N. Watts, J. Cauley, R. Jackson, A. LaCroix, Cora E. Lewis, J. Manson, J. Neuner, L. Phillips, M. Stefanick, J. Wactawski‐Wende, C. Crandall
Context The Women's Health Initiative (WHI) hormone therapy (HT) trials showed protection against hip and total fractures, but a later observational report suggested loss of benefit and a rebound increased risk after cessation of HT. Objective The purpose of this study was to examine fractures after discontinuation of HT. Design and Setting Two placebo-controlled randomized trials served as the study setting. Patients Study patients included WHI participants (N = 15,187) who continued active HT or placebo through the intervention period and who did not take HT in the postintervention period. Interventions Trial interventions included conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) in naturally menopausal women and CEE alone in women with prior hysterectomy. Main Outcome Measures Total fractures and hip fractures through 5 years after discontinuation of HT were recorded. Results Hip fractures were infrequent (∼2.5 per 1000 person-years); this finding was similar between trials and in former HT and placebo groups. There was no difference in total fractures in the CEE + MPA trial for former HT vs former placebo users (28.9 per 1000 person-years and 29.9 per 1000 person-years, respectively; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.87 to 1.09; P = 0.63); however, in the CEE-alone trial, total fractures were higher in former placebo users (36.9 per 1000 person-years) compared with the former active group (31.1 per 1000 person-years), a finding that was suggestive of a residual benefit of CEE against total fractures (HR, 0.85; 95% CI, 0.73 to 0.98; P = 0.03). Conclusions We found no evidence for increased fracture risk, either sustained or transient, for former HT users compared with former placebo users after stopping HT. There was residual benefit for total fractures in former HT users from the CEE-alone study.
{"title":"No Increase in Fractures After Stopping Hormone Therapy: Results From the Women’s Health Initiative","authors":"N. Watts, J. Cauley, R. Jackson, A. LaCroix, Cora E. Lewis, J. Manson, J. Neuner, L. Phillips, M. Stefanick, J. Wactawski‐Wende, C. Crandall","doi":"10.1210/jc.2016-3270","DOIUrl":"https://doi.org/10.1210/jc.2016-3270","url":null,"abstract":"Context\u0000The Women's Health Initiative (WHI) hormone therapy (HT) trials showed protection against hip and total fractures, but a later observational report suggested loss of benefit and a rebound increased risk after cessation of HT.\u0000\u0000\u0000Objective\u0000The purpose of this study was to examine fractures after discontinuation of HT.\u0000\u0000\u0000Design and Setting\u0000Two placebo-controlled randomized trials served as the study setting.\u0000\u0000\u0000Patients\u0000Study patients included WHI participants (N = 15,187) who continued active HT or placebo through the intervention period and who did not take HT in the postintervention period.\u0000\u0000\u0000Interventions\u0000Trial interventions included conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) in naturally menopausal women and CEE alone in women with prior hysterectomy.\u0000\u0000\u0000Main Outcome Measures\u0000Total fractures and hip fractures through 5 years after discontinuation of HT were recorded.\u0000\u0000\u0000Results\u0000Hip fractures were infrequent (∼2.5 per 1000 person-years); this finding was similar between trials and in former HT and placebo groups. There was no difference in total fractures in the CEE + MPA trial for former HT vs former placebo users (28.9 per 1000 person-years and 29.9 per 1000 person-years, respectively; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.87 to 1.09; P = 0.63); however, in the CEE-alone trial, total fractures were higher in former placebo users (36.9 per 1000 person-years) compared with the former active group (31.1 per 1000 person-years), a finding that was suggestive of a residual benefit of CEE against total fractures (HR, 0.85; 95% CI, 0.73 to 0.98; P = 0.03).\u0000\u0000\u0000Conclusions\u0000We found no evidence for increased fracture risk, either sustained or transient, for former HT users compared with former placebo users after stopping HT. There was residual benefit for total fractures in former HT users from the CEE-alone study.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"31 1","pages":"302–308"},"PeriodicalIF":0.0,"publicationDate":"2016-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78071017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Himika Chawla, S. Saha, D. Kandasamy, Raju Sharma, V. Sreenivas, R. Goswami
Context Bone mineral density (BMD) is increased in idiopathic hypoparathyroidism (IH). Parathyroid hormone (PTH) deficiency, hypocalcemic seizures, and anticonvulsants could compromise skeletal health in IH. Objective We assessed vertebral fractures (VFs) and related factors in IH and change in BMD during follow-up. Design VFs were assessed by morphometry. BMD was assessed by dual-energy X-ray absorptiometery at the lumbar spine, hip, and forearm. Change in BMD was assessed in a subset after a 10-year follow-up. Setting The endocrine clinic of All India Institute of Medical Sciences, New Delhi, India. Subjects Included were 104 patients with IH and 64 healthy controls. Hypocalcemia, hyperphosphatemia, normal kidney function, and low serum PTH levels were used to diagnose IH. Results VFs were seen in 18.3% of patients with IH and 4.7% of controls (odds ratio, 4.54; 95% confidence interval, 1.28 to 16.04). Use of anticonvulsants and menopause were significantly associated (P < 0.05) with VF. Mean BMD at lumbar spine and hip were higher by 21.4% and 8.6%, respectively, in IH than in controls (P < 0.001), respectively. BMD significantly increased during follow-up at all sites. Change in BMD correlated with maintenance of the serum calcium/phosphorus ratio during follow-up. Conclusions Despite increased BMD, prevalence of vertebral-fractures is greater in patients with IH, especially in postmenopausal women and those on anticonvulsant therapy.
{"title":"Vertebral Fractures and Bone Mineral Density in Patients With Idiopathic Hypoparathyroidism on Long-Term Follow-Up","authors":"Himika Chawla, S. Saha, D. Kandasamy, Raju Sharma, V. Sreenivas, R. Goswami","doi":"10.1210/jc.2016-3292","DOIUrl":"https://doi.org/10.1210/jc.2016-3292","url":null,"abstract":"Context\u0000Bone mineral density (BMD) is increased in idiopathic hypoparathyroidism (IH). Parathyroid hormone (PTH) deficiency, hypocalcemic seizures, and anticonvulsants could compromise skeletal health in IH.\u0000\u0000\u0000Objective\u0000We assessed vertebral fractures (VFs) and related factors in IH and change in BMD during follow-up.\u0000\u0000\u0000Design\u0000VFs were assessed by morphometry. BMD was assessed by dual-energy X-ray absorptiometery at the lumbar spine, hip, and forearm. Change in BMD was assessed in a subset after a 10-year follow-up.\u0000\u0000\u0000Setting\u0000The endocrine clinic of All India Institute of Medical Sciences, New Delhi, India.\u0000\u0000\u0000Subjects\u0000Included were 104 patients with IH and 64 healthy controls. Hypocalcemia, hyperphosphatemia, normal kidney function, and low serum PTH levels were used to diagnose IH.\u0000\u0000\u0000Results\u0000VFs were seen in 18.3% of patients with IH and 4.7% of controls (odds ratio, 4.54; 95% confidence interval, 1.28 to 16.04). Use of anticonvulsants and menopause were significantly associated (P < 0.05) with VF. Mean BMD at lumbar spine and hip were higher by 21.4% and 8.6%, respectively, in IH than in controls (P < 0.001), respectively. BMD significantly increased during follow-up at all sites. Change in BMD correlated with maintenance of the serum calcium/phosphorus ratio during follow-up.\u0000\u0000\u0000Conclusions\u0000Despite increased BMD, prevalence of vertebral-fractures is greater in patients with IH, especially in postmenopausal women and those on anticonvulsant therapy.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"101 1","pages":"251–258"},"PeriodicalIF":0.0,"publicationDate":"2016-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75453149","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Context Pancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing β-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown. Objective To investigate the PDG compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of β-cells. Design, Setting, and Participants Pancreases from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors. Results PDG cell replication was increased in T1D (6.3% ± 1.6% vs 0.6% ± 0.1%, P < 0.001, T1D vs nondiabetic), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate. Conclusion The PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.
胰管腺(PDGs)已被认为是胰腺外分泌损伤的再生来源，因此可能作为器官干细胞的生态位。有证据表明，长期存在的1型糖尿病(T1D)存在持续的β细胞形成，但其来源尚不清楚。目的研究T1D患者胰腺的PDG隔室是否具有活跃的再生特征(祖细胞的存在和增殖的增加)，特别是作为β细胞的潜在来源。设计、环境和参与者:研究了46例脑死亡器官供体(22例T1D患者，24例非糖尿病对照)的胰腺细胞的激活(增殖增加)和胰腺外分泌和内分泌祖细胞的标志物。结果T1D组spdg细胞复制增加(6.3%±1.6% vs 0.6%±0.1%，P < 0.001, T1D组vs非糖尿病组)，与胰腺炎症相关最为显著。在T1D的PDGs中有增加的祖细胞样细胞，但主要是外分泌的命运。结论PDG间室在T1D中被激活，与持续炎症反应一致，并通过由此产生的导管增生可能导致局部梗阻性胰腺炎和最终的T1D胰腺萎缩特征。然而，没有证据表明PDGs能有效形成内分泌细胞。
{"title":"Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes","authors":"A. Moin, P. Butler, A. Butler","doi":"10.1210/jc.2016-3001","DOIUrl":"https://doi.org/10.1210/jc.2016-3001","url":null,"abstract":"Context\u0000Pancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing β-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown.\u0000\u0000\u0000Objective\u0000To investigate the PDG compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of β-cells.\u0000\u0000\u0000Design, Setting, and Participants\u0000Pancreases from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors.\u0000\u0000\u0000Results\u0000PDG cell replication was increased in T1D (6.3% ± 1.6% vs 0.6% ± 0.1%, P < 0.001, T1D vs nondiabetic), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate.\u0000\u0000\u0000Conclusion\u0000The PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"10 1","pages":"200–209"},"PeriodicalIF":0.0,"publicationDate":"2016-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82466418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tae-Yon Sung, M. Jeon, Y. Lee, Y. Lee, Hyemi Kwon, J. Yoon, K. Chung, Won Gu Kim, D. Song, S. Hong
Background The objective of this study was to evaluate the usefulness of American Thyroid Association (ATA) risk classification and dynamic risk stratification (DRS) based on the response to initial therapy in pediatric patients with differentiated thyroid cancer (DTC). Methods This historical cohort study included 77 pediatric patients with DTC who underwent thyroid surgery. Clinical outcomes during median 5.3 years of follow up were assessed according to 3 ATA risk groups and 4 DRS groups. Results In ATA risk classification, 22%, 48%, and 30% of patients were in the low-, intermediate-, and high-risk groups, respectively. There was no significant difference in disease-free survival (DFS) between the indeterminate and the low-risk group. The risk of recurrent/persistent disease was significantly higher only in the high risk group [hazard ratio (HR), 18.4; P = 0.005]. In DRS, 49%, 13%, 6%, and 31% of patients were classified in the excellent, indeterminate, biochemical incomplete, and structural incomplete response groups, respectively. The risk of recurrent/persistent disease was significantly higher in the indeterminate group (HR, 10.2; P = 0.045) and in the structural incomplete group (HR, 98.7; P = 0.005) compared with the excellent response group. Conclusions DRS based on the response to initial therapy could be useful in addition to initial ATA pediatric risk classification to predict recurrent/persistent disease in pediatric patients with DTC.
{"title":"Initial and Dynamic Risk Stratification of Pediatric Patients With Differentiated Thyroid Cancer","authors":"Tae-Yon Sung, M. Jeon, Y. Lee, Y. Lee, Hyemi Kwon, J. Yoon, K. Chung, Won Gu Kim, D. Song, S. Hong","doi":"10.1210/jc.2016-2666","DOIUrl":"https://doi.org/10.1210/jc.2016-2666","url":null,"abstract":"Background\u0000The objective of this study was to evaluate the usefulness of American Thyroid Association (ATA) risk classification and dynamic risk stratification (DRS) based on the response to initial therapy in pediatric patients with differentiated thyroid cancer (DTC).\u0000\u0000\u0000Methods\u0000This historical cohort study included 77 pediatric patients with DTC who underwent thyroid surgery. Clinical outcomes during median 5.3 years of follow up were assessed according to 3 ATA risk groups and 4 DRS groups.\u0000\u0000\u0000Results\u0000In ATA risk classification, 22%, 48%, and 30% of patients were in the low-, intermediate-, and high-risk groups, respectively. There was no significant difference in disease-free survival (DFS) between the indeterminate and the low-risk group. The risk of recurrent/persistent disease was significantly higher only in the high risk group [hazard ratio (HR), 18.4; P = 0.005]. In DRS, 49%, 13%, 6%, and 31% of patients were classified in the excellent, indeterminate, biochemical incomplete, and structural incomplete response groups, respectively. The risk of recurrent/persistent disease was significantly higher in the indeterminate group (HR, 10.2; P = 0.045) and in the structural incomplete group (HR, 98.7; P = 0.005) compared with the excellent response group.\u0000\u0000\u0000Conclusions\u0000DRS based on the response to initial therapy could be useful in addition to initial ATA pediatric risk classification to predict recurrent/persistent disease in pediatric patients with DTC.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"1 1","pages":"793–800"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72775606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joel T. Rämö, Sanna M. Kaye, S. Jukarainen, L. Bogl, A. Hakkarainen, J. Lundbom, N. Lundbom, A. Rissanen, J. Kaprio, N. Matikainen, K. Pietiläinen
Context The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood. Objective We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content. Design, Setting, and Participants We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%). Results We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine. Conclusions BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.
{"title":"Liver Fat and Insulin Sensitivity Define Metabolite Profiles During a Glucose Tolerance Test in Young Adult Twins","authors":"Joel T. Rämö, Sanna M. Kaye, S. Jukarainen, L. Bogl, A. Hakkarainen, J. Lundbom, N. Lundbom, A. Rissanen, J. Kaprio, N. Matikainen, K. Pietiläinen","doi":"10.1210/jc.2015-3512","DOIUrl":"https://doi.org/10.1210/jc.2015-3512","url":null,"abstract":"Context\u0000The associations of body mass index (BMI) and liver fat (LF) with circulating prandial metabolomic markers are incompletely understood.\u0000\u0000\u0000Objective\u0000We aimed to characterize circulating metabolite excursions during an oral glucose tolerance test (OGTT) and evaluate whether the metabolomic signatures of BMI discordance coassociate with LF content.\u0000\u0000\u0000Design, Setting, and Participants\u0000We measured 80 metabolite parameters by nuclear magnetic resonance, together with glucose and insulin, during a 2-hour OGTT in 64 monozygotic (MZ) and 73 dizygotic (DZ) twin pairs (aged 22.8 to 36.2 years). Metabolite excursions during the OGTT were compared within BMI-discordant (intrapair difference, BMI ≥ 3 kg/m2) cotwins separately within MZ and DZ pairs. Insulin-based indices were calculated from the OGTT. LF was measured by magnetic resonance spectroscopy in 25 BMI-discordant MZ pairs. Metabolite profiles were compared with respect to LF discordance (ΔLF% ≥ 2%).\u0000\u0000\u0000Results\u0000We replicated many previously reported OGTT-induced metabolite excursions in all 274 individuals and report novel lipoprotein excursions. The associations between some metabolite excursions and BMI differed in MZ and DZ twins. In BMI-discordant MZ pairs (mean ΔBMI = 4.9 kg/m2) who were concordant for LF (Δ0.2%), few metabolites differed between the cotwins: very-low-density lipoprotein (VLDL) cholesterol and apolipoprotein B were elevated, and high-density lipoprotein size and concentration were decreased in the cotwins with higher BMI. In contrast, in BMI-discordant MZ pairs (ΔBMI = 6.1 kg/m2) who were discordant for LF (Δ6.8%), cotwins with higher BMI exhibited lower insulin sensitivity and widespread metabolomic differences: elevations in small VLDL and low-density lipoprotein particles, fatty acids (FAs), and isoleucine. Within all 64 MZ twin pairs, lower insulin sensitivity associated with higher levels of VLDLs, triglycerides, FAs, and isoleucine.\u0000\u0000\u0000Conclusions\u0000BMI-discordant MZ twin pairs who also are discordant for LF have more pronounced within-pair differences in metabolomics profiles during an OGTT than BMI-discordant pairs without LF discordance.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"4 1","pages":"220–231"},"PeriodicalIF":0.0,"publicationDate":"2016-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80519433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samrina Mahtab, U. Vaish, S. Saha, Archana Singh, R. Goswami, R. Rani
Context Major histocompatibility complex class I allele HLA-A*26:01 and human leukocyte antigen (HLA) supertype A01 (STA01) are increased in idiopathic hypoparathyroidism (IH). However, cell-mediated autoimmune responses directed against the calcium-sensing receptor (CaSR) have not been demonstrated. Objective To study CaSR-specific cytotoxic T-cell responses in peripheral blood mononuclear cells of IH patients. Design Twenty-four peptides of CaSR (RH1 to RH24) were evaluated for their ex vivo potential to stimulate PBMCs from IH patients and controls in interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assays. Setting Tertiary patient care center and National Institute of Immunology, New Delhi, India. Patients and Other Participants Forty-five patients with IH attending the endocrine clinic of the All India Institute of Medical Sciences and 22 healthy controls. Main Outcome Measures Major histocompatibility complex class-I restricted, CaSR-specific cytotoxic CD8+ T-cell responses evaluated by IFN-γ ELISPOT assay. Results Of IH patients, 82.2% showed IFN-γ-secreting cells when stimulated ex-vivo with CaSR peptides. Peptides RH7, RH9, and RH16 elicited HLA supertype A01-restricted responses in IH. RH8, RH14, RH15, RH20, and RH21 peptides induced significantly higher responses in STA01+ IH patients compared with healthy controls irrespective of their supertype A01 status. Conclusions Our ex vivo IFN-γ ELISPOT assays demonstrate the presence of CaSR-specific memory CD8+ T cells in the peripheral circulation of patients with IH, suggesting the role of cell-mediated autoimmune responses in the etiopathogenesis of IH.
主要组织相容性复合体I类等位基因HLA- a *26:01和人白细胞抗原(HLA)超型A01 (STA01)在特发性甲状旁腺功能减退症(IH)中升高。然而，针对钙敏感受体(CaSR)的细胞介导的自身免疫反应尚未得到证实。目的研究IH患者外周血单个核细胞对casr特异性细胞毒t细胞的反应。设计采用干扰素(IFN)-γ酶联免疫斑点法(ELISPOT)检测了24种CaSR肽(RH1至RH24)在体外刺激IH患者和对照组PBMCs的潜力。三级病人护理中心和国家免疫研究所，印度新德里。患者和其他参与者:45名在全印度医学科学研究所内分泌诊所就诊的IH患者和22名健康对照者。主要观察指标:主要组织相容性复合体i类限制性，casr特异性细胞毒性CD8+ t细胞反应通过IFN-γ ELISPOT测定。结果体外CaSR肽刺激IH患者，82.2%出现IFN-γ分泌细胞。多肽RH7、RH9和RH16在IH中引发HLA超型a01限制性反应。与健康对照者相比，与STA01+ IH患者的超型A01状态无关，RH8、RH14、RH15、RH20和RH21肽诱导的应答明显更高。结论体外IFN-γ ELISPOT检测证实IH患者外周血中存在casr特异性记忆性CD8+ T细胞，提示细胞介导的自身免疫反应在IH发病机制中的作用。
{"title":"Presence of Autoreactive, MHC Class I–Restricted, Calcium-Sensing Receptor (CaSR)–Specific CD8+ T Cells in Idiopathic Hypoparathyroidism","authors":"Samrina Mahtab, U. Vaish, S. Saha, Archana Singh, R. Goswami, R. Rani","doi":"10.1210/jc.2016-3131","DOIUrl":"https://doi.org/10.1210/jc.2016-3131","url":null,"abstract":"Context\u0000Major histocompatibility complex class I allele HLA-A*26:01 and human leukocyte antigen (HLA) supertype A01 (STA01) are increased in idiopathic hypoparathyroidism (IH). However, cell-mediated autoimmune responses directed against the calcium-sensing receptor (CaSR) have not been demonstrated.\u0000\u0000\u0000Objective\u0000To study CaSR-specific cytotoxic T-cell responses in peripheral blood mononuclear cells of IH patients.\u0000\u0000\u0000Design\u0000Twenty-four peptides of CaSR (RH1 to RH24) were evaluated for their ex vivo potential to stimulate PBMCs from IH patients and controls in interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assays.\u0000\u0000\u0000Setting\u0000Tertiary patient care center and National Institute of Immunology, New Delhi, India.\u0000\u0000\u0000Patients and Other Participants\u0000Forty-five patients with IH attending the endocrine clinic of the All India Institute of Medical Sciences and 22 healthy controls.\u0000\u0000\u0000Main Outcome Measures\u0000Major histocompatibility complex class-I restricted, CaSR-specific cytotoxic CD8+ T-cell responses evaluated by IFN-γ ELISPOT assay.\u0000\u0000\u0000Results\u0000Of IH patients, 82.2% showed IFN-γ-secreting cells when stimulated ex-vivo with CaSR peptides. Peptides RH7, RH9, and RH16 elicited HLA supertype A01-restricted responses in IH. RH8, RH14, RH15, RH20, and RH21 peptides induced significantly higher responses in STA01+ IH patients compared with healthy controls irrespective of their supertype A01 status.\u0000\u0000\u0000Conclusions\u0000Our ex vivo IFN-γ ELISPOT assays demonstrate the presence of CaSR-specific memory CD8+ T cells in the peripheral circulation of patients with IH, suggesting the role of cell-mediated autoimmune responses in the etiopathogenesis of IH.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"454 1","pages":"167–175"},"PeriodicalIF":0.0,"publicationDate":"2016-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82941362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Greeley, Mark C. Zielinski, A. Poudel, Honggang Ye, Shivani Berry, J. Taxy, D. Carmody, D. Steiner, L. Philipson, Jamie Wood, M. Hara
Context The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. β-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic β-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature β-cells as well as granules with a lighter core characteristic of immature granules. Conclusions Our results suggest that mechanisms exist that allow preservation of β-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in β-cells may be reversible.
{"title":"Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-Related Diabetes","authors":"S. Greeley, Mark C. Zielinski, A. Poudel, Honggang Ye, Shivani Berry, J. Taxy, D. Carmody, D. Steiner, L. Philipson, Jamie Wood, M. Hara","doi":"10.1210/jc.2016-2826","DOIUrl":"https://doi.org/10.1210/jc.2016-2826","url":null,"abstract":"Context\u0000The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls.\u0000\u0000\u0000Case Description\u0000Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. β-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic β-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature β-cells as well as granules with a lighter core characteristic of immature granules.\u0000\u0000\u0000Conclusions\u0000Our results suggest that mechanisms exist that allow preservation of β-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in β-cells may be reversible.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"29 1","pages":"1–5"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83438600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Davis, Matthew Cox-Martin, M. Bardsley, Karen Kowal, P. Zeitler, J. Ross
Context Klinefelter syndrome (KS) is a common condition in males, resulting in androgen deficiency and cardiometabolic diseases. These interrelated conditions may be present in prepubertal boys with KS. Objective To determine whether supplemental low-dose androgen has a beneficial effect on body composition in prepubertal boys with KS. Design, Setting, and Participants We conducted a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial in 93 boys with KS aged 4 to 12 years. Interventions Oral oxandrolone (Ox) 0.06 mg/kg/d or placebo for 2 years. Outcome Measures The primary outcome was percent body fat standard deviation score (%BF SDS) at 2 years. Secondary outcomes included additional measures of cardiometabolic health and safety. Results The %BF SDS at 2 years was significantly lower in the treatment (0.29 ± 0.76 SDS) compared with placebo group (0.81 ± 0.72 SDS) after adjusting for age and baseline %BF SDS (95% confidence interval for the difference between means -0.86 to -0.19 SDS, P = 0.009). Ox resulted in lower triglycerides (P = 0.043), but also lower high-density lipoprotein (HDL) cholesterol (P < 0.001) and a more rapid advancement in bone age (P = 0.011). Conclusions Ox has positive effects on measures of cardiometabolic health in prepubertal boys with KS; however, it does lower HDL cholesterol and advance bone age.
{"title":"Effects of Oxandrolone on Cardiometabolic Health in Boys With Klinefelter Syndrome: A Randomized Controlled Trial","authors":"S. Davis, Matthew Cox-Martin, M. Bardsley, Karen Kowal, P. Zeitler, J. Ross","doi":"10.1210/jc.2016-2904","DOIUrl":"https://doi.org/10.1210/jc.2016-2904","url":null,"abstract":"Context\u0000Klinefelter syndrome (KS) is a common condition in males, resulting in androgen deficiency and cardiometabolic diseases. These interrelated conditions may be present in prepubertal boys with KS.\u0000\u0000\u0000Objective\u0000To determine whether supplemental low-dose androgen has a beneficial effect on body composition in prepubertal boys with KS.\u0000\u0000\u0000Design, Setting, and Participants\u0000We conducted a secondary analysis of a randomized, double-blind, placebo-controlled clinical trial in 93 boys with KS aged 4 to 12 years.\u0000\u0000\u0000Interventions\u0000Oral oxandrolone (Ox) 0.06 mg/kg/d or placebo for 2 years.\u0000\u0000\u0000Outcome Measures\u0000The primary outcome was percent body fat standard deviation score (%BF SDS) at 2 years. Secondary outcomes included additional measures of cardiometabolic health and safety.\u0000\u0000\u0000Results\u0000The %BF SDS at 2 years was significantly lower in the treatment (0.29 ± 0.76 SDS) compared with placebo group (0.81 ± 0.72 SDS) after adjusting for age and baseline %BF SDS (95% confidence interval for the difference between means -0.86 to -0.19 SDS, P = 0.009). Ox resulted in lower triglycerides (P = 0.043), but also lower high-density lipoprotein (HDL) cholesterol (P < 0.001) and a more rapid advancement in bone age (P = 0.011).\u0000\u0000\u0000Conclusions\u0000Ox has positive effects on measures of cardiometabolic health in prepubertal boys with KS; however, it does lower HDL cholesterol and advance bone age.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"16 1","pages":"176–184"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79108066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Chevalley, J. Bonjour, M. Audet, F. Merminod, B. van Rietbergen, R. Rizzoli, S. Ferrari
Context Peak bone mass (PBM) and strength are important determinants of fracture risk in later life. During growth, bone is responsive to changes in nutrition and physical activity (PA), particularly before pubertal maturation. Objective In prepubertal healthy boys, protein intake (Prot-Int) enhances the impact of PA on weight-bearing bone. We hypothesized that the synergism between Prot-Int and PA on proximal femur as recorded at 7.4 years would track until PBM. Methods A total of 124 boys were followed from 7.4 to 15.2 and 22.6 years. At 7.4 years, they were dichotomized according to the median of both PA and Prot-Int. Results In boys with PA greater than the median (310 vs 169 kcal ⋅ d-1), higher vs low Prot-Int (57.7 vs 38.0 g ⋅ d-1) was associated with +9.8% greater femoral neck (FN) bone mineral content (BMC) (P = 0.027) at 7.4 years. At 15.2 and 22.6 years, this difference was maintained: FN BMC: +12.7% (P = 0.012) and +11.3% (P = 0.016), respectively. With PA greater than the median, in Prot-Int greater than vs less than the median, differences in FN BMC z scores were +0.60, +0.70, and +0.68 at 7.4, 15.2, and 22.6 years, respectively. Microfinite element analysis of distal tibia at 15.2 and 22.6 years indicated that in the 2 groups with PA greater than the median, cross-sectional area, stiffness, and failure load were greater in Prot-Int greater than vs less than the median. Conclusions This study demonstrates the crucial influence of Prot-Int on the response to enhanced PA and the importance of prepubertal years for modifying the bone growth trajectory and, thereby, for achieving higher PBM and greater strength in healthy male participants.
{"title":"Prepubertal Impact of Protein Intake and Physical Activity on Weight-Bearing Peak Bone Mass and Strength in Males","authors":"T. Chevalley, J. Bonjour, M. Audet, F. Merminod, B. van Rietbergen, R. Rizzoli, S. Ferrari","doi":"10.1210/jc.2016-2449","DOIUrl":"https://doi.org/10.1210/jc.2016-2449","url":null,"abstract":"Context\u0000Peak bone mass (PBM) and strength are important determinants of fracture risk in later life. During growth, bone is responsive to changes in nutrition and physical activity (PA), particularly before pubertal maturation.\u0000\u0000\u0000Objective\u0000In prepubertal healthy boys, protein intake (Prot-Int) enhances the impact of PA on weight-bearing bone. We hypothesized that the synergism between Prot-Int and PA on proximal femur as recorded at 7.4 years would track until PBM.\u0000\u0000\u0000Methods\u0000A total of 124 boys were followed from 7.4 to 15.2 and 22.6 years. At 7.4 years, they were dichotomized according to the median of both PA and Prot-Int.\u0000\u0000\u0000Results\u0000In boys with PA greater than the median (310 vs 169 kcal ⋅ d-1), higher vs low Prot-Int (57.7 vs 38.0 g ⋅ d-1) was associated with +9.8% greater femoral neck (FN) bone mineral content (BMC) (P = 0.027) at 7.4 years. At 15.2 and 22.6 years, this difference was maintained: FN BMC: +12.7% (P = 0.012) and +11.3% (P = 0.016), respectively. With PA greater than the median, in Prot-Int greater than vs less than the median, differences in FN BMC z scores were +0.60, +0.70, and +0.68 at 7.4, 15.2, and 22.6 years, respectively. Microfinite element analysis of distal tibia at 15.2 and 22.6 years indicated that in the 2 groups with PA greater than the median, cross-sectional area, stiffness, and failure load were greater in Prot-Int greater than vs less than the median.\u0000\u0000\u0000Conclusions\u0000This study demonstrates the crucial influence of Prot-Int on the response to enhanced PA and the importance of prepubertal years for modifying the bone growth trajectory and, thereby, for achieving higher PBM and greater strength in healthy male participants.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"7 1","pages":"157–166"},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84714676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
T. Sathyapalan, A. Rigby, S. Bhasin, N. Thatcher, E. Kilpatrick, S. Atkin
Context: Isoflavones found in soy products have a chemical structure similar to estrogen, leading to concerns of an adverse estrogenic effect in men, particularly in those with type 2 diabetes mellitus (T2DM) who have low testosterone levels due to hypogonadism. Objective: The primary outcome was change in total testosterone levels. The secondary outcomes were the changes in glycemia and cardiovascular risk markers. Design: This was a randomized double-blind parallel study. Setting: This study occurred in a secondary care setting in United Kingdom. Participants: Two hundred men with T2DM and a total testosterone level ⩽12 nmol/L were included. Intervention: Fifteen grams of soy protein with 66 mg of isoflavones (SPI) or 15 g soy protein alone without isoflavones (SP) daily as snack bars for 3 months were administered. Results: There was no change in either total testosterone or in absolute free testosterone levels with either SPI or SP. There was an increase in thyrotropin (TSH) and reduction in free thyroxine (fT4; P < 0.01) after SPI supplementation. Glycemic control improved with a significant reduction in hemoglobin A1c (−4.19 [7.29] mmol/mol, P < 0.01) and homeostasis model of assessment - insulin resistance after SPI. Cardiovascular risk improved with a reduction in triglycerides, C-reactive protein, and diastolic blood pressure (DBP; P < 0.05) with SPI vs SP supplementation. There was a 6% improvement in 10-year coronary heart disease risk after 3 months of SPI supplementation. Endothelial function improved with both SPI and SP supplementation (P < 0.01), with an increased reactive hyperemia index that was greater for the SPI group (P < 0.05). Conclusions: Testosterone levels were unchanged and there was a substantial improvement in glycaemia and cardiovascular risk markers with SPI compared with SP alone over 3 months. There was also a substantial increase in TSH and a reduction in fT4.
{"title":"Effect of Soy in Men With Type 2 Diabetes Mellitus and Subclinical Hypogonadism: A Randomized Controlled Study","authors":"T. Sathyapalan, A. Rigby, S. Bhasin, N. Thatcher, E. Kilpatrick, S. Atkin","doi":"10.1210/jc.2016-2875","DOIUrl":"https://doi.org/10.1210/jc.2016-2875","url":null,"abstract":"Context: Isoflavones found in soy products have a chemical structure similar to estrogen, leading to concerns of an adverse estrogenic effect in men, particularly in those with type 2 diabetes mellitus (T2DM) who have low testosterone levels due to hypogonadism. Objective: The primary outcome was change in total testosterone levels. The secondary outcomes were the changes in glycemia and cardiovascular risk markers. Design: This was a randomized double-blind parallel study. Setting: This study occurred in a secondary care setting in United Kingdom. Participants: Two hundred men with T2DM and a total testosterone level ⩽12 nmol/L were included. Intervention: Fifteen grams of soy protein with 66 mg of isoflavones (SPI) or 15 g soy protein alone without isoflavones (SP) daily as snack bars for 3 months were administered. Results: There was no change in either total testosterone or in absolute free testosterone levels with either SPI or SP. There was an increase in thyrotropin (TSH) and reduction in free thyroxine (fT4; P < 0.01) after SPI supplementation. Glycemic control improved with a significant reduction in hemoglobin A1c (−4.19 [7.29] mmol/mol, P < 0.01) and homeostasis model of assessment - insulin resistance after SPI. Cardiovascular risk improved with a reduction in triglycerides, C-reactive protein, and diastolic blood pressure (DBP; P < 0.05) with SPI vs SP supplementation. There was a 6% improvement in 10-year coronary heart disease risk after 3 months of SPI supplementation. Endothelial function improved with both SPI and SP supplementation (P < 0.01), with an increased reactive hyperemia index that was greater for the SPI group (P < 0.05). Conclusions: Testosterone levels were unchanged and there was a substantial improvement in glycaemia and cardiovascular risk markers with SPI compared with SP alone over 3 months. There was also a substantial increase in TSH and a reduction in fT4.","PeriodicalId":22632,"journal":{"name":"The Journal of Clinical Endocrinology & Metabolism","volume":"120 1","pages":"425–433"},"PeriodicalIF":0.0,"publicationDate":"2016-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76007209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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