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.     

Plasma Renin Activity and Hypertension in Acute Glomerulonephritis*

Summary: The relationship between plasma renin activity (PRA), plasma volume (PV) and mean arterial pressure (MAP) in children with acute glomerulonephritis was assessed in two groups of patients between the ages of three to six years. One group with normal blood pressure (13 children) and a group with significantly elevated blood pressure (20 children) were compared with a control group of ten normal children.
In patients who developed hypertension (MAP: 113 ± 3 mmHg), the mean PRA was 0±45 ± 0±1 ng/ml/hr, and the mean PV measured in ten of these children was 1526 ± 47±9 ml/M². In the group of normotensive patients with acute glomerulonephritis (MAP = 79 ± 1±8 mmHg), the mean PRA was 1±6 ± 0±32 ng/ml/hr, the mean PV in four of these patients was 1285±37±6 ml/M². The children in the control group (MAP = 77± 1±6 mmHg) had a mean PRA of 7±93 ± 0±2 ng/ml/hr and six of these children had a mean PV of 1115 ± 103 ml/M².
The results showed children who developed hypertension had significantly higher PV lower PRA than children with acute glomerulonephritis who were normotensive and the control subjects. A positive correlation was found between MAP and PV and negative correlation between MAP and PRA. There was no significant difference in MAP, PV and PRA between children with acute glomerulonephritis with normal blood pressure and children in the control group.     

Glucose and insulin levels in young subjects with different maternal histories of hypertension: The Hypertension in Pregnancy Offspring Study

Objective: To analyse whether hypertension during pregnancy is associated with early signs of impaired glucose metabolism in the offspring.
Design: Longitudinal study with a 5-year follow-up.
Setting: University Hospital, Göteborg, Sweden.
Main outcome measures: Fasting levels of glucose, insulin and C-peptide.
Subjects: Thirty-six children were born to mothers with hypertension in pregnancy. The children were divided into two groups according to their mothers' blood pressure at follow-up 7–12 years after pregnancy. Nineteen children had hypertensive mothers (HT), while 17 children had normotensive mothers at follow-up (NT). A control group (C) comprised 16 children, who were born after normotensive pregnancies to mothers who remained normotensive.
Results: Fasting plasma glucose was significantly higher in HT than in NT (5.2 vs. 4.9 mmol L⁻¹; P < 0.05). In C fasting glucose was 5.1 mmol L⁻¹. The same trend was seen for fasting insulin in HT, NT and C, respectively (6.7 vs. 4.7 vs. 5.3 μU mL⁻¹). The C-peptide level was 1.61, 155 and 1.64 ng mL⁻¹, respectively. Calculated insulin resistance was 1.5 in HT, 1.0 in NT and 1.2 in C.
Conclusions: It is suggested that hypertension during pregnancy may be associated with impaired glucose metabolism and elevated fasting glucose levels in the offspring during adolescence.     

Relationships between vitamin D, parathyroid hormone and bone mineral density in inflammatory bowel disease

Objectives. To explore the relationships between vitamin D intake, serum parathyroid hormone (PTH) and 25-hydroxyvitamin D (250HD) concentrations, and bone mineral density (BMD) in inflammatory bowel disease (IBD).
Setting. A university hospital clinic in Finland.
Subjects. One hundred and fifty randomly selected patients with IBD from the hospital register and 73 healthy controls.
Measurements. BMD of the lumbar spine and the proximal femur was measured with dual energy X-ray absorptiometry. Vitamin D intake and serum levels of 250HD and PTH were determined.
Results. The IBD patients had a lower serum 250HD concentration (28.4 [SD 12.0] nmol L^-1) than the controls (36.1 [16.7] nmol L^-1; P =0.001), whereas no differences in the vitamin D intake or the serum PTH levels were found. The serum 250HD concentrations and the vitamin D intake of the patients with ulcerative colitis ( n =67) were similar to those of the Crohn's disease patients ( n =76). The patients with Crohn's disease of the small bowel had slightly, but not significantly, lower serum 250HD concentrations (25.6 [11.0] nmol L^-1) than the other Crohn's disease patients (31.4 [14.3] nmol L^-1; P =0.061). In the IBD patients, the vitamin D intake and the serum 250HD and PTH concentrations were not associated with BMD.
Conclusions. Patients with IBD have lower serum levels of 250HD than healthy controls, but similar serum PTH concentrations and vitamin D intake. Vitamin D intake, and the serum levels of 250HD and PTH are not associated with BMD, and malabsorption is unlikely to be a major factor in the aetiology of bone loss in unselected IBD patients.     

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.     

Chronic consumers of boiled coffee have elevated serum levels of lipoprotein(a)

Objectives. Lipoprotein(a) consists of an LDL-particle attached to apolipoprotein(a), which is made by the liver. Diterpenes present in boiled coffee raise serum levels of LDL cholesterol and of the liver enzyme alanine aminotransferase in man. We investigated the association between intake of boiled coffee and serum levels of lipoprotein(a).
Design, setting and subjects. Healthy Norwegians 40–42 years of age, who habitually consumed five or more cups of boiled coffee per day ( n =150) were compared with matched filter coffee consumers ( n =159) in a cross-sectional study, as part of the Norwegian National Health Screening in 1992.
Results. The median lipoprotein(a) level was 13.0 mg  dL⁻¹ (10th and 90th percentile: 2.5 and 75.0 mg  dL⁻¹, respectively) on boiled and 7.9 mg dL^-1 (10th and 90th percentile: 1.9 and 62.5 mg dL⁻¹, respectively) on filter coffee ( P =0.048). Means±SE were 25.8±2.4 mg dL⁻¹ and 19.6±2.0 mg dL⁻¹, respectively ( P =0.04). Although not statistically significant, subjects consuming nine or more cups of coffee per day had higher lipoprotein(a) levels than those drinking five to eight cups per day in both coffee groups.
Conclusion. Chronic consumers of unfiltered, boiled coffee have higher serum levels of lipoprotein(a) than filter coffee drinkers.     

Dilated left atrium and pulmonary veins in patients with calcified coronary artery: a potential contributor to the genesis of atrial fibrillation

Introduction: Coronary artery disease (CAD) is an important etiology of atrial fibrillation (AF). Coronary artery calcification is a marker of coronary atherosclerosis and coronary events. The purpose of this study was to investigate whether larger left atrium (LA) and pulmonary veins (PVs) were seen by multidetector computed tomography (MDCT) scans in those patients with higher coronary calcium scores.
Methods and Results: A total of 166 patients undergoing MDCT for general check-up (n = 128, 77%) or suspected CAD (n = 38, 23%) were enrolled and divided into a control (calcium score = 0, n = 60), medium calcium score (calcium score = 100∼400, n = 47), and high calcium score (calcium score >400, n = 59) groups. Diameters and areas of the LA, left atrial appendage (LAA), and PVs were measured by MDCT. The high calcium score group had significantly larger PVs diameters, LAA orifice area (1.9 ± 1.4 cm², 0.9 ± 0.5 cm², 0.8 ± 0.4 cm², P < 0.005), LA anterior-posterior distance (32.2 ± 6.8 mm, 30.4 ± 6.5 mm, 27.3 ± 6.0 mm, P < 0.05), and transverse distance (52.6 ± 7.3 mm, 50.2 ± 9 mm, 49.5 ± 4.6 mm, P < 0.05) than the medium calcium score and control groups. Six (3.6%) patients with paroxysmal AF had higher calcium scores and larger diameters of LA, LAA, and PVs than those (96.4%) without paroxysmal AF. Two patients in the high calcium score group had calcified PVs localized to the right upper and left upper PVs. The incidence of calcified PVs was 1.2% for the total patients and 3.3% for the high calcium score patients.
Conclusion: In the presence of high calcium scores in this patient population, the LA, LAA, and PVs were enlarged.     

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.     

REVERSIBLE HYPERTENSION AND HYPOTHYROIDISM

Six patients with hypothyroidism and hypertension whose blood pressure fell to normal when treated with thyroxine (172.7.2/112.2.1 to 140.3.2/84.1.6 mmHg, P <0.001) are described. Plasma renin activity (1.76±0.63 ng angiotensin I.ml⁻¹.h⁻¹) was low before treatment. Hypertension with low plasma renin is consistent with sodium retention. Hypertension in the hypothyroid patient only requires further evaluation if it persists after adequate treatment with thyroxine.     

Phosphorylation of 2-chlorodeoxyadenosine (CdA) in extracts of peripheral blood mononuclear cells of leukaemic patients

2-Chlorodeoxyadenosine (CdA) is an antileukaemic agent used in treatment of hairy cell leukaemia (HCL) and chronic lymphocytic leukaemia of B- and T-cell type (B-CLL and T-CLL). The aim of this study was to elucidate the interpatient variability of CdA phosphorylation and its relation to response to CdA treatment. In extracts of peripheral blood mononuclear cells of patients with B-CLL ( n = 39), CdA phosphorylation was significantly higher than in HCL ( n = 19) when calculated per protein (391 ± 155 pmol CdA phosphorylated/mg protein/min versus 288 ± 166 pmol/mg/min, P < 0.001), but was the same when calculated per cell (12 ± 5.9 pmol/10⁶ cells/min versus 14 ± 5.9 pmol/10⁶ cells/min) due to a larger cell volume in HCL. In T-CLL ( n = 6), CdA phosphorylation was significantly lower than in B-CLL, both when calculated per protein (128 ± 68 pmol/mg/min, P < 0.001) or per cell (5.7 ± 2.7 pmol/10⁶ cells/min, P < 0.05). This low CdA phosphorylation in T-CLL was unexpected because normal B- and T-lymphocytes contain equal amounts of CdA phosphorylation. With B-CLL, 21 patients who responded (complete and partial response) to CdA treatment showed a significantly higher CdA phosphorylation than 13 patients not responding to CdA treatment (456 ± 170 pmol/mg/min versus 309 ± 97 pmol/mg/min, P < 0.01). We conclude that the level of CdA phosphorylation is correlated with the response of leukaemias to CdA treatment.     

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)     

Drug Delivery at the Aortic Valve Tissues of Healthy Domestic Pigs with a Paclitaxel-Eluting Valvuloplasty Balloon

Background: Restenosis occurs invariably within 1 year following balloon valvulopasty in aortic valve stenosis. The mechanism of restenosis seems to involve a dynamic cellular component that could be a target for drug inhibition. We investigated the feasibility of local drug delivery at the aortic valve tissues of healthy pigs with a paclitaxel-eluting balloon.
Methods: Aortic valvuloplasty was performed in eight anesthetized domestic pigs using paclitaxel-eluting balloons (3 μg/mm² balloon surface area). They were assigned to two or four times 15-second balloon inflations and were sacrificed 30 minutes after final balloon inflation.
Results: The aortic annulus to balloon diameter ratio was 1.15 ± 0.07. The mean paclitaxel concentration in the aortic valve leaflets was 0.91 ± 1.36 μg/mL (0.34 ± 0.05 μg/mL in the two-inflation group, 1.48 ± 1.86 μg/mL in the four-inflation group, P = 0.23). The percentage of the total paclitaxel dose recovered in the aortic valve leaflets was 18 ± 11⁻⁶% (13 ± 6⁻⁶% and 25 ± 14⁻⁶% in the two- and four-inflation group, P = 0.16).
Conclusion: Local drug delivery at the aortic valve leaflets of healthy pigs with a paclitaxel-eluting balloon is feasible and concentrations within the therapeutic window are detected 30 minutes after the procedure. The antirestenotic potential of this treatment should be studied.     

Thrombin generation in vitro in the presence of by-passing agents in siblings with severe haemophilia A

Summary.  Previous data have shown an inter-individual difference in the thrombin generating capacity in vitro as well as phenotypic bleeding pattern among patients with severe haemophilia A (FVIII:C activity below 1%). The reason for this is not known. In addition, there are no reports on how thrombin generation may correlate between siblings. In this study, we evaluated and compared thrombin generation in vitro using plasma samples in the presence of by-passing agents (FEIBA^® and NovoSeven^®) in 21 unrelated brother pairs with and without inhibitors enrolled in the Malmö International Brother Study (MIBS). Mean maximum thrombin formation in patients with a current inhibitor titer was 182.0 ± 52.8 mmol mL⁻¹ (FEIBA^®) and 130.7 ± 54.9 mmol mL⁻¹ (rFVIIa), respectively, and somewhat higher in those without inhibitors, 222.7 ±85.5 mmol mL⁻¹ (FEIBA^®) and 142.8 ±53.6mmol mL⁻¹ (rFVIIa) ( P  = 0.16 and 0.29). The variance regarding the maximum thrombin production within a family was significantly lower compared with the thrombin production between families ( P  < 0.001 for both FEIBA^® and NovoSeven^®). Our data indicate that genetically determined factors, other than the FVIII:C activity seems to influence the phenotypic variation in thrombin formation in the presence of by-passing agents. The nature of these determinants remains to be identified.     

Is there a role for renin profiling in selecting chronic heart failure patients for ACE inhibitor treatment?

BACKGROUND: It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation. OBJECTIVE: To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin. DESIGN: Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59-82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA 5, n = 13). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status. RESULTS: There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66. 3 (18.9) mmol/l; p = 0.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (p = 0.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (-9.6%, p = 0.335) following ACE inhibition in this subgroup of patients. CONCLUSIONS: About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn.     

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.     

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     

17.

A possible association between primary aldosteronism and a lower beta-cell function   总被引：1，自引：0，他引：1  

Mosso LM  Carvajal CA  Maiz A  Ortiz EH  Castillo CR  Artigas RA  Fardella CE 《Journal of hypertension》2007,25(10):2125-2130

OBJECTIVE: Primary aldosteronism (PA) is the most common secondary cause of hypertension and recently has been implicated as a cause of impaired glucose tolerance. We investigated the glucose insulin sensitivity and insulin secretion in patients with idiopathic primary aldosteronism. DESIGN: Thirty PA patients and 60 essential hypertensive (EH) patients as controls were included, matched (1: 2) by their body mass index (BMI) (29.9 +/- 4.3 versus 29.8 +/- 5.8 m/kg), age (53.7 +/- 9.4 versus 59.9 +/- 8.6 years old) and gender (male/female: 8/22 versus 17/43). In all patients, we measured insulin, total cholesterol, triglycerides, C-peptide and fasting glucose levels. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA of pancreatic beta-cell function (HOMA-betaF) indexes were calculated. We also evaluated the response to spironolactone in 19 PA patients. RESULTS: PA patients had higher levels of glucose (5.2 +/- 0.7 versus 4.9 +/- 0.7 mmol/l; P = 0.017). Insulin levels (10.7 +/- 6.5 versus 11.5 +/- 5.8 uUI/ml, P = 0.525) and HOMA-IR (2.51 +/- 1.59 versus 2.45 +/- 1.29 uUI/ml x mmol/l, P = 0.854) were similar in both groups. HOMA-betaF index (138.9 +/- 89.8 versus 179.8 +/- 100.2%, P = 0.049) and C-peptide (0.83 +/- 0.63 versus 1.56 +/- 0.84 ng/dl, P = 0.0001) were lower in PA patients. Potassium was normal in both groups. Negative correlations between serum aldosterone/plasma renin activity (SA/PRA) ratio and HOMA-betaF, and between C-peptide and SA levels were found in all patients. After the spironolactone treatment, we found an increase of C-peptide and insulin levels without changes in HOMA-IR or HOMA-betaF. CONCLUSION: Our results showed differences in glucose metabolism between PA patients and those with hypertension suggesting that these findings could probably be determined by a lower beta-cell function influenced by aldosterone. These findings highlight the importance of aldosterone in glucose metabolism.     

18.

Factors predictive of disease progression and death in AIDS-related Kaposi's sarcoma     

J-P Spano  Y Salhi  D Costagliola  W Rozenbaum  P-M Girard 《HIV medicine》2000,1(4):232-237

Background   The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4⁺ cell counts greater than 100/μL.
Patients and Methods   We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4⁺ and CD8⁺ cell counts, plasma HIV load, p24 antigenaemia, β₂-microglobulinaemia and immunoglobin A and G serum levels.
Results   During a median follow-up of 22 months (3–81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9–126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression ( P  < 0.05). Previous and concomitant opportunistic diseases ( P  = 0.003) and low CD4⁺ cell counts ( P  = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival.
Conclusion   Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4⁺ cell count).     

19.

Use of Captopril in the Diagnosis of Renal Hypertension     

B. P. McGrath  P. G. Matthewst †  C. I. Johnston ‡ 《Internal medicine journal》1981,11(3):359-363

Abstract: 1 . The effects of a single 25 mg oral dose of captopril on blood pressure, heart rate and circulating renin, angiotensin I, angiotensin II, bradykinin and catecholamine levels were examined in untreated patients with essential (n = 10, Group I), accelerated (n = 6, Group II) and renal hypertension (n = 8, Group III) studied on a normal sodium diet .
2 . Mean blood pressure fell only slightly in Group I patients, (113 ± 3 to 109 ± 3 mmHg at 60 minutes) but a greater fall was observed in Group II (153 ± 8 to 135 ± 11 mmHg) and a marked fall in Group III, (136 ± 3 to 114 ± 5 mmHg). There were no significant changes in heart rate in any group .
3 . Plasma angiotensin II levels were significantly reduced 30 minutes after captopril in all three groups and returned toward resting values after four hours. The falls in plasma angiotensin II levels were accompanied by reciprocal increases in blood angiotensin I and plasma renin, but blood bradykinin and plasma catecholamine concentrations remained unchanged .
4 . Resting plasma renin levels showed considerable overlap in the three groups and the mean renin values were not significantly different in the three groups. After captopril a marked rise in plasma renin concentration (>2.5 ng/ml/hr) was observed in seven patients in Group III, including all six patients with renovascular disease. In contrast, none of the patients with essential hypertension and only one patient with accelerated hypertension had such an increase. Determination of the acute renin and blood pressure responses to converting enzyme inhibition with a single oral dose of captopril appears to be useful in identifying patients with renovascular hypertension .     

20.

Pathogen reduction technology (Mirasol^®) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS     

K. Janetzko  K. Hinz  S. Marschner  R. Goodrich  & H. Klüter 《Vox sanguinis》2009,97(3):234-239

Background and Objectives  Mirasol^® pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS).
Materials and Methods  Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP.
Results  On day 5, PRT units showed a significantly lower pH (7·087 ± 0·105 vs. 7·288 ± 0·200) accompanied by a higher lactate production (0·104 ± 0014 vs. 0·063 ± 0·017 mmol/10¹²/h) and glucose consumption rate (0·039 ± 0005 vs. 0·028 ± 0·009 mmol/10¹² platelets/h). CD62p expression was higher in treated units (44·5 ± 13·0 vs. 16·5 ± 7·6%).
Conclusion  In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible.     

A possible association between primary aldosteronism and a lower beta-cell function

OBJECTIVE: Primary aldosteronism (PA) is the most common secondary cause of hypertension and recently has been implicated as a cause of impaired glucose tolerance. We investigated the glucose insulin sensitivity and insulin secretion in patients with idiopathic primary aldosteronism. DESIGN: Thirty PA patients and 60 essential hypertensive (EH) patients as controls were included, matched (1: 2) by their body mass index (BMI) (29.9 +/- 4.3 versus 29.8 +/- 5.8 m/kg), age (53.7 +/- 9.4 versus 59.9 +/- 8.6 years old) and gender (male/female: 8/22 versus 17/43). In all patients, we measured insulin, total cholesterol, triglycerides, C-peptide and fasting glucose levels. Homeostasis model assessment for insulin resistance (HOMA-IR) and HOMA of pancreatic beta-cell function (HOMA-betaF) indexes were calculated. We also evaluated the response to spironolactone in 19 PA patients. RESULTS: PA patients had higher levels of glucose (5.2 +/- 0.7 versus 4.9 +/- 0.7 mmol/l; P = 0.017). Insulin levels (10.7 +/- 6.5 versus 11.5 +/- 5.8 uUI/ml, P = 0.525) and HOMA-IR (2.51 +/- 1.59 versus 2.45 +/- 1.29 uUI/ml x mmol/l, P = 0.854) were similar in both groups. HOMA-betaF index (138.9 +/- 89.8 versus 179.8 +/- 100.2%, P = 0.049) and C-peptide (0.83 +/- 0.63 versus 1.56 +/- 0.84 ng/dl, P = 0.0001) were lower in PA patients. Potassium was normal in both groups. Negative correlations between serum aldosterone/plasma renin activity (SA/PRA) ratio and HOMA-betaF, and between C-peptide and SA levels were found in all patients. After the spironolactone treatment, we found an increase of C-peptide and insulin levels without changes in HOMA-IR or HOMA-betaF. CONCLUSION: Our results showed differences in glucose metabolism between PA patients and those with hypertension suggesting that these findings could probably be determined by a lower beta-cell function influenced by aldosterone. These findings highlight the importance of aldosterone in glucose metabolism.     

Factors predictive of disease progression and death in AIDS-related Kaposi's sarcoma

Background   The natural history of Kaposi's sarcoma (KS) is poorly documented. We attempted to identify factors predictive of progression and survival in HIV-infected patients with KS and CD4⁺ cell counts greater than 100/μL.
Patients and Methods   We studied retrospectively 78 HIV-infected patients diagnosed as having KS between 1989 and 1995. The following variables were assessed as potential predictors of progression and death, in a Cox proportional hazards model: age, sex, ethnic group, transmission group, site of the first KS lesions, duration of KS, concomitant opportunistic infections or malignancies, antiretroviral drug therapy (excluding protease inhibitors), antiherpes treatments, neutrophil counts, CD4⁺ and CD8⁺ cell counts, plasma HIV load, p24 antigenaemia, β₂-microglobulinaemia and immunoglobin A and G serum levels.
Results   During a median follow-up of 22 months (3–81 months), KS progressed in 66 of the 78 patients. The median survival time after progression was 68 months (9–126 months). Multivariate analysis identified only visceral KS, a high neutrophil count and a high serum immunoglobulin (Ig) level as independent predictors of progression ( P  < 0.05). Previous and concomitant opportunistic diseases ( P  = 0.003) and low CD4⁺ cell counts ( P  = 0.013) were independently associated with shorter survival; in contrast KS therapy did not independently influence survival.
Conclusion   Progression of KS is predicted by markers of KS severity, while overall survival is best predicted by markers of immunodeficiency (opportunistic diseases and the CD4⁺ cell count).     

Use of Captopril in the Diagnosis of Renal Hypertension

Abstract: 1 . The effects of a single 25 mg oral dose of captopril on blood pressure, heart rate and circulating renin, angiotensin I, angiotensin II, bradykinin and catecholamine levels were examined in untreated patients with essential (n = 10, Group I), accelerated (n = 6, Group II) and renal hypertension (n = 8, Group III) studied on a normal sodium diet .
2 . Mean blood pressure fell only slightly in Group I patients, (113 ± 3 to 109 ± 3 mmHg at 60 minutes) but a greater fall was observed in Group II (153 ± 8 to 135 ± 11 mmHg) and a marked fall in Group III, (136 ± 3 to 114 ± 5 mmHg). There were no significant changes in heart rate in any group .
3 . Plasma angiotensin II levels were significantly reduced 30 minutes after captopril in all three groups and returned toward resting values after four hours. The falls in plasma angiotensin II levels were accompanied by reciprocal increases in blood angiotensin I and plasma renin, but blood bradykinin and plasma catecholamine concentrations remained unchanged .
4 . Resting plasma renin levels showed considerable overlap in the three groups and the mean renin values were not significantly different in the three groups. After captopril a marked rise in plasma renin concentration (>2.5 ng/ml/hr) was observed in seven patients in Group III, including all six patients with renovascular disease. In contrast, none of the patients with essential hypertension and only one patient with accelerated hypertension had such an increase. Determination of the acute renin and blood pressure responses to converting enzyme inhibition with a single oral dose of captopril appears to be useful in identifying patients with renovascular hypertension .     

Pathogen reduction technology (Mirasol®) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS

Background and Objectives  Mirasol^® pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS).
Materials and Methods  Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP.
Results  On day 5, PRT units showed a significantly lower pH (7·087 ± 0·105 vs. 7·288 ± 0·200) accompanied by a higher lactate production (0·104 ± 0014 vs. 0·063 ± 0·017 mmol/10¹²/h) and glucose consumption rate (0·039 ± 0005 vs. 0·028 ± 0·009 mmol/10¹² platelets/h). CD62p expression was higher in treated units (44·5 ± 13·0 vs. 16·5 ± 7·6%).
Conclusion  In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible.