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.     

Characteristics of ischaemic human myocardium: a transoesophageal echocardiographic and voltammetric microelectrode study

Delayed local myocardial power development (primary asynchrony) has been suggested as a marker of ischaemic ventricular dysfunction in humans. However, to prove this, microcirculatory perfusion, microcirculatory oxygenation, and intrinsic mechanical function of the same asynchronous myocardial segment should be studied simultaneously before and after revascularisation. We performed a prospective intraoperative study of 15 patients (age 67 [SD 5] years) at baseline and 30min after left anterior descending artery grafting. Local tissue perfusion and oxygenation of the anterior left ventricular wall were quantified with a voltammetric microelectrode technique. Transesophageal M-mode echocardiograms and simultaneous high-fidelity left ventricular pressure were measured. Eight patients showed primary asynchrony and 7 did not. Patients with primary asynchrony had local mechanical depression with lower resting values of myocardial work and peak power which increased with surgery. In this group, resting perfusion consistently increased with surgery (32.1 [13] to 54 [31]mlmin^–1 100g^–1, P < 0.05). In the remaining patients, local work and power were normal, and resting perfusion was consistently higher (90 [9]Mlmin^–1 100g^–1, P < 0.05 vs primary asynchrony), and fell with surgery. Local tissue oxygen tension was similar in both groups (38 vs 44mmHg) and did not change with surgery. In patients with chronic coronary artery disease, microcirculatory perfusion, but not pO₂, is reduced in regions showing primary asynchrony and impaired mechanical function. Abnormalities in both mechanical function and perfusion normalise within 30min of revascularisation. These data provide further evidence that primary asynchrony is not only a marker of chronic ischemic ventricular dysfunction, but is associated with a modified contraction pattern in which normal oxygen tension coexists with reduced perfusion.     

Ultrasonic tissue characterization in patients with dilated cardiomyopathy: comparison with findings from right ventricular endomyocardial biopsy

Aim: The clinical usefulness of integrated backscatter (IB) imaging was compared with right ventricular endomyocardial biopsy for assessing myocardial damage in patients with dilated cardiomyopathy (DCM). Methods: We examined 15 patients with DCM and 20 healthy controls. In addition to the conventional M-mode echocardiographic parameters, we determined the cyclic variation in IB values (CV-IB) obtained from parasternal short axis views of the left ventricle just under the transducer for both the interventricular septum (IVS) and the left ventricular posterior wall (PW). The per cent fibrosis area (%) and the transverse diameter of myocytes (m) were measured in right ventricular endomyocardial biopsy specimens by computer image analysis. To analyze the relationship between pathological findings and CV-IB, we divided patients into four subgroups on the basis of the pathological characteristics of endomyocardial biopsy specimens as follows: degeneration dominant group (n=5), fibrosis dominant group (n=5), dilated phase hypertrophic cardiomyopathy (n=2), and mixed type (n=3). Results: CV-IB in the IVS and the PW was lower in patients with DCM (8.8 ± 2.9, 8.3 ± 2.7dB, respectively) than in normal subjects (14.4 ± 2.9, 13.6 ± 2.6dB, respectively). Biopsy findings showed a mean per cent fibrosis area of 24.0 ± 12.3%, and a mean myocyte diameter of 14.3 ± 2.9m in patients with DCM. CV-IB was correlated with both of these findings: per cent fibrosis area (r=–0.56 in IVS, r=–0.56 in PW) and myocyte diameter (r=0.67 in IVS, r=0.71 in PW). CV-IB was decreased in all DCM subgroups compared with normal subjects, but there was no significant difference between subgroups. Conclusions: CV-IB was correlated with both the extent of fibrosis in myocardial tissue and the myocyte diameter. These findings suggest that ultrasonic tissue characterization is a good indicator of the severity of fibrosis and myocyte atrophy in patients with DCM.     

Pulsed Doppler tissue imaging can help to identify patients with right ventricular infarction

This study was planned to assess whether tissue Doppler imaging is a useful method for the detection of the right ventricular myocardial infarction. Forty-eight patients with acute inferior myocardial infarction and 24 age- and sex-matched healthy controls were included in this study. Twenty-four patients had electrocardiographic signs of inferior myocardial infarction without right ventricular infarction (group I), and the other 24 patients had electrocardiographic signs of inferior myocardial infarction with right ventricular infarction (group II). From the echocardiographic apical four-chamber view, peak systolic, early diastolic, and late diastolic velocities of the tricuspid annulus at the right ventricular free wall were recorded with the use of pulsed-wave Doppler tissue imaging. The tricuspid annular peak tissue Doppler imaging systolic velocity was significantly lower in group I (14.03 ± 2.57cm/s, P 0.005) and in group II (8.50 ± 0.84cm/s, P 0.005) than in controls (16.63 ± 2.31cm/s). The tricuspid annular peak systolic (8.50 ± 0.84cm/s vs 16.63 ± 2.31cm/s) and peak early diastolic (10.99 ± 3.28cm/s vs 19.39 ± 4.3cm/s) velocities were significantly lower in group II than in group I, as compared with controls (P 0.001). Peak early diastolic velocity of tricuspid annulus (10.99 ± 3.28cm/s vs 19.39 ± 4.3cm/s) was significantly lower in group I than in controls (P 0.001); however, late diastolic velocity was significantly lower in group II (15.98 ± 5.08cm/s, P 0.05) than in group I (18.21 ± 2.63cm/s, P 0.05) and in controls (19.02 ± 5.29cm/s). The results of this study indicate that tricuspid annular peak systolic and early diastolic velocities are reduced in patients with right ventricular infarction. The velocity of the tricuspid annulus by tissue Doppler imaging is simple and can be used to distinguish whether patients with inferior myocardial infarction have right ventricular infarction.This study was presented at the XXIII. Congress of the European Society of Cardiology, Stockholm, Sweden, 1–5 September 2001     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

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.     

Microemboli at the Different Stages of Percutaneous Transluminal Carotid Angioplasty and Stenting in Patients with Post–carotid Endarterectomy Restenosis Compared to Primary Stenosis

Microembolization to cerebral arteries during percutaneous transluminal carotid angioplasty (PTCA) and stenting is well described, as well as different mural pathology in primary versus post–carotid endarterectomy (CEA) restenosis lesions. The purpose of this study is to investigate possible different patterns of embolization in regards to number and distribution of microembolic signals (high-intensity transient signals (HITS)) in patients with primary carotid stenosis and restenosis after CEA. We used transcranial Doppler (TCD) to monitor the ipsilateral middle cerebral artery (MCA) of 13 patients (13 procedures) with restenosis after CEA and six patients (seven procedures) with primary stenosis of the internal carotid artery (ICA) during PTCA and stenting. All the procedures were performed without protection devices. The total number of HITS recorded in all patients was 2692, including 1563 microemboli in patients with restenosis and 1129 in patients with primary stenosis. The mean number of microemboli per procedure was 120.2±65 and 161.3±70 (p=0.05) respectively. The average number of microembolic signals during the various stages of PTCA and stenting in the two groups was as follows: 1. Crossing the stenotic region with the guidewire and positioning the balloon inside the stenosis 33±6.9 and 73.4±9.4 (restenosis patients versus primary–stenosis patients, respectively, (p=0.011); 2. angioplasty, balloon inflation and deflation, 19.l±6.9 and 38.9±9.4 (restenosis versus primary lesions, respectively, p=0.09); 3. stent deployment, 39.5±6.9 and 27.3±9.4 (restenosis versus primary lesions, respectively, p=0.3); and 4. Post-stent dilatation, 29±6.9 and 21.7±9.4 (restenosis versus primary lesions, respectively, p=0.53). Microembolic signals are detected through all stages of PTCA and stenting in patients with primary or post-CEA-restenosis lesions. The number of HITS was significantly higher in patients with primary stenosis than with restenosis of ICA in stages prior to stenting. This probably stems from the difference in pathomorphologic structure between the lesions. There was no significant difference between groups during stent deployment and post-stent dilatation. The clinical significance of the phenomenon of microembolism during carotid stenting is still not clear, but our results suggest the importance of using protection devices to reduce the incidence of these events in both primary and post-CEA lesions.     

The Role of Pleural Fluid-Serum Gradient of Tumor Necrosis Factor-α Concentration in Discrimination Between Complicated and Uncomplicated Parapneumonic Effusion

In a previous preliminary study an excess of tumor necrosis factor- (TNF) was found in pleural fluid of patients with complicated parapneumonic effusion (CPPE), and its levels in pleural fluid of these patients were shown to be significantly higher than those in patients with uncomplicated parapneumonic effusion (UCPPE). This larger population study was undertaken to investigate, for the first time, the role of pleural fluid-serum gradient of TNF (TNFgradient) in discrimination between UCPPE and CPPE. Using a commercially available high sensitivity ELISA kit, levels of TNF were measured in serum and pleural fluid of 51 patients with UCPPE and 30 patients with nonempyemic CPPE. The mean±SEM values of serum TNF (TNFserum), pleural fluid TNF (TNFpf), and TNFgradient in the UCPPE group were 6.65±0.48 pg/mL, 10.85±0.74 pg/mL, and 4.2±0.38 pg/mL respectively, and in the CPPE group they were 7.59±0.87 pg/mL, 54.02±5.43 pg/mL, and 46.43±5.34 pg/mL, respectively. While no significant difference was found between the two groups regarding levels of TNFserum (p=0.31), a highly significant difference between these two groups was found regarding levels of TNFpf and TNFgradient (p < 0.0001 for both variables). A significant correlation was found between levels of TNFserum and levels of TNFpf in the UCPPE group (r=0.89, p < 0.0001), but not in the CPPE group (r=0.18, p < 0.33). TNFgradient at an optimal cut-off level of 9.0 pg/mL was found to be a good marker for discrimination between UCPPE and CPPE (sensitivity, 96.7%, specificity, 98%, accuracy, 97.5%, and p < 0.0001). In conclusion, levels of TNFpf but not TNFserum are significantly higher in CPPEs than those in UCPPEs where TNFgradient at an optimal cut-off level of 9.0 pg/mL is a good marker for discrimination between UCPPE and CPPE.     

Effect of Coronary Thrombolysis on the Plasma Concentration of Osteonectin (SPARC, BM40) in Patients with Acute Myocardial Infarction

Osteonectin is a phosphoglycoprotein exclusively located in bone and platelet -granules. Human platelet-derived osteonectin is released into plasma after thrombin-induced activation. Recognizing the unique distribution of the osteonectin pool, we first sought to investigate whether osteonectin could serve as a sensitive marker of platelet activity, and identify patients with acute myocardial infarction (AMI). The second objective was to define the effects of thrombolytic therapy in these patients on the plasma concentrations of osteonectin at prespecified time points following attempted reperfusion. Osteonectin levels by ELISA were determined in AMI patients before thrombolysis and at 3, 6, 12, and 24 hours thereafter and compared with 12 healthy controls. At baseline, soluble osteonectin plasma levels were similar between controls (447.7±20.6ng/ml) and AMI patients (425.7±43.3ng/mL; p=NS). A significant increase of the soluble osteonectin was observed at 3 hours after thrombolysis (519.4±26.9ng/mL; p=0.03), and was followed by a decrease to baseline levels at 6 hours after attempted reperfusion. Contrary to expectations, the plasma osteonectin level in our pilot study was not a sensitive marker distinguishing patients with AMI. The early peak of soluble osteonectin at 3 hours after thrombolytic therapy is most likely not related to coronary thrombolysis per se but rather to the phasic changes of platelet activity during myocardial ischemia-reperfusion. The unquestionable platelet origin of this protein and the lack of elevated plasma levels of this -granule constituent, challenge the postulate of uniform platelet activation in AMI patients.     

Anatomical structure of the isthmus between the inferior vena cava and tricuspid annulus investigated with a three-dimensional electroanatomical mapping system

We studied the anatomical structure of the isthmus between the inferior vena cava and tricuspid annulus in humans with a three-dimensional electroanatomical mapping system (CARTO, Biosense, Haifa, Israel). Fifteen patients with atrial flutter were studied. Thirteen patients had underlying heart disease. We investigated the anatomical structure of the isthmus with cross sections made from the three-dimensional right atrial map. The cross sections of the isthmus showed a concave shape in 7 patients (47%: group A), convex shape in 2 (13%: group B), and complex shape in 6 (40%: group C). The distance between the IVC and TA was 34 ± 17mm (group A), 25 ± 2mm (group B), 34 ± 16mm (group C), and 32 ± 15mm (Total), respectively. The distance between the top and bottom was 6 ± 5mm (group A), 3mm (group B), 6 ± 3mm (group C), and 6 ± 4mm (total), respectively. Seven of 15 patients exhibited an uneven surface of more than 5mm in depth and 4 of 15 patients had one of more than 10mm. The anatomical structure of the isthmus varies. To carry out precise catheter ablation, these variations should be taken into consideration to ensure an effective procedure.     

Economic Evaluation of a Community-Based Pulmonary Rehabilitation Program for Chronic Obstructive Pulmonary Disease

Pulmonary rehabilitation has been demonstrated to be efficacious in chronic obstructive pulmonary disease (COPD), however, its cost-effectiveness is largely unknown. The present study determined the cost-effectiveness of a community-based pulmonary rehabilitation program for COPD patients with mild, moderate, and severe disease. We compared the direct costs (in Canadian dollars) and disease-specific quality of life (measured by the St. Georges Respiratory Questionnaire, SGRQ) of patients with COPD (N=210) who enrolled in the rehabilitation program in Edmonton, Canada one year before and after completion of the program. To determine temporal trends in health service utilization between 2000 and 2002 we used similar data from 592 COPD patients from the same region who did not participate in the rehabilitation program. We found that the health status of patients enrolled in the program improved significantly following pulmonary rehabilitation, irrespective of the severity of disease (total SGRQ score improved by 4.85%, p=0.001). The total direct cost per 100 person-years of follow-up before the program was $122,071 (SE=29,566); after the program it was $87,704 (SE=26,146). The average reduction of total costs before and after the program was $34,367 per 100 person-years or $344 per person per year (p=0.02). Over one-year, pulmonary rehabilitation was associated with decreased health service utilization, reduced direct costs and improved health status of COPD patients. This suggests that pulmonary rehabilitation is cost-effective for patients with relatively high utilization of emergency and hospital-based services.     

Sampling Airway Surface Liquid: Non-Volatilesin the Exhaled Breath Condensate

Exhaled breath condensate (EBC) samples contain molecules that have no appreciable vapor pressure; such molecules likely derive from droplets of airway fluid. We analyzed EBC gathered from a total of 62 healthy volunteers in order to quantify the volume of airway liquid that was the source of the non-volatiles; saliva was analyzed as a reference secretion. EBC urea averaged 0.52±0.12 mol/L (n=18), an 8,600-fold dilution from predicted blood urea nitrogen levels. Protein averaged 2.3±0.3 g/ml (n=31), three orders of magnitude less than in saliva (1.4±0.1 mg/ml, n=15). EBC ammonia was 6.6±0.6 mmol/L (1/15 that of saliva) and EBC ammonium ion was 0.90±0.19 mol/L, concentrations that are incompatible with an 8,600-fold dilution from a biological source. Thus, urea-derived dilution factors may be used to interpret EBC non-volatile molecules, but not EBC volatiles.     

Effects of Piclamilast,a Selective Phosphodiesterase-4 Inhibitor,on Oxidative Burst of Sputum Cells From Mild Asthmatics and Stable COPD Patients

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 M n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC₅₀ approximately 100 nM, max. inhibition: 97.5±5% at 100 M; COPD: EC₅₀ approximately 1 M, max. inhibition: 70.6±4.5% at 100 M), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27±15%; COPD: 6±2%, both p < 0.05 vs. piclamilast) and prednisolone (asthma: 16±6%; COPD: 7.8±6.2%, both p < 0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.     

Early effects of lafutidine or rabeprazole on intragastric acidity: which drug is more suitable for on-demand use?

Background Medication for the relief of heartburn should have the rapid onset of action required for on-demand use. We studied the inhibition of gastric acid secretion by lafutidine and rabeprazole, given in single doses to fasting and postprandial subjects.Methods A total of 22 healthy male, Helicobacter pylori-negative volunteers participated in this randomized, two-way crossover study. They were randomly assigned to receive a single oral dose of 10mg lafutidine or 20mg rabeprazole after fasting overnight (12 subjects, fasting study) or after eating a test meal (noodles, 364kcal; protein, 10.1g; fat, 16g; carbohydrates, 44.9g; NaCl, 1.1g; 10 subjects, postprandial study). Intragastric pH was monitored continuously for 6h after treatment. The other drug was given after a washout period of at least 7 days, and intragastric pH was similarly monitored.Results In the fasting study, lafutidine sustained pH at >3 and >4 during the second, third, fourth, fifth, and sixth hours of the study for significantly longer than rabeprazole. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole. In the postprandial study, lafutidine sustained pH >3 and >4 for longer periods than rabeprazole during the third, fourth, fifth, and sixth hours of the study. During the first 6h after treatment, lafutidine sustained pH at more than 2, 3, 3.5, 4, 5, 6, and 7 longer than rabeprazole.Conclusions Lafutidine 10mg produces a prompter rise in intragastric pH than rabeprazole 20mg in fasting and postprandial Helicobacter pylori-negative male subjects.     

Improvement of arterial stiffness by the antioxidant and anti-inflammatory effects of short-term statin therapy in patients with hypercholesterolemia

The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 ± 9.0 years) with hypercholesterolemia (total cholesterol 220mg/dl). The patients were treated with cerivastatin (0.15mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 ± 157.1 to 1349.0 ± 223.9cm/s and from 1592.1 ± 164.8 to 1424.8 ± 245.2cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 ± 42.4 to 119.4 ± 33.5U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.     

Glutathione synthetase deficiency: is gamma-glutamylcysteine accumulation a way to cope with oxidative stress in cells with insufficient levels of glutathione?

Glutathione (GSH) plays a major role in the cellular defence against oxidative stress and other vital cellular functions. It therefore seems inevitable that patients with severe depletion of GSH will not survive. However, at least some with glutathione synthetase (GS) deficiency do. This study was done to determine whether these patients have a mechanism to compensate for their GSH deficiency. Cell-free extracts of cultured fibroblasts from 9 patients with GS deficiency and 9 control subjects were analysed by HPLC for low-molecular-weight thiol compounds. The patients cells contained 7.4nmol of GSH per mg of protein (median; range 2.8–25.2) compared to 33.0nmol in control fibroblasts (range 26.7–51.4) (p<0.01). On the other hand, the patients cells accumulated 18.1nmol of -glutamylcysteine (-GC) per mg of protein (median; range 6.9–71.7), whereas the control cells contained 0.1nmol (range 0.05–0.16) (p<0.01). The cysteine concentrations in the patients cells were 20.7nmol/mg protein (median; range 9.4–52.9) compared to 8.9nmol in control cells (range 3.0–12.4) (p<0.01). Cultured fibroblasts from patients with GS deficiency have low levels of GSH, but instead accumulate -GC. We suggest that -GC, which contains both reactive groups of GSH (i.e. the sulphydryl and -glutamyl groups), can compensate for GSH in the cellular defence against oxidative stress. Thus, -GC may alleviate, but only partly prevent, serious consequences of insufficient GSH levels in affected patients. Since the sum of the levels of GSH and -GC in GS-deficient cells (median 31.5nmol/mg protein, range 16.2–79.0) was similar to the level of GSH alone incontrol cells (33.0nmol/mg protein, range 26.7–51.4), we propose that the cultured fibroblasts may have a mechanism to regulate in a coordinated way the levels of GSH and -GC; for instance, by both compounds acting as feedback inhibitors of -GC synthetase.     

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.     

Common Carotid Intima-media Thickness in Peripheral Arterial Disease

The common carotid intima-media thickness (IMT) is regarded as a reliable predictor of cardiovascular morbidity. Patients with peripheral arterial disease (PAD) have an increased risk of cardiovascular morbidity and mortality, and PAD is associated with increases in IMT. The aim of this study was to establish whether IMT would be a suitable parameter for predicting cardiovascular risk in individual patients with PAD and the factors involved in determining IMT in these patients. This prospective study included 314 subjects: 112 patients with isolated PAD, 85 patients with PAD and additional coronary and/or cerebrovascular atherosclerosis, and 117 subjects without atherosclerotic disease. Maximum IMT (mIMT) was measured using high-resolution B-mode ultrasonography. Patients with isolated PAD were examined for influencing factors on mIMT. The mIMT in patients with isolated PAD (1.01±0.2 mm) was not significantly different from that of patients with PAD and additional systemic atherosclerosis (1.01±0.17 mm). Controls showed a significantly lower mIMT (0.71±0.15 mm). In multivariate stepwise regression analysis, the chief influencing factors on mIMT in patients with isolated PAD included age as well as fasting insulin and plasminogen activator inhibitor-1 (PAI-1). We found significant correlations between mIMT and the presence of microalbuminuria in nondiabetics with PAD. The highly increased mIMT values of patients with isolated PAD reflect the elevated cardiovascular risk which is already present in the early clinical stages of PAD. The links between fasting insulin, PAI-1, microalbuminuria, and older age with mIMT in isolated PAD are at the same time important predictors of the development of systemic atherosclerosis in PAD.     

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.     

PBC-AIH overlap syndrome with concomitant ITP and Hashimoto’s disease with positivity for anti-centromere antibody

We report a case of primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome with concurrent idiopathic thrombocytopenic purpura (ITP) and Hashimotos disease with positivity for anticentromere antibody. The patient was a 64-year-old woman with symptoms of jaundice and general fatigue. About 30 years earlier, she had been diagnosed as having ITP and had undergone splenectomy. As part of her present history, she had exhibited liver dysfunction in 1995, during the follow-up of Hashimotos disease, and a liver biopsy led to the diagnosis of PBC. In March 2000, she was admitted to hospital because of general fatigue and jaundice. Blood tests revealed: total protein (TP), 6.6g/dl; -globulin (glb), 35.9%; total bilirubin (T-bil), 9.41mg/dl; direct bilirubin (D-bil), 7.52mg/dl; aspartate aminotransferase (AST), 957U/l; alanine aminotransferase (ALT), 651U/l; alkaline phosphatase (ALP), 595U/l; -guanosine triphosphate (GTP), 129U/l; IgG, 2620mg/dl; IgM, 223mg/dl; hepatitis B surface antigen (HBsAg), negative; anti-hepatitis C virus (HCV), negative; antinuclear antibody, positive; antimitchondrial antibody (AMA), negative (by the immunofluorescence [IF] method); and anti-pyruvate dehydrogenase complex (PDC)-E2 antibody, positive (by Western blotting). Anticentromere antibody (ACA), which is an alternative diagnostic marker for PBC, was detected in this patient. Prednisolone was administered after admission and liver function test results improved markedly. The liver biopsy in 1995 had revealed infiltration of lymphocytes and plasma cells in the portal areas with fibrous expansion and periportal necrosis. Destructive cholangitis was observed, as well as scattered epitheloid cell granulomas in some portal areas. Liver biopsy after the steroid treatment revealed alleviated necrotic inflammatory responses of hepatocytes, while the destructive cholangitis persisted. This is a very rare case of PBC-AIH overlap syndrome accompanied by ITP and Hashimotos disease which provides a possible insight into the mechanisms and interplay of autoimmune diseases.