RESUMEN
BACKGROUND: Automated Item Generation (AIG) uses computer software to create multiple items from a single question model. There is currently a lack of data looking at whether item variants to a single question result in differences in student performance or human-derived standard setting. The purpose of this study was to use 50 Multiple Choice Questions (MCQs) as models to create four distinct tests which would be standard set and given to final year UK medical students, and then to compare the performance and standard setting data for each. METHODS: Pre-existing questions from the UK Medical Schools Council (MSC) Assessment Alliance item bank, created using traditional item writing techniques, were used to generate four 'isomorphic' 50-item MCQ tests using AIG software. Isomorphic questions use the same question template with minor alterations to test the same learning outcome. All UK medical schools were invited to deliver one of the four papers as an online formative assessment for their final year students. Each test was standard set using a modified Angoff method. Thematic analysis was conducted for item variants with high and low levels of variance in facility (for student performance) and average scores (for standard setting). RESULTS: Two thousand two hundred eighteen students from 12 UK medical schools participated, with each school using one of the four papers. The average facility of the four papers ranged from 0.55-0.61, and the cut score ranged from 0.58-0.61. Twenty item models had a facility difference > 0.15 and 10 item models had a difference in standard setting of > 0.1. Variation in parameters that could alter clinical reasoning strategies had the greatest impact on item facility. CONCLUSIONS: Item facility varied to a greater extent than the standard set. This difference may relate to variants causing greater disruption of clinical reasoning strategies in novice learners compared to experts, but is confounded by the possibility that the performance differences may be explained at school level and therefore warrants further study.
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Razonamiento Clínico , Estudiantes de Medicina , Humanos , Aprendizaje , Facultades de Medicina , Programas InformáticosRESUMEN
Management of Cushing's disease is informed by dedicated imaging of the sella and parasellar regions. Although magnetic resonance imaging (MRI) remains the investigation of choice, a significant proportion (30-50%) of corticotroph tumours are so small as to render MRI indeterminate or negative when using standard clinical sequences. In this context, alternative MR protocols [e.g. 3D gradient (recalled) echo, with acquisition of volumetric data] may allow detection of tumors that have not been previously visualized. The use of hybrid molecular imaging (e.g. 11C-methionine positron emission tomography coregistered with volumetric MRI) has also been proposed as an additional modality for localizing microadenomas.
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Adenoma , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT) , Neoplasias Hipofisarias , Humanos , Hipersecreción de la Hormona Adrenocorticotrópica Pituitaria (HACT)/diagnóstico por imagen , Neoplasias Hipofisarias/diagnóstico , Adenoma/diagnóstico , Imagen por Resonancia Magnética/métodos , MetioninaRESUMEN
PURPOSE: To assess the potential for 11C-methionine PET (Met-PET) coregistered with volumetric magnetic resonance imaging (Met-PET/MRCR) to inform clinical decision making in patients with poorly visualized or occult microprolactinomas and dopamine agonist intolerance or resistance. PATIENTS AND METHODS: Thirteen patients with pituitary microprolactinomas, and who were intolerant (n = 11) or resistant (n = 2) to dopamine agonist therapy, were referred to our specialist pituitary centre for Met-PET/MRCR between 2016 and 2020. All patients had persistent hyperprolactinemia and were being considered for surgical intervention, but standard clinical MRI had shown either no visible adenoma or equivocal appearances. RESULTS: In all 13 patients Met-PET/MRCR demonstrated a single focus of avid tracer uptake. This was localized either to the right or left side of the sella in 12 subjects. In one patient, who had previously undergone surgery for a left-sided adenoma, recurrent tumor was unexpectedly identified in the left cavernous sinus. Five patients underwent endoscopic transsphenoidal selective adenomectomy, with subsequent complete remission of hyperprolactinaemia and normalization of other pituitary function; three patients are awaiting surgery. In the patient with inoperable cavernous sinus disease PET-guided stereotactic radiosurgery (SRS) was performed with subsequent near-normalization of serum prolactin. Two patients elected for a further trial of medical therapy, while two declined surgery or radiotherapy and chose to remain off medical treatment. CONCLUSIONS: In patients with dopamine agonist intolerance or resistance, and indeterminate pituitary MRI, molecular (functional) imaging with Met-PET/MRCR can allow precise localization of a microprolactinoma to facilitate selective surgical adenomectomy or SRS.
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Adenoma , Hiperprolactinemia , Neoplasias Hipofisarias , Prolactinoma , Adenoma/diagnóstico por imagen , Adenoma/tratamiento farmacológico , Agonistas de Dopamina/uso terapéutico , Humanos , Hiperprolactinemia/tratamiento farmacológico , Metionina/uso terapéutico , Neoplasias Hipofisarias/diagnóstico por imagen , Neoplasias Hipofisarias/tratamiento farmacológico , Neoplasias Hipofisarias/patología , Tomografía de Emisión de Positrones/métodos , Prolactinoma/diagnóstico por imagen , Prolactinoma/tratamiento farmacológico , Prolactinoma/patologíaRESUMEN
BACKGROUND: We have previously shown that clinical examiners' scoring is not negatively impacted when a candidate has a tattoo, unnatural hair colour, or a regional accent. We investigated whether these physical attributes in exam candidates impact patient scoring. METHODS: Simulated/real patients were randomly assigned to watch five videos of simulated candidate performances of a cranial nerve examination: clear fail, borderline, good, 'clear pass' without an attribute, and 'clear pass' with one of the attributes (tattoo, purple hair, accent). Participants scored domains of communication and professionalism. We compared scores for the clear pass candidates with and without attributes. RESULTS: One hundred and eighty three patients participated. The total scores for the candidates with tattoos and purple hair were higher than the candidate with no physical attribute (p < 0.001). For the candidate with a Liverpool English accent no difference was identified (p = 0.120). CONCLUSIONS: The presence of certain physical attributes (tattoos or purple hair) was associated with higher scores given by patients to candidates in a simulated physical examination station.
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Competencia Clínica , Evaluación Educacional , Humanos , Comunicación , Examen FísicoRESUMEN
Secondary adrenal insufficiency (AI) occurs as the result of any process that disrupts normal hypothalamic and/or anterior pituitary function and causes a decrease in the secretion of steroid hormones from the adrenal cortex. The most common cause of secondary AI is exogenous corticosteroid therapy administered at supraphysiologic dosages for ≥ 1 month. AI caused by oral corticosteroids (OCS) is not well-recognized or commonly diagnosed but is often associated with reduced well-being and can be life-threatening in the event of an adrenal crisis. Corticosteroid use is common in respiratory diseases, and asthma is a representative condition that illustrates the potential challenges and opportunities related to corticosteroid-sparing therapies. For individuals with severe asthma (approximately 5%-10% of all cases), reduction or elimination of maintenance OCS without loss of control can now be accomplished with biologic therapies targeting inflammatory mediators. However, the optimal strategy to ensure early identification and treatment of AI and safe OCS withdrawal in routine clinical practice remains to be defined. Many studies with biologics have involved short evaluation periods and small sample sizes; in addition, cautious approaches to OCS tapering in studies with a placebo arm, coupled with inconsistent monitoring for AI, have contributed to the lack of clarity. If the goal is to greatly reduce and, where possible, eliminate long-term OCS use in severe asthma through the increasing adoption of biologic treatments, there is an urgent need for clinical trials that address both the speed of OCS withdrawal and how to monitor for AI.
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Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Insuficiencia Suprarrenal/inducido químicamente , Antiasmáticos/administración & dosificación , Antiasmáticos/efectos adversos , Asma/tratamiento farmacológico , Esquema de Medicación , HumanosRESUMEN
BACKGROUND: Assessments of physician competence in the work-place are common and often contribute to high-stakes assessments. Previous research suggests that assessors' judgements can be influenced by candidates' physical attributes. We investigated whether simulated candidates' scores were influenced by assessor bias based on tattoos, hair colour, and a regional accent. METHODS: We used an experimental, video-based, single-blinded, randomised, internet-based design. We created videos of simulated medical intern performances of a clinical examination at four different standards of competence. Four videos were also created of simulated candidates performing at a 'clear pass' standard, with either no stereotypical attribute (CPX), purple hair (CPH), tattoos (CPT) or a Liverpool English accent (CPA). Assessors were randomly assigned to watch five videos including the "clear pass" candidate without an attribute and one of the "clear pass" candidates with an attribute and asked to give an overall global grade for each candidate. We compared the global grades for the clear pass candidates with and without attributes. RESULTS: Ninety-eight assessors were included in the analysis. The total scores for the candidates with stereotyped attributes were not significantly lower than the candidate with no attribute. Assessors showed moderate levels of agreement between the global grades awarded for all the candidates. The global grades awarded to candidate with a stereotypical attribute were not significantly lower than for those without. CONCLUSIONS: The presence of tattoos, purple hair, or a regional accent did not systematically negatively influence the grade or score awarded by assessors to candidates in observed clinical examination scenarios.
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Evaluación Educacional , Médicos , Competencia Clínica , Humanos , Juicio , Examen FísicoRESUMEN
Phaeochromocytomas and paragangliomas (PPGLs) are catecholamine secreting neuroendocrine tumours that predispose to haemodynamic instability. Currently, surgery is the only available curative treatment, but carries potential risks including hypertensive and hypotensive crises, cardiac arrhythmias, myocardial infarction and stroke, due to tumoral release of catecholamines during anaesthetic induction and tumour manipulation. The mortality associated with surgical resection of PPGL has significantly improved from 20-45% in the early 20th century (Apgar & Papper, AMA Archives of Surgery, 1951, 62, 634) to 0-2·9% in the early 21st century (Kinney et al. Journal of Cardiothoracic and Vascular Anesthesia, 2002, 16, 359), largely due to availability of effective pharmacological agents and advances in surgical and anaesthetic practice. However, surgical resection of PPGL still poses significant clinical management challenges. Preoperatively, alpha-adrenoceptor blockade is the mainstay of management, although various pharmacological strategies have been proposed, based largely on reports derived from retrospective data sets. To date, no consensus has been reached regarding the 'ideal' preoperative strategy due, in part, to a paucity of data from high-quality evidence-based studies comparing different treatment regimens. Here, based on the available literature, we address the Clinical Question: Is there an optimal preoperative management strategy for PPGL?
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Paraganglioma/terapia , Feocromocitoma/terapia , Cuidados Preoperatorios/métodos , Antagonistas Adrenérgicos alfa/uso terapéutico , Humanos , Paraganglioma/complicaciones , Paraganglioma/cirugía , Feocromocitoma/complicaciones , Feocromocitoma/cirugía , Complicaciones Posoperatorias , Cuidados Preoperatorios/normasRESUMEN
Pituitary carcinoma occurs in ~0.2% of resected pituitary tumours and carries a poor prognosis (mean survival <4 years), with standard chemotherapy regimens showing limited efficacy. Recent evidence suggests that temozolomide (TMZ), an orally-active alkylating agent used principally in the management of glioblastoma, may also be effective in controlling aggressive/invasive pituitary adenomas/carcinomas. A low level of expression of the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) predicts TMZ responsiveness in glioblastomas, and a similar correlation has been observed in the majority of aggressive pituitary adenomas/carcinomas reported to date. Here, we report a case of a silent pituitary corticotroph adenoma, which subsequently re-presented with Cushing's syndrome due to functioning hepatic metastases. The tumour exhibited low immunohistochemical MGMT expression in both primary (pituitary) and secondary (hepatic) lesions. Initial TMZ therapy (200 mg/m² for 5 days every 28 days-seven cycles) resulted in marked clinical, biochemical [>50% fall in adrenocorticotrophic hormone (ACTH)] and radiological [partial RECIST (response evaluation criteria in solid tumors) response] improvements. The patient then underwent bilateral adrenalectomy. However, despite reintroduction of TMZ therapy (further eight cycles) ACTH levels plateaued and no further radiological regression was observed. We review the existing literature reporting TMZ efficacy in pituitary corticotroph tumours, and highlight the pointers/lessons for treating aggressive pituitary neoplasia that can be drawn from experience of susceptibility and evolving resistance to TMZ therapy in glioblastoma. Possible strategies for mitigating resistance developing during TMZ treatment of pituitary adenomas/carcinomas are also considered.
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Dacarbazina/análogos & derivados , Neoplasias Hipofisarias/tratamiento farmacológico , Adenoma Hipofisario Secretor de ACTH/tratamiento farmacológico , Adenoma Hipofisario Secretor de ACTH/patología , Adenoma/tratamiento farmacológico , Anciano , Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Resistencia a Antineoplásicos , Glioblastoma/tratamiento farmacológico , Humanos , Neoplasias Hepáticas/secundario , Masculino , O(6)-Metilguanina-ADN Metiltransferasa/metabolismo , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , TemozolomidaRESUMEN
CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure. CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/metabolismo , Neoplasias Colorrectales/metabolismo , Hidrocortisona/metabolismo , Síndromes Neoplásicos Hereditarios/metabolismo , Neoplasias de la Corteza Suprarrenal/metabolismo , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/metabolismo , Carcinoma Corticosuprarrenal/patología , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Persona de Mediana Edad , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismoAsunto(s)
Alcaptonuria , Ácido Homogentísico , Adulto , Alcaptonuria/complicaciones , Alcaptonuria/diagnóstico , Ácido Homogentísico/orina , Humanos , Masculino , OrinaRESUMEN
AIMS: Hypothalamic-pituitary axis (HPA) dysfunction is a sequela of cranial radiotherapy. The purpose of this study was to use endocrine data from existing publications to characterise the baseline endocrine status, the effects of radiotherapy on the HPA during the first follow-up year and the time dependence of radiation-induced HPA dysfunction in patients treated with radiotherapy for non-pituitary intracranial neoplasms. MATERIALS AND METHODS: A systematic search of databases was carried out for articles that reported the results of endocrine testing for patients aged 16 years and older who were treated with neurosurgery for non-pituitary intracranial neoplasms or radiotherapy for nasopharyngeal neoplasms. To analyse the radiotherapy-related changes in hormone levels over time, long-term prospective endocrine data from nasopharyngeal studies were normalised to baseline hormone data and fitted to an exponential decay model. This process was repeated with normalisation to year 1 hormone data. RESULTS: Eight unique articles met eligibility criteria. HPA dysfunction occurred in 21.6-64.7% of patients who were assessed for endocrinopathies following neurosurgery. Studies on the early effects of radiotherapy on nasopharyngeal patients showed statistically significant changes in growth hormone, luteinizing hormone and follicle stimulating hormone levels during the first year of follow-up. Time dependence modelling showed that normalisation to year 1 hormone levels yield exponential equations with stronger measures of goodness of fit. CONCLUSION: HPA dysfunction in patients treated for non-pituitary intracranial neoplasms is probably a result of both neurosurgery and radiotherapy treatments. Although statistically significant endocrine changes can occur during this first year of follow-up, those documented at year 1 may be more predictive of subsequent HPA dysfunction.
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Neoplasias Encefálicas/radioterapia , Irradiación Craneana/efectos adversos , Enfermedades Hipotalámicas/etiología , Sistema Hipotálamo-Hipofisario/efectos de la radiación , Sistema Hipófiso-Suprarrenal/efectos de la radiación , Adulto , Femenino , Humanos , Enfermedades Hipotalámicas/epidemiología , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
CONTEXT: Adiponectin has been suggested to play a role in the etiopathogenesis of at least some forms of insulin resistance, in part based on a strong correlation between plasma levels of adiponectin and measures of insulin sensitivity. OBJECTIVE: The objective of the study was to establish whether this relationship is maintained at extreme levels of insulin resistance. DESIGN/SETTING: This was a cross-sectional study in a university teaching hospital of subjects recruited from the United Kingdom and the United States. PARTICIPANTS: Participants included 75 subjects with a range of syndromes of severe insulin resistance and 872 nondiabetic controls. OUTCOME MEASURES: Fasting plasma insulin, adiponectin, and leptin were measured. RESULTS: Unexpectedly, subjects with mutations in the insulin receptor, despite having the most severe degree of insulin resistance, had elevated plasma adiponectin [median 24.4 mg/liter; range 6.6-36.6 (normal adult range for body mass index 20 kg/m(2) = 3-19 mg/liter)], whereas all other subjects had low adiponectin levels (median 2.0 mg/liter; range 0.12-11.2). Plasma leptin in all but one subject with an insulin receptoropathy was low or undetectable [median 0.5 ng/ml; range 0-16: normal adult range for body mass index of < 25 kg/m(2) = 2.4-24.4 (female) and 0.4-8.3 ng/ml (male)]. CONCLUSIONS: We conclude that the relationship between plasma adiponectin and insulin sensitivity is complex and dependent on the precise etiology of defective insulin action and that the combination of high plasma adiponectin with low leptin may have clinical utility in patients with severe insulin resistance as a marker of the presence of a genetic defect in the insulin receptor.
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Adiponectina/sangre , Resistencia a la Insulina/genética , Mutación , Receptor de Insulina/genética , Adolescente , Adulto , Índice de Masa Corporal , Niño , Preescolar , Ayuno , Femenino , Humanos , Lactante , Recién Nacido , Insulina/sangre , Leptina/sangre , Masculino , SíndromeRESUMEN
CONTEXT: Isolated central congenital hypothyroidism (CCH) is rare and evades diagnosis on TSH-based congenital hypothyroidism (CH) screening programs in the United Kingdom. Accordingly, genetic ascertainment facilitates diagnosis and treatment of familial cases. Recognized causes include TSH ß subunit (TSHB) and Ig superfamily member 1 (IGSF1) mutations, with only two previous reports of biallelic, highly disruptive mutations in the TRH receptor (TRHR) gene. CASE DESCRIPTION: A female infant presenting with prolonged neonatal jaundice was found to have isolated CCH, with TSH of 2.2 mU/L (Reference range, 0.4-3.5) and free T4 of 7.9 pmol/L (0.61 ng/dL) (Reference range, 10.7-21.8 pmol/L). Because TSHB or IGSF1 mutations are usually associated with profound or X-linked CCH, TRHR was sequenced, and a homozygous mutation (p.P81R) was identified, substituting arginine for a highly conserved proline residue in transmembrane helix 2. Functional studies demonstrated normal cell membrane expression and localization of the mutant TRHR; however, its ability to bind radio-labelled TRH and signal via Gqα was markedly impaired, likely due to structural distortion of transmembrane helix 2. CONCLUSIONS: Two previously reported biallelic, highly disruptive (nonsense; R17*, in-frame deletion and single amino acid substitution; p.[S115-T117del; A118T]) TRHR mutations have been associated with CCH; however, we describe the first deleterious, missense TRHR defect associated with this phenotype. Importantly, the location of the mutated amino acid (proline 81) highlights the functional importance of the second transmembrane helix in mediating hormone binding and receptor activation. Future identification of other naturally occurring TRHR mutations will likely offer important insights into the molecular basis of ligand binding and activation of TRHR, which are still poorly understood.
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Hipotiroidismo Congénito/genética , Mutación Missense , Receptores de Hormona Liberadora de Tirotropina/genética , Femenino , Células HEK293 , Humanos , Recién NacidoRESUMEN
Several missense mutations in the ligand-binding domain of human peroxisome proliferator-activated receptor (PPAR)gamma have been described in subjects with dominantly inherited severe insulin resistance associated with partial lipodystrophy, hypertension, and dyslipidemia. These mutant receptors behave as dominant-negative inhibitors of PPARgamma signaling when studied in transfected cells. The extent to which such dominant-negative effects extend to signaling through other coexpressed PPAR isoforms has not been evaluated. To examine these issues further, we have created a PPARalpha mutant harboring twin substitutions, Leu459Ala and Glu462Ala, within the ligand binding domain (PPARalpha(mut)), examined its signaling properties, and compared the effects of dominant-negative PPARalpha and PPARgamma mutants on basal and ligand-induced gene transcription in adipocytes and hepatocytes. PPARalpha(mut) was transcriptionally inactive, repressed basal activity from a PPAR response element-containing promoter, inhibited the coactivator function of cotransfected PPAR-gamma coactivator 1alpha, and strongly inhibited the transcriptional response to cotransfected wild-type receptor. In contrast to PPARgamma, wild-type PPARalpha failed to recruit the transcriptional corepressors NCoR and SMRT. However, PPARalpha(mut) avidly recruited these corepressors in a ligand-dissociable manner. In hepatocytes and adipocytes, both PPARalpha(mut) and the corresponding PPARgamma mutant were capable of inhibiting the expression of genes primarily regulated by PPARalpha, -gamma, or -delta ligands, albeit with some differences in potency. Thus, dominant-negative forms of PPARalpha and PPARgamma are capable of interfering with PPAR signaling in a manner that is not wholly restricted to their cognate target genes. These findings may have implications for the pathogenesis of human syndromes resulting from mutations in this family of transcription factors.
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PPAR alfa/fisiología , PPAR gamma/fisiología , Proteínas Represoras/fisiología , Secuencia de Aminoácidos , Sitios de Unión , Línea Celular , Proteínas de Unión al ADN/fisiología , Humanos , Datos de Secuencia Molecular , Proteínas Nucleares/fisiología , Co-Represor 1 de Receptor Nuclear , Co-Represor 2 de Receptor Nuclear , Transducción de SeñalRESUMEN
The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone beta receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T3 concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor beta shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.
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Mutación , Receptores de Hormona Tiroidea/genética , Receptores de Hormona Tiroidea/metabolismo , Serina/genética , Síndrome de Resistencia a Hormonas Tiroideas/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Cristalización , ADN/metabolismo , Dimerización , Femenino , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Modelos Moleculares , Estructura Molecular , Receptores de Hormona Tiroidea/química , Transfección , Triyodotironina/metabolismo , Triyodotironina/farmacologíaRESUMEN
We have investigated an Italian family with generalized resistance to thyroid hormone (RTH), consisting of two individuals with elevated serum thyroid hormones (TH) and a non-suppressed TSH, together with unaffected family members, for a mutation in the thyroid hormone receptor beta gene (hTR beta). We have identified a single nucleotide substitution (1321 CTT to GTT) corresponding to a leucine to valine substitution at codon 346 (L346V) in the predicted protein. The index case and her affected child are heterozygous for the receptor defect, with normal sequence in unaffected family members. Furthermore, both parents of the index case were unaffected, suggesting that the mutation had arisen de novo. When expressed in vitro, the L346V mutant receptor showed a marked reduction in its affinity for tri-iodothyronine (T3), impaired ligand-dependent transactivation and potent dominant negative activity. Its functional impairment could not be alleviated, even at supraphysiological concentrations of T3, suggesting that the mutation might interfere with the intrinsic ligand-dependent transactivation function (AF-2) located in the hormone binding domain of hTR beta. Finally, the presence of the L346V mutation in the son of the propositus, who died from complications associated with congenital heart disease, raises the possibility that RTH might have contributed to the pathogenesis or severity of the latter.
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Mutación , Receptores de Hormona Tiroidea/genética , Hormonas Tiroideas/fisiología , Adulto , Alelos , Secuencia de Bases , Niño , Resistencia a Medicamentos/genética , Femenino , Amplificación de Genes , Humanos , Masculino , Linaje , Receptores de Hormona Tiroidea/metabolismo , Receptores de Hormona Tiroidea/fisiología , Triyodotironina/metabolismoRESUMEN
Using a single electrode voltage clamp technique the actions of rapidly superfused thyrotropin-releasing hormone (TRH, 1 microM) on lumbar motoneurones of the isolated neonatal rat spinal cord were investigated. TRH induced a slowly developing inward current (associated with an input conductance fall) with slow recovery on washout. In the presence of TRH the normally linear current-voltage relations displayed strong inward rectification up to about -40 mV. The TRH-induced current peaked at -50 mV, reversed at -120 mV and was not blocked by Cs+, tetraethylammonium, 4-aminopyridine, Cd2+, or low Na+. Its reversal potential was sensitive to changes in extracellular K+. Ba2+ (0.2-1.5 mM) depressed the effects of TRH. It is suggested that in rat motoneurones TRH blocked an apparently novel K+ conductance (IK(T)) active at resting membrane potential.
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Neuronas Motoras/fisiología , Canales de Potasio/fisiología , Médula Espinal/fisiología , Hormona Liberadora de Tirotropina/farmacología , 4-Aminopiridina/farmacología , Animales , Animales Recién Nacidos , Femenino , Técnicas In Vitro , Masculino , Neuronas Motoras/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Ratas , Tetraetilamonio , Compuestos de Tetraetilamonio/farmacologíaRESUMEN
We report pituitary enlargement after radioiodine ablation in a patient with elevated thyroid hormones and features of hyperthyroidism. Serum thyrotropin (TSH) levels were elevated despite normal circulating thyroid hormones, suggesting inappropriate TSH secretion associated either with a TSH secreting pituitary adenoma or resistance to thyroid hormone (RTH). Normal serum glycoprotein alpha-subunit levels and a preserved TSH response to thyrotropin-releasing hormone (TRH) favored RTH and this diagnosis was confirmed by showing the patient to be heterozygous for a missense mutation (R438H) in the thyroid hormone beta receptor (TRbeta) gene. Thyroxine replacement in supraphysiological doses were required to normalize TSH levels and resulted in regression of the pituitary enlargement, suggesting hyperplasia rather than coincident tumor. This case illustrates the need to avoid thyroid ablation in RTH patients and the importance of supraphysiological thyroxine replacement to prevent pituitary hyperplasia.