Induced pluripotent stem cells alleviate lung injury from mesenteric ischemia-reperfusion.

BACKGROUND: Mesenteric ischemia-reperfusion (I/R) injury is a serious pathophysiologic process that can trigger the development of multiorgan dysfunction. Acute lung injury is a major cause of death among mesenteric I/R patients, as current treatments remain inadequate. Stem cell-based therapies are considered novel strategies for treating several devastating and incurable diseases. This study examined whether induced pluripotent stem cells (iPSCs) lacking c-myc (i.e., induced using only the three genes oct4, sox2, and klf4) can protect against acute lung injury in a mesenteric I/R mouse model. METHODS: C57BL/6 mice were randomly divided into the following groups: sham/no treatment, vehicle treatment with phosphate-buffered saline, treatment with iPSCs, and treatment with iPSC-conditioned medium. The mice were subjected to mesenteric ischemia for 45 minutes followed by reperfusion for 24 hours. After I/R, the lungs and the ileum of the mice were harvested. Lung injury was evaluated by histology, immunohistochemistry, and analyses of the levels of inflammatory cytokines, cleaved caspase 3, and 4-hydroxynonenal. RESULTS: The intravenously delivered iPSCs engrafted to the lungs and the ileum in response to mesenteric I/R injury. Compared with the phosphate-buffered saline-treated group, the iPSC-treated group displayed a decreased intensity of acute lung injury 24 hours after mesenteric I/R. iPSC transplantation significantly reduced the expression of proinflammatory cytokines, oxidative stress markers, and apoptotic factors in injured lung tissue and remarkably enhanced endogenous alveolar cell proliferation. iPSC-conditioned medium treatment exerted a partial effect compared with iPSC treatment. CONCLUSION: When considering the anti-inflammatory, antioxidant, and antiapoptotic properties of iPSCs, the transplantation of iPSCs may represent an effective treatment option for mesenteric I/R-induced acute lung injury.

[Effects of lipid-modulation and antiplatelet treatment on the endothelial lipase expression].

OBJECTIVE: To investigate the effects of lipid-modulation and antiplatelet treatment on the expression of endothelial lipase (EL) of patients with coronary artery disease (CAD), and investigate the role of EL in the development of CAD. METHODS: One hundred and fifty-seven cases were divided into three groups according to clinical manifestations and the results of coronary artery angiography: control group (n=41) with more than one risk factors of CAD and the vessel lesions was <30%; stable angina pectoris (SAP) group (n=55); acute coronary syndrome (ACS) group (n=61). The EL positive cell rate was measured 2 weeks after cessation of lipid-modulation and aspirin treatment, and 6 months after treatment with simvastatin and/or aspirin. The drug was ceased for the complications or not tolerance for the treatment. RESULTS: Except the patients in control group with aspirin treatment, the EL positive cell rate was significantly decreased among other groups [control group with simvastatin: (3.93±0.87)% vs. (5.28±1.05)%, SAP group: (8.16±2.11)% vs. (15.12±2.53)%, ACS group: (13.93±3.22)% vs. (38.44±4.36)%; SAP group with aspirin: (10.57±4.07)% vs. (14.66±2.29)%, ACS group: (18.28±5.14)% vs. (40.27±3.96)%; control group with aspirin and simvastatin: (3.13±0.87)% vs. (5.33±1.25)%, SAP group: (5.68±2.20)% vs. (14.89±2.15)%, ACS group: (7.81±3.96)% vs. (39.27±5.17)%, P<0.05 or P<0.01]. CONCLUSION: The treatment with lipid-modulation and/or antiplatelet drug may significantly decrease the expression of EL, implying that EL participates in the progression of CAD.

[Study on six-minute walk test and cardiac output response against exercise in patients with chronic heart failure].

OBJECTIVE: To evaluate the significance of cardiac output (CO) response against exercise determined by IGR method and LVEF, 6 MWT distance in patients with chronic heart failure (CHF). METHOD: To adopt 6 MWT, and before and after the test measuring the CO by the IGR method, furthermore, measure LVEF to 36 patients (heart failure group) with CHF, compare with the health groups (control group). RESULTS: The 6MWT distance of heart failure group (333.00 +/- 49.64) m decrease compared with the control group (582.56 +/- 67.97) m (P < 0.01), moreover, the distance of NYHA class III (314.82 +/- 36.27) m is significantly shorter than II (361.57 +/- 55.42) m (P < 0.05). The LVEF of heart failure group (47.0 +/- 0.4)% reduce compared with the control group (66.9 +/- 5.2)% (P < 0.01), and the data of NYHA class III (43.3 +/- 10.3)% is significantly lower than II (52.8 +/- 7.6)% (P < 0.01). The increase in CO response against exercise of heart failure group (5.97 +/- 1.89) L/min decrease compared with control group (8.88 +/- 0.52) L/min (P < 0.01), furthermore, the value of NYHA class III (5.31 +/- 1.52) L/min, compared with II (7.01 +/- 1.98)L/min, is obviously lower (P < 0.01). The 6MWT distance correlates positively with the increase in CO response against exercise (r = 0.63, P < 0.01), but the correlation is not found between the increase CO response against exercise and the LVEF (r = 0.11, P > 0.05). CONCLUSION: Our results show that CO response against exercise measured by IGR method, with the advantages of being noninvasive, safe, convenient and accurate, combining with the 6MWT can evaluate cardiac reserve in patient with CHF.

Renal diagnosis of chronic hemodialysis patients with urinary tract transitional cell carcinoma in Taiwan.

BACKGROUND: Transitional cell carcinoma (TCC) is the most common malignancy in dialysis patients of Taiwan. The reason for such a high incidence of TCC is undetermined. The correlation between the underlying renal disease and the development of TCC was investigated. METHODS: The authors retrospectively reviewed the clinical data and outcome of 1537 chronic hemodialysis (HD) patients from 1993 to 2002. The incidence of TCC was computed. The Cox regression method was used to analyze the role of potential risk factors. RESULTS: After a mean dialysis duration of 46.5 months, 26 (1.69%) patients with TCC were diagnosed. The standardized incidence ratio (SIR) of TCC was 48.2 as compared with the general population and the SIR of TCC seemed higher in women (65.1) and in the age group 50 to 54 years (173.6). Of them, most cases showed no definite etiology. All these cases showed bilateral contracted kidneys. Nonnephrotic proteinuria was found in all cases and trace glucosuria was found in 17 (65%). Painless gross hematuria was the cardinal symptom and distant metastasis was rare. Also, TCC in upper urinary tracts were common and found in 14 (54%) of patients. Age at the time of dialysis, female sex, compound analgesic use, and Chinese herb use had statistical significance as risk factors (P < .05). CONCLUSIONS: Chronic HD patients have a high risk of TCC in Taiwan, especially in female and middle-aged patients. The study indicated that chronic tubulointerstitial nephritis (CTIN) is the most likely underlying renal disease in HD patients with TCC, a high percentage of the CTIN related to the usage of Chinese herbs or compound analgesics may contribute to the development of TCC, whereas diabetes or chronic glomerulonephritis play only a minor role.

Use of unfractionated heparin and a low-molecular-weight heparin following thrombolytic therapy for acute ST-segment elevation myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is one of the most serious cardiovascular diseases, with acute ST-segment elevation myocardial infarction (STEMI) showing a higher mortality rate than non-ST-segment elevation myocardial infarction (NSTEMI). There is evidence that low-molecular-weight heparin (LMWH) shows greater efficacy than unfractionated heparin (UFH). This open-label, single-centre, randomised study was conducted to compare the efficacy and safety of parnaparin sodium, a LMWH, with UFH in patients with STEMI. PATIENTS AND METHODS: Patients with STEMI were randomised to receive either parnaparin sodium (4250IU aXa subcutaneously every 12 hours for 7 days, initiated 12 hours after thrombolysis) or UFH (100 U/kg intravenous bolus, initiated 12 hours after thrombolytic therapy, followed by 1000 U/hour as a continuous infusion for 3 days, then 7500U subcutaneously every 12 hours for 4 days). Patients were followed up for 45 days (> or =14 days in hospital). RESULTS: In total, 186 patients were randomised to receive parnaparin sodium (n = 96) or UFH (n = 90). A significantly greater reduction in the composite primary endpoint (sum of all deaths, first occurrence of recurrent MI, and first occurrence of emergency revascularisation) was seen with parnaparin sodium compared with UFH at day 45 (27.08% vs 42.22%; p = 0.03). A lower incidence of composite endpoint was seen as early as day 2 with parnaparin sodium, but this did not reach significance versus UFH. The rate of individual endpoint events (death, first occurrence of non-fatal recurrent MI and first occurrence of emergency revascularisation) was lower in the parnaparin sodium group than the UFH group at 2, 7, 14 and 45 days, but the differences were not statistically significant. At day 7, the incidences of any bleeding and heparin-induced thrombocytopenia were also lower in the parnaparin sodium group compared with the UFH group (3.13% vs 10.0%; p = 0.06 and 0% vs 3.33%; p = 0.07, respectively). CONCLUSION: The results of this study indicate that parnaparin sodium is more effective than UFH in reducing composite cardiac events in patients with STEMI following thrombolytic therapy. There was also a lower incidence of bleeding and heparin-induced thrombocytopenia with parnaparin sodium than with UFH. In view of these findings, parnaparin sodium represents an effective, convenient and well tolerated alternative to UFH.

[G protein kinase 4gammaA142V overexpression induced hypertension by downregulating D1 receptors in transgenic mice].

OBJECTIVE: Abnormalities in dopamine production and receptor function have been described in human essential hypertension and rodent models of genetic hypertension. We investigated the role of G protein kinase (GRK) 4gamma in essential hypertension in GRK4gamma mutant A142V transgenic mice. METHODS: Blood pressure, renal sodium excretion, D(1) receptor protein expression and phosphorylation were measured in GRK4gammaA142V transgenic mice and control mice. Moreover, the effects of GRK4 inhibition by antisense oligonucleotides on D(1) receptor expressions were determined in HK-2 cells. RESULTS: As compared with their control mice, GRK4gammaA142V transgenic mice had higher blood pressure, lower D(1) receptor expression (0.6 +/- 0.2 vs. 1.5 +/- 0.2, P < 0.05), higher D(1) receptor phosphorylation [(65 +/- 7) DU vs. (35 +/- 7) DU, P < 0.05] in renal cortical membranes and the diuretic and natriuretic effects after stimulation of renal D(1) receptor were impaired in GRK4gammaA142V transgenic mice. Inhibition of GRK4 expression (0.60 +/- 0.10 vs. 1.30 +/- 0.09, P < 0.05) by GRK4 antisense oligonucleotides upregulated D(1) receptor expression (1.5 +/- 0.2 vs. 0.8 +/- 0.1, P < 0.05) in HK-2 cells. CONCLUSIONS: Our results show that GRK4gammaA142V overexpression induced hypertension is mediated by dowregulated renal D(1) receptor expressions in GRK4gammaA142V transgenic mice.

[Changes of fasting serum insulin in normotensive patients with left ventricular hypertrophy].

OBJECTIVE: To explore the relationship between left ventricular hypertrophy (LVH) and serum insulin changes in normotensive patients. METHODS: Forty-two normotensive patients with LVH, who were free of hypertension, coronary artery disease and diabetes, were examined for fasting serum insulin, glucose and serum lipids, and the left ventricular mass (LVM) and left ventricular mass index (LVMI) were also measured with echocardiography, with 46 normal subjects serving as the control group. RESULTS: The levels of fasting triglyceride and insulin, as well as insulin resistance index (IRI), were higher in the LVH group than in the control group. Multifactor regression analysis showed that IRI was positively correlated to LVM and LVMI in LVH group (r=0.38, P<0.01; r=0.29, P<0.01). CONCLUSION: Hyperinsulinemia is closely correlated with LVH in these normotensive patients, and can be involved in the pathogenesis and progression of LVH.

[Use of unfractionated heparin and a low-molecular-weight heparin following thrombolytic therapy for acute ST-segment elevation myocardial infarction].

OBJECTIVE: To compare the efficacy and safety of unfractionated heparin with a low-molecular-weight heparin (parnaparin) in the management of anticoagulation following thrombolytic therapy for acute ST-segment elevation myocardial infarction. METHODS: One hundred and eighty-six patients with acute ST-segment elevation myocardial infarction undergoing thrombolytic therapy were randomly assigned to receive either unfractionated heparin (100 U/kg x b.w. intravenous bolus, 1,000 U/h continuous infusion for 3 days just 12 h after thrombolysis to maintain the activated partial thromboplastin time at 1.5 to 2.0 times as normal, then subcutaneous 7500 U every 12 h for 4 days, n=90) or parnaparin (0.4 ml subcutaneously every 12 h for 7 days 12 h after thrombolysis, n=96) in conjunction with routine therapy. The patients enrolled stayed in hospital for at least 14 days and were followed for 45 days after admission into the hospital. RESULTS: The composite triple end-point (death, recurrent myocardial infarction, emergency revascularization assessed at 2, 7, 14, 45 days) was significantly reduced in patients receiving parnaparin 42.22% vs 37.08%, P=0.03 . Compared with unfractionated heparin group, the incidences of hemorrhage 10.00% vs 3.13%, P=0.06 and heparin-induced thrombocytopenia (3.33% vs 0, P=0.07) were also lower in parnaparin group. CONCLUSION: Parnaprin is more effective in reducing composite cardiac events, hemorrhage and heparin-induced thrombocytopenia at least in 45 days as compared with unfractionated heparin during anticoagulation following thrombolytic therapy for acute ST-segment elevation myocardial infarction.

[Effects of insulin on the distribution of actins in vascular smooth muscle cells in the process of proliferation via mitogen-activated protein kinase in vitro].

Proliferation of vascular smooth muscle cells (VSMCs) is often accompanied by changes in intracellular actin distribution. The changes are controlled by the signal transduction pathways of protein kinase C/mitogenic activated protein kinase (PKC-MAPK), but the mechanism is unclear. In order to study the effect of insulin on the intracellular signal transduction (PKC-MAPK) probably involved in the modulation of proliferation and redistribution of actins in the VSMCs, the DNA synthesis, MAPK activities and its gene expression, and the redistribution of intracellular actins were investigated in the isolated VSMCs of SHR pretreated with PKC inhibitor and/or insulin, respectively. We found that insulin treatment resulted in proliferation of the VSMCs and an increase in [(3)H] TdR incorporation. Meanwhile, the activities and expression of MAPK increased significantly compared to the control group. These effects of insulin were blocked by PKC inhibitor. In addition, insulin caused a redistribution of the intracellular actins in VSMCs, which was also inhibited by PKC inhibitor. It is, therefore, suggested that these effects of insulin on VSMCs proliferation and distribution of the intracellular actins may be mediated by the MAPK signal transduction pathway.