Effect of sertraline on Ca²âº fluxes in rabbit corneal epithelial cells.

The effect of sertraline, a selective serotonin reuptake inhibitor (SSRI), on cytosolic free Ca²âº concentrations ([Ca²âº](i)) in a rabbit corneal epithelial cell line (SIRC) is unclear. This study explored whether sertraline changed basal [Ca²âº](i) levels in suspended SIRC cells by using fura-2 as a Ca²âº-sensitive fluorescent dye. Sertraline at concentrations between 10-100 µM increased [Ca²âº](i) in a concentration-dependent manner. The Ca²âº signal was reduced by 23% by removing extracellular Ca²âº. Sertraline induced Mn²âº influx, leading to quench of fura-2 fluorescence, suggesting Ca²âº influx. This Ca²âº influx was inhibited by phospholipase A2 inhibitor aristolochic acid, but not by store-operated Ca²âº channel blockers and protein kinase C/A modulators. In Ca²âº-free medium, pretreatment with the endoplasmic reticulum Ca²âº pump inhibitor thapsigargin, cyclopiazonic acid or 2,5-di-tert-butylhydroquinone greatly inhibited sertraline-induced Ca²âº release. Inhibition of phospholipase C with U73122 abolished sertraline-induced [Ca²âº](i) rise. At concentrations of 5-50 µM, sertraline killed cells in a concentration-dependent manner. The cytotoxic effect of 25 µM sertraline was not reversed by prechelating cytosolic Ca²âº with BAPTA/AM. Collectively, in SIRC cells, sertraline induced [Ca²âº](i) rises by causing phospholipase C-dependent Ca²âº release from the endoplasmic reticulum and Ca²âº influx via phospholipase A2-sensitive Ca²âº channels. Sertraline-caused cytotoxicity was mediated by Ca²âº-independent pathways.

Elevated serum retinol-binding protein 4 concentrations are associated with chronic kidney disease but not with the higher carotid intima-media thickness in type 2 diabetic subjects.

To examine the association of serum retinol-binding protein 4 (RBP4) concentrations with carotid intima-media thickness (CIMT) in type 2 diabetic subjects with chronic kidney disease (CKD). A total of 239 type 2 diabetic patients (64 ± 13 years, 154 males) were divided into two groups: one with CKD, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m(2) (n = 86), and one without (n = 153). We recorded clinical and biochemical data as well as CIMT. The patients with CKD were older, had had diabetes mellitus longer, and had higher incidence of hypertension, dyslipidemia and microalbuminuria than those without. They also had higher serum concentrations of RBP4 (44.8 ± 6.4 vs 39.5 ± 4.9 µg/mL, p < 0.001), higher mean CIMT (0.75 ± 0.16 vs 0.69 ± 0.14 mm, p = 0.0070), and higher incidence of carotid plaques (27.9 vs 11.8 %, p = 0.002). The RBP4 were negatively correlated with eGFR (r = -0.514, p < 0.001). However, the RBP4 were not correlated with mean CIMT (r = 0.065, p = 0.318). Moreover, when dividing the patients into two groups by the mean CIMT, those with mean CIMT above 0.71 mm did not have different RBP4 concentrations compared with those below (41.5 ± 5.7 vs 41.3 ± 6.3 µg/mL, p = 0.856). In conclusion, we observed an elevation of serum RBP4 concentrations and CIMT levels in type 2 diabetic subjects with CKD. However, the elevated RBP4 were not associated with the higher CIMT among these patients.

Justifying the high prevalence of microalbuminuria for type 2 diabetic patients in Taiwan with conditional probability approach--a DEMAND II study.

BACKGROUND: To examine the prevalence of microalbuminuria (MAU) and chronic kidney disease as well as the correlation between MAU and renal and cardiovascular risks of Type 2 diabetes mellitus (T2DM) patients for public health policy making in Taiwan. METHODS: This was a multicenter, hospital-based, randomly selected, and cross-sectional study. T2DM patients aged 18-80 years without a known diagnosis of proteinuria were eligible. MAU was defined as urinary albumin-to-creatinine ratio (ACR) within 30-299 mg/g, and macroalbuminuria as that greater than or equal to 300 mg/g. Two positive out of three urinary screening results were required to make the diagnosis of MAU. The adjusted prevalence of MAU was calculated by conditional probability approach. RESULTS: 51.1% of the analyzed population (n=1,827) were women, with a mean (standard deviation) age of 59.16 years (11.19 years) and mean hemoglobin A1c (HbA1c) of 8.15% (1.83%). Median duration of DM history was 6 years (interquartile range, 3-11 years). The adjusted prevalence of MAU was 26.9%. Overall prevalence of chronic kidney disease Stage 3 or higher (estimated Glomerular filtration rate (eGFR) less than 60/mL/min/1.73 m²) was 13.8%. Only 4.7% of the T2DM patients had serum albumin test recorded and 68.7% with serum creatinine test recorded within the last 6 months. After adjustment for center and gender, the odds ratios for MAU or macroalbuminuria were 1.73 (95% CI, 1.27-2.36) for age greater than or equal to 60 years, 1.54 (1.13-2.10) for abnormal waist circumference, 1.10 (1.02-1.19) for every 1% increase in hemoglobin A1c, 1.91 (1.38-2.65) for higher systolic blood pressure, and 1.92 (1.19-3.07) for abnormal serum creatinine level. CONCLUSION: This study demonstrates the application of "conditional probability" method to justify the rationale of adopting two positive out of three urinary screening tests for the diagnosis of MAU. An adjusted prevalence rate of MAU as 26.9% is reported. These results may provide a basis for cost-benefit consideration in designing preventive and interventional policies in public health. Furthermore, the awareness and practice of early monitoring of MAU for DM patients should be strengthened.

Hyperthyroidism-associated insulin resistance is not mediated by adiponectin levels.

To evaluate the relationship between circulating adiponectin and insulin sensitivity in patients with hyperthyroid Graves' disease, we studied 19 adult patients with this disease and 19 age- and sex-matched euthyroid controls. All hyperthyroid patients were treated with antithyroid drugs and were re-evaluated after thyroid function normalized. Before antithyroid treatment, the adiponectin plasma concentrations were not different comparing with those in control group. The adiponectin levels remained unchanged after treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) in hyperthyroid group was higher before treatment than after treatment. There was no significant difference in serum glucose and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. BMI-adjusted adiponectin levels were not different among three groups. On the other hand, BMI-adjusted insulin levels and HOMA-IR values were significantly decreased after management of hyperthyroidism. Pearson's correlation revealed that insulin and HOMA-IR values positively correlated with triiodothyronine (T3) and free thyroxine (FT4) levels. However, adiponectin did not correlate with T3, FT4, insulin, HOMA-IR and thyrotropin receptor autoantibody (TRAb) levels. In conclusion, insulin resistance associated with hyperthyroidism is not mediated by the levels of plasma adiponectin.

Common hemoglobin variants in southern Taiwan and their effect on the determination of HbA1c by ion-exchange high-performance liquid chromatography.

BACKGROUND: Patients with hemoglobin (Hb) variants may produce false HbA1c measurement. This study aimed to detect the common Hb variants in southern Taiwan and to evaluate their effect on the determination of HbA1c. METHODS: A total of 1,434 samples collected for HbA1c measurement at Kaohsiung Veterans General Hospital in southern Taiwan in March 2008 were submitted for Hb variant analysis by Primus CLC-385. HbA1c measurements were obtained using ion-exchange high-performance liquid chromatography (HPLC) (Tosoh HLC-723 G7) for routine analysis. Patients identified with Hb variants were recalled for boronate-affinity HPLC analysis. The values of estimated average glucose (eAG) were converted from HbA1c. Values of eAG-FPG, calculated by eAG minus fasting plasma glucose (FPG), were compared to estimate the accuracy of HbA1c measurement in patients with Hb variants. RESULTS: Among the 1,434 patients, the mean standard deviation of FPG was 162.8 +/- 60.5 mg/dL, HbA1c was 8.28 +/- 1.97%, and eAG was 190.9 +/- 56.6 mg/dL. Five Hb variants were detected in 11 patients, the incidence being 0.76%. Hb J was identified in 4 patients, Hb G in 2 patients, Hb E in 1 patient, Hb owari in 3 patients, and high fetal hemoglobin (HbF) in 1 patient. Abnormal HPLC chromatograms were seen among the patients with Hb J, E, G and HbF, but not in the patients with Hb owari. In patients with Hb variants, FPG was 149.5 +/- 39.9 mg/dL, HbA1c was 7.29 +/- 2.01%, and eAG was 162.5 +/- 57.7 mg/dL. Lower values of eAG-FPG may have occurred in the patients with Hb J and E, and in those with high HbF. On scattergrams of the relationship between HbA1c and FPG, the plots of Hb J, E and high HbF lay below the regression line of non-Hb variants. Inconsistent Hb values between both methods were only observed among some samples of patients with Hb variants. CONCLUSION: The existence of Hb variants may result in false HbA1c measurement. The possible presence of spuriously low HbA1c levels or abnormal HPLC chromatograms by using ion-exchange methods should be kept in mind.

Association of glycemic control with risk of erectile dysfunction in men with type 2 diabetes.

INTRODUCTION: Improvement in glycemic control is likely to reduce the risk of diabetic complication, while its effect on erectile dysfunction (ED) remains unclear. AIM: The aim of this study was to evaluate the association of glycemic control with risk of ED in type 2 diabetics. METHODS: A self-administered questionnaire containing Sexual Health Inventory for Men was obtained from 792 subjects with type 2 diabetes at our institution. Clinical data were obtained through chart review. MAIN OUTCOME MEASURES: The contribution of glycemic control assessed by glycated hemoglobin (HbA(1c)) level as well as age, duration of diabetes, hypertension (HT), dyslipidemia, and cigarette smoking to risk of ED was evaluated. RESULTS: Of 792 subjects, 83.6% reported having ED and 43.2% had severe ED. HbA(1c) level (%) adjusted for age and duration of diabetes was significantly associated with ED (OR 1.12, 95% CI: 1.01-1.25). None of HT, dyslipidemia, and cigarette smoking was a significant risk factor for ED after adjusted for age and duration of diabetes. HbA(1c) level, age, and duration of diabetes were significant independent risk factors for ED among the younger group (age < or = 60 years), and only age and duration of diabetes were independent risk factors among the older group (age > 60 years). For the risk of severe ED, compared with no and mild to moderate ED, HbA(1c) level, duration of diabetes, and HT were independent risk factors among the younger group, and only age was an independent factor among the older group. CONCLUSIONS: Better glycemic control probably would reduce the prevalence of ED and its severity among the younger men with type 2 diabetes. For the older group, aging was the major determinant for ED risk among this population with type 2 diabetes.

Patterns and their correlates of seeking treatment for erectile dysfunction in type 2 diabetic patients.

INTRODUCTION: Diabetic patients are at high risk of having erectile dysfunction (ED), but their doctors rarely pay attention to this association. AIM: To evaluate the treatment-seeking patterns and their correlates for ED in type 2 diabetic patients. METHODS: A questionnaire containing Sexual Health Inventory for Men and questions inquiring treatment-seeking patterns was mailed or given to 4,040 subjects who had visited our endocrinology outpatient department for diabetes during January 2004 to May 2006. MAIN OUTCOME MEASURES: The prevalence of being bothered and having interest in treatment, and the percentage having sought treatment in regard to ED and their correlates with age and ED severity. RESULTS: Of the subjects with questionnaire completed, 83.9% (708/844) had ED. Among the subjects with different severity of ED, the moderate group had the highest percentages regarding prevalence of being bothered (89.4%), having interest in treatment (78.5%), and having sought treatment (46.2%). Of all the subjects, only 14.2% had ever visited Western physicians, whereas embarrassment and misinformation about ED treatment were the leading reasons for never doing so. Over half (56.6%) of those with ED wished to discuss ED problem with their doctors, and of them 90.4% wished the doctors to initiate to broach this issue. CONCLUSIONS: The prevalence of ED and the concerns about it were high in these diabetic patients. ED severity was the major determinant of their treatment-seeking decision, whereas only few of them had ever sought professional help. Routine screening of ED in diabetic patients is recommended.

Cadmium-induced cytosolic Ca2+ elevation and subsequent apoptosis in renal tubular cells.

Cadmium (Cd2+) is an industrial and environmental metal. The effect of Cd2+ on intracellular free-Ca2+ levels ([Ca2+](i)) and viability in Madin Darby canine kidney cells was explored. Cd2+increased [Ca2+](i) in a concentration-dependent manner with an EC50 of 85 microM. Cd2+-induced Mn2+ entry demonstrated Ca2+ influx. Removal of extracellular Ca2+ decreased the [Ca2+](i) signal by 60%. The [Ca2+](i) signal was inhibited by La3+ but not by L-type Ca2+ channel blockers. In Ca2+-free medium, Cd2+-induced [Ca2+]i signal was abolished by pre-treatment with 1 microM thapsigargin (an endoplasmic reticulum Ca2+pump inhibitor) and 2 microM carbonylcyanide m-chlorophenylhydrazone (CCCP; a mitochondrial uncoupler). Cd2+-induced Ca2+ release was not altered by inhibition of phospholipase C. At concentrations between 10 and 100 microM, Cd2+killed cells in a concentration-dependent manner. The cytotoxic effect of 100 microM Cd2+was reversed by pre-chelating cytosolic Ca2+with BAPTA. Cd2+-induced apoptosis was demonstrated by propidium iodide. Collectively, this study shows that Cd2+ induced a [Ca2+](i) increase in Madin Darby canine kidney cells via evoking Ca2+ entry through non-selective Ca2+ channels, and releasing stored Ca2+ from endoplasmic reticulum and mitochondria in a phospholipase C-independent manner.

Change of visfatin, C-reactive protein concentrations, and insulin sensitivity in patients with hyperthyroidism.

The present study was undertaken to evaluate the change of circulating visfatin, C-reactive protein (CRP) concentrations, and insulin sensitivity in patients with hyperthyroidism. We studied 19 adult patients (14 women and 5 men aged 32.6 +/- 1.8 years) with hyperthyroidism due to Graves disease and 19 age- and sex-matched euthyroid controls (17 women and 2 men aged 36.7 +/- 2.7 years). All hyperthyroid patients were treated with 1 of 2 antithyroid drugs and were reevaluated after thyroid function normalized. Before antithyroid treatment, the hyperthyroid group had significantly higher visfatin plasma concentration (mean +/- standard error of the mean, 20.7 +/- 1.8 ng/mL) than the control group (16.2 +/- 1.3 ng/mL, P = .044); but the visfatin level dropped significantly after treatment (12.0 +/- 1.4 ng/mL, P < .001). The reciprocal index of homeostasis model assessment of insulin resistance (HOMA-IR) in the hyperthyroid group was higher before treatment (2.06 +/- 0.26 mmol mU/L*L) than after treatment (1.21 +/- 0.16 mmol mU/L*L, P = .027). There was no significant difference in serum glucose, high-sensitivity CRP, and insulin levels between hyperthyroid and control groups and in the hyperthyroid group before and after treatment. Body mass index-adjusted visfatin levels were significantly elevated in the hyperthyroid group. Pearson correlation revealed that visfatin, glucose, insulin, and HOMA-IR values positively correlated with triiodothyronine and free thyroxine levels. However, visfatin did not correlate with insulin and HOMA-IR levels. The results indicated that plasma visfatin concentration was elevated in hyperthyroidism due to Graves disease, but serum CRP levels were not. Plasma visfatin levels were not associated with indicators of insulin resistance in hyperthyroid patients.

The effects of different doses of atorvastatin on plasma endothelin-1 levels in type 2 diabetic patients with dyslipidemia.

We investigated the effects of three different daily doses (10 mg, 20 mg, and 40 mg) of atorvastatin, a relatively new and potent statin, on plasma endothelin (ET)-1 and highly sensitive C-reactive protein (CRP) levels in type 2 diabetic subjects. Twenty-nine type 2 diabetic patients with dyslipidemia were enrolled and randomly assigned to receive atorvastatin orally at 10 mg (A10; n = 10), 20 mg (A20; n = 10), or 40 mg (A40; n = 9) daily for 12 weeks. Levels of plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol (C) in all three studied groups were significantly decreased after treatment with atorvastatin for 12 weeks (all groups, P < 0.001). However, the greatest LDL-C lowering effect and the highest percentage of subjects achieving the National Cholesterol Education Program's Adult Treatment Panel III (NCEP-ATP III) LDL-C goal were observed in the A20 group. All diabetic subjects had a higher plasma ET-1 concentration (A10, 1.02 +/- 0.37 pg/ml, mean +/- SD; A20, 1.17 +/- 0.55 pg/ml; and A40, 0.87 +/- 0.45 pg/ml) than that of age- and sex-matched normal control subjects (0.64 +/- 0.15 pg/ml; all groups, P < 0.001). Plasma ET-1 levels showed a borderline significant decrease at the end of study, by 22% in diabetic subjects treated with 10 mg atorvastatin (P = 0.05 compared with baseline), and by 30% in subjects treated with 20 mg atorvastatin (P = 0.06, compared with baseline). Paradoxically, the 40-mg dose of atorvastatin provided an increase of 2% in plasma ET-1 levels at the end of study, which is significantly different (P < 0.05) and marginally significant (P = 0.057) from the levels of the 10- and 20-mg doses, respectively. Similarly, although insignificantly, plasma concentrations of CRP also tended to decrease by 12% and 48%, and paradoxically increased by 18% in diabetic patients treated with 10 mg, 20 mg, and 40 mg atorvastatin, respectively. The clinical significance of these biphasic lipid-independent statin effects is unknown and the present study suggests that 20 mg atorvastatin may have the best benefits in treating diabetic patients with dyslipidemia.

Hyperthyroidism is associated with higher plasma endothelin-1 concentrations.

The objective of this study was to determine the change of plasma endothelin (ET)-1 concentrations and insulin resistance index after therapy for hyperthyroidism. We studied 20 patients with hyperthyroidism (15 women and 5 men; age, 34.0 +/- 2.8 years), and 31 patients with euthyroid goiters as controls (27 women, 4 men; age, 37.0 +/- 2.4 years). All hyperthyroid patients were treated with antithyroid drugs. The patients received evaluations before and after normalization of thyroid function. The evaluations included body mass index (BMI), body fat, and measurement of circulating concentrations of thyroid hormones, glucose, insulin, and ET-1. Hyperthyroid subjects had higher plasma ET-1 concentrations than the control group (P < 0.001). No significant differences in serum glucose and insulin concentrations or insulin resistance index estimated by the R value of the homeostasis model assessment (HOMA-R) were noted between the groups. Plasma ET-1 concentrations decreased after correction of hyperthyroidism compared with pretreatment (P = 0.006). Serum glucose concentrations decreased after correction of hyperthyroidism (P = 0.005). Moreover, both body weight-adjusted insulin concentrations and the HOMA-R index were also decreased after correction of hyperthyroidism compared with pretreatment (P = 0.026 and P = 0.019, respectively). Pearson's correlation revealed that plasma ET-1 levels positively correlated with serum triiodothyronine (T3) and free thyroxine (FT4) levels. Serum insulin levels and the HOMA-R index positively correlated with BMI and body fat. The HOMA-R index also positively correlated with serum T3 and FT4 levels. Neither insulin levels nor the HOMA-R index correlated with ET-1 levels. Hyperthyroidism is associated with higher plasma ET-1 concentrations. In addition, correction of hyperthyroidism is also associated with a decrease of plasma ET-1 levels as well as the insulin resistance index calculated by HOMA-R.

Gene transfer of pro-opiomelanocortin prohormone suppressed the growth and metastasis of melanoma: involvement of alpha-melanocyte-stimulating hormone-mediated inhibition of the nuclear factor kappaB/cyclooxygenase-2 pathway.

Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, alpha-melanocyte-stimulating hormone (alpha-MSH), and beta-endorphin (beta-EP). POMC neuropeptides are potent inflammation inhibitors and immunosuppressants and may exert opposite influences during tumorigenesis. However, the role of POMC expression in carcinogenesis remains elusive. We evaluated the antineoplastic potential of POMC gene delivery in a syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptides in cultured media, which differentially regulated the secretion of pro- and anti-inflammatory cytokines in lymphocytes. POMC gene transfer significantly reduced the anchorage-independent growth of melanoma cells. Moreover, pre- or post-treatment with POMC gene delivery effectively retarded the melanoma growth in mice. Intravenous injection of POMC-transduced B16-F10 cells resulted in reduced foci formation in lung by 60 to 70% of control. The reduced metastasis of POMC-transduced B16-F10 cells could be attributed to their attenuated migratory and adhesive capabilities. POMC gene delivery reduced the cyclooxygenase-2 (COX-2) expression and prostaglandin (PG) E(2) synthesis in melanoma cells and tumor tissues. In addition, application of NS-398, a selective COX-2 inhibitor, mimicked the antineoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 down-regulation was correlated with its inhibition of nuclear factor kappaB (NFkappaB) activities. Exogenous supply of alpha-MSH inhibited NFkappaB activities, whereas application of the alpha-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFkappaB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via alpha-MSH-induced inhibition of NFkappaB/COX-2 pathway, thereby constituting a novel therapy for melanoma.

Two-year effect of rosiglitazone in chinese poorly controlled type 2 diabetic patients.

BACKGROUND: The goal of this study is to assess the 24-week efficacy of the addition of rosiglitazone 4 mg to existing full dose sulfonylurea (SU) and metformin (MET) therapy in patients with inadequately controlled type 2 diabetes, and to observe the continued follow-up efficacy and safety of this drug for up to two years. METHODS: This study consists of 32 patients. Fasting plasma glucose (FPG), free fatty acid (FFA), high sensitive C-reactive protein (HS-CRP), adiponectin, insulin and C-peptide were measured every four weeks up to week 24. After that time, the FPG continued to be checked every month. Glycated hemoglobin (HbA1c) and lipid profiles were also checked every 12 weeks for more than two years. RESULTS: HbA1c was reduced by 1.4% at week 12 and by 1.1% at week 24. However HbA1c was still above 9% throughout the whole study period. FPG was reduced significantly when comparing the baseline value to the value after treatment. The FPG values after one year and two years follow-up were similar to the value at week 24. The serum total cholesterol and low density lipoprotein (LDL) cholesterol levels increased significantly. Serum triglycerides were reduced significantly. Significant reductions in serum FFA from baseline to week 24 were observed. A gradually decrease of serum HS-CRP was noted from baseline to week 24. Serum adiponectin levels increased maximally at week 12 and then it decreased gradually, showing a significant change. Serum insulin and C-peptide levels showed significant changes from baseline to week 24. There were no acute cardiocerebral peripheral vascular disease events or liver damage within the entire study period. CONCLUSIONS: Clinical improvement in glycemic control was observed after the addition of rosiglitazone to type 2 diabetic patients receiving full dose SU and MET therapy. The maximal effect was observed at week 12 and the effect continued for at least two years. Further, the combination therapy also resulted in an improvement in lipid profiles, decreased HS-CRP and increased adiponectin levels in the short term (24 weeks). This combination therapy is also safe and beneficial for at least two years because no acute episodes of cardiocerebral peripheral vascular disease were seen.

Salivary immunoreactive endothelin in patients with upper gastrointestinal diseases.

Endothelins have been implicated in gastric mucosal damage in a variety of animal models. Furthermore, clinical reports also show elevated gastric mucosal endothelin-1 levels in patients suffering from peptic ulcer diseases. We have demonstrated, first, the presence of immunoreactive endothelin (IR-ET) in human saliva. We also show that endothelins are rather stable in human saliva. The present study was undertaken to determine whether patients with endoscopically proven upper gastrointestinal diseases have a salivary excess of IR-ET, compared with patients with a normal esophagogastroduodenoscopy. Saliva was collected from fasting subjects prior to esophagogastroduodenoscopy. The levels of IR-ET were measured by the radioimmunoassay method. The salivary concentrations of IR-ET in the studied subjects were as follows: 8.9 +/- 1.0 fmol/mL (mean +/- standard error of the mean) for patients with gastric ulcers (n = 18); 7.3 +/- 1.0 fmol/mL for patients with duodenal ulcers (n = 22); and 6.8 +/- 0.6 fmol/mL for patients with gastritis (n = 28). These values are all higher than that of normal subjects (4.4 +/- 0.5 fmol/mL, n = 20; P < 0.001, P < 0.01, and P < 0.05, respectively). No significant differences in salivary IR-ET were noted between patients with a normal esophagogastroduodenoscopy and patients with esophagitis (3.8 +/- 0.7 fmol/mL, n = 4) or gastric cancer (5.3 +/- 1.4 fmol/mL, n = 4). There were no significant differences in the salivary IR-ET levels between males and females. However, the salivary IR-ET levels in the smokers (8.0 +/- 0.6 fmol/mL, n = 38) were significantly higher (P < 0.01) than those of the non-smokers (6.0 +/- 0.4 fmol/mL, n = 58). There was no correlation of IR-ET levels with age. Our findings suggest that salivary endothelin may have a contributing role in certain gastroduodenal diseases.

Immunoreactive endothelin in Taiwanese thyroid cystic fluid.

Endothelin-1 is a major vasoconstrictor peptide, first found in endothelial cells and later in many other tissues, including the thyroid gland. It is well known that endothelins can act as autocrine and/or paracrine regulators of thyroid homeostasis and growth. Previously we have demonstrated that immunoreactive endothelins (IR-ET) are present in various human body fluids, and IR-ET has also been detected in pathologic breast and thyroid cystic fluids. In this study, the IR-ET in Taiwanese thyroid cystic fluid was measured by radioimmunoassay and characterized by chromatography. Human thyroid cystic fluid was obtained by fine needle aspiration, was centrifuged, and the supernatant was stored at -20 degrees C until IR-ET assay. IR-ET has been detected in 25 of 33 samples of thyroid cystic fluid [25 cases, 4.11 +/- 0.31 fmol/mL (mean +/- standard error of the mean); other eight cases, undetectable]. Gel permeation chromatography of the extract of pooled cystic fluid showed only one major peak at the elution position of human endothelin-1 standard. No difference in cystic IR-ET levels was found in our patients with cystic nodules in relation to differences in thyroid function. It is probable that endothelin-1 is produced by the epithelial cells lining the thyroid cysts, and the increased levels of IR-ET in cystic fluid found in our patients could either be secondary to cystic nodule development or have a role in goiter formation.

Sclerotherapy of thyroid cystic nodules.

BACKGROUND AND PURPOSE: Percutaneous ethanol injection (PEI) has been established as an effective and safe treatment for thyroid cystic nodules (TCN). Certain tetracyclines have also been used successfully as sclerosing agents, and it has been proposed that a low pH might account for their efficacy in this indication. This study compared the effectiveness of ethanol and dilute hydrochloric acid (pH 1.0) in the sclerotherapy of TCN. METHODS: A total of 27 patients with TCN with a mean cystic volume of 16.6 mL (5-45 mL) were randomly assigned to receive 1 of the following 3 treatments: 1) needle aspiration only, 9 patients; 2) PEI, 10 patients; or 3) percutaneous hydrochloric acid injection (PHI), 8 patients. The procedures were performed weekly until cure was evident. Resolution was defined as the disappearance of cyst or reduction of cystic volume to below 0.5 mL. Treatment was considered a failure if the condition did not resolve after 5 sessions of intervention. The 10 original patients treated by PEI and 14 additional patients subsequently enrolled and treated by PEI were followed for 24 months in order to evaluate the long-term effects of PEI treatment. Follow-up physical examination and ultrasound scan was performed every 3 months during the first year and every 6 months during the second year. A cystic volume of greater than 1 mL was regarded as a recurrence. RESULTS: PHI did not have a better cure rate than aspiration alone (37.5% vs 44.4%, p = 0.778). PEI had a significantly higher cure rate than PHI (90% vs 37.5%, p = 0.023) and aspiration alone (90% vs 44.4%, p = 0.038). No patient who received aspiration only complained of cervical pain. Four patients who received PEI and 3 patients who received PHI complained of self-limited cervical pain soon after sclerosant injection. Completed follow-up in the 24 patients ranged from 3 to 24 months (mean, 15.5 +/- 7.7 months), and only 3 patients (12.5%) were found to have recurrence within the first 9 months. The likelihood of recurrence was not correlated with pretreatment cystic volume. CONCLUSIONS: Use of a low-pH sclerosant (PHI) was of no benefit. PEI provides a rapid, tolerable, and sustained effect and can be used as first-line treatment in patients with TCN.

Role of endothelin in diabetic retinopathy.

Endothelin-1 (ET-1) is a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3 genes). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor compared to the other two isoforms. Besides being a very potent vasoconstrictor, ET-1 also acts as a mitogen on the vascular smooth muscle and thus it may play a role in the development of vascular diseases. There is evidence that impaired auto-regulation of blood flow is involved in the pathogenesis of diabetic microangiopathy. It is known that the ability of the diabetic's circulation to distribute blood is affected, especially during increased blood flow. In most tissues this causes no serious burden, but three tissues are usually susceptible to disturbance. They are the retina, renal cortex, and peripheral nerves. Retinal vascular auto-regulation is defined as the ability of the blood vessels to keep blood flow constant under varying perfusion pressure in order to match it to tissue oxygen and metabolic requirements. The failure of auto-regulation is an important and often early feature of diabetic retinopathy. Since human retina vessels lack extrinsic innervation, retinal vessel calibre and local blood flow are normally regulated by non-nervous mechanisms intrinsic to the retina. There is now a considerable body of evidence suggesting that retinal pericytes are the main regulators of vascular tone in the retinal capillaries because they contain components of contractile proteins similar to vascular smooth muscle cells and because they also possess ET-1 receptors. Furthermore. ET-1 has been shown to cause vasoconstriction of retinal vessels as well as to have mitogenic effects on retinal pericytes. Hence, alterations in the pericyte-ET interaction may have a role causing early hemodynamic and histopathological abnormalities found in diabetic retinopathy. On the contrary, Chakrabarti et al. demonstrate that retinas from the chronic diabetic BB/W rats (6 months) show an increase in ET-1, ET-3, ET(A) receptor and ET(B) receptor mRNA expressions when compared to those from control rats. Similar results are noted by them using immunohistochemical methods. Finally, an increased ocular, and retina tissue levels of ET-1 in diabetic rats have also been reported by Chakravarthy et al., as well as by Takagi et al. All of these findings suggest that endothelins may also be involved in the pathogenesis of more advanced diabetic retinopathy, such as capillary occlusion and subsequent neovascularization. This review summarizes the reported literature on the role of ET-1 in the development of diabetic retinopathy.