Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic ß-cell dysfunction by glutathione antioxidant system.

Progression of ß-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in ß-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in ß-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves ß-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves ß-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved ß-cell function and survival under high-glucose conditions via the glutathione redox balance.

Cadmium exposure and thyroid hormone disruption: a systematic review and meta-analysis.

INTRODUCTION: This meta-analysis aimed to analyze the effect of cadmium (Cd) exposure on thyroid hormone disruption. CONTENT: Databases including PubMed, Embase, Cochrane Library, and Scopus were searched for studies published up to December 14, 2022. Studies evaluating the association between Cd exposure (blood Cd [BCd] or urine Cd [UCd]) and thyroid function (thyroid-stimulating hormone [TSH], free thyroxine [FT4], total triiodothyronine [TT3]) or thyroid autoimmunity (thyroglobulin antibody [TgAb] or thyroperoxidase Ab [TPOAb]) were included. SUMMARY AND OUTLOOK: This systematic review included 12 cross-sectional studies. Cd exposure showed a neutral association with TSH (pooled correlation=0.016, 95 % confidence interval [CI]=-0.013 to 0.045, p=0.277), FT4 (pooled correlation=0.028, 95 % CI=-0.005 to 0.061, p=0.098), and thyroid autoimmunity (pooled odds ratio=1.143, 95 % CI=0.820-1.591, p=0.430). However, Cd exposure showed a positive association with TT3 (pooled correlation=0.065, 95 % CI=0.050-0.080, p<0.001), which was consistent with the BCd and UCd subgroup analyses (pooled correlation=0.053 and 0.081, respectively, both p<0.001). Cd exposure was not associated with TSH, FT4, or thyroid autoimmunity but tended to increase with TT3.

Predictive factors of lymph node metastasis in papillary thyroid cancer.

This study aimed to evaluate factors that predict lymph node metastasis (LNM) in papillary thyroid cancer (PTC). This retrospective cross-sectional study compared the demographic, clinical, and ultrasonographic findings of patients with PTC with and without LNM. Subgroup analysis was conducted for micro-PTCs (<1 cm). Among total (n = 512; mean age, 47.3 ± 12.7 years) and micro-PTC patients (n = 312), 35.7% and 19.6% had LNM, respectively. Younger age, male sex, tumor size, bilaterality, and suspicious ultrasound features of the tumor were associated with LNM. In multiple logistic regression analysis, among all patients, age, tumor size, and extrathyroidal extension were independent risk factors for LNM (all p<0.05). In the micro-PTC subgroup, age, extrathyroidal extension, bilaterality of tumor, and presence of autoimmune thyroid disease were independent risk and protective factors for LNM (all p<0.05). In the receiver operating characteristic analysis, the accuracy of the multivariable logistic regression model for predicting LNM among all patients and micro-PTC was acceptable (area under the curve = 0.729 and 0.733, respectively). Age, sex, tumor size, and extrathyroidal extension can assist in predicting LNM in PTC patients. Additionally, the bilaterality of tumors and presence of autoimmune thyroid disease can assist in predicting LNM in micro-PTCs.

Effect of cadmium exposure on body composition deterioration: A propensity score-matched cohort study.

This propensity score-matched cohort study investigated the effects of blood cadmium (Cd) levels on body composition. Body composition was assessed by multifrequency bioelectrical impedance analysis and categorized into three groups: metabolically healthy obesity (MHO), adiposity obesity (AO), and sarcopenic obesity (SO). At baseline, 85 and 101 participants had MHO and AO, respectively (mean age, 51 ± 7 years; male-to-female ratio, 1.0:1.3). During the 14-year follow-up, the body composition of 40 MHO and 6 AO participants deteriorated to AO and SO, respectively. The incidence of AO and SO differed according to age, sex, and blood Cd level. High blood Cd level increased the risk of body composition deterioration, particularly among those aged 60-69 years (hazard ratio [HR] = 2.14), women (HR = 1.46), and those with AO at baseline (HR = 1.63; all p < 0.05). Cd exposure deteriorates body composition in older and female individuals, particularly from AO to SO.

Interleukin-6-producing paraganglioma as a rare cause of systemic inflammatory response syndrome: a case report.

Pheochromocytomas and paragangliomas (PPGLs) may secrete hormones or bioactive neuropeptides such as interleukin-6 (IL-6), which can mask the clinical manifestations of catecholamine hypersecretion. We report the case of a patient with delayed diagnosis of paraganglioma due to the development of IL-6-mediated systemic inflammatory response syndrome (SIRS). A 58-year-old woman presented with dyspnea and flank pain accompanied by SIRS and acute cardiac, kidney, and liver injuries. A left paravertebral mass was incidentally observed on abdominal computed tomography (CT). Biochemical tests revealed increased 24-hour urinary metanephrine (2.12 mg/day), plasma norepinephrine (1,588 pg/mL), plasma normetanephrine (2.27 nmol/L), and IL-6 (16.5 pg/mL) levels. 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT showed increased uptake of FDG in the left paravertebral mass without metastases. The patient was finally diagnosed with functional paraganglioma crisis. The precipitating factor was unclear, but phendimetrazine tartrate, a norepinephrine-dopamine release drug that the patient regularly took, might have stimulated the paraganglioma. The patient's body temperature and blood pressure were well controlled after alpha-blocker administration, and the retroperitoneal mass was surgically resected successfully. After surgery, the patient's inflammatory, cardiac, renal, and hepatic biomarkers and catecholamine levels improved. In conclusion, our report emphasizes the importance of IL-6-producing PPGLs in the differential diagnosis of SIRS.

Perfluorooctane sulfonate-induced oxidative stress contributes to pancreatic ß-cell apoptosis by inhibiting cyclic adenosine monophosphate pathway: Prevention by pentoxifylline.

Endocrine-disrupting chemical perfluorooctane sulfonate (PFOS) acute exposure stimulates insulin secretion from pancreatic ß-cells. However, chronic exposure to PFOS on pancreatic ß-cells, its role in insulin secretion, and the underlying mechanisms have not been studied. We used rat insulinoma INS-1 and human 1.1b4 islet cells to investigate the chronic effects of PFOS on glucose-stimulated insulin secretion and toxicity implicated in the downregulation of ß-cell functionality. Chronic exposure of INS-1 cells or human pancreatic 1.1b4 ß-cells to PFOS stimulated the small G-protein RAC1-guanosine triphosphate-dependent nicotinamide adenine dinucleotide phosphate oxidase (NOX2/gp91phox) subunit expression and activation. Upregulated NOX2/gp91phox activation led to elevated reactive oxygen species (ROS) production with a decrease in the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway in both cell types. Inhibition of cAMP/PKA signaling induces ß-cell mitochondrial dysfunction and endoplasmic stress via the loss of PDX1-SERCA2B and glucose-stimulated insulin release. Inhibiting RAC1-NOX2/gp91phox activation or elevating cAMP by pentoxifylline, a Food and Drug Administration-approved phosphodiesterase inhibitor, significantly reduced PFOS-induced ROS production and restored insulin secretory function of pancreatic ß-cells. Enhanced secretory function in pentoxifylline-treated cells was associated with increased stability of PDX1-SERCA2B protein levels. Intriguingly, inhibition of cAMP/PKA signaling impaired pentoxifylline-induced insulin secretion caused by the activation of ROS production and mitochondrial dysfunction. Overall, our findings show that PFOS has a new and first-ever direct chronic effect on pancreatic ß-cell failure through increased RAC1-NOX2/gp91phox activation and pentoxifylline-induced cAMP/PKA signaling, which inhibits PFOS-mediated mitochondrial dysfunction.

Association between the Diabetes Drug Cost and Cardiovascular Events and Death in Korea: A National Health Insurance Service Database Analysis.

BACKGRUOUND: This study aimed to investigate the long-term effects of diabetes drug costs on cardiovascular (CV) events and death. METHODS: This retrospective observational study used data from 2009 to 2018 from the National Health Insurance in Korea. Among the patients with type 2 diabetes, those taking antidiabetic drugs and who did not have CV events until 2009 were included. Patients were divided into quartiles (Q1 [lowest]-4 [highest]) according to the 2009 diabetes drug cost. In addition, the 10-year incidences of CV events (non-fatal myocardial infarction, stroke, hospitalization for heart failure, and coronary revascularization) and CV death (death due to CV events) were analyzed. RESULTS: A total of 441,914 participants were enrolled (median age, 60 years; men, 57%). CV events and death occurred in 28.1% and 8.36% of the patients, respectively. The 10-year incidences of CV events and deaths increased from Q1 to 4. After adjusting for sex, age, income, type of diabetes drugs, comorbidities, and smoking and drinking status, the risk of CV events significantly increased according to the sequential order of the cost quartiles. In contrast, the risk of CV death showed a U-shaped pattern, which was the lowest in Q3 (hazard ratio [HR], 0.953; 95% confidence interval [CI], 0.913 to 0.995) and the highest in Q4 (HR, 1.266; 95% CI, 1.213 to 1.321). CONCLUSION: Diabetes drug expenditure affects 10-year CV events and mortality. Therefore, affording an appropriate diabetes drug cost at a similar risk of CV is an independent protective factor against CV death.

Long-Term Sex-Specific Effects of Cadmium Exposure on Osteoporosis and Bone Density: A 10-Year Community-Based Cohort Study.

This study explored the long-term effects of cadmium (Cd) exposure on osteoporosis incidence and bone mineral density (BMD). This retrospective cohort study included men aged ≥50 years and post-menopausal women from the 2001−2002 Korea Genome and Epidemiology Study. Participants previously diagnosed with osteoporosis were excluded. Blood Cd concentrations were measured and categorized as <0.5, 0.5−1.0, and >1.0 µg/L. BMD was measured using quantitative ultrasound. Osteoporosis was diagnosed when the T-score was ≤−2.5. Confounders that affect exposure and outcome were controlled. Osteoporosis incidence and differences in BMD (ΔBMD) were assessed until 2012. The osteoporosis incidence among 243 participants who were followed up for an average of 6.3 years was 22.2%. In all the participants, a dose−response relationship was observed between blood Cd and incident osteoporosis and ΔBMD (both p-for-trend < 0.01). After adjusting for age, sex, smoking, physical activity, body mass index, creatinine, and baseline BMD, a blood Cd concentration of >1.0 µg/L was an independent risk factor for incident osteoporosis and decrements in ΔBMD. In women, blood Cd concentrations of >0.5 µg/L increased the risk for osteoporosis. Exposure to Cd prospectively increases the risk for osteoporosis and decrements of ΔBMD, particularly in women, even in lower doses of Cd.

The Fate of Antibiotic Impregnated Cement Space in Treatment for Forefoot Osteomyelitis.

Forefoot osteomyelitis can be an extremely challenging problem in orthopedic surgery. Unlike conventional methods, such as amputations, antibiotic impregnated cement space (ACS) was recently introduced and perceived as a substitute for amputation. The purpose of this study was to compare clinical features between diabetic and non-diabetic groups and to evaluate the efficacy of ACS in the treatment of forefoot osteomyelitis, by identifying the clinical characteristics of ACS. We inserted ACS into the forefoot osteomyelitis patients and regularly checked up on them, then analyzed the clinical features of the patients and failure reasons, if ACS had to be removed. Average survival rate of ACS was 60% (21 out of 35 cases) and main failure reason was recurrence of infection. There was no significant clinical difference between diabetic and non-diabetic groups. We concluded that ACS could be a possible way of avoiding amputation if infection is under control. ACS seems to be an innovative method with promising results for foot osteomyelitis, but widely accepted indications need to be agreed upon.

Outbreak of COVID-19 among children and young adults in a cancer centre daycare unit.

Nosocomial transmission of COVID-19 among immunocompromised hosts can have a serious impact on COVID-19 severity, underlying disease progression and SARS-CoV-2 transmission to other patients and healthcare workers within hospitals. We experienced a nosocomial outbreak of COVID-19 in the setting of a daycare unit for paediatric and young adult cancer patients. Between 9 and 18 November 2020, 473 individuals (181 patients, 247 caregivers/siblings and 45 staff members) were exposed to the index case, who was a nursing staff. Among them, three patients and four caregivers were infected. Two 5-year-old cancer patients with COVID-19 were not severely ill, but a 25-year-old cancer patient showed prolonged shedding of SARS-CoV-2 RNA for at least 12 weeks, which probably infected his mother at home approximately 7-8 weeks after the initial diagnosis. Except for this case, no secondary transmission was observed from the confirmed cases in either the hospital or the community. To conclude, in the day care setting of immunocompromised children and young adults, the rate of in-hospital transmission of SARS-CoV-2 was 1.6% when applying the stringent policy of infection prevention and control, including universal mask application and rapid and extensive contact investigation. Severely immunocompromised children/young adults with COVID-19 would have to be carefully managed after the mandatory isolation period while keeping the possibility of prolonged shedding of live virus in mind.

Long-Term Efficacy of Ultrasound-Guided Laser Ablation for Papillary Thyroid Microcarcinoma: Results of a 10-Year Retrospective Study.

Background: The aim of this study was to evaluate the 10-year efficacy and safety of laser ablation (LA) for the treatment of solitary papillary thyroid microcarcinoma (PTMC). Methods: LA was performed on patients with low-risk PTMC (diagnosed using fine-needle aspiration cytology) who refused or were ineligible for surgery between 2008 and 2011. Ultrasonography was performed to evaluate the ablated volumes and potential recurrences on the day after the procedure, as well as at 1 week, 1, 3, and 6 months, and every 6 months thereafter for 10 years. Computed tomography (CT) with contrast enhancement and positron emission tomography/CT was performed to evaluate local recurrences and distant metastases. Results: A total of 90 PTMCs in 90 patients were treated in a single session of LA, and the procedure was well tolerated by the patients. The mean follow-up duration was 112 months. By 3-10 months after the LA, all the ablation areas had disappeared or presented as scars. The disappearance rate was 100% after 12 months. Thyroid hormone and autoantibody levels did not change significantly after the treatment. Three patients experienced transient voice changes, but each recovered within 1 month. Additional PTMC foci were subsequently detected in previously untreated areas in five patients (5.5%) 17-56 months after the treatment. A metastatic lymph node was detected in one patient (1.1%) within two months of the treatment; however, it was determined to be an undetected cancer metastasis, rather than a recurrence. All the patients with recurrence underwent surgery, and there were no instances of recurrence after >5 years. Conclusions: LA is effective and safe for the treatment of low-risk PTMCs. A thorough examination of multifocality and lymph node metastasis status is required before considering LA treatment.

The sex-specific effects of blood lead, mercury, and cadmium levels on hepatic steatosis and fibrosis: Korean nationwide cross-sectional study.

AIM: The potential effects of heavy metals on non-alcoholic fatty liver disease (NAFLD) remain unknown. We investigated the sex-specific relationships of blood lead (BPb), mercury (BHg), and cadmium (BCd) levels with hepatic steatosis (HS) and fibrosis (HF). METHOD: We included 4420 participants from the 2016-2017 Korea National Health and Nutrition Examination Survey. High-risk alcoholics and patients with chronic hepatitis B or C infections or liver cirrhosis were excluded. We calculated the hepatic steatosis index (HSI) and fibrosis-4 index (FIB-4) values; we defined the presence of HS and HF as an HSI ≥ 36 and FIB-4 score >2.67, respectively. We adjusted for age, smoking and alcohol consumption statuses, hypertension, obesity, diabetes, hypertriglyceridemia, and BPb, BHg, and BCd levels. RESULT: In males (n = 1860), the HSI was correlated negatively with the BPb level and positively with the BHg level (both p < 0.01). The FIB-4 score was correlated positively with the BPb and BCd levels (both p < 0.01). In females (n = 2560), the HSI and FIB-4 score were correlated positively with the BPb, BHg, and BCd levels (all p < 0.01). After adjustments, the BHg level increased the risk of HS in both males (OR = 1.065, p = 0.003) and females (OR = 1.061, p = 0.048), and the BCd level increased the risk of HF in females (OR = 1.668, p = 0.012). CONCLUSION: Blood heavy metal levels were generally correlated positively with the HSI and FIB4 score, more so in females than males. The BHg level was associated with HS in males and females, and the BCd level was associated with HF in females. Further studies on NAFLD progression according to heavy metal status and sex are warranted.

Risk factors affecting amputation in diabetic foot.

BACKGROUND: A diabetic foot is the most common cause of non-traumatic lower extremity amputations (LEA). The study seeks to assess the risk factors of amputation in patients with diabetic foot ulcers (DFU). METHODS: The study was conducted on 351 patients with DFUs from January 2010 to December 2018. Their demographic characteristics, disease history, laboratory data, ankle-brachial index, Wagner classification, osteomyelitis, sarcopenia index, and ulcer sizes were considered as variables to predict outcome. A chi-square test and multivariate logistic regression analysis were performed to test the relationship of the data gathered. Additionally, the subjects were divided into two groups based on their amputation surgery. RESULTS: Out of the 351 subjects, 170 required LEA. The mean age of the subjects was 61 years and the mean duration of diabetes was 15 years; there was no significant difference between the two groups in terms of these averages. Osteomyelitis (hazard ratio [HR], 6.164; 95% confidence interval [CI], 3.561-10.671), lesion on percutaneous transluminal angioplasty (HR, 2.494; 95% CI, 1.087-5.721), estimated glomerular filtration rate (eGFR; HR, 0.99; 95% CI, 0.981-0.999), ulcer size (HR, 1.247; 95% CI, 1.107-1.405), and forefoot ulcer location (HR, 2.475; 95% CI, 0.224-0.73) were associated with risk of amputation. CONCLUSION: Osteomyelitis, peripheral artery disease, chronic kidney disease, ulcer size, and forefoot ulcer location were risk factors for amputation in diabetic foot patients. Further investigation would contribute to the establishment of a diabetic foot risk stratification system for Koreans, allowing for optimal individualized treatment.

Sex-specific effects of blood cadmium on thyroid hormones and thyroid function status: Korean nationwide cross-sectional study.

Previous studies on blood cadmium (BCd) and changes in thyroid hormone levels are controversial. We investigated whether thyroid hormone levels and thyroid function status were associated with BCd according to sex in the Korean population. Our study included 1972 participants based on the 2013 Korea National Health and Nutrition Examination Survey (KNHANES) data. Participants whose thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels were altered physiologically or medically were excluded. Changes in TSH, fT4, and anti-thyroid peroxidase antibody (TPOAb) in men and women were analyzed by different characteristics: age, body mass index (BMI), smoking status, drinking status, BCd, and urine iodine-to-creatinine ratio (UI/Cre). Thyroid function status was classified as hypothyroidism, euthyroidism, and hyperthyroidism as defined by TSH and fT4 levels. Among the total participants, there was a negative correlation between BCd and fT4 (r=-0.067, p = 0.003). In men (n = 1057), fT4 levels decreased with increasing BCd quartile (p-for-trend = 0.002). After adjustment for age, BMI, smoking status, UI/Cre, and TPOAb, the association between BCd and hypothyroidism was significant in men (odds ratio = 1.813, p = 0.032) but not in women. These results suggest that cadmium accumulation is closely associated with thyroid dysfunction, and there is a difference in metabolic capacity according to sex.

Novel nomogram for screening the risk of developing diabetes in a Korean population.

AIMS: We propose a novel nomogram, which graphically expresses the numerical relationship between type 2 diabetes (T2D) and disease-related risk factors. METHODS: Data of 8999 patients from the 2013-2014 Korean National Health and Nutrition Examination Survey were analyzed. Multiple logistic regression analysis was performed to assess risk factors for T2D and a nomogram was constructed based on screened risk factors. A receiver operating curve (ROC) and calibration plot were created to evaluate the accuracy of the nomogram. RESULTS: The risk factor with the greatest impact on the prevalence of T2D was age over 60 years (95% CI 5.97-15.00, OR = 9.46), followed by presence of dyslipidemia and cardiovascular disease (95% CI 5.90-13.68, OR = 8.98), family history of T2D (95% CI 2.33-3.64, OR = 2.92), abdominal obesity (OR = 1.76), hypertension (OR = 1.75), male gender (OR = 1.55), current-smoking status (OR = 1.52), lower education level (OR = 1.42), and lower income (OR = 1.30). The area under the ROC curve (AUC) showed statistically significant determination (AUC = 0.83). The equation of the calibration plot was drawn along the ideal line; coefficient of determination was 0.864. CONCLUSION: Our proposed nomogram could accurately predict the risk of T2D from nationwide data. The novel nomogram can be a useful tool for screening patients with T2D risk in a Korean population.

Serum cystatin C is associated with subclinical atherosclerosis in patients with type 2 diabetes: A retrospective study.

BACKGROUND: The aim of this study was to investigate the association between the serum cystatin C level and cardiovascular disease risk in patients with type 2 diabetes mellitus. METHODS: We studied 523 patients with type 2 diabetes mellitus and calculated estimated 10-year risk of atherosclerotic cardiovascular disease (%). Subclinical atherosclerosis was defined as brachial-ankle pulse wave velocity ⩾1700 ms, indicating the presence of arterial stiffness. RESULTS: Cystatin C level was significantly higher in the subclinical atherosclerosis group (brachial-ankle pulse wave velocity ⩾ 1700 ms) than in the non-subclinical atherosclerosis group (brachial-ankle pulse wave velocity < 1700 ms) (7.54 ± 3.15 mg/L vs 10.04 ± 5.12 mg/L, p < 0.001). Subclinical atherosclerosis was mainly determined by age, duration of diabetes and cystatin C level, but not by serum creatinine, 10-year risk of atherosclerotic cardiovascular disease score and estimated glomerular filtration rate in the multiple linear regression analysis. In addition, an increase in cystatin C level was independently associated with the risk of subclinical atherosclerosis after adjusting for age, sex, duration of diabetes, smoking, hypertension, 10-year risk of atherosclerotic cardiovascular disease risk score, serum creatinine level, total cholesterol, high-density lipoprotein cholesterol and haemoglobin A1c (odds ratio = 1.200, 95% confidence interval: 1.04-1.38, p = 0.011). CONCLUSION: Serum cystatin C level was significantly associated with subclinical atherosclerosis. This result suggests that an increase in cystatin C level could be a valuable surrogate marker for the risk of cardiovascular disease in patients with type 2 diabetes mellitus.

Clinicopathological analysis and risk factors of advanced colorectal neoplasms incidentally detected by 18F-FDG PET-CT.

BACKGROUND: As the clinical use of fluorine-18-fluorodeoxyglucose PET-computed tomography (F-FDG PET-CT) has increased, the incidental finding of F-FDG uptake with subsequent diagnosis of advanced neoplasm at colorectum has increased. The aim of this study is to analyze the characteristics and risk factors of advanced colorectal neoplasm incidentally detected by F-FDG PET-CT. PATIENTS AND METHODS: Patients who underwent colonoscopy because of an incidental finding of F-FDG uptake at the colorectum from January 2006 to January 2015 at Yeungnam University Hospital were reviewed retrospectively. Advanced neoplasm was defined as adenoma of at least 10 mm, adenoma with serrated or villous component, high-grade dysplasia, and adenocarcinoma. RESULTS: Of the 19 798 candidates, 180 patients with incidental colorectal F-FDG uptake were included in this study. The indications of PET-CT were metastasis work-up, health screening, and others. The male to female ratio was 1.6 : 1 and the mean age was 62.7±11.4 years. A total of 156 lesions were detected in the colorectum and 86 (47.8%) were diagnosed as advanced neoplasms. Of the 86 patients with advanced neoplasms, 34 (39.5%) underwent an operation, 34 (39.5%) underwent endoscopic resection, and 18 (20.9%) underwent chemotherapy or conservative treatments. In univariate analysis, age of 62.5 years or older, carcinoembryonic antigen (CEA) of at least 3.4 ng/ml, maximum standardized uptake value (SUVmax) of at least 8.0, hypertension, F-FDG uptake on the rectosigmoid, and PET-CT for metastasis work-up showed a significant association with advanced neoplasm. In multivariate analysis, CEA (P=0.028), SUVmax (P<0.001) and an indication of PET-CT for metastasis work-up (P=0.008) were independent predictors of advanced neoplasm. CONCLUSION: Colonoscopy should be recommended in case of F-FDG uptake at the colorectum, particularly in patients with CEA of at least 3.4 ng/ml, SUVmax of at least 8.0, or metastasis work-up of malignancy.

Procoagulant and prothrombotic activation of human erythrocytes by phosphatidic acid.

Increased phosphatidic acid (PA) and phospholipase D (PLD) activity are frequently observed in various disease states including cancers, diabetes, sepsis, and thrombosis. Previously, PA has been regarded as just a precursor for lysophosphatidic acid (LPA) and diacylglycerol (DAG). However, increasing evidence has suggested independent biological activities of PA itself. In the present study, we demonstrated that PA can enhance thrombogenic activities in human erythrocytes through phosphatidylserine (PS) exposure in a Ca(2+)-dependent manner. In freshly isolated human erythrocytes, treatment of PA or PLD induced PS exposure. PA-induced PS exposure was not attenuated by inhibitors of phospholipase A(2) or phosphatidate phosphatase, which converts PA to LPA or DAG. An intracellular Ca(2+) increase and the resultant activation of Ca(2+)-dependent PKC-alpha appeared to underlie the PA-induced PS exposure through the activation of scramblase. A marginal decrease in flippase activity was also noted, contributing further to the maintenance of exposed PS on the outer membrane. PA-treated erythrocytes showed strong thrombogenic activities, as demonstrated by increased thrombin generation, endothelial cell adhesion, and erythrocyte aggregation. Importantly, these procoagulant activations by PA were confirmed in a rat in vivo venous thrombosis model, where PA significantly enhanced thrombus formation. In conclusion, these results suggest that PA can induce thrombogenic activities in erythrocytes through PS exposure, which can increase thrombus formation and ultimately contribute to the development of cardiovascular diseases.

Low-level mercury can enhance procoagulant activity of erythrocytes: a new contributing factor for mercury-related thrombotic disease.

BACKGROUND: Associations between cardiovascular diseases and mercury have been frequently described, but underlying mechanisms are poorly understood. OBJECTIVES: We investigate the procoagulant activation of erythrocytes, an important contributor to thrombosis, by low-level mercury to explore the roles of erythrocytes in mercury-related cardiovascular diseases. METHODS: We used freshly isolated human erythrocytes and ex vivo and in vivo thrombosis models in rats to investigate mercury-induced procoagulant activity. RESULTS: Prolonged exposure to low-dose mercuric ion (Hg(2+); 0.25-5 microM for 1-48 hr) induced erythrocyte shape changes from discocytes to echinocytes to spherocytes, accompanied by microvesicle (MV) generation. These MVs and remnant erythrocytes expressed phosphatidylserine (PS), an important mediator of procoagulant activation. Hg(2+) inhibited flippase, an enzyme that recovers PS into the inner leaflet of the cell membrane, and activated scramblase, an enzyme that alters lipid asymmetry in the cell membrane. Consistent with these activity changes, Hg(2+) increased intracellular calcium and depleted ATP and protein thiol. A thiol supplement reversed Hg(2+)-induced MV generation and PS exposure and inhibited the increase in calcium ion (Ca(2+)) and depletion of ATP, indicating that free-thiol depletion was critical to Hg(2+)-mediated procoagulant activity. The procoagulant activity of Hg(2+)-treated erythrocytes was demonstrated by increased thrombin generation and endothelial cell adhesion. We further confirmed Hg(2+)-mediated procoagulant activation of erythrocytes in ex vivo and in vivo rat thrombosis models, where Hg(2+) treatment (0.5-2.5 mg/kg) increased PS exposure and thrombus formation significantly. CONCLUSION: This study demonstrated that mercury could provoke procoagulant activity in erythrocytes through protein-thiol depletion-mediated PS exposure and MV generation, ultimately leading to enhanced thrombosis.