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Diabetic ketoacidosis (DKA) is an acute complication related to severe hyperglycemia. While the mortality rate for DKA is low with appropriate therapy, several complications may lead to deterioration of the clinical course. Here, we report a case of a 23-year-old patient with DKA who suffered from a rare but hemodynamically unstable cardiac arrhythmia, polymorphic ventricular tachycardia with prolonged QT interval, or Torsades de Pointes. During the recovery phase of DKA, three episodes of Torsades de Pointes suddenly occurred, and were recovered by immediate defibrillation. The patient did not have structural heart disease or a genetic predisposition. To the best of our knowledge, this is the first report of an adult with DKA complicated with QT prolongation related to Torsades de Points after correction of ketosis. To manage DKA, more attention may be needed on changes in the QT interval as well as risk factors for Torsades de Points.

Subclinical hypothyroidism (sHypo) is defined as normal serum free thyroid hormone levels coexisting with elevated serum thyroid-stimulating hormone (TSH) levels. sHypo is a common condition observed in clinical practice with several unique features. Its diagnosis should be based on an understanding of geographic and demographic differences in biochemical criteria versus a global reference range for TSH that is based on the 95% confidence interval of a healthy population. During the differential diagnosis, it is important to remember that a considerable proportion of sHypo cases are transient and reversible in nature; the focus is better placed on persistent or progressive forms, which mainly result from chronic autoimmune thyroiditis. Despite significant evidence documenting the health impacts of sHypo, the effects of levothyroxine treatment (LT4-Tx) in patients with sHypo remains controversial, especially in patients with grade 1 sHypo and older adults. Existing evidence suggests that it is reasonable to refrain from immediate LT4-Tx in most patients if they are closely monitored, except in women who are pregnant or in progressive cases. Future research is needed to further characterize the risks and benefits of LT4-Tx in different patient cohorts.

The aggregation of α-synuclein (α-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Postmortem analyses of α-syn pathology, especially that of PD, have suggested that aggregates progressively spread from a few discrete locations to wider brain regions. The neuron-to-neuron propagation of α-syn has been suggested to be the underlying mechanism by which aggregates spread throughout the brain. Many cellular and animal models has been created to study cell-to-cell propagation. Recently, it has been shown that a single injection of preformed fibrils (PFFs) made of recombinant α-syn proteins into various tissues and organs of many different animal species results in widespread α-syn pathology in the central nervous system (CNS). These PFF models have been extensively used to study the mechanism by which aggregates spread throughout the brain. Here, we review what we have learned from PFF models, describe the nature of PFFs and the neuropathological features, neurophysiological characteristics, and behavioral outcomes of the models.

Context Because subclinical hyperthyroidism increases the risk of osteoporosis and fractures, concerns are growing about the long-term skeletal safety of TSH suppression therapy after total thyroidectomy in patients with differentiated thyroid cancer (DTC). Objective We aimed to determine the effect of TSH suppression therapy on bone mineral density (BMD) in DTC patients. Methods We searched PubMed, Embase, the Cochrane library, and other sources. Eligible observational studies included DTC patients who underwent TSH suppression therapy and BMD measurement. Two independent reviewers extracted data on the studies’ characteristics and outcomes and determined their risk of bias. Data were extracted from each study for postmenopausal/premenopausal women’s and men’s lumbar spine (LS), femoral neck (FN), and total hip (TH) BMD and summed using a random-effects meta-analysis model. The weighted mean differences with 95% CIs are expressed for the differences in outcome measurements between groups. Results Seventeen studies (739 patients and 1085 controls) were included for quantitative analysis. In postmenopausal women, TSH suppression therapy showed a significant decrease in LS BMD (-0.03; -0.05, -0.02), and a similar trend was seen in TH. In premenopausal women, TSH suppression therapy significantly increased LS BMD (0.04; 0.02, 0.06) and FN BMD (0.02; 0.01, 0.04). In men, there was no significant association between TSH suppression therapy and BMD at any site compared with the controls. Conclusion Evidence from observational studies suggests that postmenopausal women treated with TSH suppression therapy are at risk for lower BMD. Attention should be paid to long-term skeletal safety in DTC survivors.

SUMMARYBackgroundAlzheimer’s disease is a major health problem, affecting ~4⋅5% of people aged 60 and older in 2016 with over 43 million affected globally1. The traditional approach for detection evaluates an individual in the presence of symptoms. However, it has been established that amyloid deposits begin to accumulate years before symptoms begin to appear2,3. With improved technology, there is increased focus on risk reduction, timely diagnosis, and early intervention. Early identification of at-risk individuals may enable patients and their families to better prepare for and reduce the impact of this condition.MethodsWe obtained data for patients from two longitudinal retrospective cohorts (Alzheimer’s Disease Neuroimaging Initiative: ADNI and National Alzheimer’s Coordinating Center: NACC), including T1-weighted MRI and genetics data. The polygenic risk score (PRS) used in this study was built based on a published Genome Wide Association Study (GWAS) that identified variants associated with Alzheimer’s disease. Quantitative MRI features were obtained using a 3D U-Net neural network for brain segmentation. Cox proportional hazards (CPH) regression models were used with subjects censored at death or the last evaluation. Time-to-event was defined as the time it takes for an individual who is dementia-free at the baseline MRI to progress to dementia as defined by the criteria described by ADNI. Time-dependent ROC areas under curve (AUCs) were estimated in the presence of censored data. The time-dependent AUCs were compared among models using the Wilcoxon rank sum test for dependent samples. Data was binned into three groups according to survival probability to eight years after baseline and Kaplan-Meier survival analysis was used to estimate the probability of surviving at least to time t. Calibration for both training and validation cohorts was evaluated using the predicted survival probability, splitting samples into five risk groups of equal size based on the predicted survival probability.FindingsWe developed a model that predicts the onset of dementia over an eight-year time window in individuals with genetics data and a T1-weighted MRI who were dementia-free at baseline. We then validated the model in an independent multisite cohort.We observed that models using PRS in addition to MRI-derived features performed significantly better as measured by time-varying AUC up to eight years in both the training (p = 0⋅0071) and validation (p = 0⋅050) cohorts. We observed improved performance of the two modalities versus MRI alone when compared with more invasive amyloid measures. The combined MRI and PRS model showed equivalent performance to cerebral spinal fluid (CSF) amyloid measurement up to eight years prior to disease onset (p = 0⋅181) and while the MRI only model performed worse (p = 0⋅040). Finally, we compared to amyloid positron emission tomography (PET) three to four years prior to disease onset with favorable results.InterpretationOur finding suggests that the two modalities are complementary measures, in that MRI reflects near-term decline and the addition of genetics extends the prediction scope of quantitative MRI by adding additional long-term predictive power.The proposed multimodal model shows potential as an alternate solution for early risk assessment given the concordance with CSF amyloid and amyloid PET. Future work will include further comparison with amyloid PET (greater than four years) and with CSF (greater than eight years) as additional long-term data becomes available. Also, the model will be evaluated for its clinical utility in the “active surveillance” of individuals who may be concerned about their risk of developing dementia but are not yet eligible for assessment by amyloid PET or CSF.RESEARCH IN CONTEXTEvidence before this studyThe most significant known genetic factor in Alzheimer’s disease (AD) is the ε4 allele for theApolipoprotein E(APOE) gene. Carriers of the allele have a three-fold increased risk of developing AD, whereas individuals who are homozygous have a 15-fold increased risk. Genome-wide association studies (GWASs) have identified many additional genetic variants that are associated with AD. Recent studies have shown that the risk for AD is better predicted by combining effects from several genetic variants into “polygenic risk scores” (PRS). Studies have also demonstrated that the age of onset for AD is better predicted using PRS rather thanAPOEstatus alone. Regional brain atrophy, as measured using volumetric MRI, is also an important biomarker for evaluating an individual’s risk of developing dementia. Previous predictions have shown that medial temporal lobe atrophy, as measured by a Hippocampal Occupancy Score (HOC) is highly associated with progression from MCI to AD.Added value of this studyIn the proposed model, the addition of genetics to MRI data lengthens the time over which the model can predict onset of dementia. The two measures appear to be complementary, with MRI showing near-term decline and genetics providing additional predictive power in the long-term. When compared to more invasive measures of amyloid, which have been shown to have long-term predictive power, we observed equivalent performance to CSF amyloid up to 8 years prior to disease onset and equivalent performance to amyloid PET three to four years prior to disease onset.Implications of all the available evidenceAlthough MRI remains relatively expensive, it is less expensive, less invasive, more accessible, and more commonly available than amyloid PET. Furthermore, MRI is already part of standard clinical practice and this model may be applied to standard clinical MRIs with no additional acquisition required. A recent survey of patients and their caregivers has highlighted a desire for access to better diagnostics, such as amyloid PET, to aid them in long-term legal, financial and healthcare planning. Our model, given the concordance with CSF and amyloid PET could be an alternate solution to fulfill this need. Furthermore, our model could facilitate the “active surveillance” of individuals who are high-risk and thereby enhance the possibility of early intervention.

Background: Insulin therapy is the treatment of choice in type 2 diabetes mellitus (T2DM) patients who are not achieving glycemic goals despite triple oral hypoglycemic agent (OHA) combination therapy. However, there is still no additional treatment option for patients who cannot afford insulin therapy or who have various clinical limitations. The purpose of this study was to evaluate the clinical efficacy and safety of four OHA combination therapy in poorly controlled T2DM patients who could not afford insulin therapy. Methods: Forty-seven T2DM patients were enrolled according to the following criteria: 1) glycosylated hemoglobin [HbA1c] > 8.5%, 2) ongoing treatment with 3 OHA combination therapy (metformin, sulfonylurea, dipeptidyl peptidase-4 inhibitor), or 3) combined limitations for applying insulin therapy. Patients were given the fourth OHA (pioglitazone) in addition to their previous treatment for 12 months. We evaluated changes in HbA1c, body weight, hypoglycemic events, and side effects. Results: At study completion, mean HbA1c and fasting plasma glucose were significantly reduced from 9.6% to 8.04% and from 198.4 mg/dL to 161.5 mg/dL, respectively (P < 0.001). Mean body weight was significantly increased from 66.7 kg to 69.3 kg. Hypoglycemia and side effects were observed 18 times and only 3 cases showed abnormal liver function tests or edema. In addition, subjects with higher initial HbA1c levels and HOMA-beta showed an independent association with a greater reduction in HbA1c. Conclusion: The 4 OHA combination therapy is effective and safe when insulin is not feasible.

Autoimmune thyroid disease (AITD) includes hyperthyroid Graves disease, hypothyroid autoimmune thyroiditis, and subtle subclinical thyroid dysfunctions. AITD is caused by interactions between genetic and environmental predisposing factors and results in autoimmune deterioration. Data on polymorphisms in the AITD susceptibility genes, related environmental factors, and dysregulation of autoimmune processes have accumulated over time. Over the last decade, there has been progress in the clinical field of AITD with respect to the available diagnostic and therapeutic methods as well as clinical consensus. The updated clinical guidelines allow practitioners to identify the most reasonable and current approaches for proper management. In this review, we focus on recent advances in understanding the genetic and environmental pathogenic mechanisms underlying AITD and introduce the updated set of clinical guidelines for AITD management. We also discuss other aspects of the disease such as management of subclinical thyroid dysfunction, use of levothyroxine plus levotriiodothyronine in the treatment of autoimmune hypothyroidism, risk assessment of long-standing antithyroid drug therapy in recurrent Graves' hyperthyroidism, and future research needs.

A major problem with antithyroid drug (ATD) therapy in Graves' disease is the high relapse rate. Therefore, clinicians have sought prognostic indicators of permanent remission. Suppression of serum thyrotropin (TSH) when ATD therapy is stopped carries a poor prognosis, but little is known regarding the significance of elevated serum TSH concentrations in the course of ATD therapy. The objective of this study was to determine if elevated serum TSH concentrations during methimazole (MMI) therapy is associated with a favorable long-term prognosis.We retrospectively studied patients with Graves' disease who were initially on MMI, in whom this drug was stopped because they had undetectable thyroid-stimulating antibodies (TSAbs) or were euthyroid after at least 24 months on MMI treatment. A strategy of high MMI doses plus T4 was not used in these patients. We identified 40 patients with elevated serum TSH concentration (10 microIU/mL) during MMI therapy (H-TSH group). Eighty-five percent of the H-TSH group had negative tests for TSAb. The H-TSH group was sex- and age-matched with 37 patients who had similar selection criteria, but did not have elevated serum TSH concentration during MMI therapy (N-TSH group). The H-TSH and N-TSH groups were similar in gross thyroid size, percentage of patients with exophthalmos, serum free thyroxine, duration of MMI treatment, TSAb status, duration that their TSAb tests remained negative, and thyroid peroxidase antibody titers. The patients were followed for 24 months after stopping MMI.In the H-TSH group, MMI-associated hypothyroidism typically occurred after 7-8 months of treatment with daily doses of 10-15 mg MMI. No patient had severe symptoms of hypothyroidism. The percentage of patients in remission at 6, 12, and 24 months after discontinuation of MMI was 90.0, 87.5, and 85.0, respectively, in the H-TSH group and 70.3, 67.6, and 54.1, respectively, in the N-TSH group (p 0.05 for the comparison of groups at 6 and 12 months and p 0.001 for comparison of the groups at 24 months).In patients with Graves' disease who are treated with MMI for at least 2 years and become euthyroid, the occurrence of elevated serum TSH concentrations during MMI treatment is a favorable indicator for long-term remission and is independent of multiple other factors including TSAb status, duration of MMI treatment, and gross parameters of goiter size.

See Article on Page 183-189 Coronary artery disease (CAD) accounts for a large fraction of the morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). T2DM is recognized as a CAD risk factor [1]. Patients with T2DM are also at greater risk for silent ischemia and infarction, with a higher prevalence of multi-vessel CAD. Delayed identification of CAD in patients with T2DM unquestionably worsens their prognoses. Thus, there is a clear need to identify patients with T2DM who are at risk for cardiovascular events before the onset of symptoms, although the utility of screening patients with T2DM for asymptomatic coronary atherosclerosis remains debatable. About 11 years ago, the American Diabetes Association suggested a risk factor-guided screening approach (e.g., considering age, gender, hypertension, and dyslipidemia) for early detection of CAD in patients with symptomatic and asymptomatic T2DM [2]. However, subsequent studies have shown that the traditional risk factors do not accurately predict the risk for cardiovascular events in T2DM patients [3]. This provides a rationale for an aggressive screening approach for CAD in asymptomatic patients with T2DM, almost independent of other risk factors. Nevertheless, there is no uniform policy regarding CAD screening in patients with T2DM, reflecting the statistical challenges of screening patients at low risk and the decisions that should be made from the resulting data. Generally, a resting electrocardiogram (ECG) and resting echocardiography are incapable of detecting asymptomatic CAD. Indeed, stress tests are needed for the early detection of CAD. The exercise ECG test is a popular stress test that has good accessibility and relatively low-cost. An exercise ECG test is an established method in subjects with known CAD, but its diagnostic accuracy is low in individuals with early atherosclerosis. Furthermore, few data exist on the relationship between exercise ECG test results and CAD risk in persons with T2DM, and most studies have involved small samples. Recently, William et al. [4] studied 2854 men with documented T2DM and showed that equivocal and abnormal exercise ECG responses in diabetic patients were associated with higher risk for all-cause cardiovascular disease and CAD mortality. William et al. [4] strongly recommended performing an exercise ECG test in patients who have had T2DM for ≥10 years and who have any family history of cardiovascular disease. Although recent studies regarding the exercise ECG test have shown good results for the early detection of CAD in diabetic patients, its value in diabetic patients is limited, because its low sensitivity requires a workload that is difficult to achieve in diabetic patients owing to comorbidities such as peripheral neuropathy, peripheral arterial diseases, and poor physical fitness. There is abundant evidence that carotid intima-media thickness (c-IMT) is a surrogate marker of subclinical CAD in both the general population and in patients with T2DM. Wagenknecht et al. [5] showed that the progression of c-IMT was 25% greater in diabetic subjects than in non-diabetic subjects. However, the measurement of c-IMT is an operator-dependent technique, making intra- and inter-observer variability an issue. Furthermore, there are no widely accepted age- and gender-adjusted reference ranges for c-IMT. Newer imaging methods such as myocardial perfusion scintigraphy using single-photon emission computed tomography (SPECT) and cardiac computed tomography angiography (CCTA) allow direct quantification of the coronary atherosclerotic burden and can predict the risk for cardiac events. Thus, these imaging tools are available for the early detection of coronary atherosclerosis. Myocardial SPECT with pharmacological stress has proved to be valuable in detecting silent CAD in asymptomatic diabetic patients, and its diagnostic accuracy is fairly high [6]. Although SPECT is more expensive than an exercise ECG test, its higher accuracy and lower non-diagnostic rate may make it a more cost-effective initial screening test. This functional imaging technique, however, does not always correlate with the anatomic situation and shows suboptimal sensitivity and specificity. Additionally, this technique cannot show the unstable plaque responsible for acute coronary syndrome. Recently, in a randomized controlled study, cardiac event rates were low and were not significantly reduced by myocardial SPECT screening for myocardial ischemia [7]. Non-invasive anatomic imaging such as CCTA with coronary artery calcium scoring can provide direct visualization of the coronary artery and has emerged as an alternative modality for the detection of occult CAD. However, most individuals with CAD have a plaque burden composition characterized by a combination of different types of plaque. Importantly, the role of coronary imaging in diabetic patients is not to document the presence of coronary atherosclerosis, but to identify those patients with more extensive disease who may benefit from further testing to reveal significant inducible myocardial ischemia [8]. Eventually, better imaging techniques will be needed to assess both the degree of plaque burden (soft and calcified) and the extent of vulnerable plaques. The combined use of anatomic atherosclerosis imaging and functional imaging is emerging as a complementary strategy [9], but the clinical application and cost-effectiveness of such an approach must be evaluated in prospective trials. For a screening test to be useful, the following conditions must be satisfied [10]: (i) it should be commonly available and relatively low-cost (cardiac SPECT and CCTA are expensive diagnostic tools), with a cost-effectiveness analysis of the screening process; (ii) it should have high positive and negative predictive values (the ability of myocardial SPECT to identify low-risk diabetic patients may not be as accurate, and the true prevalence of CAD in asymptomatic T2DM is unknown); and (iii) it should dictate decisions in clinical management that change the natural history of the disease (unfortunately, there is no randomized controlled study comparing treatment strategies in asymptomatic diabetic patients). Based on their well-designed clinical study, Yoo et al. recommended the use of an exercise ECG test for the early detection of asymptomatic CAD in patients who have had T2DM for ≥10 years and who have a family history of cardiovascular disease. From a clinical view point, this recommendation is meaningful because some factors do contribute to the early detection of asymptomatic CAD in T2DM. However, this study had some limitations. First, the number of study subjects was too small to obtain statistical significance. Second, the exercise ECG test has limited value in detecting early CAD, because of its low sensitivity. Third, the exercise ECG test may not be applicable in T2DM patients with autonomic dysfunction and/or physical unfitness. Thus, the clinical usefulness of an exercise ECG test as a tool for the early detection of asymptomatic CAD in T2DM should be cautiously interpreted. In conclusion, there is still no convincing evidence that screening programs to prevent cardiovascular events in patients with T2DM are cost-effective. Despite many uncertainties, however, we have highlighted some key points underlying the rationale for screening this high-risk population for heart disease. The detection of silent CAD in patients with T2DM will become an even greater public health issue in the future, as the number of people with T2DM increases. There are sound arguments on both sides of this issue, and the controversy can only be resolved by gathering more evidence from randomized controlled clinical trials.

We previously reported that hormones important for the normal growth and function of FRTL-5 rat thyroid cells, TSH, or its cAMP signal plus insulin or IGF-I, could transcriptionally suppress constitutive and γ-interferon (IFN)-increased synthesis of the 90K protein (also known as Mac-2BP). Here we cloned the 5′-flanking region of the rat 90K gene and identified a minimal promoter containing an interferon response element and a consensus E-box or upstream stimulator factor (USF) binding site, which are highly conserved in both the human and murine genes. We show that suppression of constitutive and γ-IFN-increased 90K gene expression by TSH/cAMP plus insulin/IGF-I depends on the ability of the hormones to decrease the binding of USF to the E-box, located upstream of the interferon response element. This site is required for the constitutive expression of the 90K gene. Transfection with USF1 and USF2 cDNAs increases constitutive promoter activity, attenuates the ability of TSH/cAMP plus insulin/IGF-I to decrease constitutive or γ-IFN-increased 90K gene expression but does not abrogate the ability of γ-IFN itself to increase 90K gene expression.

49,XXXXY syndrome is a rare sex chromosome aneuploidy and characterized by mental retardation, skeletal defects, craniofacial anomalies and hypogonadism. The increased frequency of diabetes mellitus in patients with Klinefelter syndrome and other types of X-chromosome polysomy has been reported, but no cases of diabetes mellitus in adult with 49,XXXXY syndrome have been reported so far. We report an 18-year-old patient with 49,XXXXY syndrome accompanying diabetes mellitus.

The major goal of this work was to characterize invasive ductal carcinoma and healthy fatty breast tissues noninvasively using the classification and regression tree analysis (CART) of 2D MR spectral data. 2D L-COSY spectra were acquired in 14 invasive breast carcinoma and 21 healthy fatty breasts using a GE 1.5 Tesla MRI/MRS scanner equipped with a 2-channel phased-array breast MR coil. The 2D spectra were recorded in approximately 10 minutes using a minimum voxel size of 1 ml without any water suppression technique. For healthy breasts, spectra were acquired from at least one fatty region. 2D L-COSY spectra were recorded in a total of 43 voxels. Five diagonal and six cross peak volumes were integrated and at least eighteen ratios were selected as potential features for the statistical method, namely CART. The 2D L-COSY data showed a significant increase for the majority of these ratios in invasive breast carcinomas compared to healthy fatty tissues. Better accuracy of identifying carcinomas and fatty tissues is reported using CART analysis of different combinations of ratios calculated from the relative levels of water, choline, and saturated and unsaturated lipids. This is a first report on the statistical classification of 2D L-COSY in human breast carcinomas in vivo.

A localized two-dimensional (2D) (1)H MR chemical exchange spectroscopic (L-EXSY) sequence has been implemented on a whole-body 1.5-T MRI/MRS scanner. The second spectroscopic encoding to monitor the chemical exchange was an integral part of the single-volume localization using three slice-selective 90 degrees radiofrequency (RF) pulses, thereby eliminating the need for any additional RF pulses, off-resonance/continuous wave saturation, or selective inversion, which are essential in the one-dimensional (1)H MR exchange spectroscopy. Even though the TM-crusher dephased single- and higher-order multiple-quantum coherences, the zero-quantum coherences were indistinguishable from the longitudinal magnetization leading to J-coupled 2D cross peaks similar to COSY. With TM of 300 ms, two different exchange cross peaks were recorded in human calf muscle: a first peak, between the mobile tissue water and total creatine pools, and a second peak, possibly between the olefinic and magnetically equivalent poly methylene protons of unsaturated lipids. Our preliminary results demonstrate that the intermolecular and intramolecular chemical exchange mechanisms can be monitored noninvasively in human calf muscle using 2D L-EXSY.

Differences in the epitopes of thyroid-stimulating antibodies (TSAbs) from patients with untreated Graves’ disease were compared with long-term response to antithyroid drugs. Epitopes were measured using Chinese hamster ovary cells transfected with wild-type human TSH receptor (TSHR) and two receptor chimeras, wherein TSHR residues 9–165 or 90–165 had been substituted with comparable residues of the LH/chorionic gonadotropin receptor. Of 159 patients studied, 52 (32.7%) exhibited positive TSAb activity with one or both chimera lines (heterogeneous group), and 107 (67.3%) had no activity with either (homogeneous group). Independent of all other parameters, patients with heterogeneous epitopes responded more favorably to oral antithyroid drugs than patients with homogeneous epitopes (65.4% vs. 41.9%, P = 0.011: estimated odds ratio by logistic regression, 2.17). Although most clinical parameters were not different at presentation, significant differences in the size of goiters, total T3 concentrations, and titers of TSH-binding inhibitory Igs were evident in the successfully treated group (n = 80) by comparison to the group of patients whose treatment failed (n = 79). Alone, these three parameters did not predict outcome; however, when either of these parameters were considered together with epitope heterogeneity, predictability of a positive therapeutic response was increased to nearly 80%. Thus, the presence of TSAbs with a heterogeneous epitope in a patient with Graves’ disease is not only associated with a favorable response to antithyroid drug treatment, it may help predict the response to treatment when the patient is initially seen.

The goal of this study was to evaluate the clinical significance of the blocking thyrotropin receptor antibodies (TSHRAb) in Graves' disease. The amount of blocking and stimulating TSHRAb were measured in 200 patients with untreated hyperthyroid Graves' disease using several cell lines carrying different TSHR chimera. Stimulating TSHRAb were measured in Chinese hamster ovary (CHO) cells with wild-type human TSHR (CHO-hTSHR) or a TSHR chimera with residues 90-165 (Mc2) or 8-165 (Mc1+2) substituted by equivalent residues of rat luteinizing hormone/chorionic gonadotrophin (LH/CG) receptor or in FRTL-5 cells. Blocking TSHRAb were measured in Mc2 cells. The activities of different TSHRAb were assessed and clinical features were compared to patients who were positive or negative for blocking TSHRAb antibodies. Blocking TSHRAbs were detected in 18.5% of patients (37/200) with hyperthyroid Graves' disease. Patients with blocking antibodies had significantly lower mean stimulating TSHRAb activities than those without blocking antibodies in wild-type CHO-hTSHR cells (301 +/- 179 vs. 446% +/- 537%, p = 0.005). Mean stimulating TSHRAb activities measured by FRTL-5, Mc1+2, or Mc2 cells and mean thyrotropin receptor inhibitor immunoglobulin (TBII) activities were not different between the two groups. The patients with blocking antibodies were not different from those without blocking antibodies in age, gender ratio, initial serum free thyroxine (T4) levels, or goiter size. However, the prevalence of exophthalmos was higher (35.1% vs. 17.5%, p = 0.024) in the patients with blocking antibodies than those without. In summary, the presence of blocking TSHRAb is not rare in patients with hyperthyroid Graves' disease when measured with chimeric receptor expressing cells. Blocking TSHRAb in Graves' sera do not strongly antagonize the action of stimulating TSHRAb in vivo, but could be a major factor responsible for underestimation of stimulating TSHRAb activities measured by CHO-hTSHR. The association of blocking TSHRAb with ophthalmopathy suggests that the TSHRAb repertoire of Graves' patients is different in those who do and who do not have ophthalmopathy.

Koichi Suzuki, Ph.D., Minoru Nakazato, M.D., Ph.D., Luca Ulianich, Ph.D., Atsumi Mori-Aoki, M.D., Emiko Moriyama, B.A., Hyun-Kyung Chung, M.D., Michelle Pietrarelli, Ph.D., Antonino Grassadonia, M.D., Hana Matoba, M.D., Ph.D., and Leonard D. Kohn, M.D. Cell Regulation Section, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, Laboratory of Molecular Endocrinology, MedStar Research Institute, Washington Hospital Center, 108 Irving Street, NW, Washington DC 20010, First Department of Internal Medicine, Tottori University School of Medicine, Yonago 683-8504, Japan

To determine whether there are changes in epitope recognition by stimulating TSH receptor antibodies (TSHRAbs) during treatment of hyperthyroidism and to evaluate the clinical relevance of such changes, we serially measured the activity of IgG preparations from 39 patients with Graves’ disease over an 8-month period. To measure epitope changes of the stimulating TSHRAbs, we used Chinese hamster ovary (CHO) cells transfected with wild-type human TSHR (hTSHR) or TSHR chimeras with residues 90–165 (Mc2) substituted by equivalent residues of the rat LH/CG receptor. When initially examined, 37 of the 39 patients had significant stimulating TSHRAb activity measured with wild-type CHO-hTSHR cells. Serial measurements of stimulating TSHRAb activity in Mc2 chimera-transfected cells divided the 39 patients into three distinct groups. Thus, 10 patients (heterogeneous epitope group) exhibited low but significant activity in Mc2 chimera assays at the start of the study; 10 patients who were initially negative in Mc2 chimera assays remained negative (persistently homogeneous epitope group); and 19 patients who were initially negative in Mc2 chimera assays became transiently or persistently positive during treatment, despite a simultaneous decrease in TSHRAb activity measured with wild-type TSHR (changing epitope group). The functional stimulating TSHRAb epitope thus changed from residues 90–165 to residues outside this region in the last group, which comprises nearly two-thirds of the initially Mc2-negative patients (19 of 29) and one-half of all patients (19 of 39). Patients in the changing epitope group responded more quickly and to lower doses of methimazole than patients in the persistently homogeneous epitope group, behaving in this respect exactly as the patients in the heterogeneous epitope group. Additionally, although the decrease in stimulating TSHRAb activities during the 8-month treatment period was similar in the two groups, the thyrotropin binding inhibitor immunoglobulin (TBII) activities decreased more rapidly in patients in the persistently homogeneous epitope group than in patients in the changing epitope group (P < 0.05). There were no differences in initial stimulating TSHRAb or TBII activities, degree of hyperthyroidism, goiter size, or prior duration of symptoms between the persistently homogeneous epitope group and changing epitope group. In summation, we show that the epitopes of stimulating TSHRAbs in Graves’ disease patients may change during their clinical course or treatment period, and that the change is from antibodies recognizing N-terminal TSHR residues 90–165 to antibodies recognizing other regions of the TSHR. We also show that the development of stimulating TSHRAbs with this heterogeneous epitope or their presence at the initial screening for disease activity seems to be associated with increased responsiveness to antithyroid drug therapy. We suggest, therefore, that Mc2 chimera assays may be useful to predict the response of patients to antithyroid drug therapy.

Carotid atherosclerosis, carotid autonomic neuropathy (CAN) and ischemic heart diseases are important issues in the clinical management of type 2 diabetes mellitus (T2DM). Since these cardiac problems are closely related to mortality [1], clinicians are eager to expand their knowledge in terms of the prevention of atherosclerosis and early detection of CAN. Jung et al. [2] demonstrated the association between the presence of CAN and carotid atherosclerosis presenting as carotie intima-media thickness and carotid plaque, and suggested that CAN may be an important determinant of subclinical atherosclerosis, which is a possible explanation for the excess cardiovascular mortality observed in patients with T2DM. Before expand the meaning of this study, however, I'd like to think over the significance of CAN evaluation process. In this study, the authors used the CAN scoring system, which is the sum of the score of five CAN tests. The presence of CAN was defined as the presence of two or more abnormal tests or an autonomic neuropathy score ≥2. Although it is a relatively simple method, I wonder whether these scoring systems can reflect a patient's exact CAN status. The result of each test may have different diagnostic power of atherosclerotic disease. Furthermore, the definition of two abnormal tests includes many potential combinations of different abnormal CAN tests. Since each of the five CAN test has a different meaning, each of these different combinations could also have unique clinical implications. Thus, it should again be questioned whether this definition of the presence of CAN is fully acceptable. Can we accept as "no evidence of CAN" cases with one abnormal test result? Is a ≥2 CAN score too high for early detection of atherosclerotic conditions? Further studies are needed to verify these arbitrary diagnostic criteria. Assessment of CAN is rarely accepted as first line studies in newly diagnosed patients with T2DM [3], mainly because of the cost and time requirements of CAN evaluation. Thus, further studies are needed for the development of easier, more cost-effective methods of CAN evaluation and to confirm its clinical significance, in order to expand the screening process for this important diabetic complication.

Lymphocytic hypophysitis is a rare inflammatory disorder which is caused by autoimmune destruction of the pituitary gland. Almost all reported cases have been in women and the disease is often associated with pregnancy. We describe here the first male case of lymphocytic hypophysitis in Korea. The patient presented with headache, impotence, decreased libido, and deteriorated vision. Endocrinologic studies showed panhypopituitarism, and pituitary MRI imaging revealed a homogeneously enhanced pituitary mass with a thickened stalk. Treatment with prednisolone and thyroid hormone for five months was ineffective. Transsphenoidal resection of the pituitary mass was performed successfully with normalization of the visual field defect. Histologic examination revealed diffuse lymphocytic infiltration with dense collagenous fibrosis, consistent with lymphocytic hypophysitis. Lymphocytic hypophysitis should be considered in differential diagnosis even in men with hypopituitarism and an enlarged pituitary gland.

Few reports have identified blocking thyrotropin receptor antibodies (TSHRAbs) as a pathogenic mechanism explaining spontaneous hypothyroidism after antithyroid drug (ATD) treatment of Graves' disease. Here we report 2 Graves' patients who showed different courses of hypothyroidism after ATD treatment. The first patient had Graves' hyperthyroidism and was treated with ATD for 1 year. After a short period of euthyroidism, she developed permanent hypothyroidism with blocking TSHRAb. The second patient became euthyroid after 1 year of ATD treatment. After 3 years, however, she presented with hypothyroidism with blocking TSHRAb activity. Her hypothyroidism was transient, and restoration of euthyroidism was followed by disappearance of blocking TSHRAb. Blocking and stimulating TSHRAbs activities of these 2 patients were serially measured using Chinese hamster ovary (CHO) cells transfected with wild-type human TSHR (CHO-hTSHR) and 2 TSHR chimeras with residues 8-165 (Mc1+2) or 90-165 (Mc2) substituted by equivalent residues of the luteinizing hormone/chorionic gonadotropin receptor (LH/CGR). During their hypothyroid phases, blocking TSHRAbs activities were positive in all 3 kinds of assays and stimulating TSHRAbs activities were negative in CHO-hTSHR or in Mc 1+2 assay. Mc2 stimulating TSHRAb activity was detected in sera of hypothyroid phase of the second patient who had transient hypothyroidism but not in the first whose hypothyroidism was permanent. In these 2 cases, we demonstrate the causative role of blocking TSHRAb in the development of hypothyroidism after ATD treatment in Graves' patients. Interestingly, the difference in the course of blocking TSHRAb-induced hypothyroidism was associated with the difference in epitope reactivities of TRAb during hypothyroid phase that developed after ATD treatment of Graves' disease.

초래되고 면역반응이 촉발되며, 이에 대한 면역 억제인자들의 조절 이 충분치 못할 경우 자가면역성 갑상선질환이 시작된다. 이후 각종 이차 인자들이 작용하면서 자가면역질환의 진행이 증폭되는데, 이 모든 과정은 유전적 소인과 환경인자의 복합적인 영향 하에 이어진 다[2]. 갑상선기능에 영향을 미치는 환경인자는 크게 외부 환경 물질들 과 개체 내부의 내인성 인자(endogenous factors)로 구분할 수 있다. 내인성 인자는 유전적 소인이 동일하거나 유사하더라도 환경인자에 대한 개체의 반응이 달라지는 것을 설명하는 요소이다. 내인성 인자 는 각 개체가 가지고 있는 특성이며, 외부 환경과 밀접하게 연관되어 있지만 다분히 그 개체만의 고유한 상태로 이해된다. 대부분의 내인 성 인자들은 고정적이지 않은 경우가 많고 시간이 흐름에 따라 유동 적으로 변화할 수 있는데, 임신과 출산, 영양상태, 사춘기나 갱년기, 여성과 남성의 차이, 흡연여부, 감정적 취약성(emotional vulnerability) 등과 함께, 일생 중 경험하게 되는 주요 사건(major life event)나 강한 스트레스 경험 등도 포함된다. 정도를 수치화하기 어렵다는 점 때문에 스트레스와 관련된 갑상선기능 이상을 객관적으로 연구하 는 것에는 제약이 따르지만, 극심한 공포 상황과 같은 심리적 스트 레스와 중한 질환을 앓는 등의 신체적 스트레스 모두 갑상선기능에 영향을 미칠 수 있는 것으로 알려져 있다. 강한 스트레스가 주어지 면 시상하부-뇌하수체-부신 축이 자극되면서 면역관련 호르몬의 분 비가 바뀌고, 잘 알려진 스트레스 관련 단백 heat-shock protein이 증가하는 등 신경-내분비-면역계가 상호작용하면서 자가면역성 갑상 선질환이 발생하는 것으로 생각된다[3]. 내인성 인자와 함께 갑상선기능에 영향을 미치는 외부 환경물질

Received: 2 December 2010, Accepted: 1 February 2011 Corresponding author: Dohee Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Dankook University College of Medicine, San 16-5, Anseo-dong, Dongnam-gu, Cheonan 330-715, Korea Tel: +82-41-550-3934, Fax: +82-41-556-3256, E-mail: dh9070@dankook.ac.kr Hypocalcemia can be complicated, on rare occasions, by congestive heart failure and may also be associated with labor and lactation in some cases. Herein, we report a 30-year-old woman with hypocalcemia-induced heart failure secondary to primary idiopathic hypoparathyroidism precipitated by lactation. The patient presented with chest pain and paresthesia in both arms and legs during breast-feeding after her second delivery. She had severe hypocalcemia and low parathyroid hormone levels. Hypocalcemiainduced rhabdomyolysis further aggravated her hypocalcemia symptoms. The echocardiogram showed global hypokinesia with an ejection fraction of 47%. After calcium and vitamin D replacement, her symptoms and ventricular function improved. Hypocalcemia needs to be considered in patients with heart failure, because it is readily reversible. To the best of our knowledge, this is the first report of a patient with heart failure and rhabdomyolysis induced by primary hypoparathyroidism during lactation. (Endocrinol Metab 26:268-271, 2011)

One of the rare diseases for differential diagnosis of subacute thyroiditis is metastases within the thyroid gland. We report here on a 72-year-old-woman with painful goiter and signs of hyperthyroidism. Her serum concentration of thyroid hormone was in the up-per limit of normal, and the uptake of radioactive iodine by the thyroid was completely depressed. Although subacute thyroiditis was suspected, an additional work up that included a chest CT scan was done for the combined cough and chronic weakness. The result was lung cancer with metastatic involvement of the thyroid and multiple lymph nodes. She refused further anti-cancer therapy and died 5 months after the diagnosis. For the differential diagnosis of such a rare case, careful examination is important even in patients with the typical symptoms and laboratory findings of subacute thyroiditis. (

Sheehan's syndrome is postpartum hypopituitarism due to the necrosis of the pituitary gland. It is usually the result of severe hypotension or shock caused by massive hemorrhage during or after delivery. Patients with Sheehan's syndrome have varying degrees of anterior pituitary hormone deficiency. They are accompanied with amenorrhea and ovulation dysfunction, and so they rarely get pregnant naturally. Ovulation induction is necessary if these patients desire to become pregnant. However, spontaneous pregnancy may be possible in some patients who have a preserved gonadotrophin reserve. We experienced a case of 29-year-old woman who was diagnosed Sheehan's syndrome 20 months after delivery and we medicated her with prednisolone and thyroxine. She got pregnant spontaneously after 18 months of hormone replacement therapy although she had amenorrhea and irregular menstrual cycles. She successfully delivered a baby by cesarean section. Here we report on this case with a review of the relevant literature concerned with pregnancy and Sheehan's syndrome.

Background: Type 2 diabetes mellitus (DM) is a growing health problem of the elderly population. Diabetes education based on effective patient-provider communication pla ys a major role in treatment of type 2 DM. In this study, as an effort for making better communication, we examined how older patients with type 2 DM report their healthcare goals, what factors influencing their goals and control their self-care behaviors. Methods: Subjects were thirty three patients with type 2 DM aged 65 and older. An interviewer conducted one-on-one interviews using open questions about 5 categories: concept of “health,” purpose of DM management, causes of DM, practical aspects of DM management, and decision making related to DM management. Interviews were audiotaped, transcribed and two investigators independently reviewed. Results: The majority of our sample (79%) expressed their management go als in a socio-functional language, rather than medical issues. They defined “Healthy” as a status of keeping daily life without any symptoms. Many subjects has not altered their diet habits (33%) and making no efforts to exercise (64%) due to physical and psychological limitations though almost all (91%) older patients recognized the importance of diet control and exercise. Conclusion: When introduce the goal of DM management, it would be better to use socio-functional terms in diabetes education of elderly patients with type 2 DM. To improve the self-care behaviors, it is essential to make efforts not only to give knowledge but also to find their physical and psychological limitations related to poor performances. (Korean Diabetes J 33:439-447, 2009)

Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant syndrome characterized by the presence of a medullary thyroid carcinoma, pheochromocytoma and hyperparathyroidism. MEN2A arises due to germline missense mutations of the RET proto-oncogene. Specific RET mutations correlate with the onset of age and the aggressiveness of a medullary thyroid carcinoma. However, the clinical presentation varies even within families, where patients carry the same mutation. Recently, it has been reported that polymorphisms of RET may have a modifier effect on the presentation. We experienced a case of 42-year-old man, whose bilateral pheochromocytoma and medullary thyroid carcinoma were incidentally found. Genetic testing detected a mutation in codon 634 (C634R) and a polymorphism in codon 691 (G691S) of the RET proto-oncogene. His mother, younger brother and his only son had the same mutation and polymorphism. We report this case with a review of the literature about RET gene polymorphisms. (J Kor Endocr Soc 22:453~459, 2007)

Background: Since various thyroid diseases have dominant prevalence in women, it has been suggested that female sex hormone have important role on thyroid cell physiology. Interestingly, many thyroid disorders are newly diagnosed or changed their course around the period of high estrogen status, such as pregnancy. In this study, we questioned whether high concentration of estrogen could modulate thyroid cell function. Methods: We treated normal rat thyroid FRTL-5 cell line with different time and concentration of estradiol. Using cell count, FACscan, and Northern blot analysis, we compared the changes of cell growth, cell cycle progression and thyroid specific genes expression. To evaluate the influence of thyroid stimulating hormone (TSH), all experiment was designed as two different sets, with (6H) or without TSH (5H). Results: The concentration of 10-1000 nM estradiol had definite stimulatory function on thyroid cell growth in 5H condition as concentration dependent manner. FACscan revealed the increased cell growths were related to G1/S progression. The Pax-8, TTF-1 and NIS gene expressions were dramatically increased in 10-1000 nM of estradiol, too. With TSH (6H), however, we could not find any cell growth stimulating effects with 10-1000 nM of estradiol. Conclusion: High concentration of estradiol is one of important control factor for thyroid growth and thyroid specific genes expression, especially in 5H condition. It indicate that exposure to high concentration of female sex hormone, such as pregnancy, can be a direct stimulating factor to various thyroid function and related to autoimmune or nodular thyroid diseases around the period of pregnancy (J Kor Soc Endocrinol 21:32~39, 2006).