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1.
Am J Physiol Renal Physiol ; 320(2): F203-F211, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33308018

RESUMO

Chronic kidney disease mineral bone disorder (CKD-MBD) is a virtually universal complication of kidney diseases, starting early in the course of disease and resulting in devastating clinical consequences ranging from bone fragility to accelerated atherosclerosis and early cardiovascular death. Guidelines for therapeutic goals for CKD-MBD have been published, and achievement of these guidelines is associated with improved survival. However, the incomplete understanding of CKD-MBD and the individual variability in the manifestations of CKD-MBD have made it difficult to achieve these guidelines. We hypothesized that the progression of MBD through all stages of CKD, including end-stage kidney disease, could be represented by a quantitative systems pharmacology/systems biology (QSP) model. To address this hypothesis, we constructed a QSP model of CKD-MBD, building on an open-source model of calcium and phosphorus metabolism. Specifically, we estimated and validated the model using data from 5,496 patients with CKD enrolled in the Chronic Renal Insufficiency Cohort study. Our model accurately predicted changes in markers of mineral metabolism related to progressing CKD. We demonstrated that the incorporation of fibroblast growth factor 23 and the soft tissue compartment is essential for accurate modeling of the changes in calcium, phosphorus, intact parathyroid hormone, and calcitriol in CKD-MBD. We conclude that our systems biology model accurately represents CKD-MBD disease progression and can be used as a test bench for improving therapeutic interventions.


Assuntos
Doenças Ósseas Metabólicas/metabolismo , Cálcio/metabolismo , Aprendizado de Máquina , Modelos Biológicos , Fosfatos/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Doenças Ósseas Metabólicas/etiologia , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica , Humanos , Hormônio Paratireóideo/metabolismo , Insuficiência Renal Crônica/complicações
2.
PLoS One ; 15(7): e0235082, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634148

RESUMO

Kidney donation results in reductions in kidney function and lasting perturbations in phosphate homeostasis, which may lead to adverse cardiovascular sequelae. However, the acute effects of kidney donation on bone mineral parameters including regulators of calcium and phosphate metabolism are unknown. We conducted a prospective observational controlled study to determine the acute effects of kidney donation on mineral metabolism and skeletal health. Biochemical endpoints were determined before and after donation on days 1, 2 and 3, 6 weeks and 12 months in donors and at baseline, 6 weeks and 12 months in controls. Baseline characteristic of donors (n = 34) and controls (n = 34) were similar: age (53±10 vs 50±14 years, p = 0.33), BMI (26.3±2.89 vs 25.9±3.65, p = 0.59), systolic BP (128±13 vs 130±6 mmHg, p = 0.59), diastolic BP (80±9 vs 81±9 mmHg, p = 0.68) and baseline GFR (84.4±20.2 vs 83.6±25.2 ml/min/1.73m2, p = 0.89). eGFR reduced from 84.4±20.2 to 52.3±17.5 ml/min/1.73m2 (p<0.001) by day 1 with incomplete recovery by 12 months (67.7±22.6; p = 0.002). Phosphate increased by day 1 (1.1(0.9-1.2) to 1.3(1.1-1.4) mmol/L, p <0.001) but declined to 0.8(0.8-1.0) mmol/L (p<0.001) before normalizing by 6 weeks. Calcium declined on day 1 (p = 0.003) but recovered at 6 weeks or 12 months. PTH and FGF-23 remained unchanged, but α-Klotho reduced by day 1 (p = 0.001) and remained low at 6 weeks (p = 0.02) and 1 year (p = 0.04). In this study, we conclude that kidney donation results in acute disturbances in mineral metabolism characterised by a reduced phosphate and circulating α-Klotho concentration without acute changes in the phosphaturic hormones FGF23 and PTH.


Assuntos
Densidade Óssea , Transplante de Rim , Minerais/metabolismo , Doadores de Tecidos , Adulto , Estudos de Casos e Controles , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/metabolismo , Fosfatos/metabolismo , Estudos Prospectivos , Fatores de Tempo
3.
Nat Commun ; 11(1): 2087, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350260

RESUMO

Antibodies conjugated to bioactive compounds allow targeted delivery of therapeutics to cell types of choice based on that antibody's specificity. Here we develop a new type of conjugate that consists of a nanobody and a peptidic ligand for a G protein-coupled receptor (GPCR), fused via their C-termini. We address activation of parathyroid hormone receptor-1 (PTHR1) and improve the signaling activity and specificity of otherwise poorly active N-terminal peptide fragments of PTH by conjugating them to nanobodies (VHHs) that recognize PTHR1. These C-to-C conjugates show biological activity superior to that of the parent fragment peptide in vitro. In an exploratory experiment in mice, a VHH-PTH peptide conjugate showed biological activity, whereas the corresponding free peptide did not. The lead conjugate also possesses selectivity for PTHR1 superior to that of PTH(1-34). This design approach, dubbed "conjugation of ligands and antibodies for membrane proteins" (CLAMP), can yield ligands with high potency and specificity.


Assuntos
Receptores Acoplados a Proteínas-G/metabolismo , Anticorpos de Domínio Único/metabolismo , Sequência de Aminoácidos , Animais , Feminino , Células HEK293 , Humanos , Ligantes , Camundongos , Modelos Moleculares , Hormônio Paratireóideo/metabolismo , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo
4.
PLoS Genet ; 16(5): e1008772, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32365064

RESUMO

In the postgenomics era, comparative genomics have advanced the understanding of evolutionary processes of neuropeptidergic signaling systems. The evolutionary origin of many neuropeptidergic signaling systems can be traced date back to early metazoan evolution based on the conserved sequences. Insect parathyroid hormone receptor (iPTHR) was previously described as an ortholog of vertebrate PTHR that has a well-known function in controlling bone remodeling. However, there was no sequence homologous to PTH sequence in insect genomes, leaving the iPTHR as an orphan receptor. Here, we identified the authentic ligand insect PTH (iPTH) for the iPTHR. The taxonomic distribution of iPTHR, which is lacking in Diptera and Lepidoptera, provided a lead for identifying the authentic ligand. We found that a previously described orphan ligand known as PXXXamide (where X is any amino acid) described in the cuttlefish Sepia officinalis has a similar taxonomic distribution pattern as iPTHR. Tests of this peptide, iPTH, in functional reporter assays confirmed the interaction of the ligand-receptor pair. Study of a model beetle, Tribolium castaneum, was used to investigate the function of the iPTH signaling system by RNA interference followed by RNA sequencing and phenotyping. The results suggested that the iPTH system is likely involved in the regulation of cuticle formation that culminates with a phenotype of defects in wing exoskeleton maturation at the time of adult eclosion. Moreover, RNAi of iPTHRs also led to significant reductions in egg numbers and hatching rates after parental RNAi.


Assuntos
Neuropeptídeos/metabolismo , Hormônio Paratireóideo/metabolismo , Receptores de Hormônios Paratireóideos/genética , Tribolium/anatomia & histologia , Animais , Evolução Molecular , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Fenótipo , Filogenia , Receptores de Hormônios Paratireóideos/metabolismo , Análise de Sequência de RNA , Tribolium/genética , Tribolium/metabolismo , Asas de Animais/anatomia & histologia
5.
Clin Nucl Med ; 45(7): 555-556, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32453086

RESUMO

Tc-MIBI has long been used to localize hyperfunctioning parathyroid tissue in patients with hyperparathyroidism. This tracer can also concentrate in various neoplastic tissues including prostate adenocarcinoma. We herein report a case with parathyroid hormone-secreting metastatic prostate cancer mimicking an ectopic parathyroid adenoma on the Tc-MIBI scan. We conclude that metastatic prostate cancer should be included as one of the differential diagnoses when interpreting Tc-MIBI scan.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/metabolismo , Hormônio Paratireóideo/metabolismo , Neoplasias das Paratireoides/diagnóstico , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Tecnécio Tc 99m Sestamibi , Adenocarcinoma/patologia , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias da Próstata/patologia , Cintilografia
6.
Endocrinol. diabetes nutr. (Ed. impr.) ; 67(5): 310-316, mayo 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-191306

RESUMO

INTRODUCCIÓN: El síndrome del hueso hambriento (SHH) es una complicación tras la cirugía paratiroidea que puede causar una hipocalcemia grave y prolongada. El objetivo fue conocer los factores de riesgo de SHH después de la cirugía por hiperparatiroidismo primario y su relación con los niveles de calcio sérico y de hormona paratiroidea (PTH). MATERIALES Y MÉTODOS: Se realizó un estudio analítico observacional de casos y controles en pacientes operados por hiperparatiroidismo primario en los últimos 10 años (2008-2017). Se estudió la evolución analítica del calcio, la PTH y las características generales de los pacientes. RESULTADOS: La incidencia de SHH en nuestra serie fue del 12,2%. Se encontró una asociación significativa de SHH con la cirugía tiroidea en el mismo acto quirúrgico (odds ratio ajustada [ORa] = 17,241), con la edad mayor de 68 años (Ora = 6,666) y con el tamaño de la lesión mayor a 1,7cm (Ora = 7.165). Observamos una relación estadísticamente significativa entre presentar SHH con un valor mayor a la media de calcio sérico corregido el día después de la cirugía, a la semana y a los 3 meses, así como con un valor mayor de la media de PTH preoperatoria, en la cirugía y un día después de la cirugía. CONCLUSIÓN: Los factores de riesgo independientes para el desarrollo de SHH en nuestra serie fueron la edad del paciente, el tamaño de la lesión y si la intervención se acompaña de cirugía tiroidea, lo que obliga a una monitorización más estrecha del metabolismo mineral durante el perioperatorio


INTRODUCTION: Hungry bone syndrome (HBS) is a complication occurring after parathyroid surgery that can cause severe and prolonged hypocalcemia. The study objective was to know the risk factors for HBS after surgery for primary hyperparathyroidism and its relationship with serum calcium and parathyroid hormone levels. MATERIAL AND METHODS: A case-control, observational, analytical study was conducted in patients who had undergone surgery for primary hyperparathyroidism in the past 10 years (2007-2016). Changes over time in serum calcium and PTH levels and the general characteristics of patients were analyzed. RESULTS: The incidence rate of HBS in our series was 12.2%. HBS was found to be significantly associated to thyroid surgery during the surgical procedure itself (adjusted odds ratio [aOR] = 17.241), to age older than 68 years (aOR = 6.666), and to lesions greater than 1.7cm (aOR = 7.165). A statistically significant relationship was seen between presence of HBS and corrected serum calcium levels higher than the mean the day after surgery and one week and 3 months later, and also with PTH levels higher than the mean before, during, and one day after surgery. CONCLUSIÓN: In our series, independent risk factors for development of HBS included patient age, lesion size, and whether or not the procedure was accompanied by thyroid surgery, which requires closer monitoring of mineral metabolism during the perioperative period


Assuntos
Humanos , Masculino , Feminino , Idoso , Hormônio Paratireóideo/metabolismo , Paratireoidectomia , Hiperparatireoidismo/cirurgia , Hiperparatireoidismo Primário , Doenças Ósseas Metabólicas/diagnóstico , Complicações Pós-Operatórias/terapia , Cálcio/sangue , Fatores de Risco , Hiperparatireoidismo Primário/etiologia , Complicações Pós-Operatórias/diagnóstico , Estudos de Casos e Controles , Cálcio/administração & dosagem , Cálcio/metabolismo , Modelos Logísticos
7.
PLoS One ; 15(3): e0230130, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32155210

RESUMO

Parathyroid gland disorders are rare conditions with an incidence that displays great variability among populations. Its direct influence in calcium homeostasis originates variable symptoms that affect bone remodelling among other processes. This study aimed to provide data on the epidemiology and characteristics of patients admitted with these disorders in Spain between 2003 and 2017, and to analyse disease management and direct medical costs. Medical records in which a disorder of the parathyroid gland was registered as the admission motive were extracted from a nationwide hospital-discharge database via the Spanish Ministry of Health. Records from 12,903 patients were obtained, with predominance of female patients (74.70%) and of admissions due to hyperparathyroidism (90.23%). The number of patients admitted per year increased over the study period along the incidence of these disorders. The year 2017 incidence of hyperparathyroidism was 2.95 per 10,000, 4.03 per 10,000 in females and 1.37 in males; the same year, the incidence of hypoparathyroidism was 0.17 per 10,000. Length of hospital stay was significantly extended in patients with hypoparathyroidism (7.16 days), admitted mostly due to emergencies. Heart failure was diagnosed in more than 20% of admissions in patients with secondary and tertiary hyperparathyroidism and hypoparathyroidism, while this last group displayed the highest levels of mineral metabolism disruption. Parathyroidectomy was performed in 78.95% of all admissions for primary hyperparathyroidism. The total annual direct medical cost parathyroid gland disorders has increased over the study period, due to the increase of the costs associated to hyperparathyroidism, whereas the cost per patient remained relatively stable, with an average of €3,748, €3,430 and €3,737 for patients with hyperparathyroidism, hypoparathyroidism and other disorders of the parathyroid gland, respectively. This study provides novel data to extend the scarce available knowledge on parathyroid gland disorders' epidemiology and management in Spain.


Assuntos
Doenças das Paratireoides/epidemiologia , Doenças das Paratireoides/terapia , Glândulas Paratireoides/fisiopatologia , Adulto , Feminino , Humanos , Hiperparatireoidismo Primário/epidemiologia , Hipoparatireoidismo/epidemiologia , Incidência , Masculino , Pessoa de Meia-Idade , Doenças das Paratireoides/economia , Hormônio Paratireóideo/metabolismo , Paratireoidectomia/economia , Paratireoidectomia/métodos , Estudos Retrospectivos , Espanha
8.
Proc Natl Acad Sci U S A ; 117(13): 7455-7460, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32184323

RESUMO

cAMP production upon activation of Gs by G protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mechanisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gαq/11 We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gßγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR-ßarrestin-Gßγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.


Assuntos
AMP Cíclico/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Animais , Arrestinas/metabolismo , Membrana Celular/metabolismo , Depsipeptídeos/farmacologia , Endossomos/metabolismo , Células HEK293 , Humanos , Camundongos , Osteoblastos/metabolismo , Hormônio Paratireóideo/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Cultura Primária de Células , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/fisiologia , beta-Arrestinas/metabolismo
9.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188359, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32222610

RESUMO

Advanced cancer patients exhibit cachexia, a condition characterized by a significant reduction in the body weight predominantly from loss of skeletal muscle and adipose tissue. Cachexia is one of the major causes of morbidity and mortality in cancer patients. Decreased food intake and multi-organ energy imbalance in cancer patients worsen the cachexia syndrome. Cachectic cancer patients have a low tolerance for chemo- and radiation therapies and also have a reduced quality of life. The presence of tumors and the current treatment options for cancer further exacerbate the cachexia condition, which remains an unmet medical need. The onset of cachexia involves crosstalk between different organs leading to muscle wasting. Recent advancements in understanding the molecular mechanisms of skeletal muscle atrophy/hypertrophy and adipose tissue wasting/browning provide a platform for the development of new targeted therapies. Therefore, a better understanding of this multifactorial disorder will help to improve the quality of life of cachectic patients. In this review, we summarize the metabolic mediators of cachexia, their molecular functions, affected organs especially with respect to muscle atrophy and adipose browning and then discuss advanced therapeutic approaches to cancer cachexia.


Assuntos
Estimulantes do Apetite/uso terapêutico , Caquexia/patologia , Atrofia Muscular/patologia , Neoplasias/complicações , Apoio Nutricional/métodos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/efeitos da radiação , Antineoplásicos/efeitos adversos , Estimulantes do Apetite/farmacologia , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/efeitos da radiação , Caquexia/etiologia , Caquexia/metabolismo , Caquexia/terapia , Citocinas/metabolismo , Suplementos Nutricionais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Glucocorticoides/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/efeitos da radiação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Fígado/efeitos da radiação , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/efeitos da radiação , Atrofia Muscular/etiologia , Atrofia Muscular/metabolismo , Neoplasias/terapia , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/efeitos da radiação , Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Qualidade de Vida , Radioterapia/efeitos adversos , Ganho de Peso/efeitos dos fármacos
10.
J Laparoendosc Adv Surg Tech A ; 30(5): 547-552, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32045316

RESUMO

Objective: This study aimed to investigate the application of nanocarbon in surgical endoscopy in patients with thyroid cancer for the clinical tracing of level VI sentinel lymph nodes (SLNs) and for parathyroid gland protection. Materials and Methods: Ninety-three patients with papillary thyroid carcinoma (PTC) who underwent an endoscopic thyroid cancer operation were included. We randomly divided these patients into a control group (n = 42) and a nanocarbon group (n = 51). For the nanocarbon group, after thyroid exposure, nanocarbon was injected into the thyroid gland, and the SLNs were resected and subjected to frozen sectioning and routine pathological examination. In addition, the postoperative calcium and parathyroid hormone (PTH) levels of both groups were analyzed to compare the features of the nanocarbon application. Results: The number of central lymph (level VI) nodes dissected and the number of metastatic lymph nodes identified were analyzed in both groups. The number of dissected lymph nodes from both unilateral and bilateral thyroid surgeries was significantly larger in the nanocarbon group than in the control group. At the same time, the number of identified metastasis lymph nodes dissected were higher in the nanocarbon group than in the control group. We assessed the postoperative calcium and PTH level to evaluate the parathyroid function. Our results show that the nanocarbon group had a better protective effect on parathyroid function than the control group. Conclusions: As a lymph node trace agent, nanocarbon could better evaluate and permit a more clear lymph dissection for patients with PTC. Nanocarbon contributes to a decrease in the incidence rate of parathyroid damage, which has great clinical value.


Assuntos
Carbono/química , Nanopartículas/química , Glândulas Paratireoides/cirurgia , Câncer Papilífero da Tireoide/cirurgia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Adulto , Mama/cirurgia , Dissecação , Endoscopia , Feminino , Secções Congeladas , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/metabolismo , Período Pós-Operatório , Estudos Prospectivos , Linfonodo Sentinela/cirurgia , Adulto Jovem
11.
Adv Exp Med Biol ; 1226: 37-50, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32030674

RESUMO

Parathyroid tumors are the second most common endocrine neoplasia, and it is almost always associated with hypersecretion of the parathormone (PTH), involved in calcium homeostasis, causing primary hyperparathyroidism (PHPT). Parathyroid neoplasia has a stromal component particularly represented in atypical adenomatous and carcinomatous lesions. Recently, data about the features and the function of the parathyroid tumor microenvironment (TME) have been accumulated. Parathyroid TME includes heterogeneous cells: endothelial cells, myofibroblasts, lymphocytes and macrophages, and mesenchymal stem cells have been identified, each of them presenting a phenotype consistent with tumor-associated cells. Parathyroid tumors overexpress proangiogenic molecules including vascular endothelial growth factor (VEGF-A), fibroblast growth factor-2 (FGF-2), and angiopoietins that promote both recruitment and proliferation of endothelial cell precursors, thus resulting in a microvessel density higher than that detected in normal parathyroid glands. Moreover, parathyroid tumor endocrine cells operate multifaceted interactions with stromal cells, partly mediated by the CXCL12/CXCR4 pathway, while, at present, the immune landscape of parathyroid tumors has just begun to be investigated. Studies about TME in parathyroid adenomas provide an example of the role of TME in benign tumors, whose molecular mechanisms and functions comprehension are limited.


Assuntos
Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/patologia , Microambiente Tumoral , Humanos , Glândulas Paratireoides/metabolismo , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/metabolismo
12.
Dtsch Med Wochenschr ; 145(3): 171-174, 2020 02.
Artigo em Alemão | MEDLINE | ID: mdl-32018291

RESUMO

Calcium is pivotal for neuromuscular function, coagulation, and signal transduction. An imbalance of enteral calcium uptake, deposition in and resorption from bones, and renal calcium elimination causes hypercalcemia. The dissociation between total serum calcium and ionized calcium has important implications in diagnosing hypercalcemia. The calcium sensing receptor (CaSR) regulates parathyroid hormone release and renal calcium reabsorption. Knowing the actions of the CaSR is important for diagnosing and treating patients with hyperparathyroidism. Diuretics can cause hypercalcemia, but also provide a clinical tool to lower serum calcium.


Assuntos
Hipercalcemia , Cálcio/metabolismo , Cálcio/fisiologia , Humanos , Hormônio Paratireóideo/metabolismo , Hormônio Paratireóideo/fisiologia , Receptores de Detecção de Cálcio/metabolismo , Receptores de Detecção de Cálcio/fisiologia
13.
J Steroid Biochem Mol Biol ; 199: 105611, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32007562

RESUMO

Gestational hypercalcemia is associated with an increased risk of maternal, fetal and neonatal morbidity and mortality. Hypercalcemia may develop during pregnancy in individuals who were previously asymptomatic. The increased sensitivity during pregnancy may be related to physiological, gestational alterations in vitamin D and calcium metabolism and may be influenced by gene variants. The prevalence is unknown. We investigated the prevalence of hypercalcemia in trimester 3 (T3) in a population representative prospective cohort study (n = 1832) in South-West Sweden. Women with serum albumin (Alb) adjusted calcium (CaAlb) ≥ 2.65 mmol/L in T3 (n = 30) were matched to normo-calcemic controls, and markers of calcium and vitamin D metabolism were investigated in trimester 1 (T1) and T3. Serum concentrations of Ca, phosphate (P), Magnesium (Mg), Alb and creatinine (Cr), parathyroid hormone (PTH; T3 only), vitamin D metabolites (total 25(OH)D, 1,25(OH)2D, 24,25(OH)2D, and free 25(OH)D) were analysed in T1 and T3. CaAlb (Payne; inter-laboratory difference: UEA = 0.15 + 0.9*UGOT; UEA 2.54 = UGOT 2.65) and estimated glomerular filtration rate (eGFR; modified 4-variable MDRD) and vitamin D metabolites ratios (VMR) were calculated. Normally and non-normally distributed data were presented as mean (SD) or median (95 %CI). Group differences in relationships between vitamin D metabolites and with PTH were investigated with multiple regression analyses. Hypercalcemia in T3 was found in 1.7 % of women. PTH concentrations suggestive of primary hyperparathyroidism was found in 1 woman and none had 25(OH)D or 24,25(OH)2D concentrations in the toxicity range or suggestive of mutations in the CYP24A1 gene. CaAlb was significantly higher in hypercalcemic cases compared to controls in T1 (2.44 (2.30-2.80) vs 2.37 (2.25-2.49) mmol/L) and T3 (2.63 (2.52-2.78) vs 2.46 (2.31-2.58) mmol/L). Serum P was higher among cases than controls in T3 (1.12 (0.16) vs 1.07 (0.18) mmol/L) but not in T1 (1.12 (0.18) and 1.12 (0.16) mmol/L). PTH in T3 was lower in cases (1.6 (1.6-2.8) vs 2.3 (2.1-2.8) pmol/L) but 1,25(OH)2D concentrations were similar. There were no significant group differences in serum 25(OH)D, free 25(OH)D, 24,25(OH)2D, Mg, Alb, Cr and eGFR. Regression analyses did not show significant differences between cases and controls in relationships between vitamin D metabolites and with PTH, except for the free 25(OH)D-PTH relationship and a higher free:total 25(OH)D ratio in cases at T1. In conclusion, most common causes of hypercalcemia were excluded in the majority of women. Hypercalcemic women had a relatively high serum 1,25(OH)2D concentration despite an appropriately suppressed PTH, suggestive of abnormal gestational adaptions.


Assuntos
Cálcio/sangue , Hipercalcemia/metabolismo , Complicações na Gravidez/metabolismo , Vitamina D/metabolismo , Adulto , Cálcio/metabolismo , Cálcio na Dieta/uso terapêutico , Creatinina/sangue , Feminino , Humanos , Hipercalcemia/sangue , Hipercalcemia/epidemiologia , Magnésio/sangue , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/metabolismo , Fosfatos/sangue , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/epidemiologia , Albumina Sérica/metabolismo , Suécia/epidemiologia , Vitamina D/sangue
14.
Biochem Biophys Res Commun ; 523(3): 816-821, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31954520

RESUMO

Parathyroid hormone (PTH) enhances cystic fibrosis transmembrane conductance regulator (CFTR)-mediated anion secretion by the human intestinal epithelial cell line Caco-2. With the patch-clamp and Ussing chamber techniques, we investigated how PTH stimulates CFTR activity in Caco-2 cells. Cell-attached recordings revealed that PTH stimulated the opening of CFTR-like channels, while impedance analysis demonstrated that PTH increased apical membrane capacitance, a measure of membrane surface area. Using ion substitution experiments, the PTH-stimulated increase in short-circuit current (Isc), a measure of transepithelial ion transport, was demonstrated to be Cl-- and HCO3--dependent. However, the PTH-stimulated increase in Isc was unaffected by the carbonic anhydrase inhibitor acetazolamide, but partially blocked by the intermediate-conductance Ca2+-activated K+ channel (IKCa) inhibitor clotrimazole. TRAM-34, a related IKCa inhibitor, failed to directly inhibit CFTR Cl- channels in cell-free membrane patches, excluding its action on CFTR. In conclusion, PTH enhances CFTR-mediated anion secretion by Caco-2 monolayers by increasing the expression and function of CFTR in the apical membrane and IKCa activity in the basolateral membrane.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Mucosa Intestinal/metabolismo , Hormônio Paratireóideo/metabolismo , Ânions/metabolismo , Células CACO-2 , Regulador de Condutância Transmembrana em Fibrose Cística/análise , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mucosa Intestinal/citologia , Transporte de Íons , Regulação para Cima
15.
Korean J Radiol ; 21(2): 236-247, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31997599

RESUMO

OBJECTIVE: Our aim was to assess the diagnostic performance of F-18 fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) in detecting hyperfunctioning parathyroid tissue (HPT) in patients with elevated parathyroid hormone levels with negative or inconclusive conventional imaging results and to compare the findings with those obtained using technetium-99m sestamibi (MIBI) scintigraphy and neck ultrasonography (US). MATERIALS AND METHODS: Images of 105 patients with hyperparathyroidism who underwent FCH PET/CT, dual-phase MIBI parathyroid scintigraphy (median interval: 42 days), and neck US were retrospectively analyzed. The gold standard was histopathological findings for 81 patients who underwent parathyroidectomy and clinical follow-up findings in the remaining 24 patients. Sensitivities, positive predictive values (PPVs), and accuracies were calculated for all imaging modalities. RESULTS: Among the 81 patients who underwent parathyroidectomy, either parathyroid adenoma (n = 64), hyperplasia (n = 9), neoplasia (n = 4), or both parathyroid adenoma and hyperplasia (n = 1) were detected, except 3 patients who did not show HPT. Of the 24 (23%) patients who were followed-up without operation, 22 (92%) showed persistent hyperparathyroidism. FCH PET/CT showed significantly higher sensitivity than MIBI scintigraphy and US in detection of HPT (p < 0.01). Sensitivity, PPV, and accuracy of FCH PET/CT were 94.1% (95/101), 97.9% (95/97), and 92.4% (97/105), respectively. The corresponding values for MIBI scintigraphy and US were 45.1% (46/102), 97.9% (46/47), and 45.7% (48/105) and 44.1% (45/102), 93.8% (45/48), and 42.9% (45/105), respectively. Among the 35 patients showing negative MIBI scintigraphy and neck US findings, 30 (86%) showed positive results on FCH PET/CT. FCH PET/CT could demonstrate ectopic locations of HPT in 11 patients whereas MIBI and US showed positive findings in only 6 and 3 patients, respectively. CONCLUSION: FCH PET/CT is an effective imaging modality for detection of HPT with the highest sensitivity among the available imaging techniques. Therefore, FCH PET/CT can be recommended especially for patients who show negative or inconclusive results on conventional imaging.


Assuntos
Colina/análogos & derivados , Hiperparatireoidismo/diagnóstico por imagem , Hormônio Paratireóideo/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Colina/química , Feminino , Humanos , Hiperparatireoidismo/patologia , Hiperparatireoidismo/cirurgia , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Glândulas Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/diagnóstico por imagem , Neoplasias das Paratireoides/patologia , Paratireoidectomia , Estudos Retrospectivos , Tecnécio Tc 99m Sestamibi/química , Adulto Jovem
16.
Am J Physiol Endocrinol Metab ; 318(4): E480-E491, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961709

RESUMO

Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.


Assuntos
Tecido Adiposo/crescimento & desenvolvimento , Microbioma Gastrointestinal/fisiologia , Osteoporose/metabolismo , Probióticos/farmacologia , Verrucomicrobia/metabolismo , Tecido Adiposo/metabolismo , Animais , Canais de Cálcio/metabolismo , Colo/efeitos dos fármacos , Colo/microbiologia , Feminino , Fêmur/efeitos dos fármacos , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Hormônio Paratireóideo/metabolismo , Pasteurização , Proteína Amiloide A Sérica/metabolismo , Coluna Vertebral/efeitos dos fármacos , Linfócitos T Reguladores , Canais de Cátion TRPV/metabolismo
17.
Diabetes Res Clin Pract ; 160: 107985, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31866526

RESUMO

AIMS: This pilot study aimed to evaluate differences in glycemic parameters between patients with prediabetes and normocalcemic primary hyperparathyroidism (NPHPT) and controls with prediabetes and normal parathyroid hormone (PTH) and calcium concentrations. METHODS: 20 patients with NPHPT and prediabetes and 42 age-, gender-, and body mass index-matched controls with prediabetes were included. Glycemic parameters [fasting glucose (fGlu), glycosylated hemoglobin (HbA1c), fasting insulin (fIns)] were evaluated. Homeostasis Model Assessment was used for estimating insulin secretion (HOMA-B) and resistance (HOMA-IR). Participants underwent a 75-g oral glucose tolerance test. RESULTS: HbA1c (5.9 ± 0.0 vs 5.9 ± 0.0%, p = 0.44), HOMA-IR (3.7 ± 1.2 vs 2.9 ± 0.2, p = 0.48), HOMA-B (117.8 ± 31.8 vs 146.9 ± 22.0%, p = 0.14), fIns (14.0 ± 4.3 vs 12.2 ± 1.1 µIU/ml, p = 0.53) and 2-hour post-load glucose concentrations (157.2 ± 2.2 vs 152.2 ± 2.0 mg/dl, p = 0.07), were nondifferent in the two groups. Higher fGlu levels were evident in the NPHPT, compared to the control group (105.6 ± 2.8 vs 98.2 ± 1.8 mg/dl, p = 0.01). fGlu demonstrated a positive correlation with PTH concentrations (rho = 0.374, p = 0.005). CONCLUSIONS: Individuals with NPHPT and prediabetes present an unfavorable glycemic profile compared to age-matched people with prediabetes, suggesting a direct adverse effect of elevated PTH on glucose homeostasis.


Assuntos
Glicemia/metabolismo , Hiperparatireoidismo Primário/complicações , Hormônio Paratireóideo/metabolismo , Estado Pré-Diabético/complicações , Idoso , Jejum , Feminino , Humanos , Hiperparatireoidismo Primário/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estado Pré-Diabético/sangue
18.
Nephrol Dial Transplant ; 35(3): 411-421, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504790

RESUMO

BACKGROUND: Vitamin D (VD) and phosphate (Pi) load are considered as contributors to cardiovascular disease in chronic kidney disease and the general population, but interactive effects of VD and Pi intake on the heart are not clearly illustrated. METHODS: We fed normal male rats with three levels of dietary VD (100, 1100 or 5000 IU/kg chow) and Pi (0.2, 0.6 or 1.6%) (3X3 design) for 8 weeks and examined renal and cardiac function and histology. RESULTS: High dietary Pi decreased plasma and renal Klotho and plasma 25-hydroxyvitamin D, and increased plasma Pi, fibroblast growth factor 23 and parathyroid hormone without affecting renal function, while low Pi increased plasma and renal Klotho. Both low and high VD diets enhanced high Pi-reduced Klotho expression. Low dietary VD reduced-plasma Klotho was rescued by a low Pi diet. High dietary Pi reduced-cardiac ejection fraction was not modified by a low or high VD diet, but the dietary VD effects on cardiac pathologic changes were more complex. High dietary Pi-induced cardiac hypertrophy was attenuated by a low VD and exacerbated by a high VD diet. In contrast, high dietary Pi -induced cardiac fibrosis was magnified by a low VD and attenuated by a high VD diet. CONCLUSIONS: High Pi diet induces hypertrophy and fibrosis in left ventricles, a low VD diet accelerates high Pi-induced fibrosis, and a high VD diet exacerbated high Pi -induced hypertrophy. Therefore, cardiac phosphotoxicity is exacerbated by either high or low dietary VD in rats with normal kidney function.


Assuntos
Dieta , Rim/metabolismo , Fosfatos/farmacologia , Remodelação Ventricular/fisiologia , Vitamina D/análogos & derivados , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Glucuronidase/metabolismo , Rim/efeitos dos fármacos , Masculino , Hormônio Paratireóideo/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos , Vitamina D/administração & dosagem
19.
Asian J Surg ; 43(7): 759-764, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31699571

RESUMO

BACKGROUND: Primary hyperparathyroidism is a prevalent disease with proven benefits for appropriately selected patients who undergo parathyroidectomy. The ability to accurately predict expected single adenoma gland weight as the cause based on preoperative biochemical tests could improve cure rates in a minimally invasive approach. OBJECTIVE: To assess the correlation between parathyroid weight and preoperative parathyroid hormone and calcium levels in patients with primary hyperparathyroidism with a solitary adenoma and determine if these could be used to predict expected parathyroid weight. METHODS: Patients with primary hyperparathyroidism who underwent curative parathyroidectomy from 2013 to 2018 was retrospectively analysed. RESULTS: There is a strong positive correlation r = 0.602 between preoperative PTH levels with respect to parathyroid weight (p < 0.001). There was a moderate correlation r = 0.474 between preoperative adjusted Calcium and PTH weight (p < 0.001). An algorithm was developed to calculate predicted weight of a single adenoma but when tested against cases with hyperplasia and double adenomas during the period, the variability of predicted weight meant it was impossible to differentiate between the causes. Hyperplasia was excluded and 95% of double adenomas excluded however, when parathyroid weight exceeded 1200 mg CONCLUSION: There is a strong correlation between preoperative PTH levels and calcium levels with parathyroid weight. The large variability of predicted parathyroid weight however, precludes the use of biochemical tests alone preoperatively in being able to differentiate between a single adenoma, double adenoma or hyperplasia as the cause in primary hyperparathyroidism. At parathyroid predicted weights above 1200 mg however, all cases of hyperplasia, and 95% of double adenomas excluded.


Assuntos
Adenoma/metabolismo , Adenoma/patologia , Cálcio/metabolismo , Hipertireoidismo/metabolismo , Hipertireoidismo/patologia , Glândulas Paratireoides/patologia , Hormônio Paratireóideo/metabolismo , Neoplasias das Paratireoides/metabolismo , Neoplasias das Paratireoides/patologia , Cuidados Pré-Operatórios , Adenoma/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/cirurgia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Neoplasias das Paratireoides/diagnóstico , Paratireoidectomia , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
20.
Animal ; 14(2): 330-338, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31337460

RESUMO

Calcium homeostasis is crucial for the normal function of the organism. Parathyroid hormone, calcitriol and calcitonin play critical roles in the homeostatic regulation of calcium. Serotonin and prolactin have also been shown to be involved in the regulation of calcium homeostasis. In modern dairy cows, the endocrine pathways controlling calcium homeostasis during non-lactating and non-pregnant physiological states are unable to fully support the increased demand of calcium required for milk synthesis at the onset of lactation. This review describes different endocrine systems associated with the regulation of calcium homeostasis in mammalian species around parturition with special focus on dairy cows. Additionally, classic and novel strategies to reduce the incidence of hypocalcemia in parturient dairy cows are discussed.


Assuntos
Cálcio na Dieta/metabolismo , Doenças dos Bovinos/metabolismo , Sistema Endócrino/metabolismo , Hipocalcemia/veterinária , Leite/metabolismo , Animais , Bovinos , Feminino , Homeostase , Hipocalcemia/metabolismo , Lactação , Glândulas Mamárias Animais/metabolismo , Hormônio Paratireóideo/metabolismo , Parto , Gravidez , Prolactina/metabolismo , Serotonina/metabolismo
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