Sural nerve sensory response in diabetic distal symmetrical polyneuropathy.

INTRODUCTION: The sural sensory nerve action potential (SNAP) amplitude is a measure of the number of axons. We tested the hypothesis that sural SNAP amplitude can be used as a marker in screening, severity evaluation, and follow-up of diabetic distal symmetrical polyneuropathy (DSPN). METHODS: Patients with type 2 diabetes underwent nerve conduction studies and were followed for 6 years. Composite amplitude scores (CASs) were determined to evaluate DSPN severity. RESULTS: Sural SNAP amplitudes were negatively correlated with CAS (r = -.790, P < .0001), and changes in sural SNAP amplitudes were negatively correlated with those of CAS after controlling for follow-up duration (r = -.531, P = .028). DISCUSSION: When a patient's baseline sural SNAP amplitude is above zero, it can be used as one measure of DSPN in screening, severity evaluation, and follow-up. However, if the patient's sural SNAP value is zero, CAS can be used as a follow-up measure.

Long-term outcomes of extracorporeal shockwave therapy for chronic foot ulcers.

BACKGROUND: Recent studies showed that extracorporeal shockwave therapy (ESWT) is effective in the treatment of chronic foot ulcers in short term. However, the long-term effects of ESWT in chronic foot ulcers are unknown. The purpose of this study was to evaluate the long-term outcomes of ESWT in chronic foot ulcers with 5-y follow-up. METHODS: The study cohort consisted of 67 patients with 72 ulcers including 38 patients with 40 ulcers in the diabetes mellitus (DM) group and 29 patients with 32 ulcers in the non-diabetes mellitus (non-DM) group. Each patient received ESWT to the affected foot twice per week for 3 wk for a total of six treatments. The evaluations included clinical assessment for the ulcer status, local blood flow perfusion, and analysis of mortality and morbidity. RESULTS: The results showed completely healed ulcers in 55.6% and 57.4% of total series, 48% and 43% of DM group, and 66% and 71% of non-DM group at 1 and 5 y (P = 0.022 and P = 0.027), respectively. The mortality rate was 15% in total series, 24% in DM group, and 3% in non-DM group (P = 0.035). The rate of amputation was 11% in total series, 17% in DM group, and 3.6% in non-DM group (P = 0.194). The blood flow perfusion rate significantly increased after ESWT for up to 1 yr but decreased from 1-5 y in both groups. However, the non-DM group showed significantly better blood flow perfusion than the DM group at 5 y (P = 0.04). CONCLUSIONS: ESWT appears effective in chronic diabetic and nondiabetic foot ulcers. However, the effects decreased from 1-5 y after treatment.

Long-term outcomes of distant metastasis from differentiated thyroid carcinoma.

BACKGROUND: The aim of this study was to identify the prognostic factors of long-term survival and optimal therapeutic protocol for patients with distant metastasis secondary to differentiated thyroid carcinoma (DTC). METHODS: A retrospective review of 1665 patients with DTC treated at a regional tertiary hospital in Taiwan between 1986 and 2010 was performed. Among them, 207 patients were found to have distant metastasis. For a long-term outcome survey, 126 patients that had received at least 5 years (mean 9·6 ± 5·2 years) of follow-up after the diagnosis of distant metastasis were analysed for this study. Prognostic factor analysis included age, sex, histology, disease stage, type of surgical procedure, site of metastatic foci, (131) I avidity of tumour, thyroglobulin (Tg) level and accumulated therapeutic dose of radioiodine (RAI). RESULTS: The mean age at diagnosis of distant metastasis was 46·4 ± 17·2 years. The female-to-male ratio was 2·1:1. The 10- and 15-year survival rates were 70·6% and 64·9%, respectively. The independent predictors of survival were younger age, surgical dissection of neck lymph nodes (LNs) and low TSH-stimulated Tg level (<400 µg/l) at the discovery of metastasis. Most cases of resolved (131) I-avid disease (79·2%) and disease-free remission (87·5%) received a cumulative dose no >600 mCi of (131) I. The mean cumulative doses of (131) I in both deceased and living patients were similar. CONCLUSION: The prognosis of patients with distant metastasis from DTC within this study was found to be favourable. Survival may be improved by surgical dissection of neck LNs, but repeated (131) I therapy >600 mCi is not advised unless there is a high probability that it would benefit the patient.

Albuminuria is an independent risk factor of erectile dysfunction in men with type 2 diabetes.

INTRODUCTION: Erectile dysfunction (ED) is a frequent comorbidity in men with diabetes and is frequently overlooked in routine clinical evaluation. Albuminuria, a marker of endothelial dysfunction, may link to ED. AIM: The study evaluated the association of albuminuria with risk factors of ED in men with type 2 diabetes. METHODS: The diagnosis of ED was based on a self-administered questionnaire containing Sexual Health Inventory for Men. Urinary albumin excretion rate was determined by urine albumin-to-creatinine ratio (UACR) in spot urine. MAIN OUTCOME MEASURES: The clinical variables and diabetes-associated complications to risk of ED were evaluated. RESULTS: Of 666 patients who received the questionnaire, 455 patients completed it. Among them, 82.0%, 28.1%, and 35.8% reported having ED, severe ED, and albuminuria, respectively. The UACR level was significantly higher in ED (0.20 ± 0.83) and severe ED (0.34 ± 1.18) groups compared with non-ED group (0.07 ± 0.33). The presence of albuminuria adjusted for age and duration of diabetes was significantly associated with ED (OR = 2.76), and macroalbuminuria has stronger impact (OR = 4.49) than microalbuminuria (OR = 2.48). The other associated risk factors included hypertension, higher level of systolic blood pressure, lower level of serum hemoglobin, and estimated glomerular filtration rate. The presence of retinopathy, neuropathy, insulin therapy, using calcium channel blocker, and higher level of HbA1c further correlated with severe ED. Men with severe ED have higher prevalence of subnormal testosterone than the no ED patients. The high sensitivity C-reactive protein level, and the presence of metabolic syndrome were not risk factors. The 211 nonrespondents to the questionnaire had similar or worse risk profiles compared with the ED patients. CONCLUSION: Albuminuria is an important independent risk factor of ED in men with diabetes after adjustment of age and diabetes mellitus duration. Identification and control of albuminuria and other associated risk factors might play a role in the prevention or reversal of ED.

The presence of overactive bladder wet increased the risk and severity of erectile dysfunction in men with type 2 diabetes.

INTRODUCTION: Diabetes is a common risk factor for overactive bladder (OAB) syndrome and erectile dysfunction (ED). AIM: The study evaluated the risk factors of OAB and association of OAB and ED in type 2 diabetic men. METHODS: The diagnosis of ED and OAB was based on a self-administered questionnaire containing Sexual Health Inventory for Men (SHIM) and OAB symptom score (OABSS, 0-15, indicating increasing severity of symptoms), respectively. MAIN OUTCOME MEASURES: The clinical variables and diabetes-associated complications, including ED, which are risk factors for OAB, were evaluated. RESULTS: Of 453 consecutive subjects attending outpatient diabetic clinic with a mean age of 60.6 years, 25.4%, 10.2%, 81.9%, and 28.3% reported having OAB, OAB wet, ED, and severe ED, respectively. The OABSS is inversely associated with SHIM (correlation coefficient-0.275). The patients with OAB have significantly lower SHIM score, testosterone level, and serum albumin level, have more proportion of severe ED, were older, and have longer duration of diabetes mellitus (DM). After adjustment for age and duration of DM, the presence of severe ED was associated with OAB (odds ratio [OR] = 1.58), and severe ED (OR = 2.36), SHIM score (OR = 0.92), and serum albumin level (OR = 0.24) were risk factors for OAB wet (patients with urgency incontinence, once a week or more). The OR of ED in patients with OAB or OAB wet compared with no OAB was 1.82, and 3.61, respectively. Among the OAB components, urgency incontinence has the strongest impact on ED (OR = 4.06), followed by nocturia, urgency, and frequency. About 15.1% (N = 68) without OAB and ED are younger and have shorter DM duration, lower systolic BP, and higher serum albumin level after multivariate analysis compared with patients with OAB or ED. CONCLUSION: The presence of severe ED was significantly associated with OAB, especially OAB wet. The presence of OAB wet increased the risk and severity of ED.

An upstream regulatory element confers orientation-independent enhancement of the TSG101 promoter activity in transformed cells.

Tumor susceptibility gene 101 (TSG101), a mammalian homologue of yeast vps23, is involved in protein sorting, vesicular trafficking and maintenance of genomic integrity. Upregulation of the TSG101 gene was found in human thyroid papillary and breast tumors. Here, we define the proximal promoter of human TSG101 at -1 to -436 by reporter assay. Intact Sp1 and MAZ binding sequences within this region are essential, and mutation of both sites eliminates proximal promoter activity implying cooperation between these two cis-elements. Chromatin immunoprecipitation and DNA affinity precipitation assay confirmed in vivo Sp1 binding on the GGGGCGGGTT sequence. MAZ protein was essential for TSG101 promoter activity because its knockdown using siRNA decreased reporter activity. An upstream regulatory element (URE) at the -1280 to -1757 region was identified to confer the orientation-independent enhancement of the promoter activity in transformed COS-1, ARO and WRO cell lines but not in a normal thyroid FRTL cell line. The sequence of this URE region contains putative binding sites for thyroid transcription factor 2 (TTF-2) and thyroid hormone receptor (T3R), which might be relevant to differential regulation of TSG101 promoter activity in transformed and primary cells.

Increased complement factor H with decreased factor B determined by proteomic differential displays as a biomarker of tai chi chuan exercise.

BACKGROUND: Exhaustive exercise can be associated with short-term immune suppression, but moderate exercise such as tai chi chuan (TCC) has been shown to have beneficial effects on immunity. The mechanisms for the health benefits of exercise remain to be determined, and no potential biomarkers for these beneficial health effects have been identified. This study investigated serum proteomic markers in individuals participating in TCC exercise. METHODS: Two-dimensional fluorescence difference gel electrophoresis was used to compare proteomic markers in 3 individuals before and after 12 weeks of TCC exercise. The different protein spots were identified by mass spectrometry and validated in an additional 20 individuals by western blot analysis. RESULTS: We identified 39 protein spots for 18 proteins with a noticeable increase or decrease after TCC exercise. Validation of the differentially displayed proteins with 20 paired pre- and postexercise samples revealed a significant increase in complement factor H (P = 0.0034) associated with decreases in C1 esterase inhibitor (P = 0.0038) and complement factor B (P = 0.0029). CONCLUSIONS: In this first study of proteomic biomarkers of TCC exercise, we found an increase in complement factor H associated with a decrease in complement factor B. Complement factor H is involved in protection from microangiopathy and macular degeneration and may represent a useful marker of the health effects of exercise.

The role of blink reflex R1 latency as an electrophysiological marker in diabetic distal symmetrical polyneuropathy.

OBJECTIVE: Studies showed a relatively prolonged blink R1 latency in patients with diabetic distal symmetrical polyneuropathy (DSPN) compared to that without DSPN. We tested the hypothesis that blink R1 latency would provide a diagnostic alternative to nerve conduction studies (NCS) in DSPN and act as a marker of the severity of NCS abnormalities in DSPN. METHOD: A total of 109 patients with type 2 diabetes underwent blink reflex studies and NCS. We used the composite amplitude scores of nerve conductions (CAS), which consisted of motor (tibial, peroneal and ulnar) and sensory (sural and ulnar) amplitudes for estimating the severity of NCS. RESULTS: Patients with DSPN had longer blink R1, R2, and contralateral R2 latencies (P < 0.0001, P = 0.001, and P = 0.031, respectively) and higher CAS (P < 0.0001). Area under curve on receiver operating characteristic curve analysis in diagnosing occurrence of DSPN in blink R1 latency was 0.772 (P < 0.0001). Multiple linear regression analysis showed that blink R1 latency was independently associated with CAS. CONCLUSION: Blink R1 latency may be valuable in auxiliary diagnosis and in determining the severity of NCS abnormalities in DSPN. SIGNIFICANCE: Blink R1 latency can be added as a supplemental marker of severity of NCS in DSPN, especially if the patient's sural amplitudes has a floor effect.

Extracorporeal shockwave treatment for chronic diabetic foot ulcers.

BACKGROUND: This prospective study compared extracorporeal shockwave treatment (ESWT) with hyperbaric oxygen therapy (HBO) in chronic diabetic foot ulcers. PATIENTS AND METHODS: Seventy-two patients with 72 chronic diabetic foot ulcers were randomly divided into two groups of similar demographics with 34 patients with 36 ulcers in the ESWT group and 36 patients with 36 ulcers in the HBO group. Patients in the ESWT group received 300 + 100/cm(2) impulses of shockwave at 0.11 mJ/cm(2) energy flux density every 2 wk for 6 wk, whereas patients in the HBO group received HBO daily for 20 treatments. The evaluations included clinical assessment of the ulcers with photo-documentation, blood flow perfusion scan, bacteriological examination, histological study, and immunohistochemical analysis. RESULTS: The overall results showed completely healed in 31%, improved in 58%, and unchanged in 11% for the ESWT group and 22% completely healed, 50% improved, and 28% unchanged for the HBO group. The ESWT group showed significantly better clinical results and local blood flow perfusion, higher cell concentration, and activity than the HBO group. On immunohistochemical analysis, the ESWT group demonstrated significant increases in endothelial nitric oxide synthase, vessel endothelial growth factor, and proliferation cell nuclear antigen expressions and a decrease in transference-mediated digoxigenin-deoxy-UTP nick end-labeling expression than the HBO group. CONCLUSIONS: ESWT appears to be more effective than HBO in chronic diabetic foot ulcers.

Factors determining cardiovascular and renal outcomes after adrenalectomy in patients with aldosterone-producing adrenal adenoma.

Primary aldosteronism is an important cause of secondary hypertension, because it is potentially curable, especially in case of unilateral aldosterone-producing adrenal adenoma (APA). However, the information is limited concerning the cardiovascular and renal outcomes in this patient population. We studied 52 patients with APA in order to determine the pre-operative and post-operative factors predicting cardiovascular and renal outcomes. All 52 patients were hypertensive before the operation. Among 35 patients who underwent pre-operative electrocardiogram, 23 patients had left ventricular hypertrophy (LVH). Patients with LVH had lower estimated glomerular filtration rate (eGFR). Adrenalectomy successfully normalized or improved hypertension, hypokalemia, and aldosterone excess. One month after the adrenalectomy, 32 patients (62%) became normotensive, but 20 patients (38%) remained hypertensive. However, after an average follow-up period of 51 months, only 18 patients remained normotensive, while 34 patients were hypertensive. Thus, the rate of recurrent hypertension after adrenalectomy was high (14/32, 43%). Pre-operative systolic blood pressure (BP), diastolic BP, and post-operative plasma aldosterone concentrations were the only variables significantly different between the hypertensive and normotensive patients. Using pre-operative BP 165/110 mmHg as a cutoff has good positive predictive values (73-92%) for post-operative long-term hypertension. Patients whose renal function worsened after adrenalectomy had significantly higher pre-operative plasma active renin levels. Thus, in patients with APA, the presence of LVH is correlated with impaired renal function (lower eGFR). In conclusion, pre-operative BP and post-operative plasma aldosterone are important in predicting post-adrenalectomy hypertension, and a lower pre-operative plasma renin predicts the improvement in renal function after adrenalectomy.

HbA1C Variability Is Strongly Associated With the Severity of Cardiovascular Autonomic Neuropathy in Patients With Type 2 Diabetes After Longer Diabetes Duration.

BACKGROUND: Variability in the glycated hemoglobin (HbA1c) level is associated with a higher risk of microvascular complications in patients with type 2 diabetes. We tested the hypothesis that HbA1c variability is not only strongly associated with the presence but also the degree of severity of cardiovascular autonomic neuropathy (CAN) in patients with long diabetes durations (more than 10 years). METHODS: For each patient, the intrapersonal mean, standard deviation (SD), and coefficient of variation (CV) for HbA1c were calculated using all measurements obtained 3 years before the study. We constructed the composite autonomic scoring scale (CASS) as a measure of the severity of cardiovascular autonomic functions. Stepwise logistic regression and linear regression analyses were performed to evaluate the presence of CAN and the influence of independent variables on the mean CASS, respectively. RESULTS: Those with CAN had a higher mean age, a higher low-density lipoprotein cholesterol (LDL-C), HbA1c-SD, HbA1c-CV, mean HbA1c, and index HbA1c, higher prevalence of retinopathy as the underlying disease, and lower high-density lipoprotein (HDL) levels. Stepwise logistic regression showed that HbA1c-SD and retinopathy were risk factors that were independently associated with the presence of CAN. Mean HbA1c, HbA1c-CV, HbA1c-SD, and index HbA1c were positively correlated with mean CASS, and a multiple linear regression analysis revealed that HbA1c-SD was independently associated with the mean CASS. CONCLUSION: HbA1c variability is strongly associated with not only the presence but also the degree of severity of CAN. A longitudinal study is required to confirm whether controlling blood glucose level is effective in reducing CAN progression.

Close relationship between cardiovagal function and sural sensory nerve action potential in type 2 diabetes.

OBJECTIVE: Both diabetic distal symmetrical polyneuropathy (DSPN) and cardiac autonomic neuropathy (CAN) indicate the length-dependent pattern of disease. Decreased parasympathetic activity has been found in the early phase of CAN and sural sensory nerve action potential (SNAP) imply axonal loss in DSPN. METHOD: All patients with type 2 diabetes underwent cardiovascular autonomic function and nerve conduction studies (NCS). We constructed modified composite autonomic scoring scale (CASS) and composite score of NCS to measure the severity of CAN and DSPN, respectively. RESULTS: Patients with a longer duration of diabetes had a lower heart rate response to deep breathing (HR_DB), Valsalva ratio (VR), and baroreflex sensitivity (BRS), higher CASS, a higher percentage of CAN, lower sural SNAP, higher composite score of NCS, and a higher percentage of DSPN. Multiple linear regression analysis showed that only sural SNAPs were independently associated with mean HR_DB. CONCLUSION: Sural SNAP was closely correlated with parameters of cardiovagal functions in patients with different durations of diabetes. The percentage and severity of CAN and DSPN increase with longer duration of diabetes. SIGNIFICANCE: The independent association of sural sensory nerve action potential amplitude and heart rate response to deep breathing with type 2 diabetes is important because combined testing increases diagnostic sensitivity and specificity.

Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves' disease relapse after antithyroid drug withdrawal: a follow-up study.

CONTEXT: We previously showed an association between the exon1 +49 A/G single nucleotide polymorphism (SNP) and the relapse of Graves' disease (GD). The G allele was associated with early relapse. OBJECTIVE: In this follow-up study, we sought to replicate the result by genotyping nine additional polymorphisms and recruiting another 60 GD patients. DESIGN AND PARTICIPANTS: The GD patients were divided into three groups: recurred within 9 months, between 10-36 months, and more than 36 months. There were 65 patients with early recurrence, 55 with medium recurrence, and 88 with late recurrence. Although several SNPs were associated with recurrence, the most significant marker was still exon1 +49 A/G. Separate analysis of the genotypes for the 60 newly enrolled patients indicated that our present study was not biased by the previous samples. Once exon1 +49 A/G was included in the model to predict recurrence, other markers would not add more predictive information. Haplotype analysis did not show an additional value once exon1 +49 A/G was compulsorily included. RESULTS: Multivariate logistic regression analysis showed that GG genotype of exon1 +49 A/G SNP had an adjusted odds ratio of 2.2 (95% confidence interval, 1.1-4.4) compared with the combined group of GA plus AA. Other significant predictors were large goiter size at the end of the treatment and positive TSH-binding inhibitory Ig at the end of the treatment. CONCLUSIONS: This follow-up study confirms the usefulness of the exon1 +49 A/G SNP of the cytotoxic T lymphocyte-associated molecule-4 gene in predicting recurrence after cessation of treatment. There is no additional power by including other polymorphisms to predict recurrence.

Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: a meta-analysis.

CONTEXT: Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) polymorphisms have been widely examined for their associations with autoimmune thyroid diseases [Graves' disease (GD) and Hashimoto thyroiditis (HT)], but their relative population effect remains unclear. OBJECTIVE: The aim was to generate large-scale evidence on whether the CTLA-4 polymorphisms (A49G and CT60) and haplotypes thereof increase the susceptibility to GD and/or HT. DESIGN, SETTING, AND PARTICIPANTS: Meta-analyses of group-level data were reviewed from 32 (11,019 subjects) and 12 (4,479) published and unpublished studies for the association of the A49G polymorphism with GD and HT, respectively (PubMed and HuGeNet search until July 2006). There were 15 (n = 7246) and six (n = 3086) studies available for the CT60 polymorphism, respectively. Meta-analyses of individual-level data from 10 (4906 subjects) and five (2386) collaborating teams for GD and HT, respectively, were also reviewed. MAIN OUTCOME MEASURES: Association of gene variants and haplotypes with GD and HT was measured. RESULTS: Group-level data suggested significant associations with GD and HT for both A49G [odds ratios 1.49 (P = 6 x 10(-14)) and 1.29 (P = 0.001) per G allele, respectively] and CT60 [1.45 (P = 2 x 10(-9)) and 1.64 (P = 0.003) per G allele, respectively]. Results were consistent between Asian and Caucasian descent subjects. Individual-level data showed that compared with the AA haplotype, the risk conferred by the GG haplotype was 1.49 (95% confidence interval 1.31,1.70) and 1.36 (95% confidence interval 1.16,1.59) for GD and HT, respectively. Data were consistent with a dose-response effect for the G allele of CT60. CONCLUSION: The CT60 polymorphism of CTLA-4 maps an important genetic determinant for the risk of both GD and HT across diverse populations.

Sequential follow-up of serum thyroglobulin and whole body scan in thyroid cancer patients without initial metastasis.

OBJECTIVE: To investigate the usefulness of whole body scan (WBS) and serum thyroglobulin (Tg) measurement after thyroxine withdrawal during sequential follow-ups in patients with differentiated thyroid cancer (DTC). DESIGN: Two hundred and sixty-five consecutive DTC patients were enrolled. They were previously treated with near-total thyroidectomy and I-131 remnant ablation, without initial metastases or Tg antibodies. All had the first follow-up WBS and serum Tg measurement 6-12 months after initial treatment, and 165 patients received the second follow-up without further therapy. Positive/negative predictive values (PPV/NPV) were calculated by the outcome of patients being followed up for more than 8 years (mean+/-SD: 133+/-26 months). RESULTS: Serum Tg levels while the patients were off thyroxine therapy decreased spontaneously in 39.3% of the cases without further therapy. The NPV of the first follow-up serum Tg level was excellent: <2 microg/L and <0.5 microg/L were 95.1% and 98.2%, respectively. However, the PPV of the first follow-up serum Tg level was low: >10 microg/L and 2-10 microg/L were 40% and 9.6%, respectively. The trend of Tg levels was more informative; the PPV was 62.5% in cases with an increase of serum Tg of >10 microg/L and 16.6% with an increase of <5 microg/L. However, decreasing Tg levels may associate with rapid deterioration of disease, in which cases decrease of Tg indicated dedifferentiation of the tumor. The diagnostic WBS showed the same picture in 91.5% of the patients. Only one patient (0.6%) turned from negative study to positive during the follow-up. In the meanwhile his serum Tg levels increased from 0.56 to 13.6 microg/L. CONCLUSION: It is most informative when both the trend and the levels of Tg during sequential follow-up are considered. The diagnostic WBS may be performed for selected patients with indication based on Tg levels to localize the disease.

Nocturia indicates a poor health status and increases mortality in male patients with type 2 diabetes mellitus.

OBJECTIVES: To investigate the association between nocturia and erectile dysfunction, androgen deficiency, overactive bladder and systemic diseases in men with type 2 diabetic mellitus. METHODS: A self-administered questionnaire containing overactive bladder symptom score and sexual health inventory for men was obtained from subjects with type 2 diabetic mellitus. Nocturia and severe nocturia were defined as rising ≥2 or ≥3 per night to void, respectively. Patient characteristics and diabetes-related complications to risk of nocturia were evaluated. RESULTS: Of 632 consecutive subjects, 56.0 and 24.2 % reported having nocturia and severe nocturia, respectively. After adjustment of age, diabetic mellitus duration, and overactive bladder, the presence of erectile dysfunction, stroke, hypertension, and higher serum creatinine level was associated with nocturia and severe nocturia. The patients with the lowest quartile of testosterone level (2.21 ± 0.51 ng/mL) had higher prevalence of nocturia (65.1 %) and severe nocturia (32.9 %) than the sum of the other three quartiles. The patients with severe nocturia had threefold higher mortality than the other group after 3.5-year follow-up. CONCLUSIONS: The presence of nocturia was associated with erectile dysfunction, systemic vascular events, higher mortality, and indicated poor health in male with type 2 diabetic mellitus.

Diabetic Retinopathy Is Strongly Predictive of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes.

A well-established, comprehensive, and simple test battery was used here to re-evaluate risk factors for cardiovascular autonomic neuropathy (CAN) in type 2 diabetes. One hundred and seventy-four patients with type 2 diabetes were evaluated through the methods of deep breathing and Valsalva maneuver for correlation with factors that might influence the presence and severity of CAN. The Composite Autonomic Scoring Scale (CASS) was used to grade the severity of autonomic impairment, and CAN was defined as a CASS score ≥2. Results showed that nephropathy, duration of diabetes, blood pressure, uric acid, and the presence of retinopathy and metabolic syndrome significantly correlated with the CASS score. Age may not be a risk factor for diabetic CAN. However, the effects of diabetes on CAN are more prominent in younger patients than in older ones. Diabetic retinopathy is the most significant risk factor predictive of the presence of CAN in patients with type 2 diabetes.

IRAK1, a Target of miR-146b, Reduces Cell Aggressiveness of Human Papillary Thyroid Carcinoma.

CONTEXT: MicroRNA (miR)-146b is overexpressed in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal invasion, advanced tumor stage, and poor prognosis. However, the underlying mechanism of miR-146b in relation to its oncogenic behavior in PTC and its putative targets remain unknown. OBJECTIVE: The purpose was to investigate IL-1 receptor-associated kinase 1 (IRAK1) as the potential miR-146b target gene and its involvement in PTC. DESIGN: We used genome-wide microarray, computational analysis, and 3' UTR reporter gene assays to identify IRAK1 as a miR-146b target gene. In vitro gain/loss-of-function experiments were further performed to determine the effects of IRAK1 on proliferation, colony formation, and wound-healing in PTC cancer cell lines. Expression levels of miR-146b and IRAK1 of 50 cases of PTC and its adjacent normal thyroid specimens were assessed via qRT-PCR. RESULTS: Microarray expression profile revealed that the mRNA level of IRAK1 gene was down-regulated by miR-146b. The 3' UTR of IRAK1 mRNA was found to be a molecular target of miR-146b posttranscriptional repression in BCPAP cells by reporter gene assays. MiR-146b promoted the migration and proliferation of PTC cells by down-regulating IRAK1 expression, whereas restoration of IRAK1 expression reversed this effect. In addition, the expression of IRAK1 mRNA was significantly lower in PTC clinical tissue samples than normal adjacent thyroid specimens and showed a strong inverse correlation with the expression of miR-146b in PTC specimens. CONCLUSION: Our results demonstrated that IRAK1 is a direct target of miR-146b and has functional roles to inhibit various aggressive PTC cell activities. In conjunction with current therapeutic regimens, targeting the miR-146b-IRAK1 axis may provide a potential approach for PTC management.

Overexpression of tumor susceptibility gene TSG101 in human papillary thyroid carcinomas.

Functional inactivation of tumor susceptibility gene tsg101 leads to cellular transformation and tumorigenesis in mice. While human TSG101 is located in a region where frequent loss of heterozygosity can be detected in a variety of cancers, no genomic deletion in TSG101 gene has been reported, casting a doubt on the role of TSG101 as a classical tumor suppressor. Some studies have revealed that TSG101 is a frequent target of splicing defects, which correlate with cellular stress and p53 status. Furthermore, recent reports have identified TSG101 as a part of the MDM2/p53 regulatory circuitry, a well-recognized circuitry that upon deregulation results in tumorigenesis. Interestingly, overexpression of tsg101 from an adventitious promoter also leads to neoplastic transformation. On the basis of this information, we have analysed TSG101 gene expression in 20 human papillary thyroid carcinomas (PTCs) by immunohistochemistry and demonstrated that the overexpression of TSG101 protein is closely associated with human PTCs. Further sequence analysis reveals no mutation in cDNA region encoding steadiness box in these PTC specimens, indicating that the upregulation of TSG101 protein is not caused by the alteration of this region. In situ hybridization analysis confirms that overexpression of TSG101 also occurs at the transcriptional level. In addition, semi-quantitative RT-PCR and subsequent Southern hybridization verify that the amounts of TSG101 transcripts are indeed lower in three normal thyroid tissues than in PTC specimens. Here we report the upregulation of TSG101 expression in PTC cells, providing the first evidence of the association of TSG101 overexpression with human tumors and suggesting that upregulation of TSG101 steady-state level might play a role in mediating tumorigenesis of human PTC.

Association of mitochondrial deoxyribonucleic acid 16189 variant (T->C transition) with metabolic syndrome in Chinese adults.

OBJECTIVE: A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T-->C transition) has been associated with small birth size, adulthood hyperglycemia, and insulin resistance in Caucasians. In this study, we investigated whether mtDNA 16189 variant is associated with metabolic syndrome in Chinese subjects. METHODS: Six hundred fifteen Chinese adults, aged 40 yr or older, were recruited in this study. The 16189 variant of mtDNA was detected using PCR and restriction enzyme digestion. Metabolic syndrome was diagnosed on modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using body mass index (BMI) instead of waist circumference. An association study was performed with chi2 test and logistic regression analysis. RESULTS: The prevalence of the 16189 variant was higher in patients with metabolic syndrome than in those without: 44% (125 of 284) vs. 33.2% (110 of 331) (P = 0.006). The association between this 16189 variant of mtDNA and metabolic syndrome (P = 0.021) remained significant even after correcting for age and BMI. As to the individual traits, the prevalence of fasting plasma glucose of at least 110 mg/dl (> or =6.1 mmol/liter) [(51.5% (121 of 235) vs. 42.1% (160 of 380); P = 0.023], type 2 diabetes mellitus [48.1% (113 of 235) vs. 39.2% (149 of 380); P = 0.031], and hypertriglyceridemia [44.3% (104 of 235) vs. 35.8% (136 of 380); P = 0.037] were significantly higher in subjects harboring the 16189 variant of mtDNA than those with the wild type. However, the prevalence of hypertension [53.2% (125 of 235) vs. 47.6% (181 of 380); P = 0.180], BMI greater than 25 kg/m2 [48.5% (114 of 235) vs. 43.9% (167 of 380); P = 0.270], and low high-density lipoprotein cholesterol [61.3% (144 of 235) vs. 54.7% (208 of 380); P = 0.111] did not reach a significant difference between the two groups. Furthermore, there was a trend of increasing frequency of occurrence of the 16189 variant in individuals having an increasing number of components of metabolic syndrome (Ptrend < 0.005). CONCLUSION: Our data strongly suggest that mtDNA 16189 variant underlies susceptibility to metabolic syndrome in the Chinese population.