Angiotensin-converting enzyme gene polymorphism,left ventricular remodeling,and exercise capacity in strength-trained athletes

The mechanisms that regulate the development of human physiological cardiac hypertrophy remain poorly understood. The renin-angiotensin system, which is modulated by genetic polymorphism, plays an important role in the regulation of vascular tone and myocardial hypertrophy. Although a few studies have analyzed the association of angiotensin-converting enzyme (ACE) polymorphism and left ventricular (LV) hypertrophy in isotonic exercise-trained subjects who developed eccentric cardiac hypertrophy, there has been no research done in power athletes who developed concentric cardiac hypertrophy. We have hypothesized that ACE genotypic modulation characteristics may affect LV mass in power athletes. This study included 29 elite Caucasian wrestlers (mean age, 22.6 years) and 51 age-matched sedentary subjects. According to the absence or presence of the insertion segment in the polymerase chain reaction (PCR) product, the subjects were classified as homozygous deletion-deletion (DD), insertion-insertion (II), or heterozygous insertion-deletion (ID). The association of LV hypertrophy with ACE gene insertion/deletion (I/D) polymorphism was analyzed. Left ventricular mass and index were determined by echocardiography. Angiotensin-converting enzyme genotyping was performed on peripheral leukocytes using the polymerase chain reaction technique. The study and control group subjects were similar in height and weight. Left ventricular hypertrophy in the athletes was more apparent than in the controls. Angiotensin-converting enzyme genotype II frequency was 17.2% (5) in the athletes, 17.6% (9) in the controls; ID frequency was 51.7% (15) in the athletes, 56.8% (29) in the controls; and the DD frequency was 31% (9) in the athletes and 25.4% (13) in the controls. Left ventricular mass and mass index were found to be higher in genotype DD (126.2 ± 2.9g/m²) than genotype II (85.5 ± 4.0g/m²) or genotype ID (110.1 ± 2.3g/m²) in the athletes (P < 0.001). Furthermore, maximal oxygen consumption in genotype DD was found to be higher than in II and ID. An association was found between ACE gene I/D polymorphism and LV hypertrophy in strength-trained athletes.     

Burn injury sensitizes rat Kupffer cells via mechanisms dependent on gut-derived endotoxin

Background Bacterial translocation occurs after thermal injury in association with intestinal barrier loss. Recently, we found that sensitization of Kupffer cells involved gut-derived endotoxin; therefore, the purpose of this work was to study the mechanisms of sensitization of Kupffer cells in burn injury.Methods Rats received a 30% body surface area full-thickness steam burn 24h before experiments. Serum alanine aminotransferase (ALT) was measured to assess liver damage, and plasma endotoxin in the portal vein were measured. Kupffer cells were isolated 24h after the burn. Intracellular calcium ([Ca²⁺]_i) in Kupffer cells was measured using a microspectrofluorometer with the fluorescent indicator, fura-2, and tumor necrosis factor (TNF)- was measured by enzyme-linked immunosorbent assay (ELISA).Results Lipopolysaccharide (LPS)-induced mortality was increased by burn treatment. This increase was blocked by gadolinium chloride, a Kupffer-cell toxicant. Accordingly, Kupffer cells were involved in this system. The LPS-induced increase of ALT was upregulated by the burn injury. This increase was blocked by pretreatment with antibiotics. Endotoxin levels were increased to almost 300pg/ml (normal, <20pg/ml) in the portal veins of rats that received a burn. This increase was blunted by antibiotics. In Kupffer cells isolated from untreated control rats, [Ca²⁺]_i increased to 82 ± 7nM after the addition of LPS (100ng/ml). Levels were elevated twofold over control levels in the cells from rats with burn (174 ± 15nM). In addition, TNF- production by Kupffer cells isolated from rats with burn was increased fourfold over the based level. Sterilization of the gut with antibiotics completely blocked all effects of the burn on [Ca²⁺]_i and TNF- release.Conclusions Kupffer cells isolated from rats with burn exhibited sensitization to LPS, involving gut-derived endotoxin. It is concluded that burns sensitize Kupffer cells to LPS via mechanisms that are dependent on gut-derived endotoxin.     

Selective A2A adenosine agonist ATL-146e attenuates acute lethal liver injury in mice

Background d-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor- (TNF-) plays a pivotal role. We examined the effects of a highly selective adenosine A_2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure.Methods Mice were given an intraperitoneal dose of GalN (800mg/g body weight)/LPS (100ng/g body weight) with and without ATL-146e (0.01µg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF- levels in the serum were determined.Results The serum liver enzyme (ALT) level in vehicle-treated mice was 20960 ± 2800IU/ml and was reduced by 63% to 7800 ± 1670IU/ml by treatment with 0.01µg/kg per minute ATL146e, P < 0.05. Treatment with ATL-146e significantly reduced serum TNF- and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12h from 65% to 13%.Conclusion The present findings suggest that the highly selective adenosine A_2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF- secretion.     

Evaluation of venous thromboembolism and coagulation-fibrinolysis markers in Japanese patients with inflammatory bowel disease

Background Arterial or venous thromboembolism is rarely encountered clinically as an extradigestive tract complication in inflammatory bowel disease (IBD). However, it is one of the important prognostic factors for IBD patients. The present study was designed to evaluate the relationship between pulmonary embolism (PE) and deep vein thrombosis (DVT) with coagulation-fibrinolysis markers in patients with active IBD.Methods In 47 consecutive cases hospitalized due to active IBD [26 with Crohns disease (CD) and 21 with ulcerative colitis (UC)], we evaluated the disease severity, blood tests, pulmonary ventilation-perfusion scan (V/Q scan), and magnetic resonance venography (MRV) or conventional venography.Results PE was diagnosed by V/Q scan in 5 (2 with CD and 3 with UC; 10.6%). DVT was diagnosed in 5 (2 with CD and 3 with UC; 10.6%). Of the 47 patients, 8 (17.0%) had venous thromboembolism (either PE or DVT), and 2 of them (4.3%) had both conditions. In UC patients, the thrombosis group was in more severe stages based on endoscopic grading than the nonthrombosis group. In all patients, the thrombosis group were older (50.3 ± 14.3 years) than the nonthrombosis group (29.2 ± 11.7 years). Furthermore, the thrombosis group had higher thrombin–antithrombin III complex (13.1 ± 17.7ng/ml) and d-dimer (964 ± 1402ng/ml) values than the nonthrombosis group (5.3 ± 5.5ng/ml, P = 0.0245, and 207 ± 192ng/ml, P = 0.0016, respectively). There were no significant differences in leukocyte and platelet counts, C-reactive protein, and fibrinogen between the two groups.Conclusions A high incidence of venous thromboembolism was suggested in Japanese patients with active IBD. We should be careful with thrombosis in treatment of IBD patients, especially those who are of older age and in more severe stages.     

Metoprolol, a Β-1 selective blocker, can be used safely in coronary artery disease patients with chronic obstructive pulmonary disease

The coexistence of coronary artery disease (CAD) and chronic obstructive pulmonary disease (COPD) is frequent because of common etiological factors. -Blockers remain underutilized in patients with CAD who also have COPD. This study was performed to evaluate the safety of -1 selective blocker agents in CAD patients with COPD. Fifty patients (aged 57.3 ± 10.1 years) were enrolled in this study; 27 patients received metoprolol CR (controlled release), and 23 received metoprolol (conventional). The patients were stratified according to the severity of COPD (21 severe, 21 moderate, and 8 mild), started on metoprolol CR or conventional metoprolol, and titrated up to the maximum tolerated dose. The clinical controls were done during the first week and then at the first and third month. Patients received a mean total daily dose of 92.5 ± 18mg of metoprolol CR or 189 ± 36.7mg of metoprolol. Seven patients could not receive the maximum dose. There was no significant decrease in forced expiratory volume in 1s (FEV₁) in either group (basal vs last FEV₁: 54.5% ± 13.4% vs 54.3% ± 13% in the metoprolol CR group and 49.6% ± 14.5% vs 53.2% ± 12.8% in the metoprolol group). No adverse event was experienced. Metoprolol, a -1 selective blocker, can be used safely at the maximum dose in CAD patients with COPD.     

Acetaldehyde accumulation suppresses Kupffer cell release of TNF-Α and modifies acute hepatic inflammation in rats

Background Alcohol-related diseases have multiple and varied associations with acetaldehyde, a highly toxic product of ethanol oxidation that accumulates in the absence of active aldehyde dehydrogenase (ALDH). This study was designed to clarify the role of acetaldehyde in liver injury, specifically in vivo and in vitro effects on Kupffer cell release of the inflammatory cytokine tumor necrosis factor-alpha (TNF-).Methods Rats pretreated overnight with the ALDH inhibitor disulfiram (or saline control) were ethanol loaded and challenged with lipopolysaccharide (LPS), and their blood and histological parameters were examined 3h later. Similarly, isolated rat Kupffer cells were pretreated with disulfiram or cyanamide incubated in ethanol (1h), then challenged with LPS and evaluated 2h later for TNF- and acetaldehyde levels in the culture medium. TNF- release from Kupffer cells after LPS challenge was also evaluated following incubation in acetaldehyde and acetate for comparison with ethanol loading.Results Higher blood acetaldehyde concentration following disulfiram pretreatment significantly attenuated acute hepatic inflammation in the ethanol-loaded, LPS-challenged rat (18 ± 2.9 vs 30 ± 3.7 polymorphonuclear cells/portal area; P = 0.01). After LPS challenge, ALDH inhibitor pretreatment attenuated Kupffer cell release of TNF- in the presence of disulfiram at 5063 ± 151pg/ml and cyanamide at 4390 ± 934pg/ml, versus no inhibitor, 5869 ± 265pg/ml (P 0.01), but not in the absence of ethanol. Acetaldehyde significantly suppressed Kupffer cell TNF- release (P 0.05), but acetate treatment did not.Conclusions Acetaldehyde accumulation suppresses macrophage function, at least suppressing TNF- release, which plays a role in modifying acute hepatic inflammation in rats.     

Clinical usefulness of carotid arterial wave intensity in assessing left ventricular systolic and early diastolic performance

Wave intensity (WI) is a novel hemodynamic index, which is defined as (dP/dt)·(dU/dt) at any site of the circulation, where dP/dt and dU/dt are the derivatives of blood pressure and velocity with respect to time, respectively. However, the pathophysiological meanings of this index have not been fully elucidated in the clinical setting. Accordingly, we investigated this issue in 64 patients who underwent invasive evaluation of left ventricular (LV) function. WI was obtained at the right carotid artery using a color Doppler system for blood velocity measurement combined with an echo-tracking method for detecting vessel diameter changes. The vessel diameter changes were automatically converted to pressure waveforms by calibrating its peak and minimum values by systolic and diastolic brachial blood pressures. The WI of the patients showed two sharp positive peaks. The first peak was found at the very early phase of LV ejection, while the second peak was observed near end-ejection. The magnitude of the first peak of WI significantly correlated with the maximum rate of LV pressure rise (LV max. dP/dt) (r = 0.74, P 0.001). The amplitude of the second peak of WI significantly correlated with the time constant of LV relaxation (r = –0.77, P 0.001). The amplitude of the second peak was significantly greater in patients with the inertia force of late systolic aortic flow than in those without the inertia force (3080 ± 1741 vs 1890 ± 1291mmHgms^–3, P 0.01). These findings demonstrate that the magnitude of the first peak of WI reflects LV contractile performance, and the amplitude of the second peak of WI is determined by LV behavior during the period from late systole to isovolumic relaxation. WI is a noninvasively obtained, clinically useful parameter for the evaluation of LV systolic and early diastolic performance at the same time.     

CHF-1024, A DA2/α2 Agonist, Blunts Norepinephrine Excretion and Cardiac Fibrosis in Pressure Overload

We compared the effects of an ACE inhibitor, captopril, with those of a DA₂-dopaminergic/₂-adrenergic receptor agonist (CHF-1024) on neuroendocrine activation and cardiac fibrosis in a model of pressure-overload hypertrophy. Interrenal aortic stenosis was performed in 89 rats, treated with CHF-1024 (0.33, 2 or 6 mg kg^–1 day^–1), or captopril (1 g/L). Hemodynamic variables were recorded. Cardiac and renal weights, plasma aldosterone, renin activity and urinary catecholamine excretion were measured, as well as cardiac collagen. Blood pressure was lower in stenotic animals treated with CHF-1024 compared to vehicle (161 ± 10 vs 219 ± 10 mmHg, p < 0.01), but LV weight was similar. CHF-1024 elicited a marked dose-dependent attenuation of urinary norepinephrine excretion (1.80 ± 0.18 in controls compared to 0.40 ± 0.14 g/24 h at the highest dose, p < 0.01) and of LV perivascular fibrosis. Captopril provoked a marked hypotension, reduced cardiac and body weights, plasma aldosterone concentration, dopamine excretion and perivascular collagen. The DA₂/₂ agonist CHF-1024 effectively blunts adrenergic drive and cardiac fibrosis in a rat model of pressure overload.     

Clinical application of wave intensity for the treatment of essential hypertension

Wave intensity analysis is a method of studying intravascular flow wave propagation, calculated as the product of the rate of change in pressure (dP/t) and the rate of change in velocity (dU/dt). The typical pattern of wave intensity seen during the cardiac cycle has two dominant peaks. The larger first peak (FP) occurs during early systole when a forward traveling compression wave is generated by the left ventricle. The second smaller peak (SP) follows a period of relatively little net wave production during mid-systole. Wave reflection is seen as a small backward-traveling compression wave occurring just after the first peak of wave intensity (NP). In this study, we investigated the usefulness of parameters from the wave intensity for estimating the efficacy of the -1 blocker, doxazosin, to reduce blood pressure, by the reduction of peripheral vascular resistance. We examined 20 patients with essential hypertension. Patients were included if their diastolic blood pressure was 95mmHg on at least three separate visits to the clinic. The study consisted of a 2-week baseline phase followed by a 2–4-week dose-adjusted phase with doxazosin. Treatment began with 1mg/day doxazosin, and the dose was doubled fortnightly until the diastolic blood pressure was 90mmHg. Blood–pressure measurements and side effects were recorded at intervals of 2 weeks. Before and after 4 weeks of stable treatment with doxazosin, a comprehensive clinical evaluation was given. Doxazosin reduced systolic and diastolic blood pressure. Both FP and SP increased and NP decreased. MBP (change in mean blood pressure) correlated well with NP before and after the antihypertensive therapy. The efficacy of doxazosin was confirmed by the decreased reflection wave of aortic flow from wave intensity analysis. Thus, patients with a significant reflection wave may be good candidates for antihypertensive treatment by a vasodilator, such as doxazosin.     

Efficacy of mizoribine treatment in patients with SjÖgren’s syndrome: an open pilot trial

The aim of this study was to evaluate the efficacy and safety of mizoribine in patients with SjÖgrens syndrome. Forty patients with sicca syndrome, whose conditions were definitely diagnosed as SjÖgrens syndrome, were given mizoribine orally at a dosage of 150mg/day for 12 months. The percentage change in salivary secretion after 3, 6, and 12 months of the therapy increased to +112.2% (P 0.001), +119.9% (P 0.01), and +147.3% (P 0.001), respectively, compared with the baseline. Serum IgG levels decreased significantly throughout the study, and the level was 1969.4 ± 620.0mg/dl after treatment for 12 months compared with the pretreatment value of 2094.3 ± 746.6mg/dl (P 0.05). The patients assessment of clinical signs and symptoms on a 10-cm visual analog scale improved significantly from 7.2 ± 2.3cm at the start of the treatment to 5.0 ± 1.9cm after 12 months (P 0.001). There was a similar improvement in the physicians assessment using the 10-cm visual analog scale: 7.1 ± 1.6cm at the start of the treatment and 5.2 ± 1.9cm after 12 months (P 0.001). With regard to safety, no serious adverse reactions were observed. Although a controlled study would be required to clarify the efficacy of mizoribine, these preliminary observations indicate its efficacy for ameliorating glandular symptoms through improvements in immune abnormalities in patients with SjÖgrens syndrome.     

Effect of gold therapy on CD5+ B-cells and TCR γδ + T-cells in patients with rheumatoid arthritis

Summary Circulating CD5⁺ B-cell levels in 15 patients with rheumatoid arthritis (RA) not receiving remittive therapy was significantly increased when compared to 17 normal controls (mean±SE: RA, 19.7±2.85%; controls, 11.6±1.67%; P<0.02). In contrast, 24 patients with RA receiving gold sodium thiomalate therapy (GST) had similar CD5⁺ B-cell levels (11.88±1.65) when compared to controls and significantly reduced levels when compared to the RA group not receiving remittive agents (P<0.01). Furthermore, TCR ⁺ T-cell levels were also assessed in these patients groups. These values were not significantly different between any of the groups (controls, 4.46±1.36%; GST, 6.88±1.73%; RA, 2.73±0.55%), although 42% of the GST treated group had ⁺ T-cell levels higher than the entire untreated RA group. No correlation was observed between the levels of TCR ⁺ T-cells and CD5⁺ B-cells in any of these groups. These results suggested that therapy does influence the level of CD5⁺ B-cells and ⁺ T-cells in these patients.     

Clinical features and management of congenital long QT syndrome: a report on 54 patients from a national registry

To assess the clinical features and the management of congenital long QT syndrome (LQTS) in China, we collected the clinical data of 54 LQTS patients (14 males and 40 females) from our newly established national registry. All patients were symptomatic, with syncope being the most common symptom. The average age when the first symptoms occurred was 17.9 ± 15.6 (range, 0.5–62) years; 55.6% of them had the first symptoms before the age of 20. The most common triggers of the symptoms were physical exercise or emotional stress. The average corrected QT interval was 0.55 ± 0.08s. Using ECG criteria, there were 14 (25.9%) LQT1 patients, 28 (51.9%) LQT2, and 2 (3.7%) LQT3. Thirty (55.6%) patients were treated with -blockers at the time of enrollment, with propranolol being the most commonly used drug, with an average daily dose of 57.5 ± 39.1mg. Four patients underwent left cardiac sympathectomy. After an average follow-up of 24.9 ± 13.2 months, 3.1% (1/32) of patients with antiadrenergic therapy and 9.1% (2/22) without antiadrengergic therapy died of sudden cardiac death (P 0.05). We concluded that LQT2 might be the most common subtype in these patients. Antiadrenergic treatment was underused, raising the urgent need for educating both physicians and patients on the nature of the disease and its optimal antiadrenergic therapy.     

Assessment of aortic stiffness and ventricular diastolic functions in patients with Behçet’s disease

Background: Behçets disease is a systemic vasculitis in which studies have given conflicting results about ventricular diastolic functions. However, tissue Doppler echocardiography has never been used in any of these studies. Aortic stiffness, a cardiovascular risk factor, may also precede ventricular dysfunction. Objectives: The aim of this study was to assess aortic stiffness and biventricular diastolic functions in patients with Behçets disease. Methods: A total of 26 patients with Behçets disease (mean age; 33±10 years) and 20 age- and sex-matched controls (mean age; 33±7 years) were included. Aortic stiffness was evaluated by aortic strain and distensibility. Ventricular diastolic functions were evaluated with both conventional and tissue Doppler echocardiography. Mitral E and A wave, E/A ratio of E wave, deceleration time, and isovolumic relaxation time were calculated. Results: There was no significant difference in diastolic Doppler parameters between patients and controls. Similarly, there was no significant difference in mitral annular E and A velocities between these two groups. Aortic strain in patients with Behçets disease was found to be significantly less than in the controls (8.3±4.9% and 15.7±2.7% respectively, p<0.001). Aortic distensibility was also significantly low in patients with Behçets disease when compared to controls (0.45±0.28 and 0.78±0.13 respectively, p<0.001). Beta index values were significantly high in Behçets patients (7.23±5.93 and 2.69±0.55 respectively, p<0.001). Conclusion: No significant diastolic dysfunction was found in left and right ventricles in patients with Behçets disease by using both conventional and tissue Doppler echocardiography. However, an increase in aortic stiffness was found, suggesting an inflammatory involvement of proximal aorta.     

Cardiac involvement in Wilson disease

Background: Wilson disease is an inherited autosomal recessive disorder of copper metabolism resulting in pathological accumulation of copper in the liver, brain and other tissues. One of the reported manifestations is cardiac involvement. Methods: We studied 42 patients with Wilson disease (19 men and 23 women, mean age 34±10y) and 42 age- and sex-matched healthy volunteers. All subjects underwent complete echocardiographic examination; 24h ECG Holter monitoring was performed in 23 Wilson disease patients. Results: In comparison to healthy subjects, patients with Wilson disease had increased thickness of the interventricular septum (9.5±1.4 vs 8.6±1.1mm, p<0.01) and left ventriclular (LV) posterior wall (9.1±1.3 vs 8.2±1.0mm, p<0.01). While the two groups did not differ in LV mass index, relative LV wall thickness was significantly increased in Wilson disease patients compared to control subjects (0.39±0.06 vs 0.34±0.04 p<0.001). Concentric LV remodelling was present in 9 patients (21%) and LV hypertrophy in one patient. Systolic LV function showed a nonsignificant trend towards lower values in Wilson disease patients (EF 62±5% vs 64±5%, p=0.06). Diastolic filling and the frequency of valvular abnormalities were comparable in both groups. The established echocardiographic abnormalities did not correlate with the type of Wilson disease manifestation, the presence of the His1069Gln mutation, laboratory parameters or the duration and type of therapy. Twenty-four-hour ECG Holter monitoring detected ECG abnormalities in 10 patients (42%), the most frequent findings being runs of supraventricular tachycardias and frequent supraventricular ectopic beats. Conclusions: Cardiac involvement in Wilson disease patients was mild, characterized by LV parietal thickening with an increased prevalence of concentric LV remodelling and a relatively high frequency of benign supraventricular tachycardias and extrasystolic beats.     

Alterations of epithelial permeability by Helicobacter and IL-1beta in vitro: protective effect of rebamipide

Infection with Helicobacter increases the transcellular passage of macromolecules across the epithelium, and this effect can be prevented by a gastroprotective agent rebamipide. The aim was to gain insight into the mechanisms involved. The HT29-19A intestinal epithelial cells grown on microporous filters as monolayers were incubated in the presence or absence of rebamipide (1 or 2 mM) with: (1) suspension of a wild H. pylori strain, (2) IL-1 (0.5 ng/ml) + IFN- (2 units/ml). After incubation, the monolayers were submitted to evaluation of apoptosis by using the apoptotic cell death detection ELISA kit and to assessment of epithelial permeability in Ussing chamber where the ionic conductance (G), fluxes of mannitol (J_Man) and of horseradish peroxidase in both intact (J_HRPi)- and degraded (J_D) form, were measured. H. pylori increased the intact HRP fluxes across the barrier (J_HRPi = 17 ± 20 vs 97 ± 70 ng/hr/cm², P < 0.007), an effect prevented by rebamipide (J_HRPi = 33 ± 34 ng/hr/cm², P < 0.006). IL-1 increased the ionic conductance (G = 5.5 ± 1.0 and 21.0 ± 7.0 mS/cm², P < 0.006), the intact HRP fluxes (J_HRPi = 18 ± 15 and 476 ± 344 ng/hr/cm², P < 0.006), and the apoptotic index of the cells (AI = 1 ± 0 vs 3.7 ± 0.8), all effects prevented by rebamipide (G = 12 ± 4.9 mS/cm², J_HRPi = 79 ± 38, AI = 1.6 ± 0.6, P < 0.03 as compared to IL--treated cells). In basal conditions, rebamipide increased the integrity of the barrier (G = 7.5 ± 2.3 vs 6.0 ± 1.8 mS/cm² for controls, P < 0.007). In conclusion, H. pylori as well as IL-1, may alter epithelial permeability and rebamipide may exert its protective effect on gastric mucosa by reinforcing the epithelial barrier in normal conditions and by counteracting the deleterious effect of Helicobacter pylori and IL-1 on macromolecular permeability.     

Lymphocyte apoptosis and macrophage function: correlation with disease activity in systemic lupus erythematosus

Increased lymphocyte apoptosis and defects in macrophage removal of apoptotic cells have been suggested to contribute to the development of systemic lupus erythematosus (SLE). The aim of this study was to investigate the relationship between peripheral lymphocyte apoptosis, macrophage function as determined by the serum levels of neopterin and interferon- (IFN-), and SLE disease activity. Peripheral apoptotic lymphocytes (AL) were detected by annexin V-fluorescein isothiocyanate (FITC) staining and flow cytometry. Serum levels of neopterin and IFN- were measured by enzyme-linked immunosorbent assay (ELISA). SLE disease activity was determined using the systemic lupus activity measure (SLAM) and the serum titer of anti-dsDNA antibodies. The percentage of AL in the peripheral blood of active SLE patients was significantly higher (13.07±7.39%, n=30) than that of the inactive SLE patients (4.08±3.55%, n=8, p<0.01) and normal controls (5.13±3.37%, n=11, p<0.01). Serum levels of neopterin in active SLE patients were significantly higher (1.39±1.10 g/dl, n=22) than in controls (0.26±0.19 g/dl, n=20, p<0.01). Serum levels of IFN- in active SLE patients were elevated (58.97±34.52 ng/l, n=15) when compared with controls (28.06±2.35 ng/l, n=16, p<0.05). The percentage of AL correlated significantly with serum levels of neopterin (r=0.446, p<0.05, n=22) and SLAM score (r=0.533, p<0.001, n=38), but not with the serum levels of IFN-. The SLAM score also correlated with the serum levels of neopterin (r=0.485, p<0.05, n=22), but not with those of IFN-. Our study supported the hypothesis that increased lymphocyte apoptosis has a pathogenic role in SLE. The increased levels of serum neopterin may suggest an attempt of the patients macrophage system to remove the apoptotic cell excess. Since serum levels of neopterin correlated with the overall lupus disease activity, they may be regarded as an index of SLE disease activity.     

Lavage Administration of Dilute Surfactant in a Piglet Model of Meconium Aspiration

Maldistribution of exogenous surfactant may preclude any clinical response in acute lung injury associated with surfactant dysfunction. Our previous studies have shown the effectiveness of surfactant lavage after homogenous lung injury. The present study utilizes a histologically confirmed non-homogeneous lung injury model induced by saline lung-lavage followed by meconium injected into a mainstem bronchus. Piglets were then treated with Infasurf® or Exosurf® by lavage (I-LAVAGE, n=7; E-LAVAGE, n=5) or bolus (I-BOLUS, n=8; E-BOLUS, n=5), or went untreated (CONTROL, n=4). Lavage administration utilized a dilute surfactant (35 ml/kg; 4 mg phospholipid/ml) instilled into the lung, followed by gravity drainage. The retained doses of the respective surfactant in the lavage and bolus groups were similar. Results showed that the surfactant distribution was more uniform in the lavage groups compared to the bolus groups. Significant and consistent increases in PaO₂ were observed in the lavage groups compared to the bolus groups and the controls. PaO₂ (mmHg) at 240 min posttreatment: I-LAVAGE=297±54, E-LAVAGE= 280±57; I-BOLUS=139±31; E-BOLUS=152±29; C=119±73 (mean± SEM). Other improved pulmonary function parameters favored lavage administration. We conclude that better surfactant distribution achieved by lavage administration can be more effective than bolus administration in this type of non-homogeneous lung injury.     

Synovial nitric oxide concentrations are increased and correlated with serum levels in patients with active Behçet’s disease: a pilot study

Behçets disease (BD) is a relapsing immunoinflammatory vasculitis of unknown etiology characterized by endothelial dysfunction. Articular symptoms and signs are present in about 75% of cases and characterized by seronegative arthritis and nonspecific synovitis. We demonstrated that both serum and erythrocyte nitric oxide (NO^·) levels, the most abundant free radical in the body, were elevated in BD and associated with disease activity. This study further investigated NO^· levels in the synovial fluid and serum from patients with active and inactive BD. A total of 23 BD patients with articular involvement (14 men and 9 women) satisfying International Study Group criteria and 15 age- and sex-matched healthy control subjects (9 men and 6 women) undergoing elective arthroscopy were included in this case-control investigation. The synovial fluid and serum were obtained from BD patients and controls. Clinical and laboratory findings including neutrophil count and erythrocyte sedimentation rate (ESR) were used to classify BD patients as active (n=11) or inactive (n=12). Synovial as well as serum NO^· levels were compared between the groups and correlation analysis was performed. Acute phase reactant levels were significantly higher (for each, p<0.01) in BD patients than control subjects in the active period. The mean synovial NO^· level in active Behçets patients (mean±SD 76.61±11.95 mol/l) was significantly higher than in inactive patients (46.16±8.89 mol/l, p<0.001) and healthy control subjects (39.60±8.03 mol/l, p<0.001). The difference between inactive patients and controls was not significant (p>0.05). Active BD patients had significantly higher serum NO^· levels (38.84±9.15 mol/l) than inactive patients (30.91±5.88 mol/l, p=0.018) and control subjects (28.86±5.91 mol/l, p=0.002). In addition, synovial NO^· levels were positively correlated with serum levels (r²=0.621, p<0.001). Increased synovial NO^· levels in active BD patients probably reflect a nonspecific inflammatory process of the synovium and, therefore, arthralgia and arthritis as a common finding of BD.     

Effect of atrial pressure increase on sinus node automaticity

There is evidence suggesting that atrial electrophysiological properties may be changed by an acute increase in atrial pressure. The aim of the present study was to investigate the effect of alteration, in atrial pressure on sinus node recovery time. Twelve patients (8 men and 4 women, mean age 61.3 ± 14.1 years) were included in this study. None of the patients had organic heart disease. Sinus node recovery time (SNRT) was measured following atrial pacing and atrioventricular (AV) pacing at sequential cycle lengths of 600, 545, 500, 461, 428, and 400ms with two different AV intervals (150, 0ms). Peak and minimal atrial pressure increased significantly from 8.5 ± 2.8 to 20.1 ± 2.9mmHg (11.56 ± 3.8 to 27.3 ± 3.9cmH₂O) (P = 0.001) and from 2.06 ± 1.69 to 5.33 ± 2.9mmHg (2.8 ± 2.29 to 7.2 ± 3.9cmH₂O), respectively (P = 0.002) during AV interval modification. Sinus node recovery time did not change despite the increase in atrial pressure. Autonomic blockade had no effect on SNRT. This study demonstrates that atrial pressure increase does not significantly affect sinus node automaticity expressed by SNRT.     

Different effects of glucose and glyburide on insulin secretion in rat pancreatic islets pre-exposed to interleukin-1β. Possible involvement of K+ and Ca2+ channels

Summary In vitro islet exposure to interleukin 1 inhibits the beta-cell response to glucose. We have studied whether a similar inhibition also occurs in response to the sulphonylurea glyburide. Rat pancreatic islets were cultured for 24 h in the presence or absence of 50 U/ml interleukin 1 and then stimulated with either glucose or glyburide for 1 h at 37 °C. In control islets basal insulin secretion was 117±32 pg · islet^–1 · h^–1 (mean ± SEM, n=7) and greatly increased in response to 16.7 mmol/l glucose (2140±293) or 10 mol/l glyburide (1464±234). When islets were pre-exposed to interleukin 1, insulin release was significantly reduced in response to glucose (323±80, p<0.001) but not in response to glyburide (1316±185). Since both glucose and glyburide influence beta-cell K⁺ and Ca²⁺ efflux, to further investigate this different response in islets exposed to interleukin 1 we measured both Rb⁺ efflux (as index of the ATP-sensitive K⁺ channel activity) and Ca²⁺ uptake. In control islets, the increased insulin secretion in response to 16.7 mmol/l glucose or 10 mol/l glyburide was associated with a reduction of ⁸⁶Rb efflux (decrement of –50±1.2 % and –49±2.3 %, respectively, mean ± SEM, n=5). In contrast, in interleukin 1pre-exposed islets both glucose and glyburide stimulation only slightly modified ⁸⁶Rb efflux (decrement of –19±1.9% and –5.3±3.1 %, respectively, n=5, p<0.001). ⁴⁵Ca²⁺ uptake in control islets was 2.6±0.4 pmol · islet^–1 · 20 min^–1 under basal conditions (at 2.8 mmol/l glucose), and increased to 16.8±3.2 and 10.7±2.1 pmol · islet^–1 · 20 min^–1 in islets stimulated with 16.7 mmol/l glucose or 10 mol/l glyburide, respectively (mean ± SEM, n=6). ⁴⁵Ca²⁺ uptake in interleukin 1 treated islets was higher than in control islets under basal conditions (4.6±0.6 pmol · islet^–1 · 20 min^–1 at 2.8 mmol/l glucose, p<0.05), but was significantly reduced in response to glucose 16.7 mmol/l (7.1±1.1, p<0.01 with respect to control islets). In contrast to glucose, 10 mol/l glyburide was able to stimulate calcium uptake in interleukin 1 treated islets in a similar way to control islets (12.8±2.5). The present data demonstrate that rat pancreatic islets treated with interleukin 1 for 24 h lose their responsivity to glucose, but not to glyburide. The difference between the two secretagogues is associated with the persistent ability of glyburide to influence Ca²⁺ uptake even in islets with impaired K⁺-channel function.