Association between plasma renin activity and metabolic cardiovascular risk factors in essential hypertension

Objectives. To study the relationships between plasma renin activity and metabolic cardiovascular risk factors in patients with essential hypertension.
Subjects and design. Patients with uncomplicated essential hypertension ( n =36) with a diastolic blood pressure of 95–115 mmHg were studied. Assessment of plasma renin activity (PRA) related to urinary sodium excretion was used to define subgroups with high ( n =12), medium ( n =16) and low renin profiles ( n =8).
Main outcome measures. Fasting plasma lipid levels were determined. Glucose, insulin and C-peptide responses to standard oral glucose tolerance test (OGTT) were measured.
Results. Patients with high PRA had higher levels of plasma cholesterol (6.13±0.81 versus 4.67±0.7 mmol L^-1, P <0.05) and triglycerides (2.14±0.18 versus 0.98±0.13 mmol L^-1, P <0.05), than the low PRA group. HDL-cholesterol levels were lower in the high renin group than in the low renin group (1.05±0.04 versus 1.26±0.09 mmol L^-1, P <0.05). Insulin and C-peptide sums were higher in high PRA group (33.8±1.2 versus 25.1±0.9 and 2.6±0.3 versus 1.9±0.4 ng L^-1, P <0.05), than in the low PRA group.
Conclusions. Essential hypertensive patients with a high renin profile display more pronounced dyslipidaemia and higher levels of plasma insulin than patients with a low renin profile. This may be one explanation for higher incidence of cardiovascular disease previously reported in high PRA group.     

I(Ks) block by HMR 1556 lowers ventricular defibrillation threshold and reverses the repolarization shortening by isoproterenol without rate-dependence in rabbits

Introduction: The slow delayed rectifier K⁺ current (I_Ks) contributes little to ventricular repolarization at rest. It is unclear whether I_Ks plays a role during ventricular fibrillation (VF) or ventricular repolarization at rapid rates during β-adrenergic stimulation.
Methods and Results: In an in vivo rabbit model, we evaluated the effects of HMR 1556 (1 mg Kg⁻¹+ 1 mg kg ⁻¹ hr ⁻¹ i.v.), a selective I_Ks blocker, on monophasic action potential duration at 90% repolarization (MAPD₉₀), ventricular effective refractory period (VERP), and defibrillation threshold (DFT). In perfused rabbit hearts, the effects of HMR 1556 (10 and 100 nM) in the presence of isoproterenol (5 nM) on MAPD₉₀ and VERP were studied at cycle lengths (CLs) 200–500 msec. In vivo , HMR 1556 prolonged MAPD₉₀ by 6 ± 1 msec at CL 200 msec (P < 0.01, n = 6), lowered DFT from 558 ± 46 V to 417 ± 31 V (P < 0.01), and decreased the coefficient of variation in the VF inter-beat deflection intervals from 8.9 ± 0.6% to 6.5 ± 0.4% (P < 0.05) compared with control. In perfused rabbit hearts, isoproterenol shortened MAPD₉₀ by 5 ± 1 msec at CL 200 msec and 11 ± 4 msec at CL 500 msec (P < 0.05, n = 7). This shortening was reversed by HMR 1556 (P < 0.05), and both effects were rate-independent.
Conclusion: I_Ks block increases VF temporal organization and lowers DFT, and I_Ks that is activated following β-adrenergic stimulation contributes to ventricular repolarization without rate dependence.     

Na+/Ca2+ Exchanger Expression and Function in a Rabbit Model of Myocardial Infarction

Introduction: In general, sarcolemmal Na⁺/Ca²⁺ exchanger (NCX) protein and activity is increased in hearts with ventricular dysfunction. However, in a subset of studies, reduced activity of NCX has been reported. Left ventricular dysfunction (LVD) was induced in the rabbit eight weeks after an apical myocardial infarction.
Methods: Using single microelectrode voltage clamp to assess the NCX activity in isolated ventricular cells, a decrease in NCX activity by ∼30% was observed. Immunoblot analysis indicated increased NCX protein levels by ∼20% in the LVD group. The cause of this paradox is unknown. Overexpression of the protein sorcin increased the activity of NCX without affecting NCX protein levels.
Results: Sorcin protein (dimer) levels were significantly lower in the LVD group (0.67 ± 0.05 n = 15, P < 0.05) compared to sham (1.0 ± 0.16, n = 15). Sorcin monomer levels were not significantly different (sham: 1.0 ± 0.26, LVD: 0.83 ± 0.13). Mathematical modeling of NCX suggests that a reduction of NCX activity during diastole to that in LVD could be achieved by holding the diastolic membrane potential at −60 mV instead of −80 mV. Holding E_m at −60 mV decreased NCX-mediated Ca²⁺ efflux rates to values comparable to those seen in LVD and increased SR Ca²⁺ content and peak systolic [Ca²⁺] in sham and LVD cardiomyocytes.
Conclusions: In conclusion, reduced sorcin expression may be linked to the lower NCX activity in the rabbit model of LVD. Reduced NCX activity during diastole increases SR Ca²⁺ content and Ca²⁺ transient amplitude.     

TISSUE CHARACTERIZATION TO DIFFERENTIATE PATHOLOGICAL FROM PHYSIOLOGICAL HYPERTROPHY IN PATIENTS WITH HYPERTENSION AND ATHLETES

Precedents: In pathological left ventricular (LV) hypertrophy (H) of hypertensive patients (P) there is a deposition of collagen. Myocardial fibrosis is one of the factors responsible for systolic and diastolic dysfunction. Athletes increase their ventricular mass as physiological ventricular H. Integrated backscatter (IB) demonstrates changes in myocardial acoustic properties, depending upon their composition and function.
Objectives: (1).Assess the capability of IB to differentiate physiological from pathological H. (2).Correlate IB with overall and regional systolic and diastolic functions.
Methods: Group I(GI):13 hypertensive P with an LV mass index (LVMI)>124 gr/m², Group II(G2):11 athletes, Group III(G3): 8 volunteers. We determined overall systolic and diastolic functions and regional function of the basal septum, IB and cyclic variation of the IB (CVIB) of the posterior wall.
Results: Age (years): G1:52 ± 15, G2:28 ± 8 G3:35 ± 8 p = 0.000; Sex: G1:m/f 12/1, G2: m/f 9/2, G3: m/f 4/4, LVMI: G1: 180.1 ± 58 gr/m², G2:130.2 ± 20 gr/m² G3: 90.2 ± 16 gr/m² p = 0.000. Left atrial area (LAA): G1: 22 ± 4 cm², G2: 18.8 ± 1.8 cm², G3: 15.8 cm² p = 0.001, mid-wall shortening fraction (MWSF): G1:26.9 ± 3.5, G2:27.5 ± 4 G3:25 ± 3 p = NS; CVIB: G1:5,3 ± 2,5 G2:7.6 ± 2,1 G3:6.4 ± 1.1 P = 0.048.Correlation of IB and MWSF, p = NS; IB and MWSF p = NS, IB and CVIB:-0.56 p = 0.005.  

  TABLE     

5.

Prednisone and low-dose activated prothrombin complex concentrates for FVIII inhibitor in nonhaemophilic patients     

Linxiang JI  Renchi Yang  Deguang Yang  Zhongkai Chen  Shuhua Xing  Mengsu Tian  & Yin Sun 《Haemophilia》1998,4(5):721-724

Eight nonhaemophilic patients with factor VIII (FVIII) inhibitors were reported. There was no difference in sex distribution. Median age at diagnosis was 62 years (ranging from 14 to 73 years). No associated disorders were revealed and all the patients were presented with severe muscular or arthral bleeding. Inhibitor titre was measured by the Bethesda method, which were 6.4, 126.0, 155.0, 4.8, 56.0, 13.5, 35.0 and 150.0 BU mL⁻¹, respectively, at diagnosis. FVIII:C levels were less than 1 U dL⁻¹ in seven patients and less than 2 U dL⁻¹ in one patient. The median vWF:Ag level was 210% (ranging from 80% to 340%). All the patients had good response to activated prothrombin complex concentrates for acute bleeding episodes and prednisone for inhibitor elimination. Inhibitors completely eliminated in seven patients within a follow-up duration over 1 year, and one patient died of intracranial haemorrhage when her inhibitor titre decreased to 4.5 BU mL⁻¹ and FVIII:C increased to 21 U dL⁻¹.     

6.

Pharmacokinetics, efficacy and safety of Humate-P^® in von Willebrand disease     

Dobrkovska  Krzensk  & Chediak 《Haemophilia》1998,4(S3):33-39

In a pharmacokinetic study with Humate-P^® including six patients with various types of von Willebrand disease, a median half-life of 11.3 h for vWF:RCoF and of 15.2 h for vWF:Ag was found. The median value of in vivo recovery (IVR) was estimated for vWF:RCoF as 2.10 IU dL⁻¹ plasma per 1 substituted IU kg⁻¹ b.w. (or 73%), for vWF:Ag as 1.88 IU dL⁻¹ plasma per 1 substituted IU kg⁻¹ b.w. (or 69%); and for FVIII:C as 2.69 IU dL⁻¹ plasma per 1 IU kg⁻¹ b.w. (or 99%). Transient postinfusion shortening or normalization of previously prolonged bleeding time was observed in all patients. In a retrospective study involving 97 patients with various von Willebrand disease types, clinical efficacy and safety of treatment with Haemate-P^® in 73 surgical interventions, 344 separate bleeding events, 93 other events and 20 cycles of prophylactic treatment were evaluated. The clinical efficacy was rated good to excellent in 99% of the surgeries, in 97% of the bleeding episodes, in 86% of the other events, and in all prophylactic treatments. The overall tolerability was good. Adverse events possibly or probably associated with use of Humate-P^®/Haemate-P^® were rare, of non-serious nature and mild to moderate in their intensity.     

7.

Intrapulmonary administration of insulin to healthy volunteers   总被引：5，自引：0，他引：5  

J. H. JENDLE  & B. E. KARLBERG 《Journal of internal medicine》1996,240(2):93-98

Objectives. To study the biological effects of nebulized insulin, administered intrapulmonary, to healthy volunteers.
Design. A double-blind, randomized, controlled intervention study.
Setting. The department of Internal Medicine, University Hospital, Linköping, Sweden.
Subjects. Eight healthy, non-smoking volunteers, with a mean age of 28 (range 22 to 56) years.
Interventions. Regular human insulin 100 U mL^-1 (Actrapid®) or 0.9% saline was given randomly as an oral inhalation. Insulin was given in three different doses (40, 80 and 160 U). Aerosol was generated by a new jet nebulizer.
Main outcome measures. Blood glucose, serum insulin, and serum C-peptide.
Results. After the 160 U insulin dose the blood glucose concentration (mean±SE) fell from 4.3±0.2 to 2.8±0.2 mmol L^-1 ( P <0.001), concomitant with an increase in mean serum insulin concentrations, rising from 9.5±1.5 to 26.1±2.5 mU L^-1 ( P <0.001). Serum C-peptide concentrations simultaneously decreased from 0.48±0.03 to 0.12±0.02 mmol L^-1 ( P <0.001). All changes were dose dependent. No adverse reactions were noted and no significant changes in lung function tests.
Conclusions. Intrapulmonary insulin administration to healthy subjects can induce a significant hypoglycaemia and cause a clinically relevant increase in serum insulin concentrations. If similar results can be obtained when administering insulin to diabetic subjects, this insulin administration route can be a future complement to certain groups of patients.     

8.

Relationship Between Serum Levels of Anti-Low-Density Lipoprotein-Acetaldehyde-Adduct Antibody and Aldehyde Dehydrogenase 2 Heterozygotes in Patients With Alcoholic Liver Injury     

Naruhiko Nagata  Norihito Watanabe  Michio Tsuda  Hideo Tsukamoto  Shohei Matsuzaki 《Alcoholism, clinical and experimental research》1999,23(S4):24S-28S

We prepared low-density lipoprotein (LDL)-acetaldehyde-adduct (hereafter abbreviated as LDL-adduct) and anti-LDL-adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti-LDL-adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti-LDL-adduct antibody levels were 25 ± 13 μ g/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti-LDL-adduct antibody in alcoholic disease groups, 17 ± 9 μ g/ml for the patients with the fatty liver group, 21 ± 14 μ g/ml for the hepatic fibrosis group, 70 ± 21 μ g/ml for the alcoholic hepatitis group, 41 ± 50 μ g/ml for the alcoholic cirrhosis group, and 19 ± 18 μ g/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH2¹/2² in the liver injury group to have relatively mild liver lesions. When comparing anti-LDL-adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH2¹/2¹ (36 ± 40 μ g/ml) were significantly higher than those for patients with ALDH¹/2² (11 ± 5 μ g/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.     

9.

Antimony in plasma and skin of patients with cutaneous leishmaniasis – relationship with side effects after treatment with meglumine antimoniate     

Diana Brito da Justa Neves  Eloisa Dutra Caldas  Raimunda Nonato Ribeiro Sampaio 《Tropical medicine & international health : TM & IH》2009,14(12):1515-1522

Objective  To evaluate the levels of antimony in plasma and skin of patients being treated with pentavalent antimonials (Glucantime^®) and their relationship with side effects.
Methods  We evaluated 19 patients treated endovenously at the conventional dose (20 mg Sb^v/kg/day), two at a smaller dose (5 mg Sb^v/kg/day) and three treated intralesionally (up to 4.0 ml/week). During treatment, patients underwent periodic blood exams and were interviewed weekly about the incidence of adverse symptoms. The levels of antimony in plasma and skin samples were determined by Inductively Coupled Plasma with Mass Spectrometry (ICP-MS).
Results  The patients under conventional treatment presented a mean initial antimony plasma concentration of 3.39 μg/l; at the end of treatment, these levels were 0.21 before Glucantime^® application and 125.8 mg after Glucantime^® application. The mean antimony level in their skin at the end of the treatment was 9.24 μg/g. The main adverse symptoms were arthralgia and myalgia; laboratory results showed mainly lymphocytosis and eosinophilia.
Conclusions  We found some significant correlations between antimony concentrations, adverse symptoms and laboratory alterations, strengthening the hypothesis of a dose–dependent relationship between antimony concentration in plasma and skin and side effects.     

10.

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision     

Vethakkan SR  Walters JM  Gooley JL  Boston RC  Ward GM 《Clinical endocrinology》2009,70(1):47-52

Background  The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma.
Objective  To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour.
Subjects and methods  FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data.
Results  Si was lower in insulinoma patients before, compared with after surgery (3·37 ± 0·62 vs. 6·24 ± 1·09 SE [×10⁻⁴] min⁻¹µU⁻¹ ml, P  < 0·05). Sg was similar in patients pre- and post-surgery (3·0 ± 0·67 vs. 2·4 ± 0·6 [×10⁻²] min⁻¹, NS).
Conclusions  Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.     

11.

The Phosphodiesterase III Inhibitor Olprinone Decreases Sensitivity of Rat Kupffer Cells to Endotoxin     

Nobuyuki Enomoto  Yoshiyuki Takei  Miyoko Hirose  Shunhei Yamashina  Kenichi Ikejima  Tsuneo Kitamura  Nobuhiro Sato 《Alcoholism, clinical and experimental research》2004,28(S2):145S-147S

Background: Sensitivity of Kupffer cells to endotoxin [lipopolysaccharide (LPS)] and overproduction of tumor necrosis factor-α (TNF-α) are critical for progression of alcoholic liver injury. Therefore, suppression of TNF-α should prove useful for treatment of alcoholic liver injury. However, a transient increase of intracellular calcium ([Ca²⁺]_i) is required for LPS-induced TNF-α production by the macrophage cell line. The phosphodiesterase III inhibitor olprinone has been shown to suppress [Ca²⁺]_i level in vascular smooth muscle cells. Accordingly, the purpose of this study was to determine whether olprinone could prevent sensitization of Kupffer cells to endotoxin.
Methods: Kupffer cells were isolated by collagenase digestion and differential centrifugation. LPS was added to Kupffer cells 24 hr after incubation with or without olprinone (0.1 μmol/liter). After addition of LPS (10 μg/ml) to culture media, [Ca²⁺]_i was measured using a fluorescent indicator, fura-2.
Results: LPS increased [Ca²⁺]_i of Kupffer cells in control rats from basal levels (28 ± 4 nmol/liter) to 280 ± 14 nmol/liter. This increase was blunted by olprinone (91 ± 8 nmol/liter). Similarly, olprinone diminished the LPS (1 μg/ml)-induced TNF-α production by Kupffer cells by 30% (2220 ± 116 vs. 1386 ± 199 pg/ml; p < 0.05).
Conclusions: These results indicate that olprinone decreases sensitivity of Kupffer cells to endotoxin.     

12.

Recirculating Delivery Improves Myocardial Cell Engraftment     

MELISSA J. BYRNE  Ph  .D.  AMANDA ZATTA  Ph  .D.  CESERE GALLI  Ph  .D.  JOHN M. POWER  Ph  .D.  DAVID M. KAYE  M.D.  Ph  .D. 《Journal of interventional cardiology》2010,23(1):14-17

Introduction: Despite pharmacological advances for heart failure, morbidity and mortality remain unacceptably high. As a result, alternative approaches such as cell therapy have been suggested to hold potential promise. However, a major obstacle is the optimization of cell delivery to the heart. Therefore, we investigated the efficacy of a percutaneous recirculation system for the delivery of cells to the heart.
Methods: Ovine fibroblasts were delivered to the ovine heart (3 × 10⁷ cells) using the V-Focus system, a "closed" recirculatory system that draws blood from the coronary sinus and returns it to the coronary artery via an oxygenator, or intracoronary (IC) infusion, followed by a 2-hour recovery period. Animals were euthanized and cardiac tissue collected to determine presence of cells.
Results: There was a significant difference (P < 0.05) in the number of cells delivered to the heart by the V-Focus compared to direct coronary infusion for left ventricular freewall (V-Focus 1.39 ± 0.63/mm², IC 0.11 ± 0.06/mm²), septum (V-Focus 3.18 ± 0.88/mm², IC 0.38 ± 0.19/mm²), and right ventricle (V-Focus 0.46 ± 0.23/mm², IC 0.05 ± 0.04/mm²).
Conclusions: These results suggest that potential therapeutic cells are optimally delivered to the large animal heart using the V-Focus cardiac delivery system in an ovine heart. (J Interven Cardiol 2010;23:14–17)     

13.

Mechanisms of Late Stent Malapposition After Primary Stenting in ST-Elevation Myocardial Infarction: A Subanalysis of the Selection Trial     

TANIA CHECHI  M.D.    SABINE VECCHIO  M.D.    ALESSIO LILLI  M.D.    GABRIELE GIULIANI  M.D.    GAIA SPAZIANI  M.D.    GIORGIO BALDERESCHI  M.D.    ALESSIO MONTEREGGI  M.D.    REA RUBBOLI  M.D.    MASSIMO MARGHERI  M.D. 《Journal of interventional cardiology》2009,22(3):201-206

Background: One of the major predictors of late stent malapposition (LSM) is primary stenting in acute myocardial infarction. However, mechanisms of LSM are still under debate.
Methods: Patients with ST-elevation myocardial infarction (STEMI) and enrolled in the SELECTION trial (38 patients in the paclitaxel-eluting stent, PES, and 35 in the bare metal stent, BMS, cohort) were retrospectively analyzed to evaluate LSM, by means of intravascular ultrasound (IVUS) data recorded at the index and 7-month follow-up procedures.
Results: Stent malapposition was documented in 21 lesions in 21 patients (28.8%): in 8 of these 21 patients (38.1%) it was LSM. Although statistical significance was not reached, LSM was more frequent after PES than BMS implantation (15.8% vs. 5.7%). LSM was mainly located within the body of the stent (62.5% of the cases). At the LSM segment, a significant increase of vessel area (19.2 ± 3.3 mm² vs. 21.9 ± 5.3 mm², P = 0.04) and a reduction of plaque area (12.6 ± 4.6 mm² vs. 9.1 ± 3.9 mm², P = 0.04) were observed at IVUS between the index and follow-up procedure.
Conclusions: After primary stenting for STEMI, LSM seems to be more frequent after PES rather than BMS implantation. In the STEMI setting, possible mechanisms leading to LSM include positive remodeling and plaque mass decrease.     

14.

Boiled coffee increases serum low density lipoprotein concentration   总被引：1，自引：0，他引：1  

A Aro  J Tuomilehto  E Kostiainen  U Uusitalo  P Pietinen 《Metabolism: clinical and experimental》1987,36(11):1027-1030

The effects of boiled coffee, filtered coffee, and tea on serum lipoprotein lipids and apoproteins were compared in 42 middle-aged hypercholesterolemic subjects (21 men and 21 women). The subjects consumed the beverages, eight cups a day, in random order during successive 4-week periods with 2-week run-in intervals in a crossover design. The diet was kept unchanged. Statistically significant differences were found between the periods in serum total cholesterol (P less than .0001 ANOVA), LDL cholesterol (P less than .01), and apoprotein B (P less than .01) levels. All differences were due to significantly higher levels during boiled coffee as compared with filtered coffee and tea. No statistically significant differences were found between the filtered coffee and tea periods. There were no differences in serum VLDL cholesterol or triglyceride, HDL cholesterol, and apoprotein A-I concentrations between the periods. Consumption of boiled coffee thus increased the concentration of low density lipoprotein in the serum without affecting its lipid-protein composition. The effect seemed to be determined by the method of brewing.     

15.

The European Exenatide study of long-term exenatide vs. glimepiride for type 2 diabetes: rationale and patient characteristics     

C. Kazda  B. Gallwitz  R. Simó  J. R. Guzmán  P. Kraus  C. Nicolay  L. Rose  G. Schernthaner 《Diabetes, obesity & metabolism》2009,11(12):1131-1137

Aim: To describe the rationale for the European Exenatide (EUREXA) clinical study and describe the characteristics of the patient cohort.
Methods: EUREXA is a multinational study of long-term effects of add-on exenatide vs. glimepiride in patients with type 2 diabetes and failure of diet/lifestyle plus metformin monotherapy. Metformin failure was defined as hemoglobin A1c (HbA1c) ≥ 6.5% and patients were overweight/obese (BMI ≥ 25 to < 40 kg/m²). The primary end point is time to failure of combination treatment, defined from HbA1c concentration according to current criteria. At baseline, an oral glucose tolerance test (OGTT) was performed, fasting blood was taken for lipid profile and patients were randomized to add-on exenatide (5 μg b.i.d. for 4 weeks then 10 μg b.i.d.) or glimepiride (1 mg/day titrated to maximum dose).
Results: A total of 1039 patients were entered in the study, with mean (± s.d.) age 57.2 ± 9.6 years, body mass index (BMI) 32.4 ± 4.1 kg/m², duration of diabetes 5.6 ± 4.5 years and HbA1c 7.4 ± 0.7%. A history of cardiovascular disease (CVD) was present for 64.8% of patients overall and duration of diabetes was statistically significantly longer for patients with CVD than without (p = 0.010). Lipid abnormalities were reported for 48.9% of patients and 40.9% were taking at least one lipid-lowering medication.
Conclusion: Patients included in the EUREXA study had early failure of glucose control with metformin and presented typical features of type 2 diabetes: overweight/obesity and high prevalence of lipid abnormalities and CVD. In this population, the effects of exenatide vs. glimepiride will be evaluated over at least 2.5 years.     

16.

Dissociated incretin response to oral glucose at 1 year after restrictive vs. malabsorptive bariatric surgery     

M. Guldstrand  B. Ahrén  E. Näslund  J. J. Holst  U. Adamson 《Diabetes, obesity & metabolism》2009,11(11):1027-1033

Aim: Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery.
Methods: Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26–39 years, with severe obesity [body mass index (BMI) 46.6 ± 2.3 kg/m²]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h.
Results: At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC_GIP was significantly higher after VBG than after JIB (53 ± 8 vs. 26 ± 6 pmol/l/min, p = 0.003). In contrast, AUC_GLP−1 was significantly higher after JIB than after VBG (49 ± 5 vs. 20 ± 3 pmol/l/min, p = 0.007).
Conclusions: We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.     

17.

Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans   总被引：1，自引：0，他引：1  

Vladimir M. Mishin  M.D.  Ph.D.    Alan S. Rosman  M.D.    Prithwijit Basu  M.D.    Irina Kessova  Ph.D.    Carl M. Oneta  M.D.    Charles S. Lieber  M.D. 《The American journal of gastroenterology》1998,93(11):2154-2161

Objective: Previous in vitro studies have demonstrated that hepatic P4502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measurement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could serve as a marker of hepatic P4502E1 content.
Methods: Three subject groups were included: recently drinking alcoholics (  N = 6  ), abstinent alcoholics (  N = 5  ), and nonalcoholic subjects with liver disease (  N = 5  ) undergoing liver biopsy. Excess tissue was procured for immunochemical determination of hepatic P4502E1 content. Within an hour of the biopsy, 750 mg CZX was administered orally and serial plasma samples were collected for 6 h.
Results: Recently drinking alcoholic subjects had a higher area under the curve for plasma 6-OH-CZX (1.354 ± 0.258 μg · min · ml⁻¹) then abstinent alcoholic subjects (0.296 ± 0.080 μg · min · ml⁻¹, p < 0.005) and subjects with nonalcoholic liver disease (0.428 ± 0.061 μg · min · ml⁻¹,   p < 0.005  ). The use of the plasma 6-OH-CZX/CZX ratio at 90, 120, and 180 min discriminated between recently drinking alcoholic and nondrinking subjects. Hepatic P4502E1 content significantly correlated with the maximal 6-OH-CZX concentration (  r = 0.76  , p = 0.001) and other pharmacokinetic parameters. In the recently drinking group, the area under the curve for plasma 6-OH-CZX significantly decreased after 8 days of abstinence.
Conclusions: Measurement of plasma 6-OH-CZX after administration of a CZX challenge can serve as a marker of hepatic P4502E1 activity and thus help avoid adverse drug reactions secondary to P4502E1 induction, particularly in heavy drinkers.     

18.

Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations     

SERGE SICOURI  M.D.  LUIZ BELARDINELLI  M.D.  †  LEIF CARLSSON  Ph  .D.‡  CHARLES ANTZELEVITCH  Ph  .D. 《Journal of cardiovascular electrophysiology》2009,20(7):803-810

Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation.
Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF).
Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks).
Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD₉₀) and a significant use-dependent reduction in V_max leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 μM), high calcium ([Ca²⁺]_o= 5.4 mM), isoproterenol (Iso, 1 μM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. V_max, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals.
Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.     

19.

Rosiglitazone (PPARgamma-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model     

Levi Z  Shaish A  Yacov N  Levkovitz H  Trestman S  Gerber Y  Cohen H  Dvir A  Rhachmani R  Ravid M  Harats D 《Diabetes, obesity & metabolism》2003,5(1):45-50

Background: The administration of peroxisome proliferator-activated receptor γ (PPARγ) agonists to low-density lipoprotein (LDL)-receptor-deficient mice resulted in a reduction in the atherosclerotic lesion area in male mice, but not in female mice. The male mice also exhibited reduction in insulin resistance while the female mice did not. To further examine the relationship between PPARγ agonists, insulin resistance and atherosclerosis, we used the model of accelerated atherosclerosis in male apolipoprotein E (apoE)-deficient mice rendered diabetic by low-dose streptozotocin (STZ).
Methods: Male, apoE-deficient mice ( n  = 48) were randomly divided into four groups. To induce diabetes, two groups received low-dose STZ and two groups served as controls. After diabetes induction, rosiglitazone (a PPARγ agonist) was administered by oral gavage to one of the diabetic and one of the non-diabetic groups.
Results: Rosiglitazone reduced significantly the atherosclerotic aortic plaque area in both diabetic and non-diabetic apoE-deficient mice: 340 ± 54 vs. 201 ± 27 μmol² (p = 0.001) in diabetic mice; 243 ± 22 vs. 158 ± 27 μmol² (p = 0.001) in non-diabetic mice. Also, rosiglitazone reduced the correlation coefficient between plasma glucose and the degree of atherosclerosis (p < 0.0025) without affecting plasma glucose levels. The rosiglitazone-treated mice, both diabetic and non-diabetic, had higher lipid levels.
Conclusions: Rosiglitazone-treated animals showed less atherosclerosis despite higher lipid levels and similar glucose levels. These data suggest a direct anti-atherogenic effect of rosiglitazone on the arterial wall.     

20.

A randomized study on coffee and blood pressure     

A A Bak  D E Grobbee 《Journal of human hypertension》1990,4(3):259-264

The effects of coffee on blood pressure and heart-rate and the mediating effect of two common brewing methods, were studied in a randomized trial in 107 young, normotensive adults. After a three-week run-in period, subjects were randomly assigned to one of three groups, receiving either (1) 4-6 cups filtered coffee per day, (2) 4-6 cups boiled coffee per day, or (3) no coffee at all for a period of nine weeks. Because all participants consumed filtered coffee before the trial, the group continuing on filtered coffee was considered as the reference group. Both systolic (SBP) and diastolic blood pressure (DBP) decreased in the abstinence group. Compared to the filter group, only the fall in SBP after 9 weeks was statistically significant, -6.1 mmHg (95% confidence limits -10.8, -1.4). After adjustment for SBP at baseline and body weight change during the study, the observed reduction decreased, to -3.4 mmHg (-7.1, 0.3). The patterns for SBP and DBP were remarkably similar in the groups using either filtered coffee or boiled coffee. After 9 weeks of boiled coffee, mean changes from baseline for SBP and DBP were 0.4 mmHg (-3.7, 4.5) and -0.1 mmHg (-3.4, 3.2), compared to the filter group. The heart rate showed a slight, non-significant decrease in the abstinence group. In conclusion, these findings suggest that abstinence from coffee for a period of several weeks may slightly reduce blood pressure in young normotensive subjects.     

Prednisone and low-dose activated prothrombin complex concentrates for FVIII inhibitor in nonhaemophilic patients

Eight nonhaemophilic patients with factor VIII (FVIII) inhibitors were reported. There was no difference in sex distribution. Median age at diagnosis was 62 years (ranging from 14 to 73 years). No associated disorders were revealed and all the patients were presented with severe muscular or arthral bleeding. Inhibitor titre was measured by the Bethesda method, which were 6.4, 126.0, 155.0, 4.8, 56.0, 13.5, 35.0 and 150.0 BU mL⁻¹, respectively, at diagnosis. FVIII:C levels were less than 1 U dL⁻¹ in seven patients and less than 2 U dL⁻¹ in one patient. The median vWF:Ag level was 210% (ranging from 80% to 340%). All the patients had good response to activated prothrombin complex concentrates for acute bleeding episodes and prednisone for inhibitor elimination. Inhibitors completely eliminated in seven patients within a follow-up duration over 1 year, and one patient died of intracranial haemorrhage when her inhibitor titre decreased to 4.5 BU mL⁻¹ and FVIII:C increased to 21 U dL⁻¹.     

Pharmacokinetics, efficacy and safety of Humate-P® in von Willebrand disease

In a pharmacokinetic study with Humate-P^® including six patients with various types of von Willebrand disease, a median half-life of 11.3 h for vWF:RCoF and of 15.2 h for vWF:Ag was found. The median value of in vivo recovery (IVR) was estimated for vWF:RCoF as 2.10 IU dL⁻¹ plasma per 1 substituted IU kg⁻¹ b.w. (or 73%), for vWF:Ag as 1.88 IU dL⁻¹ plasma per 1 substituted IU kg⁻¹ b.w. (or 69%); and for FVIII:C as 2.69 IU dL⁻¹ plasma per 1 IU kg⁻¹ b.w. (or 99%). Transient postinfusion shortening or normalization of previously prolonged bleeding time was observed in all patients. In a retrospective study involving 97 patients with various von Willebrand disease types, clinical efficacy and safety of treatment with Haemate-P^® in 73 surgical interventions, 344 separate bleeding events, 93 other events and 20 cycles of prophylactic treatment were evaluated. The clinical efficacy was rated good to excellent in 99% of the surgeries, in 97% of the bleeding episodes, in 86% of the other events, and in all prophylactic treatments. The overall tolerability was good. Adverse events possibly or probably associated with use of Humate-P^®/Haemate-P^® were rare, of non-serious nature and mild to moderate in their intensity.     

Intrapulmonary administration of insulin to healthy volunteers

Objectives. To study the biological effects of nebulized insulin, administered intrapulmonary, to healthy volunteers.
Design. A double-blind, randomized, controlled intervention study.
Setting. The department of Internal Medicine, University Hospital, Linköping, Sweden.
Subjects. Eight healthy, non-smoking volunteers, with a mean age of 28 (range 22 to 56) years.
Interventions. Regular human insulin 100 U mL^-1 (Actrapid®) or 0.9% saline was given randomly as an oral inhalation. Insulin was given in three different doses (40, 80 and 160 U). Aerosol was generated by a new jet nebulizer.
Main outcome measures. Blood glucose, serum insulin, and serum C-peptide.
Results. After the 160 U insulin dose the blood glucose concentration (mean±SE) fell from 4.3±0.2 to 2.8±0.2 mmol L^-1 ( P <0.001), concomitant with an increase in mean serum insulin concentrations, rising from 9.5±1.5 to 26.1±2.5 mU L^-1 ( P <0.001). Serum C-peptide concentrations simultaneously decreased from 0.48±0.03 to 0.12±0.02 mmol L^-1 ( P <0.001). All changes were dose dependent. No adverse reactions were noted and no significant changes in lung function tests.
Conclusions. Intrapulmonary insulin administration to healthy subjects can induce a significant hypoglycaemia and cause a clinically relevant increase in serum insulin concentrations. If similar results can be obtained when administering insulin to diabetic subjects, this insulin administration route can be a future complement to certain groups of patients.     

Relationship Between Serum Levels of Anti-Low-Density Lipoprotein-Acetaldehyde-Adduct Antibody and Aldehyde Dehydrogenase 2 Heterozygotes in Patients With Alcoholic Liver Injury

We prepared low-density lipoprotein (LDL)-acetaldehyde-adduct (hereafter abbreviated as LDL-adduct) and anti-LDL-adduct antibody by using Watanabe hyperlipidemic rabbits, and determined values of serum anti-LDL-adduct antibody levels by the ELISA method in healthy adults and patients with alcoholic liver injury. In the nondrinking group in healthy adults, values of anti-LDL-adduct antibody levels were 25 ± 13 μ g/ml, and there was no significant difference between moderate drinkers without diseases and the nondrinking group in healthy adults. Values of anti-LDL-adduct antibody in alcoholic disease groups, 17 ± 9 μ g/ml for the patients with the fatty liver group, 21 ± 14 μ g/ml for the hepatic fibrosis group, 70 ± 21 μ g/ml for the alcoholic hepatitis group, 41 ± 50 μ g/ml for the alcoholic cirrhosis group, and 19 ± 18 μ g/ml for the alcoholic pancreatitis group. Examinations of aldehyde dehydrogenase 2 (ALDH2) genetic variations by the polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) method in the healthy group and the liver injury group revealed a tendency for patients with ALDH2¹/2² in the liver injury group to have relatively mild liver lesions. When comparing anti-LDL-adduct antibody levels between ALDH2 genetic variations, those for the patients with ALDH2¹/2¹ (36 ± 40 μ g/ml) were significantly higher than those for patients with ALDH¹/2² (11 ± 5 μ g/ml). Results of the present study suggest that genetic variation may influence the progression of liver injury.     

Antimony in plasma and skin of patients with cutaneous leishmaniasis – relationship with side effects after treatment with meglumine antimoniate

Objective  To evaluate the levels of antimony in plasma and skin of patients being treated with pentavalent antimonials (Glucantime^®) and their relationship with side effects.
Methods  We evaluated 19 patients treated endovenously at the conventional dose (20 mg Sb^v/kg/day), two at a smaller dose (5 mg Sb^v/kg/day) and three treated intralesionally (up to 4.0 ml/week). During treatment, patients underwent periodic blood exams and were interviewed weekly about the incidence of adverse symptoms. The levels of antimony in plasma and skin samples were determined by Inductively Coupled Plasma with Mass Spectrometry (ICP-MS).
Results  The patients under conventional treatment presented a mean initial antimony plasma concentration of 3.39 μg/l; at the end of treatment, these levels were 0.21 before Glucantime^® application and 125.8 mg after Glucantime^® application. The mean antimony level in their skin at the end of the treatment was 9.24 μg/g. The main adverse symptoms were arthralgia and myalgia; laboratory results showed mainly lymphocytosis and eosinophilia.
Conclusions  We found some significant correlations between antimony concentrations, adverse symptoms and laboratory alterations, strengthening the hypothesis of a dose–dependent relationship between antimony concentration in plasma and skin and side effects.     

Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma: insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision

Background  The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma.
Objective  To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour.
Subjects and methods  FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data.
Results  Si was lower in insulinoma patients before, compared with after surgery (3·37 ± 0·62 vs. 6·24 ± 1·09 SE [×10⁻⁴] min⁻¹µU⁻¹ ml, P  < 0·05). Sg was similar in patients pre- and post-surgery (3·0 ± 0·67 vs. 2·4 ± 0·6 [×10⁻²] min⁻¹, NS).
Conclusions  Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.     

The Phosphodiesterase III Inhibitor Olprinone Decreases Sensitivity of Rat Kupffer Cells to Endotoxin

Background: Sensitivity of Kupffer cells to endotoxin [lipopolysaccharide (LPS)] and overproduction of tumor necrosis factor-α (TNF-α) are critical for progression of alcoholic liver injury. Therefore, suppression of TNF-α should prove useful for treatment of alcoholic liver injury. However, a transient increase of intracellular calcium ([Ca²⁺]_i) is required for LPS-induced TNF-α production by the macrophage cell line. The phosphodiesterase III inhibitor olprinone has been shown to suppress [Ca²⁺]_i level in vascular smooth muscle cells. Accordingly, the purpose of this study was to determine whether olprinone could prevent sensitization of Kupffer cells to endotoxin.
Methods: Kupffer cells were isolated by collagenase digestion and differential centrifugation. LPS was added to Kupffer cells 24 hr after incubation with or without olprinone (0.1 μmol/liter). After addition of LPS (10 μg/ml) to culture media, [Ca²⁺]_i was measured using a fluorescent indicator, fura-2.
Results: LPS increased [Ca²⁺]_i of Kupffer cells in control rats from basal levels (28 ± 4 nmol/liter) to 280 ± 14 nmol/liter. This increase was blunted by olprinone (91 ± 8 nmol/liter). Similarly, olprinone diminished the LPS (1 μg/ml)-induced TNF-α production by Kupffer cells by 30% (2220 ± 116 vs. 1386 ± 199 pg/ml; p < 0.05).
Conclusions: These results indicate that olprinone decreases sensitivity of Kupffer cells to endotoxin.     

Recirculating Delivery Improves Myocardial Cell Engraftment

Introduction: Despite pharmacological advances for heart failure, morbidity and mortality remain unacceptably high. As a result, alternative approaches such as cell therapy have been suggested to hold potential promise. However, a major obstacle is the optimization of cell delivery to the heart. Therefore, we investigated the efficacy of a percutaneous recirculation system for the delivery of cells to the heart.
Methods: Ovine fibroblasts were delivered to the ovine heart (3 × 10⁷ cells) using the V-Focus system, a "closed" recirculatory system that draws blood from the coronary sinus and returns it to the coronary artery via an oxygenator, or intracoronary (IC) infusion, followed by a 2-hour recovery period. Animals were euthanized and cardiac tissue collected to determine presence of cells.
Results: There was a significant difference (P < 0.05) in the number of cells delivered to the heart by the V-Focus compared to direct coronary infusion for left ventricular freewall (V-Focus 1.39 ± 0.63/mm², IC 0.11 ± 0.06/mm²), septum (V-Focus 3.18 ± 0.88/mm², IC 0.38 ± 0.19/mm²), and right ventricle (V-Focus 0.46 ± 0.23/mm², IC 0.05 ± 0.04/mm²).
Conclusions: These results suggest that potential therapeutic cells are optimally delivered to the large animal heart using the V-Focus cardiac delivery system in an ovine heart. (J Interven Cardiol 2010;23:14–17)     

Mechanisms of Late Stent Malapposition After Primary Stenting in ST-Elevation Myocardial Infarction: A Subanalysis of the Selection Trial

Background: One of the major predictors of late stent malapposition (LSM) is primary stenting in acute myocardial infarction. However, mechanisms of LSM are still under debate.
Methods: Patients with ST-elevation myocardial infarction (STEMI) and enrolled in the SELECTION trial (38 patients in the paclitaxel-eluting stent, PES, and 35 in the bare metal stent, BMS, cohort) were retrospectively analyzed to evaluate LSM, by means of intravascular ultrasound (IVUS) data recorded at the index and 7-month follow-up procedures.
Results: Stent malapposition was documented in 21 lesions in 21 patients (28.8%): in 8 of these 21 patients (38.1%) it was LSM. Although statistical significance was not reached, LSM was more frequent after PES than BMS implantation (15.8% vs. 5.7%). LSM was mainly located within the body of the stent (62.5% of the cases). At the LSM segment, a significant increase of vessel area (19.2 ± 3.3 mm² vs. 21.9 ± 5.3 mm², P = 0.04) and a reduction of plaque area (12.6 ± 4.6 mm² vs. 9.1 ± 3.9 mm², P = 0.04) were observed at IVUS between the index and follow-up procedure.
Conclusions: After primary stenting for STEMI, LSM seems to be more frequent after PES rather than BMS implantation. In the STEMI setting, possible mechanisms leading to LSM include positive remodeling and plaque mass decrease.     

Boiled coffee increases serum low density lipoprotein concentration

The effects of boiled coffee, filtered coffee, and tea on serum lipoprotein lipids and apoproteins were compared in 42 middle-aged hypercholesterolemic subjects (21 men and 21 women). The subjects consumed the beverages, eight cups a day, in random order during successive 4-week periods with 2-week run-in intervals in a crossover design. The diet was kept unchanged. Statistically significant differences were found between the periods in serum total cholesterol (P less than .0001 ANOVA), LDL cholesterol (P less than .01), and apoprotein B (P less than .01) levels. All differences were due to significantly higher levels during boiled coffee as compared with filtered coffee and tea. No statistically significant differences were found between the filtered coffee and tea periods. There were no differences in serum VLDL cholesterol or triglyceride, HDL cholesterol, and apoprotein A-I concentrations between the periods. Consumption of boiled coffee thus increased the concentration of low density lipoprotein in the serum without affecting its lipid-protein composition. The effect seemed to be determined by the method of brewing.     

The European Exenatide study of long-term exenatide vs. glimepiride for type 2 diabetes: rationale and patient characteristics

Aim: To describe the rationale for the European Exenatide (EUREXA) clinical study and describe the characteristics of the patient cohort.
Methods: EUREXA is a multinational study of long-term effects of add-on exenatide vs. glimepiride in patients with type 2 diabetes and failure of diet/lifestyle plus metformin monotherapy. Metformin failure was defined as hemoglobin A1c (HbA1c) ≥ 6.5% and patients were overweight/obese (BMI ≥ 25 to < 40 kg/m²). The primary end point is time to failure of combination treatment, defined from HbA1c concentration according to current criteria. At baseline, an oral glucose tolerance test (OGTT) was performed, fasting blood was taken for lipid profile and patients were randomized to add-on exenatide (5 μg b.i.d. for 4 weeks then 10 μg b.i.d.) or glimepiride (1 mg/day titrated to maximum dose).
Results: A total of 1039 patients were entered in the study, with mean (± s.d.) age 57.2 ± 9.6 years, body mass index (BMI) 32.4 ± 4.1 kg/m², duration of diabetes 5.6 ± 4.5 years and HbA1c 7.4 ± 0.7%. A history of cardiovascular disease (CVD) was present for 64.8% of patients overall and duration of diabetes was statistically significantly longer for patients with CVD than without (p = 0.010). Lipid abnormalities were reported for 48.9% of patients and 40.9% were taking at least one lipid-lowering medication.
Conclusion: Patients included in the EUREXA study had early failure of glucose control with metformin and presented typical features of type 2 diabetes: overweight/obesity and high prevalence of lipid abnormalities and CVD. In this population, the effects of exenatide vs. glimepiride will be evaluated over at least 2.5 years.     

Dissociated incretin response to oral glucose at 1 year after restrictive vs. malabsorptive bariatric surgery

Aim: Compare the response to oral glucose of the two incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) at 1 year after restrictive vs. malabsorptive bariatric surgery.
Methods: Vertical banded gastroplasty (VBG, n = 7) or jejunoileal bypass (JIB, n = 5) was performed in 12 women, aged 26–39 years, with severe obesity [body mass index (BMI) 46.6 ± 2.3 kg/m²]. After 1 year, 75 g glucose was administered and plasma levels of glucose, insulin, GIP and GLP-1 were determined regularly during the following 2 h.
Results: At 1 year after operation, reduction in body weight, actual body weight, fasting glucose or insulin, or the glucose and insulin responses to oral glucose did not differ significantly between the groups. Similarly, fasting GIP and GLP-1 levels did not differ significantly between the groups. In contrast, the GIP and GLP-1 responses to oral glucose were different between the groups in a dissociated pattern. Thus, AUC_GIP was significantly higher after VBG than after JIB (53 ± 8 vs. 26 ± 6 pmol/l/min, p = 0.003). In contrast, AUC_GLP−1 was significantly higher after JIB than after VBG (49 ± 5 vs. 20 ± 3 pmol/l/min, p = 0.007).
Conclusions: We conclude that at 1 year after bariatric surgery, the two incretins show dissociated responses in that the GIP secretion is higher after VBG whereas GLP-1 secretion is higher after JIB. This dissociated incretin response is independent from reduction in body weight, glucose tolerance or insulin secretion.     

Chlorzoxazone pharmacokinetics as a marker of hepatic cytochrome P4502E1 in humans

Objective: Previous in vitro studies have demonstrated that hepatic P4502E1 metabolizes chlorzoxazone (CZX, a commonly used muscle relaxant) to 6-hydroxychlorzoxazone (6-OH-CZX). We thus assessed whether measurement of the plasma 6-OH-CZX/CZX ratio after a CZX challenge could serve as a marker of hepatic P4502E1 content.
Methods: Three subject groups were included: recently drinking alcoholics (  N = 6  ), abstinent alcoholics (  N = 5  ), and nonalcoholic subjects with liver disease (  N = 5  ) undergoing liver biopsy. Excess tissue was procured for immunochemical determination of hepatic P4502E1 content. Within an hour of the biopsy, 750 mg CZX was administered orally and serial plasma samples were collected for 6 h.
Results: Recently drinking alcoholic subjects had a higher area under the curve for plasma 6-OH-CZX (1.354 ± 0.258 μg · min · ml⁻¹) then abstinent alcoholic subjects (0.296 ± 0.080 μg · min · ml⁻¹, p < 0.005) and subjects with nonalcoholic liver disease (0.428 ± 0.061 μg · min · ml⁻¹,   p < 0.005  ). The use of the plasma 6-OH-CZX/CZX ratio at 90, 120, and 180 min discriminated between recently drinking alcoholic and nondrinking subjects. Hepatic P4502E1 content significantly correlated with the maximal 6-OH-CZX concentration (  r = 0.76  , p = 0.001) and other pharmacokinetic parameters. In the recently drinking group, the area under the curve for plasma 6-OH-CZX significantly decreased after 8 days of abstinence.
Conclusions: Measurement of plasma 6-OH-CZX after administration of a CZX challenge can serve as a marker of hepatic P4502E1 activity and thus help avoid adverse drug reactions secondary to P4502E1 induction, particularly in heavy drinkers.     

Potent Antiarrhythmic Effects of Chronic Amiodarone in Canine Pulmonary Vein Sleeve Preparations

Objectives: To examine the effects of chronic amiodarone on the electrophysiology of canine pulmonary vein (PV) sleeve preparations and left ventricular wedge preparation.
Background: Amiodarone is commonly used for the treatment of ventricular and supraventricular arrhythmias. Ectopic activity arising from the PV plays a prominent role in the development of atrial fibrillation (AF).
Methods: Standard microelectrode techniques were used to evaluate the electrophysiological characteristics of superfused PV sleeve (left superior or inferior) and arterially perfused left ventricular (LV) wedge preparations isolated from untreated and chronic amiodarone-treated dogs (amiodarone, 40 mg/kg daily for 6 weeks).
Results: In PV sleeves, chronic amiodarone (n = 6) induced a significant increase in action potential duration at 90% repolarization (APD₉₀) and a significant use-dependent reduction in V_max leading to 1:1 activation failure at long cycle lengths (basic cycle length of 124 ± 15 ms in control vs 420 ± 320 ms after chronic amiodarone [P < 0.01]). Diastolic threshold of excitation increased from 0.3 ± 0.2 to 1.8 ± 0.7 mA (P < 0.01). Delayed and late phase 3 early afterdepolarizations and triggered activity could be induced in PV sleeve preparations using acetylcholine (ACh, 1 μM), high calcium ([Ca²⁺]_o= 5.4 mM), isoproterenol (Iso, 1 μM), or their combination in 6 of 6 untreated PV sleeves, but in only 1 of 5 chronic amiodarone-treated PV sleeve preparations. V_max, conduction velocity, and 1:1 activation failure were much more affected in PV sleeves versus LV wedge preparations isolated from amiodarone-treated animals.
Conclusions: The results point to potent effects of chronic amiodarone to preferentially suppress arrhythmogenic substrates and triggers arising from the PV sleeves of the dog.     

Rosiglitazone (PPARgamma-agonist) attenuates atherogenesis with no effect on hyperglycaemia in a combined diabetes-atherosclerosis mouse model

Background: The administration of peroxisome proliferator-activated receptor γ (PPARγ) agonists to low-density lipoprotein (LDL)-receptor-deficient mice resulted in a reduction in the atherosclerotic lesion area in male mice, but not in female mice. The male mice also exhibited reduction in insulin resistance while the female mice did not. To further examine the relationship between PPARγ agonists, insulin resistance and atherosclerosis, we used the model of accelerated atherosclerosis in male apolipoprotein E (apoE)-deficient mice rendered diabetic by low-dose streptozotocin (STZ).
Methods: Male, apoE-deficient mice ( n  = 48) were randomly divided into four groups. To induce diabetes, two groups received low-dose STZ and two groups served as controls. After diabetes induction, rosiglitazone (a PPARγ agonist) was administered by oral gavage to one of the diabetic and one of the non-diabetic groups.
Results: Rosiglitazone reduced significantly the atherosclerotic aortic plaque area in both diabetic and non-diabetic apoE-deficient mice: 340 ± 54 vs. 201 ± 27 μmol² (p = 0.001) in diabetic mice; 243 ± 22 vs. 158 ± 27 μmol² (p = 0.001) in non-diabetic mice. Also, rosiglitazone reduced the correlation coefficient between plasma glucose and the degree of atherosclerosis (p < 0.0025) without affecting plasma glucose levels. The rosiglitazone-treated mice, both diabetic and non-diabetic, had higher lipid levels.
Conclusions: Rosiglitazone-treated animals showed less atherosclerosis despite higher lipid levels and similar glucose levels. These data suggest a direct anti-atherogenic effect of rosiglitazone on the arterial wall.     

A randomized study on coffee and blood pressure

The effects of coffee on blood pressure and heart-rate and the mediating effect of two common brewing methods, were studied in a randomized trial in 107 young, normotensive adults. After a three-week run-in period, subjects were randomly assigned to one of three groups, receiving either (1) 4-6 cups filtered coffee per day, (2) 4-6 cups boiled coffee per day, or (3) no coffee at all for a period of nine weeks. Because all participants consumed filtered coffee before the trial, the group continuing on filtered coffee was considered as the reference group. Both systolic (SBP) and diastolic blood pressure (DBP) decreased in the abstinence group. Compared to the filter group, only the fall in SBP after 9 weeks was statistically significant, -6.1 mmHg (95% confidence limits -10.8, -1.4). After adjustment for SBP at baseline and body weight change during the study, the observed reduction decreased, to -3.4 mmHg (-7.1, 0.3). The patterns for SBP and DBP were remarkably similar in the groups using either filtered coffee or boiled coffee. After 9 weeks of boiled coffee, mean changes from baseline for SBP and DBP were 0.4 mmHg (-3.7, 4.5) and -0.1 mmHg (-3.4, 3.2), compared to the filter group. The heart rate showed a slight, non-significant decrease in the abstinence group. In conclusion, these findings suggest that abstinence from coffee for a period of several weeks may slightly reduce blood pressure in young normotensive subjects.