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1.
Eur J Endocrinol ; 185(4): 577-586, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374651

RESUMO

Objective: Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. Design: Retrospective cohort study. Methods: Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression analyses. Results: The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). Conclusions: The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.


Assuntos
Insulinoma/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Finlândia/epidemiologia , Seguimentos , História do Século XX , História do Século XXI , Humanos , Incidência , Insulinoma/complicações , Insulinoma/diagnóstico , Insulinoma/mortalidade , Pessoa de Meia-Idade , Morbidade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo
2.
Endocrine ; 74(2): 387-395, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34036515

RESUMO

PURPOSE: Ectopic ACTH syndrome (EAS) is rare. We established a national cohort to increase awareness and address unmet needs. METHODS: The Finnish national EAS cohort includes 60 patients diagnosed in 1997-2016. We assessed clinical features, diagnostic work-ups, treatments, incidence, and outcomes of subgroups occult tumor (OT), well-differentiated neuroendocrine tumor G1/G2 (NETG1/G2) and NET G3/neuroendocrine carcinoma (NETG3/NEC). RESULTS: The distribution of OT, NETG1/G2, and NETG3/NEC was 10 (17%), 20 (33%), and 30 (50%), respectively; and median follow-up 22 months (0-249). Annual incidence (0.20-0.93 per million inhabitants) and tumor subgroups (OT vs. NEC) varied across the country. The longest diagnostic delay from EAS onset to radiological tumor identification was 48 months. In NET/NEC, 6/50 (12%) were diagnosed 1-24 years before EAS onset. Osteoporotic fractures (32%) and severe infections (55%) were common. The CRH stimulation test accurately diagnosed EAS in 25/31 (81%). Metyrapone (≤6 g daily, prescribed in 88%) was well tolerated. In NETG1/G2, 13/20 (65%) underwent curative resection of the primary tumor; four experienced recurrence within 2-12 years. In OT, 70% underwent bilateral adrenalectomy. Five-year overall survival in OT, NETG1/G2, and NETG3/NEC was 90%, 55%, and 0%, respectively (P < 0.001). Morning cortisol, hypokalemia, infections, metastatic disease, and acute onset were negative, whereas resection of the primary tumor and bilateral adrenalectomy were positive predictors of survival. CONCLUSIONS: NET/NEC may precede EAS onset by several years. In NETG1/G2, recurrences may occur > 10 years after successful primary surgery. Tumor subgroup (OT, NETG1/G2, NEC) was an independent predictor of survival.

3.
Menopause ; 28(9): 1053-1059, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34010935

RESUMO

OBJECTIVE: We investigated whether more advanced climacteric stage in the mid-40s is associated with thyroid autoimmunity and dysfunction. METHODS: This cross-sectional cohort study included 2,569 46-year-old women. Thyroid hormone, thyroid peroxidase antibodies, and follicle-stimulating hormone levels were determined. Using menstrual history and follicle-stimulating hormone levels, the participants were divided into climacteric (n = 340) and preclimacteric (n = 2,229) groups. Women diagnosed with premature ovarian insufficiency (menopause by 40 y of age) were excluded. The use of thyroid medication was evaluated from the medication reimbursement register. The prevalence of thyroid medication use, laboratory-based thyroid dysfunction, and thyroid peroxidase antibody positivity was compared between the two groups. The association between climacteric status and thyroid disorders was investigated using a logistic regression model including smoking and thyroid antibody status. RESULTS: At 46 years old, climacteric women used thyroid medication more often than preclimacteric women (9.1% vs 6.1%; P = 0.04). There was no difference in the prevalence of subclinical or clinical hypothyroidism and hyperthyroidism in nonmedicated participants (5.5% vs 5.0%; P = 0.7) or thyroid peroxidase antibody positivity (14.0% vs 15.0%, P = 0.7). In the regression model, being climacteric (OR = 1.6; 95% CI 1.1-2.3; P = 0.02) and antibody positivity (OR 4.9; 95% CI 3.6-6.6; P < 0.001) were associated with a higher prevalence of thyroid dysfunction. CONCLUSIONS: More advanced climacteric stage in the mid-40s was slightly associated with thyroid dysfunction but not thyroid autoimmunity.


Assuntos
Hipotireoidismo , Doenças da Glândula Tireoide , Autoimunidade , Estudos Transversais , Feminino , Humanos , Hipotireoidismo/epidemiologia , Pessoa de Meia-Idade , Doenças da Glândula Tireoide/epidemiologia , Tireotropina
4.
Clin Endocrinol (Oxf) ; 94(2): 250-257, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32974918

RESUMO

OBJECTIVE: Insulinomas are rare pancreatic neoplasms, which can usually be cured by surgery. As the diagnostic delay is often long and the prolonged hyperinsulinemia may have long-term effects on health and the quality of life, we studied the long-term health-related quality of life (HRQoL) in insulinoma patients. DESIGN, PATIENTS AND MEASUREMENTS: The HRQoL of adults diagnosed with an insulinoma in Finland in 1980-2010 was studied with the 15D instrument, and the results were compared to those of an age- and gender-matched sample of the general population. The minimum clinically important difference in the total 15D score has been defined as ±0.015. The clinical characteristics, details of insulinoma diagnosis and treatment, and the current health status of the subjects were examined to specify the possible determinants of long-term HRQoL. RESULTS: Thirty-eight insulinoma patients participated in the HRQoL survey (response rate 75%). All had undergone surgery with a curative aim, a median of 13 (min 7, max 34) years before the survey. The insulinoma patients had a clinically importantly and statistically significantly better mean 15D score compared with the controls (0.930 ± 0.072 vs 0.903 ± 0.039, P = .046) and were significantly better off regarding mobility, usual activities and eating. Among the insulinoma patients, younger age at the time of survey, higher level of education and smaller number of chronic diseases were associated with better overall HRQoL. CONCLUSIONS: In the long term, the overall HRQoL of insulinoma patients is slightly better than that of the general population.

5.
Menopause ; 28(1): 70-79, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32960849

RESUMO

OBJECTIVE: To investigate whether the early-onset menopausal transition is associated with deteriorated glucose tolerance in women in their mid-forties. METHODS: A cross-sectional analysis of a cohort study including 2,632 women of the Northern Finland Birth Cohort 1966. The participants were divided into two groups by their menstrual history and follicle-stimulating hormone values at age 46: climacteric and preclimacteric women. Glucose and insulin parameters, as well as mathematical indices derived from them to evaluate insulin sensitivity, were compared between the groups. The results were adjusted for measured body mass index and smoking. The possible effect of hormone therapy was investigated in subanalyses excluding hormone therapy users. RESULTS: Climacteric women (n = 379) were more often current smokers at age 46 (P = 0.008), and their body mass indices increased more from 31 to 46 years (P = 0.013), compared to preclimacteric women (n = 2,253). In a multivariable generalized linear model, being climacteric at age 46 was associated with several findings suggesting decreased insulin sensitivity: increased glycated hemoglobin (P < 0.001), 2-hour oral glucose tolerance test 30- and 60-minute insulin (P = 0.040 and 0.006, respectively), and area under the insulin curve (P = 0.005). Being climacteric also was associated with a decreased the McAuley (P = 0.024) and Belfiore indices (P = 0.027) and glucose tolerance test 60-minute glucose (P = 0.015). In subanalyses excluding hormone therapy users (n = 94), the results did not change significantly. CONCLUSIONS: Earlier onset of climacteric transition is associated with impaired insulin sensitivity in middle-aged women.


Assuntos
Climatério , Resistência à Insulina , Glicemia , Índice de Massa Corporal , Estudos de Coortes , Estudos Transversais , Feminino , Finlândia/epidemiologia , Humanos , Insulina , Menopausa , Pessoa de Meia-Idade
6.
Neuroendocrinology ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-32721955

RESUMO

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA) have low sensitivity and specificity. This is a first pre-planned interim analysis (NORDIC non-interventional, exploratory, EXPLAIN study (NCT02630654)). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy in SI-NETs. METHODS: At time of diagnosis, prior any disease specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age and gender matched controls (n=143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed sensitivity (SEN) and specificity (SPE) of 89% and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90% and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In thirty patients with normal CgA concentrations the model provided diagnostic SPE of 98%, a SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrate that a multi-biomarker/machine learning strategy improve diagnostic accuracy of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

7.
JBMR Plus ; 3(4): e10114, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31044184

RESUMO

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism with rather poor prognosis. Apart from surgery, no evidence-based treatments exist. A 48-year-old woman presented with weight loss, nausea, constipation, hypercalcemic crisis, and a recurrent neck tumor 5 years after primary surgery of a parathyroid tumor that primarily was classified as an adenoma. Histopathological reevaluation of the original tumor revealed the correct diagnosis to be parathyroid carcinoma (PC). The patient underwent surgery of the recurrent tumor, which was locally invasive with metastatic spread to the mediastinum and neck lymph nodes. Computed tomography demonstrated large lytic bone lesions in both iliac bones including, on the right, a soft tissue mass compatible with bone metastasis. The patient was treated with cinacalcet, repeated zoledronic acid infusions, and temozolomide cycles for 1 year. She underwent two additional neck surgeries for PC and sternotomy for resection of mediastinal metastases. Massive osteolytic lesions in both femoral necks caused imminent fracture risk and therefore both femurs were prophylactically stabilized by intramedullary nail. Serum calcium normalized after the third neck surgery, cinacalcet was discontinued, and parathyroid hormone gradually normalized during continued treatments with temozolomide, adjuvant radiotherapy, and zoledronic acid, with no signs of active disease on imaging and normal biochemistry. The patient remains in remission 17 years after successful combined treatments for recurrent, metastasized PC. The parathyroid tumor tissue demonstrated high O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, a known predictor of positive temozolomide treatment response in other tumors. In addition, synergistic effects of multiple treatments may have accounted for the favorable response. © 2018 The Authors. JBMR Plus is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.

8.
J Clin Endocrinol Metab ; 104(7): 2701-2711, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30753521

RESUMO

CONTEXT: Menopausal transition is associated with increased cardiovascular risks. Available data on the effect of earlier climacterium on these risks are limited. OBJECTIVE: To compare cardiovascular risk-associated parameters at the ages of 14, 31, and 46 in relation to climacteric status at the age of 46. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study including 2685 women from the Northern Finland Birth Cohort 1966. MAIN OUTCOME MEASURES: Follicle-stimulating hormone, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), blood pressure (BP), body composition, cholesterol levels, testosterone (T) levels, free androgen index (FAI), high-sensitivity C-reactive protein (hs-CRP), and liver enzymes. RESULTS: Women who were climacteric at the age of 46 had lower BMIs (P = 0.029), T levels (P = 0.018), and FAIs (P = 0.009) at the age of 31. At the age of 46, they had less skeletal muscle (P < 0.001), a higher fat percentage (P = 0.016), higher cholesterol levels [total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), high-density lipoprotein cholesterol (HDL-C; P = 0.022), and triglycerides (P = 0.008)], and higher alanine aminotransferase (P = 0.023) and γ-glutamyltransferase (P < 0.001) levels compared with preclimacteric women. Waist circumference, WHR, BP, and hs-CRP levels did not differ between the groups. Of the climacteric women, 111/381 were using hormone-replacement therapy (HRT). In subanalysis that excluded the HRT users, triglycerides, HDL-C, and body fat percentage did not differ among the groups. CONCLUSIONS: Earlier climacterium is associated with mainly unfavorable metabolic changes.


Assuntos
Composição Corporal , Terapia de Reposição de Estrogênios , Perimenopausa/metabolismo , Pós-Menopausa/metabolismo , Pré-Menopausa/metabolismo , Tecido Adiposo , Alanina Transaminase/metabolismo , Aspartato Aminotransferases/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Colesterol/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Estudos de Coortes , Feminino , Finlândia , Hormônio Foliculoestimulante/metabolismo , Humanos , Menopausa/metabolismo , Pessoa de Meia-Idade , Músculo Esquelético , Estudos Prospectivos , Testosterona/metabolismo , Triglicerídeos/metabolismo , Relação Cintura-Quadril , gama-Glutamiltransferase/metabolismo
9.
Int J Endocrinol ; 2018: 2059481, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30425741

RESUMO

Objective: Insulinomas are rare pancreatic tumours. Population-based data on their incidence, clinical picture, diagnosis, and treatment are almost nonexistent. The aim of this study was to clarify these aspects in a nationwide cohort of insulinoma patients diagnosed during three decades. Design and Methods: Retrospective analysis on all adult patients diagnosed with insulinoma in Finland during 1980-2010. Results: Seventy-nine patients were diagnosed with insulinoma over the research period. The median follow-up from diagnosis to last control visit was one (min 0, max 31) year. The incidence increased from 0.5/million/year in the 1980s to 0.9/million/year in the 2000s (p = 0.002). The median diagnostic delay was 13 months and did not change over the study period. The mean age at diagnosis was 52 (SD 16) years. The overall imaging sensitivity improved from 39% in the 1980s to 98% in the 2000s (p < 0.001). Seventy-one (90%) of the patients underwent surgery with a curative aim, two (3%) had palliative surgery, and 6 (8%) were inoperable. There were no significant differences in the types of surgical procedures between the 1980s, 1990s, and 2000s; tumour enucleations comprised 43% of the operations, distal pancreatic resections 45%, and pancreaticoduodenectomies 12%, over the whole study period. Of the patients who underwent surgery with a curative aim, 89% had a full recovery. Postoperative complications occurred in half of the patients, but postoperative mortality was rare. Conclusions: The incidence of insulinomas has increased during the past three decades. Despite the improved diagnostic options, diagnostic delay has remained unchanged. To shorten the delay, clinicians should be informed and alert to consider the possibility of hypoglycemia and insulinoma, when symptomatic attacks are investigated in different sectors of the healthcare system. Developing the surgical treatment is another major target, in order to lower the overall complication rate, without compromising the high cure rate of insulinomas.

10.
J Am Coll Cardiol ; 72(15): 1763-1773, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30286918

RESUMO

BACKGROUND: Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES: The goal of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS: Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabolic outcomes was performed. RESULTS: Among 5,687 European-American subjects (mean age 54 ± 6 years; 47% male), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (ß-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (ß = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (ß = -3.2; 95% CI: -6.4 to -0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS: Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions.


Assuntos
Doenças Cardiovasculares , Teste de Tolerância a Glucose/métodos , Absorção Intestinal/genética , Transportador 1 de Glucose-Sódio/genética , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Variação Genética , Glucose/metabolismo , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/genética , Mutação com Perda de Função , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Fatores de Proteção , Medição de Risco/métodos , Estados Unidos , Sequenciamento Completo do Exoma/métodos
11.
Clin Endocrinol (Oxf) ; 88(2): 303-310, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29154445

RESUMO

OBJECTIVES: Thyroid hormone suppression therapy has been widely used in the treatment of thyroid cancer, but concerns have been raised about the cardiovascular risks of this treatment. The objective of this study was to evaluate long-term cardiovascular morbidity and mortality in patients treated for differentiated thyroid cancer (DTC) and to assess the effect of TSH suppression and radioiodine (RAI) treatment on the cardiovascular outcome. DESIGN: Retrospective cohort study. PATIENTS AND MEASUREMENTS: Patients (n = 901) treated for DTC between 1981 and 2002 at 2 Finnish University hospitals were compared with a randomly chosen reference group (n = 4485) matched for age, gender and the place of residence. Kaplan-Meier and Cox regression analyses were used to estimate the risk of morbidity or death due to different cardiovascular diseases (CVD) after the diagnosis of DTC. RESULTS: Morbidity due to any CVD (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.05-1.28) and due to all arrhythmias (HR 1.25, CI 1.06-1.48) and atrial fibrillation (AF) (HR 1.29, CI 1.06-1.57) was more frequent in the DTC patients than in the controls. The increased cardiovascular morbidity was confined to patients with a mean TSH level below 0.1 mU/L (HR 1.27, CI 1.03-1.58) and to those treated with RAI (HR 1.18, CI 1.05-1.31). Cardiovascular mortality, however, was lower among the patients than the controls (HR 0.73, CI 0.58-0.92), due to a lower mortality from coronary artery disease. CONCLUSIONS: Differentiated thyroid cancer patients have an increased CVD morbidity, which is mostly accountable to AF and to TSH suppression below 0.1 mU/L.


Assuntos
Radioisótopos do Iodo/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/terapia , Tireotropina/uso terapêutico , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Hormônios Tireóideos/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/mortalidade
12.
Duodecim ; 133(3): 301-4, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29205832

RESUMO

This case report comprises three cases of antipsychotic drug-induced hypoglycemia and hypothermia. The mechanisms behind these side-effects are not known, but in hypoglycemia we describe signs of inappropriate insulin secretion. We assume that antipsychotic drug-induced hypoglycemia and hypothermia are underdiagnosed. Antipsychotic drugs are, however, widely used and these rare adverse-effects may occur in the clinical practice. It is of utmost importance to measure blood glucose and body temperature of patients taking these drugs who have unspecific symptoms.


Assuntos
Antipsicóticos/efeitos adversos , Hipoglicemia/induzido quimicamente , Hipotermia/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
13.
Nat Commun ; 8(1): 1289, 2017 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-29097701

RESUMO

Familial growth hormone deficiency provides an opportunity to identify new genetic causes of short stature. Here we combine linkage analysis with whole-genome resequencing in patients with growth hormone deficiency and maternally inherited gingival fibromatosis. We report that patients from three unrelated families harbor either of two missense mutations, c.347G>T p.(Arg116Leu) or c.1106C>T p.(Pro369Leu), in KCNQ1, a gene previously implicated in the long QT interval syndrome. Kcnq1 is expressed in hypothalamic GHRH neurons and pituitary somatotropes. Co-expressing KCNQ1 with the KCNE2 ß-subunit shows that both KCNQ1 mutants increase current levels in patch clamp analyses and are associated with reduced pituitary hormone secretion from AtT-20 cells. In conclusion, our results reveal a role for the KCNQ1 potassium channel in the regulation of human growth, and show that growth hormone deficiency associated with maternally inherited gingival fibromatosis is an allelic disorder with cardiac arrhythmia syndromes caused by KCNQ1 mutations.


Assuntos
Fibromatose Gengival/genética , Hormônio do Crescimento Humano/deficiência , Canal de Potássio KCNQ1/genética , Mutação de Sentido Incorreto , Adolescente , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Alelos , Substituição de Aminoácidos , Animais , Arritmias Cardíacas/genética , Criança , Pré-Escolar , Feminino , Fibromatose Gengival/metabolismo , Humanos , Canal de Potássio KCNQ1/química , Canal de Potássio KCNQ1/metabolismo , Masculino , Herança Materna/genética , Camundongos , Pessoa de Meia-Idade , Modelos Moleculares , Linhagem , Mapas de Interação de Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Adulto Jovem
14.
Nat Genet ; 49(12): 1758-1766, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29083408

RESUMO

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.


Assuntos
Exoma/genética , Estudos de Associação Genética/métodos , Variação Genética , Lipídeos/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Degeneração Macular/sangue , Degeneração Macular/genética , Fenótipo , Fatores de Risco
15.
Endocr Relat Cancer ; 23(6): 469-80, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27185871

RESUMO

OBJECTIVE: It is unclear whether mortality still is increased in acromegaly and whether there are gender-related differences. We dynamically assessed outcome during long-term follow-up in our nationwide cohort. PATIENTS AND METHODS: We studied standardized mortality ratios (SMRs) relative to the general population and causes of death in acromegaly (n=333) compared with age- and gender-matched controls (n=4995). RESULTS: During 20 (0-33) years follow-up, 113 (34%) patients (n=333, 52% women) and 1334 (27%) controls (n=4995) died (P=0.004). SMR (1.9, 95% CI: 1.53-2.34, P<0.001) and all-cause mortality (OR 1.6, 95% CI: 1.2-2.2, P<0.001) were increased in acromegaly. Overall distribution of causes of death (P<0.001) differed between patients and controls but not cardiovascular (34% vs 33%) or cancer deaths (27% vs 27%). In acromegaly, but not in controls, causes of deaths shifted from 44% cardiovascular and 28% cancer deaths during the first decade, to 23% cardiovascular and 35% cancer deaths during the next two decades. In acromegaly, cancer deaths were mostly attributed to pancreatic adenocarcinoma (n=5), breast (n=4), lung (n=3) and colon (n=3) carcinoma. In acromegaly, men were younger than women at diagnosis (median 44.5 vs 50 years, P<0.001) and death (67 vs 76 years, P=0.0015). Compared with controls, women (36% vs 25%, P<0.01), but not men (31% vs 28%, P=0.44), had increased mortality. CONCLUSIONS: In acromegaly, men are younger at diagnosis and death than women. Compared with controls, mortality is increased during 20 years of follow-up, especially in women. Causes of deaths shift from predominantly cardiovascular to cancer deaths.


Assuntos
Acromegalia/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
16.
Endocr Relat Cancer ; 22(5): 745-57, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26187128

RESUMO

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 - X-linked acrogigantism (X-LAG) - occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.


Assuntos
Acromegalia/genética , Gigantismo/genética , Gigantismo/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Adolescente , Adulto , Cromossomos Humanos X/genética , Feminino , Seguimentos , Humanos , Agências Internacionais , Masculino , Prognóstico , Adulto Jovem
17.
Duodecim ; 130(12): 1215-22, 2014.
Artigo em Finlandês | MEDLINE | ID: mdl-25016667

RESUMO

Half of diabetic ulcers are ischaemic, almost all neuropathic and the problem is often worsened by infection. Ischaemia can often be repaired if diagnosed and treated early enough. At present, ischaemia is often diagnosed far too late. International recommendations emphasize an immediate need for a paradigm change. Ischaemia should always be suspected as a cause of diabetic ulcer unless proven otherwise. Every diabetic patient with a foot ulcer should undergo an immediate clinical and noninvasive vascular assessment. Early diagnosis and undelayed treatment with vascular consultation and necessary revascularizations are prerequisites for successful treatment as "time is tissue".


Assuntos
Pé Diabético/diagnóstico , Pé Diabético/terapia , Diagnóstico Precoce , Humanos , Isquemia/diagnóstico , Isquemia/terapia , Guias de Prática Clínica como Assunto
18.
Acta Ophthalmol ; 92(8): 749-52, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24862935

RESUMO

PURPOSE: To evaluate the prevalence and stage of diabetic retinopathy (DR) in a population-based cohort of young Finnish adults who have had type 1 diabetes (T1D) since childhood. MATERIAL AND METHODS: The cohort includes all 5- to 16-year-old patients with T1D who lived in the Northern Ostrobothnia Hospital District of Finland, in 1989 (n = 216). DR was evaluated from fundus photographs taken in 1989-1990 and again in 2007. The patients were 7 ± 4 years age (range 0-15 years) at the time of diagnosis of T1D, and the average duration of diabetes at the re-evaluation was 23 ± 4 years (range 17-32 years). RESULTS: The prevalence of DR was analysed in 172 patients (80% of the original cohort) at 22-35 years. Proliferative DR (PDR) was observed in 35% (60/172) and non-proliferative DR in 59% (101/172), with no signs of DR being present in the remaining 6% (11/172) of the subjects. The prevalence of DR did not differ by gender (p = 0.356). CONCLUSIONS: After the 18-year follow-up, a high prevalence of DR and PDR (94% and 35%, respectively) was found in patients who have had T1D since childhood, with no difference between the genders.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Retinopatia Diabética/epidemiologia , Adulto , Idade de Início , Estudos de Coortes , Diabetes Mellitus Tipo 1/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Finlândia/epidemiologia , Humanos , Masculino , Prevalência , Fatores de Tempo , Adulto Jovem
19.
J Nucl Med ; 52(12): 1855-63, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22052128

RESUMO

UNLABELLED: Serum calcitonin and carcinoembryonic antigen (CEA) are markers of recurrent or persistent disease in medullary thyroid cancer (MTC). However, conventional imaging often fails to localize metastatic disease. Our aim was to compare fluorine-labeled dihydroxyphenylalanine ((18)F-DOPA) and (18)F-FDG PET/CT with multidetector CT (MDCT) and MRI in recurrent or persistent MTC. METHODS: Nineteen MTC patients with increased calcitonin or CEA on follow-up (mean ± SD, 93 ± 91 mo; range, 4-300 mo) after primary therapy were prospectively imaged with 4 techniques: (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI. Images were analyzed for pathologic lesions, which were surgically removed when possible. The correlation between the detection rate for each method and the calcitonin and CEA concentrations and histopathologic findings was investigated. RESULTS: On the basis of histology and follow-up, one or more imaging methods accurately localized metastatic disease in 12 (63%) of 19 patients. The corresponding figures for (18)F-DOPA PET/CT, (18)F-FDG PET/CT, MDCT, and MRI were 11 (58%) of 19, 10 (53%) of 19, 9 (47%) of 19, and 10 (59%) of 17, respectively. Calcitonin and CEA correlated with (18)F-DOPA PET/CT (P = 0.0007 and P = 0.0263, respectively) and (18)F-FDG PET/CT findings (both P < 0.0001). In patients with an unstable calcitonin doubling time (n = 8), (18)F-DOPA and (18)F-FDG PET/CT were equally sensitive. In contrast, for patients with an unstable CEA doubling time (n = 4), (18)F-FDG PET/CT was more accurate. CONCLUSION: For most MTC patients with occult disease, (18)F-DOPA PET/CT accurately detects metastases. In patients with an unstable calcitonin level, (18)F-DOPA PET/CT and (18)F-FDG PET/CT are complementary. For patients with an unstable CEA doubling time, (18)F-FDG PET/CT may be more feasible. MRI is sensitive but has the highest rate of false-positive results.


Assuntos
Di-Hidroxifenilalanina/análogos & derivados , Fluordesoxiglucose F18 , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Calcitonina/metabolismo , Antígeno Carcinoembrionário/metabolismo , Carcinoma Neuroendócrino , Proliferação de Células , Feminino , Seguimentos , Humanos , Antígeno Ki-67/metabolismo , Cinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Prospectivos , Recidiva , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia
20.
Int J Circumpolar Health ; 70(3): 329-38, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21703131

RESUMO

OBJECTIVES: To assess an interactive 2-step training and management model for nurses in glucose point-of-care testing (POCT). STUDY DESIGN: The training of the nursing staff by the point-of-care coordinator of the laboratory started with interactive sessions with contact persons who subsequently trained their nursing colleagues at the Oulu University Hospital in northern Finland. The 2-step training model was applied in blood glucose testing as a pilot study. METHODS: Functional quality was assessed through interviews with clinical contact persons and a questionnaire was given to the trained nurses. Technical quality was assessed through control measurements by laboratory and nursing staff. RESULTS: Training succeeded because of basic resources (trainers' knowledge and skills, organized contents of training and place), interpersonal communication and high-quality interactions. Nurses were especially satisfied with the prerequisite training of the contact persons (mean score 1.58, Likert scale from -2 to +2, strongly disagree - strongly agree). Day-to-day repeatabilities of less than 3% were achieved in control measurements by both nursing and laboratory staff. CONCLUSIONS: The interactive 2-step training and management model could be implemented in the clinical units using a reasonable amount of laboratory resources. The goal of good functional and technical quality in point-of-care testing in the clinical units was achieved. Despite successful implementation, POCT needs continuous support from the laboratory.


Assuntos
Glicemia/análise , Modelos Teóricos , Sistemas Automatizados de Assistência Junto ao Leito , Ensino/métodos , Finlândia , Humanos , Entrevistas como Assunto , Enfermeiras e Enfermeiros , Inquéritos e Questionários
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