent with severe, uncontrolled eosinophilic asthma.

6.
BMJ Open ; 9(9): e032550, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558462

RESUMO

OBJECTIVES: The study aimed to compare candidate performance between traditional best-of-five single-best-answer (SBA) questions and very-short-answer (VSA) questions, in which candidates must generate their own answers of between one and five words. The primary objective was to determine if the mean positive cue rate for SBAs exceeded the null hypothesis guessing rate of 20%. DESIGN: This was a cross-sectional study undertaken in 2018. SETTING: 20 medical schools in the UK. PARTICIPANTS: 1417 volunteer medical students preparing for their final undergraduate medicine examinations (total eligible population across all UK medical schools approximately 7500). INTERVENTIONS: Students completed a 50-question VSA test, followed immediately by the same test in SBA format, using a novel digital exam delivery platform which also facilitated rapid marking of VSAs. MAIN OUTCOME MEASURES: The main outcome measure was the mean positive cue rate across SBAs: the percentage of students getting the SBA format of the question correct after getting the VSA format incorrect. Internal consistency, item discrimination and the pass rate using Cohen standard setting for VSAs and SBAs were also evaluated, and a cost analysis in terms of marking the VSA was performed. RESULTS: The study was completed by 1417 students. Mean student scores were 21 percentage points higher for SBAs. The mean positive cue rate was 42.7% (95% CI 36.8% to 48.6%), one-sample t-test against ≤20%: t=7.53, p<0.001. Internal consistency was higher for VSAs than SBAs and the median item discrimination equivalent. The estimated marking cost was £2655 ($3500), with 24.5 hours of clinician time required (1.25 s per student per question). CONCLUSIONS: SBA questions can give a false impression of students' competence. VSAs appear to have greater authenticity and can provide useful information regarding students' cognitive errors, helping to improve learning as well as assessment. Electronic delivery and marking of VSAs is feasible and cost-effective.

7.
Best Pract Res Clin Endocrinol Metab ; 33(2): 101278, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31208872

RESUMO

Decision-making in pituitary disease is critically dependent on high quality imaging of the sella and parasellar region. Magnetic resonance imaging (MRI) is the investigation of choice and, for the majority of patients, combined T1 and T2 weighted sequences provide the information required to allow surgery, radiotherapy (RT) and/or medical therapy to be planned and long-term outcomes to be monitored. However, in some cases standard clinical MR sequences are indeterminate and additional information is needed to help inform the choice of therapy for a pituitary adenoma (PA). This article reviews current recommendations for imaging of PA, examines the potential added value that alternative MR sequences and/or CT can offer, and considers how the use of functional/molecular imaging might allow definitive treatment to be recommended for a subset of patients who would otherwise be deemed unsuitable for (further) surgery and/or RT.


Assuntos
Adenoma/diagnóstico , Diagnóstico por Imagem/tendências , Neoplasias Hipofisárias/diagnóstico , Adenoma/patologia , Adenoma/terapia , Diagnóstico Diferencial , Diagnóstico por Imagem/métodos , Humanos , Imagem por Ressonância Magnética/métodos , Neuroimagem/métodos , Neuroimagem/tendências , Doenças da Hipófise/diagnóstico , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/terapia
8.
Clin Endocrinol (Oxf) ; 90(5): 670-679, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30721535

RESUMO

OBJECTIVE: To describe clinical practice experience of 11 C-Metomidate PET/CT as an adjunct to adrenal vein sampling (AVS) in the lateralization of aldosterone-producing adenomas (APA) in primary aldosteronism (PA). CONTEXT: Accurate lateralization of APA in the setting of PA offers the potential for surgical cure and improved long-term cardiovascular outcomes. Challenges associated with AVS, the current gold standard lateralization modality, mean that only a small proportion of potentially eligible patients currently make it through to surgery. This has prompted consideration of alternative strategies for lateralization, including the application of novel molecular PET tracers such as 11 C-Metomidate. DESIGN: Clinical Service Evaluation/Retrospective audit. PATIENTS: Fifteen individuals with a confirmed diagnosis of PA, undergoing lateralization with 11 C-Metomidate PET/CT prior to final clinical decision on surgical vs medical management. MEASUREMENTS: All patients underwent screening aldosterone renin ratio (ARR), followed by confirmatory testing with the seated saline infusion test, according to Endocrine Society Clinical Practice Guidelines. Adrenal glands were imaged using dedicated adrenal CT. 11 C-Metomidate PET/CT was undertaken due to equivocal or failed AVS. Management outcomes were assessed by longitudinal measurement of blood pressure, ARR, number of hypertensive medications following adrenalectomy or institution of medical therapy. RESULTS: We describe the individual lateralization and clinical outcomes for 15 patients with PA. CONCLUSION: 11 C-Metomidate PET/CT in conjunction with adrenal CT and AVS provided useful information which aided clinical decision-making for PA within a multidisciplinary hypertension clinic.

9.
Clin Endocrinol (Oxf) ; 89(6): 813-823, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30086211

RESUMO

OBJECTIVE: Loss-of-function mutations in IGSF1 result in X-linked central congenital hypothyroidism (CeCH), occurring in isolation or associated with additional pituitary hormone deficits. Intrafamilial penetrance is highly variable and a minority of heterozygous females are also affected. We identified and characterized a novel IGSF1 mutation and investigated its associated phenotypes in a large Irish kindred. DESIGN, PATIENTS AND MEASUREMENTS: A novel hemizygous IGSF1 mutation was identified by direct sequencing in two brothers with CeCH, and its functional consequences were characterized in vitro. Genotype-phenotype correlations were investigated in the wider kindred. RESULTS: The mutant IGSF1 protein (c.2318T > C, p.L773P) exhibited decreased plasma membrane expression in vitro due to impaired trafficking from the endoplasmic reticulum. Ten hemizygous males and 11 heterozygous females exhibited characteristic endocrine deficits. Ireland operates a TSH-based CH screening programme, which does not detect CeCH; therefore, genetic ascertainment preceded biochemical diagnosis of moderate CH in five of seven boys as well as their 75-year-old grandfather. Clinical features potentially attributable to hypothyroidism were variable; normal free T3 (FT3) and low/low normal reverse T3 (rT3) concentrations suggested that preferential deiodination of FT4 to FT3 may help maintain tissue euthyroidism in some individuals. However, neonatal jaundice, delayed speech or growth, and obesity were observed in seven subjects in whom diagnosis was delayed. CONCLUSIONS: As observed with other IGSF1 mutations, p.L773P results in variably penetrant IGSF1 deficiency syndrome. Our observations emphasize the need for multi-generation genetic ascertainment in affected families, especially where TSH-based CH screening programmes may fail to detect CeCH at birth.


Assuntos
Hipotireoidismo Congênito/genética , Imunoglobulinas/genética , Proteínas de Membrana/genética , Mutação/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Hipotireoidismo Congênito/diagnóstico , Feminino , Humanos , Lactente , Irlanda , Masculino , Pessoa de Meia-Idade , Tiroxina/sangue , Tri-Iodotironina/sangue , Adulto Jovem
10.
Artigo em Inglês | MEDLINE | ID: mdl-29472987

RESUMO

Activating mutations in AVPR2 are associated with nephrogenic syndrome of inappropriate antidiuresis (NSIAD). NSIAD causes hyponatremia, decreased serum osmolality and clinical symptoms, which may present from birth or in infancy and include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life are often less specific and include malaise, dizziness, confusion, tiredness and headache. NSIAD is a rare X-linked condition, which is associated with a variable phenotype in males, of whom some present in infancy but others do not become symptomatic until adulthood, or occasionally, never. Female carriers may present with episodes of hyponatremia, usually found incidentally. Literature in this field is limited; namely, two clinical reports describing a female proband, both diagnosed in infancy. We describe, for the first time, the case of an adult female proband with NSIAD, who had longstanding associated symptoms of tiredness, headache, temporary memory loss and mood changes as well as hyponatremia and decreased serum osmolality. A water load test demonstrated an inability to dilute urine and gene sequencing confirmed a recurrent activating mutation in AVPR2. The variant was inherited from the proband's mother who had had longstanding episodes of transient asymptomatic hyponatremia. This is the third report of a female proband with NSIAD and is the first female reported who sought medical treatment for chronic symptoms from adulthood. This case acts as a reminder of the importance of considering NSIAD as a diagnosis in females of all ages with unexplained hyponatremia. Learning points: Activating mutations in the AVPR2 gene are associated with the rare X-linked condition nephrogenic syndrome of inappropriate antidiuresis.NSIAD is associated with hyponatremia, decreased serum osmolality and inappropriately increased urinary osmolality. Early clinical symptoms in infancy include hypotonia, irritability, vomiting and/or seizures. Symptoms in later life include malaise, dizziness, confusion, tiredness and headache.NSIAD should be considered in female, as well as male, patients who present with unexplained hyponatremia and decreased serum osmolality. Family history may reveal relevant symptoms or biochemical features in other family members. However, family history may not always be informative due to the variable nature of the condition or if the proband has a de novo pathogenic variant.A water load test with measurement of AVP may be informative in distinguishing NSIAD from SIADH. Measurement of co-peptin levels may be considered, in substitution for direct measurement of AVP.Patients with NSIAD should be counseled about appropriate daily fluid volume intake. Potential episodes of fluid overload should be avoided.

11.
Endocrinol Diabetes Metab ; 1(1): e00001, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30815538
12.
Clin Case Rep ; 5(11): 1768-1771, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29152267

RESUMO

A 60-year-old man with a pre-existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult.

13.
CERN Ideasq J Exp Innov ; 1(1): 3-12, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29177202

RESUMO

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

14.
J Neurol Neurosurg Psychiatry ; 88(11): 971-981, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28860331

RESUMO

Pituitary dysfunction is a recognised, but potentially underdiagnosed complication of traumatic brain injury (TBI). Post-traumatic hypopituitarism (PTHP) can have major consequences for patients physically, psychologically, emotionally and socially, leading to reduced quality of life, depression and poor rehabilitation outcome. However, studies on the incidence of PTHP have yielded highly variable findings. The risk factors and pathophysiology of this condition are also not yet fully understood. There is currently no national consensus for the screening and detection of PTHP in patients with TBI, with practice likely varying significantly between centres. In view of this, a guidance development group consisting of expert clinicians involved in the care of patients with TBI, including neurosurgeons, neurologists, neurointensivists and endocrinologists, was convened to formulate national guidance with the aim of facilitating consistency and uniformity in the care of patients with TBI, and ensuring timely detection or exclusion of PTHP where appropriate. This article summarises the current literature on PTHP, and sets out guidance for the screening and management of pituitary dysfunction in adult patients with TBI. It is hoped that future research will lead to more definitive recommendations in the form of guidelines.


Assuntos
Lesões Encefálicas Traumáticas/diagnóstico , Lesões Encefálicas Traumáticas/terapia , Hipopituitarismo/diagnóstico , Hipopituitarismo/terapia , Programas de Rastreamento , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/fisiopatologia , Insuficiência Adrenal/terapia , Adulto , Lesões Encefálicas Traumáticas/fisiopatologia , Diagnóstico Precoce , Intervenção Médica Precoce , Feminino , Seguimentos , Humanos , Hipopituitarismo/fisiopatologia , Síndrome de Secreção Inadequada de HAD/diagnóstico , Síndrome de Secreção Inadequada de HAD/fisiopatologia , Síndrome de Secreção Inadequada de HAD/terapia , Masculino , Admissão do Paciente , Testes de Função Hipofisária , Adeno-Hipófise/fisiopatologia , Reino Unido
15.
Hypertension ; 70(2): 357-364, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28584012

RESUMO

Heterogeneity among aldosterone-producing adenomas (APAs) has been highlighted by the discovery of somatic mutations. KCNJ5 mutations predominate in large zona fasciculata (ZF)-like APAs; mutations in CACNA1D, ATP1A1, ATP2B3, and CTNNB1 are more likely to be found in small zona glomerulosa (ZG)-like APAs. Microarray comparison of KCNJ5 mutant versus wild-type APAs revealed significant differences in transcriptomes. NEFM, encoding a neurofilament subunit which is a D1R (dopamine D1 receptor)-interacting protein, was 4-fold upregulated in ZG-like versus ZF-like APAs and 14-fold more highly expressed in normal ZG versus ZF. Immunohistochemistry confirmed selective expression of NEFM (neurofilament medium) polypeptide in ZG and in ZG-like APAs. Silencing NEFM in adrenocortical H295R cells increased basal aldosterone secretion and cell proliferation; silencing also amplified aldosterone stimulation by the D1R agonist, fenoldopam, and inhibition by the D1R antagonist, SCH23390. NEFM coimmunoprecipitated with D1R, and its expression was stimulated by fenoldopam. Immunohistochemistry for D1R was mainly intracellular in ZG-like APAs but membranous in ZF-like APAs. Aldosterone secretion in response to fenoldopam in primary cells from ZF-like APAs was higher than in cells from ZG-like APAs. Transfection of mutant KCNJ5 caused a large reduction in NEFM expression in H295R cells. We conclude that NEFM is a negative regulator of aldosterone production and cell proliferation, in part by facilitating D1R internalization from the plasma membrane. Downregulation of NEFM in ZF-like APAs may contribute to a D1R/D2R imbalance underlying variable pharmacological responses to dopaminergic drugs among patients with APAs. Finally, taken together, our data point to the possibility that ZF-like APAs are in fact ZG in origin.


Assuntos
Adenoma , Neoplasias das Glândulas Suprarrenais , Aldosterona/biossíntese , Hipertensão/metabolismo , Proteínas de Neurofilamentos , Receptores de Dopamina D1 , Zona Fasciculada/fisiologia , Zona Glomerulosa/fisiologia , Adenoma/complicações , Adenoma/genética , Adenoma/patologia , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Regulação da Expressão Gênica , Humanos , Hiperaldosteronismo/etiologia , Hiperaldosteronismo/metabolismo , Proteínas de Neurofilamentos/genética , Proteínas de Neurofilamentos/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo
17.
Hypertension ; 69(6): 1207-1216, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28416583

RESUMO

Primary aldosteronism is a common cause of hypertension, which becomes refractory if undiagnosed, but potentially curable when caused by an aldosterone-producing adenoma (APA). The discovery of somatic mutations and differences in clinical presentations led to recognition of small but common zona glomerulosa (ZG)-like adenomas, distinct from classical large zona fasciculata-like adenomas. The inverse correlation between APA size and aldosterone synthase expression prompted us to undertake a systematic study of genotype-phenotype relationships. After a microarray comparing tumor subtypes, in which NPNT (nephronectin) was the most highly (>12-fold) upregulated gene in ZG-like APAs, we aimed to determine its role in physiological and pathological aldosterone production. NPNT was identified by immunohistochemistry as a secreted matrix protein expressed exclusively around aldosterone-producing glomeruli in normal adrenal ZG and in aldosterone-dense ZG-like APAs; the highest expression was in ZG-like APAs with gain-of-function CTNNB1 mutations, whose removal cured hypertension in our patients. NPNT was absent from normal zona fasciculata, zona fasciculata-like APAs, and ZG adjacent to an APA. NPNT production was regulated by canonical Wnt pathway, and NPNT overexpression or silencing increased or reduced aldosterone, respectively. NPNT was proadhesive in primary adrenal and APA cells but antiadhesive and antiapoptotic in immortalized adrenocortical cells. The discovery of NPNT in the adrenal helped recognition of a common subtype of APAs and a pathway by which Wnt regulates aldosterone production. We propose that this arises through NPNT's binding to cell-surface integrins, stimulating cell-cell contact within glomeruli, which define ZG. Therefore, NPNT or its cognate integrin could present a novel therapeutic target.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica , Hiperaldosteronismo/genética , Glomérulos Renais/metabolismo , Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Neoplasias do Córtex Suprarrenal/cirurgia , Aldosterona/sangue , Citocromo P-450 CYP11B2/metabolismo , Humanos , Hiperaldosteronismo/patologia , Hiperaldosteronismo/cirurgia , Hipertensão/genética , Hipertensão/fisiopatologia , Imuno-Histoquímica , Análise em Microsséries , Reação em Cadeia da Polimerase em Tempo Real/métodos , Papel (figurativo) , Células Tumorais Cultivadas , Regulação para Cima , Via de Sinalização Wnt/genética , Zona Glomerulosa/metabolismo
18.
Med Educ ; 51(6): 612-620, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28295495

RESUMO

OBJECTIVES: Given the absence of a common passing standard for students at UK medical schools, this paper compares independently set standards for common 'one from five' single-best-answer (multiple-choice) items used in graduation-level applied knowledge examinations and explores potential reasons for any differences. METHODS: A repeated cross-sectional study was conducted. Participating schools were sent a common set of graduation-level items (55 in 2013-2014; 60 in 2014-2015). Items were selected against a blueprint and subjected to a quality review process. Each school employed its own standard-setting process for the common items. The primary outcome was the passing standard for the common items by each medical school set using the Angoff or Ebel methods. RESULTS: Of 31 invited medical schools, 22 participated in 2013-2014 (71%) and 30 (97%) in 2014-2015. Schools used a mean of 49 and 53 common items in 2013-2014 and 2014-2015, respectively, representing around one-third of the items in the examinations in which they were embedded. Data from 19 (61%) and 26 (84%) schools, respectively, met the inclusion criteria for comparison of standards. There were statistically significant differences in the passing standards set by schools in both years (effect sizes (f2 ): 0.041 in 2013-2014 and 0.218 in 2014-2015; both p < 0.001). The interquartile range of standards was 5.7 percentage points in 2013-2014 and 6.5 percentage points in 2014-2015. There was a positive correlation between the relative standards set by schools in the 2 years (Pearson's r = 0.57, n = 18, p = 0.014). Time allowed per item, method of standard setting and timing of examination in the curriculum did not have a statistically significant impact on standards. CONCLUSIONS: Independently set standards for common single-best-answer items used in graduation-level examinations vary across UK medical schools. Further work to examine standard-setting processes in more detail is needed to help explain this variability and develop methods to reduce it.


Assuntos
Competência Clínica/normas , Educação de Graduação em Medicina/normas , Avaliação Educacional/métodos , Faculdades de Medicina , Estudantes de Medicina/estatística & dados numéricos , Estudos Transversais , Currículo , Humanos , Competência Profissional , Padrões de Referência , Reino Unido
19.
Horm Behav ; 92: 13-19, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28174099

RESUMO

A contribution to a special issue on Hormones and Human Competition. Financial markets are periodically destabilized by bubbles and crashes during which investors display respectively what has been called "irrational exuberance" and "irrational pessimism". How can we best study these pathologies in competitive and risk-taking behaviours? In this article, we argue that a science of risk-taking and of the financial markets needs to draw heavily on physiology and especially endocrinology, due to their central roles in moderating human behaviour. Importantly, this science of competition and risk requires the same spectrum of research protocols as is found in mature biological and medical sciences, a spectrum running from field work conducted within financial institutions themselves to more controlled laboratory studies, which permit cause to be distinguished from effect. Such a spectrum of studies is especially important for translational behavioural science.


Assuntos
Investimentos em Saúde , Assunção de Riscos , Estresse Psicológico/psicologia , Humanos
20.
BJR Case Rep ; 3(2): 20160098, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30363212

RESUMO

A 54-year-old male presented with visual loss owing to a giant, infiltrative pituitary adenoma. Following decompressive trans-sphenoidal surgery, the patient was referred for adjuvant radiotherapy. We describe the potential utility of 11carbon methionine positron emission tomography imaging in confirming the true extent of tumour infiltration, which included the cavernous sinuses and the bones of the skull base. The co-registration of positron emission tomography imaging to planning MR and CT imaging provided assurance of complete radiotherapy coverage of the target volume and assisted with the minimisation of collateral radiation dose to adjacent organs at risk.

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