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A systematic review of genetic studies of thyroid disorders in Taiwan identified studies of gene mutations involved in the synthesis and binding of thyroid hormone, as well as mutations of proto-oncogenes and tumor suppressor genes in thyroid cancer. Studies related to gene polymorphisms in patients with autoimmune thyroid disease (AITD) and thyroid cancer were also reviewed. The most prevalent mutations in the Han-Chinese population were c.2268insT in the thyroid peroxidase (TPO) gene and c.919-2A>G in the Pendred syndrome (PDS) gene. Additional mutations have also been revealed in the genes encoding TPO (n = 5), thyroglobulin (TG; n = 6), pendrin (n = 2), and thyroxine-binding globulin (TBG; n = 2), which were novel at the time they were reported. The prevalence of various somatic mutations in differentiated thyroid cancer was similar in Taiwan and Western countries, with the RAS kinase mutation and tyrosine receptor kinase (TRK) and rearranged during transfection (RET) proto-oncogenes being detected in lower frequencies and the B-type RAF kinase (BRAF) mutation accounting for the majority of cases. Recent microRNA analysis revealed an association between miR146b and the BRAF mutation, which was associated with poor prognosis of papillary thyroid carcinoma (PTC). Susceptibility to Graves' disease (GD) was linked to the human leukocyte antigen (HLA) region. The associated alleles were different in Han-Chinese and Caucasians; HLA-DPB1*0501, the major allele in Taiwan, has a low frequency in the West. By contrast, a high frequency of HLA-DRB1*0301 was detected in Caucasians but not Han-Chinese. In addition to the HLA region, cytotoxic T lymphocyte-associated molecule-4 (CTLA4) gene polymorphisms +49G>A and +6230G>A (CT60) were positively associated with GD. The GG genotype and G allele of single nucleotide polymorphism (SNP) +49G>A were also related to relapse of Graves' hyperthyroidism after antithyroid drug withdrawal. Differences in the genetic patterns between Han-Chinese and Caucasians for some thyroid disorders suggest the importance of variable genetic influences in different populations., (Copyright © 2014. Published by Elsevier Taiwan.)

Objective: Patients with type 2 diabetes mellitus (T2DM) and peripheral arterial disease are classified as having very high cardiovascular risks. We therefore sought to determine whether assessments of the ankle brachial index (ABI) and brachial ankle pulse wave velocity (baPWV) together exhibited a superior association with the outcomes of T2DM., Methods: A retrospective analysis of patients receiving ABI and baPWV during the period 2005-2007 was performed. Patients A total of 452 subjects were enrolled and followed-up for a mean 5.8 years after being grouped according to the ABI (<0.9 vs. ≥0.9) and baPWV (<1,700 cm/s vs. ≥1,700 cm/s)., Results: The outcomes were all-cause mortality and composite events (all-cause mortality, hospitalization for coronary artery disease, stroke, re-vascularization, amputation and diabetic foot). Inter-group differences in the smoking rate, duration of diabetes, systolic and pulse blood pressure, anti-platelet drugs, estimated glomerular filtration rate, and urine albumin excretion were significant. During the follow-up period, 17 (3.7%) individuals died and composite events were recorded in 64 cases (14.1%). A low ABI plus high baPWV was found be associated with poor outcomes compared with a normal ABI plus low baPWV (p<0.001). Meanwhile, a low ABI plus high baPWV was associated with an increased risk of all-cause mortality [hazard ratio (HR) 17.01, 95% confidence interval (CI) 1.57-183.73, p=0.019] and composite events (HR 8.53, 95% CI 3.31-21.99, p<0.001)., Conclusion: In this study, the outcomes of patients with a low ABI plus high baPWV were the worst, while the subjects with a low ABI plus low baPWV or normal ABI exhibited similar outcomes. Therefore, the ABI plus baPWV exhibits a better association with the outcomes of T2DM.

Background: Adrenocortical carcinoma is a rare malignancy and rare cause of Cushing's syndrome., Case Presentation: A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia. However, his serum aldosterone and plasma renin activity were within normal limits. Instead, Cushing's syndrome was diagnosed by elevated urine free cortisol and a non-suppressible dexamethasone test. Abdominal computed tomography showed a 7.8 × 4.8 cm mass lesion at the right adrenal gland with liver invasion. Etomidate infusion was performed to reduce his cortisol level before the patient received a right adrenalectomy and liver wedge resection. The pathology report showed adrenocortical carcinoma with liver and lymph node metastasis. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the tumor was classified as T4N1M1, stage IV. Recurrent hypercortisolism was found shortly after surgery. The patient died of Fournier's gangrene with septic shock on the 59th day after diagnosis., Conclusions: We report a case of rapidly progressive stage IV adrenocortical carcinoma with initial presentations of hypokaelmia and hypertension, mimicking hyperaldosteronism.

Objective The six core competencies designated by Accreditation Council for Graduate Medical Education (ACGME) are essential for establishing a patient centre holistic medical system. The authors developed a faculty programme to promote the postgraduate year 1 (PGY(1)) resident, ACGME six core competencies. The study aims to assess the clinical instructors' perception, attitudes and subjective impression towards the various sessions of the 'faculty development programme for teaching ACGME competencies.' Methods During 2009 and 2010, 134 clinical instructors participated in the programme to establish their ability to teach and assess PGY(1) residents about ACGME competencies. Results The participants in the faculty development programme reported that the skills most often used while teaching were learnt during circuit and itinerant bedside, physical examination teaching, mini-clinical evaluation exercise (mini-CEX) evaluation demonstration, training workshop and videotapes of 'how to teach ACGME competencies.' Participants reported that circuit bedside teaching and mini-CEX evaluation demonstrations helped them in the interpersonal and communication skills domain, and that the itinerant teaching demonstrations helped them in the professionalism domain, while physical examination teaching and mini-CEX evaluation demonstrations helped them in the patients' care domain. Both the training workshop and videotape session increase familiarity with teaching and assessing skills. Participants who applied the skills learnt from the faculty development programme the most in their teaching and assessment came from internal medicine departments, were young attending physician and had experience as PGY(1) clinical instructors. Conclusions According to the clinical instructors' response, our faculty development programme effectively increased their familiarity with various teaching and assessment skills needed to teach PGY(1) residents and ACGME competencies, and these clinical instructors also then subsequently apply these skills.

Background: Thyroglobulin (TG) defect is a rare cause of congenital hypothyroidism. Although only 44 mutations of the human TG gene have been identified, we have suspected a TG defect in 38% of Taiwan Chinese children/adolescents presenting with moderate or severe thyroidal dyshormonogenesis., Study Objective: The aim of the study is to report the discovery of new TG gene mutations and associated clinical manifestations of the defective TG protein., Patients and Results: In seven patients from six families, we detected six new TG gene mutations, including c.1348delT, p.R432X (c.1351C>T), g.IVS3 + 2T>G, c.1712delT, p.Q1765X (c.5350C>T), and c.6047delA. The c.1348delT and p.R432X mutations were the most common, detected in 33 and 25%, respectively, of alleles studied. Haplotype analysis suggested that the c.1348delT and g.IVS3 + 2T>G mutations are due to founder effects, whereas p.R432X is probably due to independently recurrent de novo mutations. mRNA transcript of the g.IVS3 + 2T>G mutant, detected in whole blood by reverse transcription-nested PCR, showed skipping of exon 3 (98-bp deletion) and a frameshift, with a terminal signal after 17 altered amino acid residues., Conclusions: TG defects have an important role in severe thyroidal dyshormonogenesis (pretreatment, or after a 3-wk T(4) withdrawal, plasma T(4) < or = 30 nmol/liter) in Taiwanese. Its genetic characteristics are markedly different from those described in other populations presenting with mutations of the TG gene.

Context: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism., Objective: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred., Design: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR., Results: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband's parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR., Conclusion: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

Objective: To evaluate whether treatment with insulin is advantageous compared with oral antidiabetes agents in newly diagnosed type 2 diabetes with severe hyperglycemia after short-term intensive insulin therapy., Research Design and Methods: Newly diagnosed type 2 diabetic patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for 10-14 days. The oral glucose tolerance test (OGTT) was performed after intensive insulin treatment. After discharge, the patients were randomized to receive either insulin injections or oral antidiabetes drugs (OADs) for further management. The OGTT was repeated 6 months later, and beta-cell function and insulin sensitivity were evaluated again. These subjects were continually followed up for another 6 months to evaluate their long-term glycemic control., Results: At the 6th month of the study, the A1C level was significantly lower in the insulin group than in the OAD group (6.33 +/- 0.70% vs. 7.50 +/- 1.50%; P = 0.002). During the follow-up visit, the A1C level was still better in the insulin group (6.78 +/- 1.21% vs. 7.84 +/- 1.74%; P = 0.009). All parameters regarding beta-cell function measured in the OGTT were improved significantly in both groups after 6 months of treatment. Compared with the OAD group, the homeostasis model assessment of beta-cell function index, insulin area under the curve, and insulinogenic index were better in the insulin group., Conclusions: A 6-month course of insulin therapy, compared with OAD treatment, could more effectively achieve adequate glycemic control and significant improvement of beta-cell function in new-onset type 2 diabetic patients with severe hyperglycemia.

Background: Hirschsprung's disease (HSCR), or aganglionic megacolon, is a hereditable disease of the enteric nervous system. It is an embryonic developmental disorder characterized by the absence of ganglion cells in the lower enteric plexus. Gut motility is compromised in HSCR, with consequent risk of intestinal obstruction., Methods: We sequenced the RET gene and characterized the clinical manifestations in 15 unrelated Chinese patients (9 males, 6 females; age range, 2-21 years) with sporadic HSCR. Genomic DNA extraction, PCR and DNA sequence analysis were performed according to standard procedures., Results: We identified heterozygous RET gene mutations in 2 patients. The mutations included a missense mutation in exon 2 (CGC --> CAC) resulting in a substitution of arginine by histidine at codon 67 (patient 1), and a missense mutation in exon 3 (TAC --> AAC) resulting in a substitution of tyrosine by asparagine at codon 146 (patient 2). The pathological findings disclosed short-segment HSCR in patient 1 and long-segment HSCR in patient 2, respectively., Conclusion: We identified RET gene mutations in 2 of 15 patients with HSCR in Taiwan. The Y146N mutation we identified was novel.

Objective: To investigate whether the effects of regular diabetes health education or a holiday-specific pamphlet before the Chinese New Year holiday period could improve glycemic control during the winter holidays among patients with type 2 diabetes mellitus., Study Design: Randomized controlled trial., Methods: The study was conducted from October 2004 to December 2005 in Taipei Veterans General Hospital. Subjects were randomized to program 1 (receipt of regular diabetes education between October 20 and November 25, 2004, and then every 3-4 months) or to program 2 (receipt of a special reminder pamphlet during the holidays). The patients were seen and blood samples obtained on 4 occasions during the holidays and then every 4 months through December 2005., Results: Ninety-three subjects completed the first 4 visits during the Chinese New Year holidays, and 89 subjects completed 12 months of the study. Fructosamine levels in program 1 increased more during the preholiday period than those in program 2 (mean [standard deviation] 7.4 [5.2] vs -5.3 [8.3] mumol/L, P = .03) during the preholiday period. Changes in fructosamine levels during the holiday and postholiday periods were similar in the 2 groups. At the end of the holidays, changes in glycosylated hemoglobin (A1C) levels were 0.34% (95% confidence interval, 0.03%-0.85%) in program 1 and 0.09% (95% confidence interval, -0.23% to 0.42%) in program 2. After the Chinese New Year holidays, the groups had similar changes in A1C levels, with a slight downward decline thereafter., Conclusion: A special educational reminder pamphlet for the holidays led to improvements in glycemic control during the Chinese New Year holidays.

Background: A unique genomic difference between human and civet severe acute respiratory syndrome coronaviruses (SARS-CoVs) is that the former has a deletion of 29 nucleotides from open reading frame (orf) 8a' that results in the generation of orf8a and orf8b. The objectives of the present study were to analyze antibody reactivity to ORF8a in patients with SARS and to elucidate the function of ORF8a., Methods: Western-blot and immunofluorescent antibody assays were used to detect anti-ORF8a antibody. SARS-CoV HKU39849 was used to infect stable clones expressing ORF8a and cells transfected with small interfering RNA (siRNA). The virus loads (VLs) and cytopathic effects (CPEs) were recorded. Confocal microscopy and several mitochondria-related tests were used to study the function of ORF8a., Results: Two (5.4%) of 37 patients with SARS had anti-ORF8a antibodies. The VLs in the stable clones expressing ORF8a were significantly higher than those in control subjects 5 days after infection. siRNA against orf8a significantly reduced VLs and interrupted the CPE. ORF8a was found to be localized in mitochondria, and overexpression resulted in increases in mitochondrial transmembrane potential, reactive oxygen species production, caspase 3 activity, and cellular apoptosis., Conclusions: ORF8a not only enhances viral replication but also induces apoptosis through a mitochondria-dependent pathway.

Background: This study compares the cardiovascular autonomic function in type 2 diabetes with and without microalbuminuria, in order to identify the possible links between early nephropathy and diabetic autonomic neuropathy (DAN)., Methods: Cardiovascular reflex tests were performed to determine the cardiovascular autonomic function. Thirty cases of type 2 diabetes with microalbuminuria were studied for evidence of DAN to compare with a normoalbuminuric group of 56 diabetic patients., Results: There was an increased prevalence of autonomic dysfunction in patients with microalbuminuria (63.3% in the microalbuminuria group vs. 40.0% in the normoalbuminuric controls, p = 0.001). These patients had lower heart rate variability during single breathing tests (6.9 +/- 4.3 vs. 9.6 +/- 3.6 beats/minute, p = 0.005), during 6 consecutive breathings (5.8 +/- 3.6 vs. 8.2 +/- 3.3 beats/minute, p = 0.005), after standing up (12.2 +/- 4.6 vs. 15.0 +/- 5.2 beats/ minute, p = 0.012), and during the Valsalva maneuver (11.3 +/- 3.5 vs. 13.2 +/- 3.6 beats/minute, p = 0.022). The heart rate variability with these stresses was revealed to be less favorable in subjects with microalbuminuria. However, blood pressure (BP) changes from the sitting to standing position were not significantly different for systolic BP (11.5 +/- 10.7 vs. 10.7 +/- 7.8 mmHg, p = 0.741) and diastolic BP (5.2 +/- 4.4 vs. 5.9 +/- 4.0 mmHg, p = 0.451) between the 2 groups., Conclusion: Type 2 diabetic patients with microalbuminuria have diminished heart rate variability in response to deep breathing, change of position and the Valsalva maneuver, but they preserve BP response to postural change. Therefore, microalbuminuria seems to be associated with early DAN, but not with advanced DAN.

Objective: In the U.K. Prospective Diabetes Study, A1C increased from 1.2 to 1.7% and fasting plasma glucose from 1.0 to 2.8 mmol/l over 10 years in type 2 diabetic patients. It is not known whether the blood glucose increase observed in long-term studies of type 2 diabetes results from small, steady increases throughout the year or from increases during discrete periods., Research Design and Methods: To estimate the variation of actual glycemic control and its relation to holiday times, we measured A1C and fructosamine in 110 patients with type 2 diabetes. These measurements were performed four times at intervals of 4-6 weeks; therefore, glycemic change was determined for three periods: preholiday period (from between November 13 and December 20 to between December 20 and January 20), holiday period (from between December 20 and January 20 to between January 28 and February 28), and postholiday period (from between January 28 and February 28 to between March 1 and April 10). A final measurement of A1C was obtained from 90 subjects in the following December or January., Results: The mean A1C increased, but not significantly, during the preholiday (increase 0.135 +/- 0.723%, P = 0.055) and holiday (increase 0.094 +/- 0.828%, P = 0.239) periods. The mean A1C decreased, but not significantly, during the postholiday period (decrease 0.022 +/- 0.588%, P = 0.695). Altogether, the A1C change during these three periods increased significantly (increase 0.207 +/- 0.943%, P = 0.024). The mean fructosamine increased significantly during the preholiday period (increase 0.151 +/- 0.460 mmol/l, P = 0.001), but there was no significant change during the holiday period (increase 0.057 +/- 0.593 mmol/l, P = 0.321). However, fructosamine decreased significantly during the postholiday period (decrease 0.178 +/- 0.448 mmol/l, P < 0.001). Altogether, the fructosamine changes during the study periods showed no significant difference (increase 0.030 +/- 0.566 mmol/l, P = 0.579). Between March or early April and the following December or January, there was no additional change in A1C (decrease 0.009 +/- 1.039%, P = 0.935) for the 90 participants who returned for follow-up treatment., Conclusions: The present study demonstrates an influence of winter holidays on the glycemic control of patients who have type 2 diabetes, and this poor glycemic control might not be reversed during the summer and autumn months. Therefore, the cumulative effects of the yearly A1C gain during the winter holidays are likely to contribute to the substantial increase in A1C that occurs every year among type 2 diabetic individuals.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder characterized by high penetrance of relatively benign, lifelong persistent hypercalcemia and hypocalciuria. By contrast, neonatal severe hyperparathyroidism represents a life-threatening form of hypercalcemia that can cause the early newborn mortality if immediate intervention is not undertaken. Both disorders are due to inactivation mutation of the human calcium-sensing receptor (CaSR) gene on chromosome 3q21-24. Up to now, more than 30 mutations in the CaSR gene associated with FHH have been described. In this study, we analyzed one 79-yr-old male with hypocalciuric hypercalcemia without siblings or children to compare with an additional group of 50 normal Chinese subjects in Taiwan. DNA sequence analysis of the CaSR gene was performed. The result showed that the proband had a heterozygous nonsense mutation in exon 7 of the CaSR gene at codon 648 (CGA-->TGA/Arg-->Ter). This mutation, located in the COOH-terminal of the first intracellular loop of the CaSR, predicts a markedly truncated protein. We have identified a novel R648X mutation in the CaSR gene in one patient with FHH in Taiwan

A 59-year-old man, who presented to hospital with a large expansile bone tumour over the left elbow and a mass in the right side of the neck, was eventually found to have parathyroid adenoma manifesting clinically as severe hypercalcaemia. Histological examination of a section of the neck mass showed parathyroid adenoma and the bone biopsy specimen revealed a 'brown tumour', consistent with hyperparathyroid bone disease.