BACKGROUND/AIMS: Recent epidemiological studies revealed a striking inverse relationship between vitamin D levels, glucose intolerance/insulin resistance (IR), and cardiovascular disease. However, few interventional studies have evaluated the effect of vitamin D supplementation on cardiovascular risk, such as IR and arterial stiffness, in diabetes. We investigated the role of vitamin D supplementation on cardiovascular risk in type 2 diabetes patients, including metabolic parameters, IR, and arterial stiffness. METHODS: We enrolled patients who were taking antidiabetic medications or managed their diabetes using lifestyle changes. We excluded patients who were taking vitamin D or calcium supplements. We randomized participants into the vitamin D group (cholecalciferol 2,000 IU/day + calcium 200 mg/day, n = 40) or the placebo group (calcium 200 mg/day, n = 41). We compared their IR (homeostasis model of assessment [HOMA]-IR) and arterial stiffness (brachial-ankle pulse wave velocity and radial augmentation index) before and after 24 weeks of intervention. RESULTS: The baseline characteristics of the two groups were similar. A total of 62 participants (placebo, 30; vitamin D, 32) completed the study protocol. At the end of the study period, the 25-hydroxyvitamin D [25(OH)D] levels were significantly higher in the vitamin D group than in the placebo group (35.4 +/- 8.5 ng/mL vs. 18.4 +/- 7.3 ng/mL, p < 0.001). There was no difference in HOMA-IR or changes in arterial stiffness (placebo, 21, vitamin D, 24) between the groups. CONCLUSIONS: Our data suggest that high-dose vitamin D supplementation might be effective in terms of elevating 25(OH)D levels. However, we identified no beneficial effects on cardiovascular risk in type 2 diabetes, including IR and arterial stiffness.
Calcium, Dietary/administration & dosage ; Cholecalciferol/*administration & dosage ; Diabetes Mellitus, Type 2/complications/*drug therapy/physiopathology ; Double-Blind Method ; Female ; Humans ; *Insulin Resistance ; Male ; Middle Aged ; Prospective Studies ; Vascular Stiffness/*drug effects ; Vitamin D/analogs & derivatives/blood ; Vitamin D Deficiency/blood/complications/drug therapy

We aimed to identify a vasoreactive subset of patients with idiopathic pulmonary arterial hypertension (IPAH) in Korea and to show their clinical characteristics and prognosis. Data on patients who were diagnosed with IPAH at Asan Medical Center between January 1994 and March 2013 were retrospectively collected. Acute vasodilator testing was performed with inhaled nitric oxide during diagnostic right heart catheterization. A positive acute response was defined as a reduction in mean pulmonary arterial pressure (PAP) > or =10 mmHg to an absolute level of mean PAP <40 mmHg without a decrease in cardiac output. Among a total of 60 IPAH patients included for analysis, 9 (15%) showed a positive acute response to acute vasodilator testing. Acute responders showed significantly lower peak velocity of a tricuspid regurgitation jet on echocardiography (4.1+/-0.3 m/s vs. 4.6+/-0.6 m/s; P=0.01) and significantly lower mean PAP hemodynamically (47+/-10 mmHg vs. 63+/-17 mmHg; P=0.003) than non-responders at baseline. The survival rate of acute responders was 88% at 1, 3, 5, and 10 yr, respectively, which was significantly higher than that of non-responders (85%, 71%, 55%, and 40%, respectively; P=0.029). In conclusion, Korean IPAH patients with vasoreactivity showed better baseline hemodynamic features and survival than those without vasoreactivity.
Adolescent ; Adult ; Aged ; Female ; Humans ; Hypertension, Pulmonary/*diagnosis/*mortality/physiopathology ; Male ; Middle Aged ; Prevalence ; Prognosis ; Reproducibility of Results ; Republic of Korea/epidemiology ; Risk Factors ; Sensitivity and Specificity ; Survival Rate ; Vascular Resistance/*drug effects ; Vasodilator Agents/*diagnostic use ; Young Adult

People complain about nasal stuffiness after SO2 exposure. This study was to investigate the acute effects of SO2 on nasal vascular and airway resistances in anaesthetized pigs for elucidating the underlying vascular and control mechanisms. Controlled ventilation was passed to the lungs or retrogradely through each nasal cavity. Nasal airway and lower airway pressures were measured to reflect airflow resistance changes. Systemic arterial pressure and nasal arterial flow were measured to calculate nasal vascular resistance. Nasal and pulmonary SO2 challenges were given. At 2 ppm, SO2 decreased systemic blood pressure and nasal vascular resistance but increased nasal airway and lower airway resistances. With increasing level to 8 ppm, SO2 increased systemic arterial pressure, nasal vascular and lower airway resistances but decreased nasal airway resistance. Nasal and pulmonary challenges induced similar responses. Ipsilateral nasal challenge elicited bilateral responses. Ruthenium red abolished the responses to nasal challenges. Bilateral vagosympathectomy eliminated the responses to lung challenges. Hence, SO2 at 2 ppm causes nasal congestion through sensory reflex vasodilatation but at higher levels nasal decongestion through sensory reflex vasoconstriction. Nasal congestion coupled with bronchoconstriction at levels of SO2 below short-term exposure limit (STEL) (≤ 2 ppm) would limit SO2 entering the lungs. Nasal decongestion at levels of SO2 beyond STEL (> 2 ppm) can effectively decrease total airway resistance as concurrent strong bronchoconstriction may impair ventilation.
Administration, Inhalation ; Airway Resistance ; drug effects ; Animals ; Lung ; drug effects ; Nasal Cavity ; drug effects ; Respiration ; Sulfur Dioxide ; pharmacology ; Swine ; Vascular Resistance ; drug effects ; Vasodilation

OBJECTIVEAs an important method of hemodynamic assessment in idiopathic pulmonary arterial hypertension (IPAH), cardiac catheterization combined with pulmonary vasoreactivity testing remains with limited experience in children, and the acute pulmonary vasodilator agents as well as response criteria for vasoreactivity testing remain controversial. The aim of this study was to investigate the clinical importance, agent selection, and responder definition of cardiac catheterization combined with pulmonary vasoreactivity testing in pediatric IPAH.

METHODThe patients admitted to Department of Pediatric Cardiology of Beijing Anzhen Hospital between April 2009 and September 2013 with suspected IPAH, under 18 years of age, with WHO functional class II or III, were enrolled. All the patients were arranged to receive left and right heart catheterization and pulmonary vasoreactivity testing with inhalation of pure oxygen and iloprost (PGI2) respectively. Hemodynamic changes were analyzed, and two criteria, the European Society of Cardiology recommendation criteria (Sitbon criteria) and traditional application criteria (Barst criteria), were used to evaluate the test results.

RESULTThirty-nine cases of children with suspected IPAH underwent cardiac catheterization. In 4 patients IPAH was excluded; 4 patients developed pulmonary hypertension crisis. The other 31 patients received standard cardiac catheterization and pulmonary vasoreactivity testing. Baseline mean pulmonary artery pressure (mPAP) was (66 ± 16) mmHg (1 mmHg = 0.133 kPa), and pulmonary vascular resistance index (PVRI) (17 ± 8) Wood U · m². After inhalation of pure oxygen, mPAP fell to (59 ± 16) mmHg, and PVRI to (14 ± 8) Wood U · m² (t = 4.88 and 4.56, both P < 0.001) . After inhalation of PGI2, mPAP fell to (49 ± 21) mmHg, and PVRI to (12 ± 9) Wood U · m² (t = 7.04 and 6.33, both P < 0.001). According to the Sitbon criteria, the proportion of pure oxygen responders was 6.5% (3/31) , while PGI2 responders was 35.5%, and the difference was significant (P = 0.004). According to the Barst criteria, the proportion of pure oxygen responders was 16.1% (5/31), while PGI2 responders was 51.6% (16/31), and the difference was significant (χ² = 0.09, P = 0.001).

CONCLUSIONFor children with IPAH, cardiac catheterization combined with pulmonary vasoreactivity testing has important value in differential diagnosis, severity estimation, and treatment (including the emergency treatment) choices. Pulmonary hypertension crisis is an important complication of cardiac catheterization in pediatric IPAH. Younger age, general anesthesia, crisis history, and poor heart function are important risk factors for pulmonary hypertension crisis. PGI2 is a relatively ideal agent for vasoreactivity testing in children with IPAH, which has more responders than traditionally used pure oxygen.

RESULTSof responders are not completely consistent using different criteria, and comprehensive evaluation should be done according to the goals of treatment in clinical practice.

Administration, Inhalation ; Adolescent ; Anesthesia, General ; Cardiac Catheterization ; Child ; Child, Preschool ; Familial Primary Pulmonary Hypertension ; diagnosis ; physiopathology ; Female ; Hemodynamics ; Humans ; Iloprost ; administration & dosage ; Infant ; Male ; Pulmonary Artery ; physiopathology ; Pulmonary Circulation ; drug effects ; Pulmonary Wedge Pressure ; drug effects ; Severity of Illness Index ; Vascular Resistance ; drug effects ; Vasodilator Agents ; administration & dosage

No abstract available.
Cholecalciferol/*administration & dosage ; Diabetes Mellitus, Type 2/*drug therapy ; Female ; Humans ; *Insulin Resistance ; Male ; Vascular Stiffness/*drug effects

PURPOSE: Hypoxia-inducible factor-1alpha (HIF-1alpha) increases transcription of the vascular endothelial growth factor (VEGF) gene. Inhibition of VEGF abolishes VEGF mediated induction of HIF-1alpha. Recent reports suggested that HIF-1alpha also mediated the induction of class III beta-tubulin (TUBB3) in hypoxia. TUBB3 confers resistance to taxanes. Inhibition of VEGF may decrease the expression of HIF-1alpha and TUBB3. This study was undertaken to investigate the roles of vascular endothelial growth factor receptor (VEGFR) in gastric cancer cell behavior and to identify methods to overcome paclitaxel resistance in vitro. MATERIALS AND METHODS: The protein expression levels of HIF-1alpha and TUBB3 were measured in human gastric cancer cell lines (AGS) under normoxic and hypoxic conditions. The relationship between TUBB3 and paclitaxel resistance was assessed with small interfering TUBB3 RNA. AGS cells were treated with anti-VEGFR-1, anti-VEGFR-2, placental growth factor (PlGF), bevacizuamb, and paclitaxel. RESULTS: Hypoxia induced paclitaxel resistance was decreased by knockdown of TUBB3. Induction of HIF-1alpha and TUBB3 in AGS is VEGFR-1 mediated and PlGF dependent. Hypoxia-dependent upregulation of HIF-1alpha and TUBB3 was reduced in response to paclitaxel treatment. Expressions of HIF-1alpha and TUBB3 were most decreased when AGS cells were treated with a combination of paclitaxel and anti-VEGFR-1. AGS cell cytotoxicity was most increased in response to paclitaxel, anti-VEGFR-1, and anti-VEGFR-2. CONCLUSION: We suggest that blockade of VEGFR-1 and VEGFR-2 enhances paclitaxel sensitivity in TUBB3-expressing gastric cancer cells.
Angiogenesis Inhibitors/pharmacology ; Antibodies, Monoclonal, Humanized/pharmacology ; Antineoplastic Agents, Phytogenic/*pharmacology ; Cell Hypoxia ; Cell Line, Tumor ; *Drug Resistance, Neoplasm ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Knockdown Techniques ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Paclitaxel/*pharmacology ; Pregnancy Proteins/pharmacology ; Stomach Neoplasms/drug therapy/genetics ; Tubulin/genetics/metabolism ; Vascular Endothelial Growth Factor Receptor-1/antagonists & inhibitors/*physiology ; Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors/*physiology

The effects of class I PI3K inhibitor NVP-BKM120 on cell proliferation, cell cycle distribution, cellular apoptosis, phosphorylation of several proteins of the PI3K/AKT signaling pathway and the mRNA expression levels of HIF1-α, VEGF and MMP9 in the acquired gefitinib resistant cell line H1975 were investigated, and whether NVP-BKM120 can overcome the acquired resistance caused by the EGFR T790M mutation and the underlying mechanism were explored. MTT assay was performed to detect the effect of gefitinib, NVP-BKM120, NVP-BKM120 plus 1 μmol/L gefitinib on growth of H1975 cells. The distribution of cell cycle and apoptosis rate of H1975 cells were examined by using flow cytometry. The mRNA expression levels of tumor-related genes such as HIF1-α, VEGF and MMP9 were detected by using real-time quantitative PCR. Western blotting was used to detect the expression level of phosphorylated proteins in the PI3K/AKT signaling pathway, such as Ser473-p-AKT, Ser235/236-p-S6 and Thr70-p-4E-BP1, as well as total AKT, S6 and 4E-BP1. The results showed that the NVP-BKM120 could inhibit the growth of H1975 cells in a concentration-dependent manner, and H1975 cells were more sensitive to NVP-BKM120 than gefitinib (IC50:1.385 vs. 15.09 μmol/L respectively), whereas combination of NVP-BKM120 and gefitinib (1 μmol/L) did not show more obvious effect than NVP-BKM120 used alone on inhibition of cell growth (P>0.05). NVP-BKM120 (1 μmol/L) increased the proportion of H1975 cells in G0-G1 phase and the effect was concentration-dependent, and 2 μmol/L NVP-BKM120 promoted apoptosis of H1975 cells. There was no significant difference in the proportion of H1975 cells in G0-G1 phase and apoptosis rate between NVP-BKM120-treated alone group and NVP-BKM120 plus genfitinib (1 μmol/L)-treated group or between DMSO-treated control group and gefitinib (1 μmol/L)-treated alone group (P>0.05 for all). It was also found that the mRNA expression levels of these genes were down-regulated by NVP-BKM120 (1 μmol/L), and NVP-BKM120 (1 μmol/L) or NVP-BKM120 (1 μmol/L) plus gefitinib (1 μmol/L) obviously inhibited the activation of Akt, S6 and 4E-BP1 as compared with control group, but single use of gefitinib (1 μmol/L) exerted no significant effect. These data suggested that NVP-BKM120 can overcome gefitinib resistance in H1975 cells, and the combination of NVP-BKM120 and gefitinib did not have additive or synergistic effects. It was also concluded that NVP-BKM120 could overcome the acquired resistance to gefitinib by down-regulating the phosphorylated protein in PI3K/AKT signal pathways in H1975 cells, but it could not enhance the sensitivity of H1975 cells to gefitinib.
Adenocarcinoma ; metabolism ; Aminopyridines ; pharmacology ; Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit ; genetics ; metabolism ; Lung Neoplasms ; metabolism ; Matrix Metalloproteinase 9 ; genetics ; metabolism ; Morpholines ; pharmacology ; Phosphatidylinositol 3-Kinases ; antagonists & inhibitors ; Quinazolines ; pharmacology ; RNA, Messenger ; genetics ; metabolism ; Vascular Endothelial Growth Factor A ; genetics ; metabolism

OBJECTIVETo investigate the sensitivity of imatinib mesylate (IM) on Sup-B15 Ph⁺ acute lymphoblastic leukemia (ALL) cells knockdown of VE-cadherin (CD144), and to further explore its mechanism.

METHODSCD144 in Sup-B15 leukemia cells was stably knock downed via lentivirus-mediated RNA interference (named as Sup-B15/shVEC). The inhibitory effects of IM on Sup-B15/shVEC and Sup-B15 leukemia cells were measured by CCK-8 test, and the apoptosis of those cells was determined by AnnexinV/7-AAD dyeing using flow cytometry, the percentage of CD34⁺CD38⁻ leukemia cells also by flow cytometry. ALDH1 mRNA levels were detected by real-time RT-PCR, and protein levels of CD144, CD133, Bcr-abl and β-catenin by Western blot.

RESULTSIM treatment presented inhibitory effects on Sup-B15/shVEC and Sup-B15 leukemia cells at multiple concentrations of IM. The IC50 of IM on Sup-B15/shVEC and Sup-B15 leukemia cells were 25.1μmol/L and 18.7μmol/L, respectively (P<0.05). After 48h of 20 μmol/L IM treatment, the percentages of apoptosis cell in Sup-B15/shVEC cells and Sup-B15 cell were (13.52±2.06)% and (3.03±0.72) %, respectively (P<0.05). The percentage of CD34⁺CD38⁻ cells in Sup-B15 cells was significantly higher than in Sup-B15/shVEC cells [(2.39±0.28)% vs (0.96±0.07)%, P<0.05). As compared to Sup-B15 cells, the transcription of ALDH1 in Sup-B15/shVEC was remarkably downregulated, and the CD133 protein level was also downregulated in Sup-B15/shVEC cells. Both cytoplasmic and nucleic β-catenin protein levels (but not for Bcr-abl levels) decreased in Sup-B15/shVEC cells as compare to Sup-B15 cells.

CONCLUSIONKnockdown of CD144 sensitized Sup-B15 Ph+ ALL cells to IM. The possible mechanisms underlying this phenomenon might be via inhibiting β-catenin nucleic translocation and facilitating β-catenin degradation.

Antigens, CD ; genetics ; Benzamides ; pharmacology ; Cadherins ; genetics ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; genetics ; Endothelium, Vascular ; drug effects ; metabolism ; Gene Knockdown Techniques ; Humans ; Imatinib Mesylate ; Piperazines ; pharmacology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; metabolism ; Pyrimidines ; pharmacology ; RNA Interference ; beta Catenin ; metabolism

OBJECTIVETo evaluate the effects of Tiangou Jiangya capsule on blood pressure and hemodynamics in anesthetized Beagle dogs.

METHODAnesthetized dogs were divided into five groups: Tiangou Jiangya capsule 3-dose groups as 1.6, 3.2, 6.4 g x kg(-1), positive control group was giving captopril, negative control was giving 0.5% CMC-Na, duodenal administration. The blood pressure and hemodynamic changes were observed.

RESULTThe systolic blood pressure of middle-dose Tiangou Jiangya capsule group was significantly reduced at 30 min after administration. The systolic blood pressure (SAP) and diastolic blood pressure (DAP) of high-dose group of Tiangou Jiangya capsule was significantly reduced at 15 min to 90 min after administration. High-dose Tiangou Jiangya capsule can also significantly reduce cardiac work (LVW) and total peripheral resistance (TPR). Tiangou Jiangya capsule had no significant effect on the other hemodynamic parameters and myocardial oxygen consumption.

CONCLUSIONTiangou Jiangya capsule has a significant effect on reducing blood pressure, which is related to the reducing total peripheral resistance and reducing cardiac work. The result can provide a reference to further clarify the Tiangou Jiangya capsule mechanism on reducing blood pressure.

Animals ; Antihypertensive Agents ; administration & dosage ; pharmacology ; therapeutic use ; Benzyl Alcohols ; pharmacology ; therapeutic use ; Blood Pressure ; drug effects ; Disease Models, Animal ; Dogs ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; therapeutic use ; Female ; Flavonoids ; pharmacology ; therapeutic use ; Furans ; pharmacology ; therapeutic use ; Glucosides ; pharmacology ; therapeutic use ; Heart Rate ; drug effects ; Hemodynamics ; drug effects ; Hypertension ; drug therapy ; Lignans ; pharmacology ; therapeutic use ; Male ; Oxygen Consumption ; drug effects ; Vascular Resistance ; drug effects

Color Doppler imaging (CDI) was carried out to evaluate the effects of anti-glaucoma drugs on ophthalmic circulation using CDI-derived resistive index (RI) values. CDI was performed on nine Beagle dogs, and RI values were calculated for the medial long posterior ciliary artery before and after the administration of anti-glaucoma drugs. A significant increase in RI values was found after topical administration of levobunolol (p < 0.05) or dipivefrin (p < 0.05). Pilocarpine showed no effects on RI values after topical administration. The results suggest that some anti-glaucoma drugs could affect ophthalmic blood flow.
Adrenergic Agonists/pharmacology ; Animals ; Ciliary Arteries/*drug effects/*ultra ; Dogs ; Epinephrine/analogs & derivatives/therapeutic use ; Eye/*blood supply ; Female ; Glaucoma/*drug therapy ; Levobunolol/therapeutic use ; Male ; Ocular Physiological Phenomena ; Pilocarpine/therapeutic use ; Ultra ; *Vascular Resistance