Effects of DA-9801 on the inflammation and apoptosis induced by angiotensin II in human dermal microvascular endothelial cells.

DA-9801, a plant-based drug used for the treatment of diabetic neuropathy, is known to improve angiotensin II (Ang II)-induced vascular endothelial cell dysfunction. However, the underlying mechanism is not fully understood. We aimed to determine whether the protective effect of DA-9801 against Ang II-induced endothelial cell dysfunction was mediated via inhibition of endothelial cell inflammation and apoptosis. Ang II-induced oxidative stress was attenuated by pretreatment of human dermal microvascular endothelial cells (HDMECs) with DA-9801. This prevented the Ang II-induced upregulation of NAD(P)H oxidase (the NOX4 and p22phox subunits) and reactive oxygen species. Further, pretreatment of HDMECs with DA-9801 ameliorated Ang II-mediated nuclear factor kappa B activity via prevention of the upregulation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. It also decreased the Ang II-stimulated increase in inducible nitric oxide synthase (NOS) and decreased endothelial NOS protein expression. DA-9801 decreased Ang II-induced upregulation of intercellular adhesion molecule 1, vascular adhesion molecule, and E-selectin in HDMECs. Moreover, TUNEL and annexin V-FITC fluorescence staining for apoptosis and the activities of caspases 9, 7, and 3 decreased in HDMECs pretreated with DA-9801, indicating that the drug enhanced anti-apoptotic pathways. Thus, DA-9801 modulated Ang II-induced endothelial cell dysfunction via inflammatory and apoptotic pathways.

Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea.

BACKGROUND: Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV). METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes. RESULTS: Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by -3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms² in the ALA group, whereas it declined by -15.04 ms² in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by -0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events. CONCLUSION: Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.

Recombinant human TSH stimulated thyroglobulin levels at remnant ablation predict structural incomplete response to treatment in patients with differentiated thyroid cancer.

In patients with differentiated thyroid cancer, stimulated thyroglobulin (sTg) levels after thyroid hormone withdrawal (THW) at remnant ablation (RA) and at 6 to 12 months are known to have good prognostic value. This study aimed to evaluate the prognostic impacts and best cutoff values of sTg levels under recombinant human thyroid stimulating hormone (rhTSH) treatment at RA and at follow-up. A total of 151 patients were enrolled, of whom 77 were followed up with rhTSH-stimulated Tg (rhTSH-sTg) and 74 with THW-stimulated Tg (THW-sTg) at 6 to 12 months after rhTSH-aided RA. Risk stratification, response to treatment (excellent, indeterminate, biochemical incomplete, and structural incomplete response [SIR]), and clinical outcome were accessed by revised American Thyroid Association (ATA) guideline criteria. Seven out of 151 (4.6%) patients were confirmed to have SIR during the median follow-up of 79.0 months; 3 in the rhTSH group and 4 in the THW group. One hundred thirty-two out of 151 (87.4%) patients were confirmed to have excellent response; 68 (51.5%) in the rhTSH group and 64 (48.5%) in the THW group. The cutoff values of sTg for predicting SIR to treatment at rhTSH-aided RA, THW-sTg, and rhTSH-sTg were 4.64 ng/mL (sensitivity 85.7%, specificity 76.4%, negative predictive value [NPV] 99.2%), 2.41 ng/mL (sensitivity 100%, specificity 94.3%, NPV 100%), and 1.02 ng/mL (sensitivity 66.7%, specificity 94.6%, NPV 98.6%), respectively. sTg levels using rhTSH at both RA and follow-up has a high NPV and are as effective as using THW for predicting SIR. The risk classification according to the revised ATA guidelines can be used effectively to supplement rhTSH-aided sTg levels to predict better clinical outcomes.

Refractory Graves' Disease Successfully Cured by Adjunctive Cholestyramine and Subsequent Total Thyroidectomy.

The three major forms of treatment for Graves thyrotoxicosis are antithyroid drugs, radioactive iodine therapy and thyroidectomy. Surgery is the definitive treatment for Graves thyrotoxicosis that is generally recommended when other treatments have failed or are contraindicated. Generally, thyrotoxic patients should be euthyroid before surgery to minimize potential complications which usually requires preoperative management with thionamides or inorganic iodine. But several cases of refractory Graves' disease have shown resistance to conventional treatment. Here we report a 40-year-old female patient with Graves' disease who complained of thyrotoxic symptoms for 7 months. Her thyroid function test and thyroid autoantibody profiles were consistent with Graves' disease. One kind of thionamides and ß-blocker were started to control her disease. However, she was resistant to nearly all conventional medical therapies, including ß-blockers, inorganic iodine, and two thionamides. She experienced hepatotoxicity from the thionamides. What was worse is her past history of serious allergic reaction to corticosteroids, which are often used to help control symptoms. A 2-week regimen of high-dose cholestyramine improved her uncontrolled thyrotoxicosis and subsequent thyroidectomy was successfully performed. In conclusion, cholestyramine could be administered as an effective and safe adjunctive agent for preoperative preparation in patients with severe hyperthyroid Graves's disease that is resistant to conventional therapies.

Accelerated disease progression after discontinuation of sorafenib in a patient with metastatic papillary thyroid cancer.

Distant metastases from papillary thyroid carcinoma (PTC) are rare and are associated with a poor prognosis. Here, we describe a patient with metastatic PTC who was treated with a tyrosine kinase inhibitor (TKI, sorafenib) for several months that was acutely exacerbated by discontinuation. A 43-year-old male was diagnosed with PTC in February 2004 and underwent total thyroidectomy followed by two courses of high-dose radioactive iodine (RAI) therapy. Despite two additional courses of high-dose RAI therapy, lung and muscle metastases were developed. Treatment with sorafenib was begun in September 2010. After 11 months treatment of sorafenib, newly developed metastatic lesions were found in mediastinal lymph nodes, liver, and bones. Considered as treatment failure, the administration of sorafenib was discontinued. Two weeks after sorafenib treatment was stopped, the disease progressed abruptly and caused death of the patient by respiratory failure. In our patient, PTC progressed rapidly after the cessation of sorafenib treatment. Patients with several other types of cancer have also experienced such rapid disease progression, termed "flare-ups." Physicians should be aware that flare-ups may occur in advanced PTC patients following the cessation of TKI therapy.

Combination of initial stimulation thyroglobulins and staging system by revised ATA guidelines can elaborately discriminate prognosis of patients with differentiated thyroid carcinoma after high-dose remnant ablation.

PURPOSE: The aim of this study was to evaluate prognostic role of thyroglobulin (Tg) levels at the time of ablation (A-Tg) and stimulation Tg levels at 6-12 months after remnant ablation (S-Tg) combined with revised American Thyroid Association (ATA) guidelines risk stratification. PATIENTS AND METHODS: Data of 359 patients (median follow-up duration: 66.3 months) with papillary thyroid carcinoma who had high-dose remnant ablation were analyzed. The cutoff value of A-Tg to predict the persistent/recurrent disease was calculated by receiver operating characteristic curve analysis. In each risk group by ATA guidelines, the association of A-Tg with persistent/recurrent disease was evaluated. The role of A-Tg and ATA risk stratification in each S-Tg group (group with S-Tg <2 ng/mL, 2-10 ng/mL, or >10 ng/mL) was also evaluated. Tg response was determined by the difference between A-Tg and S-Tg with consideration of the dose of radioactive iodine ablation. RESULTS: A-Tg above 5.22 ng/mL was associated with persistent/recurrent disease in all risk groups by ATA guidelines. A-Tg above the cutoff value and ATA risk assessment was related to persistent/recurrent disease in patients with S-Tg 2 to 10 ng/mL (P = 0.003) and S-Tg above 10 ng/mL (P = 0.019). However, no difference in the incidence of persistent/recurrent disease was found according to Tg response. The scoring system made up of A-Tg, S-Tg, and ATA staging showed elaborate discrimination of prognosis. CONCLUSION: Risk stratification using combined scoring with initial stimulated Tg levels, including A-Tg and S-Tg, and staging system by revised ATA guidelines can effectively predict persistent/recurrent disease in patients with papillary thyroid carcinoma.

Role of [(18)F]-fluorodeoxy-D-glucose positron emission tomography and computed tomography in the early detection of persistent/recurrent thyroid carcinoma in intermediate-to-high risk patients following initial radioactive iodine ablation therapy.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) scan has a role in the surveillance of patients with a history of thyroid carcinoma. Its efficacy after remnant ablation as far as detecting persistent or recurrent thyroid carcinoma before other surveillance methods is not known, however. In intermediate-to-high risk thyroid carcinoma patients we studied whether PET/CT scan, performed 6-12 months after the first remnant ablation, could provide more information than ultrasonography (US) and thyrotropin-stimulated serum thyroglobulin (Tg) determination with diagnostic whole-body scan (DxWBS). METHODS: We studied 71 subjects with differentiated thyroid cancer (DTC) who were intermediate-to-high risk for persistent/recurrent disease and who had received PET/CT scan, US, and DxWBS simultaneously with stimulated Tg levels 6-12 months after remnant ablation. To evaluate the diagnostic efficacy of PET/CT scan, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated. RESULTS: Ten subjects (14%) had persistent/recurrent disease detected 6-12 months after remnant ablation. Persistence/recurrence was detected in nine (12.7%) of these patients by conventional methods, including US and DxWBS, along with stimulated Tg levels. The remaining case was detected solely by a PET/CT scan, which showed a mediastinal prevascular lesion; this was confirmed by a therapeutic WBS after additional radioiodine therapy. Among the six patients whose PET/CT scan showed positive results, five had persistent/recurrent disease. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of PET/CT scan for detecting persistent/recurrent thyroid carcinoma were 50%, 98.4%, 83.3%, 92.3%, and 91.5%, respectively. CONCLUSION: In intermediate-to-high risk patients with DTC seen 6-12 months after their first remnant ablation, there is almost no complementary role for adding a PET/CT scan to conventional follow-up methods, an US and a DxWBS simultaneously with stimulated Tg levels.

Clinical significance of observation without repeated radioiodine therapy in differentiated thyroid carcinoma patients with positive surveillance whole-body scans and negative thyroglobulin.

BACKGROUND/AIMS: Currently, there is no consensus on the necessity of repeated radioiodine therapy (RAI) in patients who show iodine uptake in the thyroid bed on a diagnostic whole-body scan (DxWBS) despite undetectable thyroglobulin (Tg) levels after remnant ablation. The present study investigated the clinical outcomes of scan-positive, Tg-negative patients (WBS+Tg-) who did or did not receive additional RAI. METHODS: We retrospectively reviewed 389 differentiated thyroid carcinoma patients who underwent a total thyroidectomy and received high-dose RAI from January 2003 through December 2005. The patients were classified according to surveillance DxWBS findings and TSH-stimulated Tg levels 6 to 12 months after the initial RAI. RESULTS: Forty-four of the 389 patients (11.3%) showed thyroid bed uptake on a DxWBS despite negative Tg levels (WBS+Tg-). There was no difference in clinical and pathological parameters between WBS+Tg- and WBS-Tg- patients, except for an increased frequency of thyroiditis in the WBS+Tg- group. Among the 44 WBS+Tg- patients, 27 subjects were treated with additional RAI; 25 subjects showed no uptake in subsequent DxWBS. Two patients were evaluated only by ultrasonography (US) and displayed no persistent/recurrent disease. The other 17 patients received no further RAI; Eight patients and two patients showed no uptake and persistent uptake, respectively, on subsequent DxWBS. Six patients presented negative subsequent US findings, and one was lost to follow-up. Over the course of 53.2 ± 10.1 months, recurrence/persistence was suspicious in two patients in the treatment group. CONCLUSIONS: There were no remarkable differences in clinical outcomes between observation and treatment groups of WBS+Tg- patients. Observation without repeated RAI may be an alternative management option for WBS+Tg- patients.

Short-term changes in bone and mineral metabolism following gastrectomy in gastric cancer patients.

Changes in bone and mineral metabolism that occur after gastrectomy have long been recognized. Gastrectomy has been identified as a risk factor for decreased bone mass and the increased fracture incidence. Previous investigations concerning postgastrectomy bone disease have been observational studies. No prospective studies have been reported that quantify the amount of bone loss after gastrectomy within the same patients. This study investigated 46 patients undergoing gastrectomy for gastric adenocarcinoma and analyzed 36 patients (58.1+/-10.8 years, 24 men and 12 women) who had dual energy X-ray absorptiometry (DXA) performed before and 1 year after gastrectomy. Systemic adjuvant chemotherapy was administered to 14 patients. Blood was sampled from all patients to determine serum calcium, phosphorous, and bone turnover marker levels before gastrectomy and at 1, 3, 6 and 12 months after surgery and for serum parathyroid hormone (PTH) and 25-hydroxyvitamin D levels before and 12 months after surgery. The mean bone loss in the lumbar spine, total hip, femoral neck, and trochanter, which was calculated as the percentage change from the baseline to the level measured at 12 months, was 5.7% (P<0.01), 5.4% (P<0.01), 6.6% (P<0.01) and 8.7% (P<0.01), respectively. Bone loss was generally greater in the group receiving chemotherapy. The serum calcium and phosphorous levels were not changed significantly and remained within the normal range throughout the observation period. After gastrectomy, the level of ICTP increased and reached a peak at 1 and 3 months, and progressively declined to baseline by 12 months. The osteocalcin levels were not coupled to an increase before 6 months. The level of 25-hydroxyvitamin D at 12 months postgastrectomy was not significantly changed compared to the baseline, however, the PTH levels increased by a mean of 63.6% at 12 months compared to the baseline (P<0.01). Significant correlations were found between the percent change in the BMD at the lumbar spine and total hip and the percentage change for the PTH level from their baselines to 12 months. The changes in the BMD at total hip, femoral neck, and trochanter also correlated to the change in body weight at 12 months. The data obtained by this study provides evidence that profound bone loss occurs in the setting of a bone remodeling imbalance during the early postgastrectomy period and allows the speculation that the gastrectomy related bone loss may be partially due to an overproduction of PTH.