Marked efficacy of combined three-drug therapy (Sodium Valproate, Topiramate and Stiripentol) in a patient with Dravet syndrome.

WHAT IS KNOWN AND OBJECTIVE: Dravet syndrome (DS) is an intractable epilepsy syndrome. The three-drug combination therapy of sodium valproate (VPA), clobazam (CLB) and stiripentol (STP) is recommended worldwide. CASE SUMMARY: We present a case of DS, in which treatment with CLB could not be continued because of the appearance of adverse reactions to it. Replacement with topiramate (TPM) proved to be markedly effective. WHAT IS NEW AND CONCLUSION: It is suggested that combination therapy with VPA, TPM and STP is for DS epilepsy.

Role of genetic factors (CETP gene Taq I B polymorphism and Apo A-I gene Msp I polymorphism) in serum HDL-C levels in women.

BACKGROUND AND AIM: Plasma high density lipoprotein cholesterol (HDL-C) levels are determined by a variety of environmental and genetic factors. The cholesteryl ester transfer protein (CETP) and apolipoprotein A-I (Apo A-I) are considered to be associated with HDL-C metabolism. The aim of this study was to investigate the relationship between the CETP gene Taq I B and Apo A-I gene Msp I polymorphisms and plasma lipid levels taking into account environmental factors, and to determine the combined effects of these polymorphisms on HDL-C levels in Japanese women. METHODS AND RESULTS: The study involved 270 Japanese women aged 30-69 years. We found a significant association between the CETP genotypes and HDL-C levels (p=0.0020), which were also associated with the Apo A-I gene (M1) polymorphism. Stepwise multiple regression analysis revealed that both the CETP Taq I B and Apo A-I gene (M1) genotypes were independent predictive variables. The strength of the association between the Apo A-I (M1) subgroup and HDL-C levels was reduced in the subjects with a high Body Mass Index (BMI). The combination of genotypes provided more detailed information about HDL-C levels. The "high risk" combination of the M1+ (M1+/+) and B1B1 genotypes was associated with the lowest HDL-C level (1.52+/-0.36 mmol/L), and the "low risk" combination of the M1- (M1+/- or M1-/-) and B2B2 genotypes was associated with the highest HDL-C levels (2.06+/-0.34 mmol/L). CONCLUSIONS: Our results suggest that the combination of the two polymorphisms influences HDL-C levels in women, and that the association between genetic factors and HDL-C levels is altered by environmental factors. They may also help to detect individuals with low HDL-C levels at high risk for coronary artery syndrome.

Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension.

OBJECTIVE: To investigate the effect of beraprost sodium, an orally active prostacyclin analogue, on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. PATIENTS AND DESIGN: Symptom limited cardiopulmonary exercise testing was performed before and 3 (1) months (mean (SEM)) after beraprost treatment in 30 patients with precapillary pulmonary hypertension (14 with primary pulmonary hypertension and 16 with chronic thromboembolic pulmonary hypertension). RESULTS: Long term treatment with beraprost resulted in significant increases (mean (SEM)) in peak workload (87 (4) W to 97 (5) W, p < 0.001) and peak oxygen consumption (peak VO2, 14.9 (0.7) ml/kg/min to 16.8 (0.7) ml/kg/min, p < 0.001). Beraprost decreased the ventilatory response to carbon dioxide production during exercise (VE-VCO2 slope, 42 (2) to 37 (1), p < 0.001). No significant difference in the responses of these variables to beraprost treatment was observed between patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. CONCLUSIONS: Oral administration of beraprost sodium may improve exercise capacity and ventilatory efficiency in patients with both primary and chronic thromboembolic pulmonary hypertension.

Pulmonary artery reflection for differentially diagnosing primary pulmonary hypertension and chronic pulmonary thromboembolism.

OBJECTIVES: The purpose of this investigation was to differentiate chronic pulmonary thromboembolism (CPTE) from primary pulmonary hypertension (PPH) by means of the indexes of pulmonary arterial reflection. BACKGROUND: These differences in the primary lesions would make pulmonary artery reflection occur earlier in CPTE than in PPH. Although the analysis of pulsatility of pulmonary arterial pressure is useful in the differential diagnosis of PPH and CPTE, it is not known whether the analysis of pulmonary artery reflection can differentiate CPTE from PPH. METHODS: Since CPTE predominantly involves the proximal arteries, whereas PPH involve the peripheral arteries, we hypothesized that patients with CPTE have a large augmentation index and a short inflection time. For this study, we enrolled 62 patients who had CPTE (31 patients) and PPH (31 patients). We measured pulmonary arterial pressure using a fluid filled system that included a balloon-tipped flow directed catheter. To quantify the pulmonary artery reflection, we used the augmentation index and inflection time. RESULTS: The augmentation index was markedly higher in CPTE than it was in PPH (27.4% +/- 15.2% [SD] and -25.1% +/- 26.9%, respectively, p < 0.001) and was diagnostic in separating the two groups. Inflection time separated the two groups reasonably well (97 +/- 20 ms and 210 +/- 49 ms, respectively, p < 0.001). CONCLUSIONS: The analysis of pulmonary arterial reflection is useful in the differential diagnosis of CPTE and PPH.

Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: To assess acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN: Cardiopulmonary exercise testing was performed in 20 patients with CTEPH before thromboendarterectomy (baseline), one month after (early phase), and four months after (late phase). Peak oxygen uptake (peak VO(2)) and the ventilatory response to carbon dioxide production (VE-VCO(2) slope) were measured for assessment of exercise capacity and ventilatory efficiency. Right heart catheterisation was performed in all patients before and one month after surgery. RESULTS: Baseline peak VO(2) decreased and VE-VCO(2) slope increased along with the increase in pulmonary vascular resistance in patients with CTEPH. After thromboendarterectomy, the VE-VCO(2) slope decreased greatly from baseline to the early phase (mean (SD), 50 (9) to 37 (7), p < 0.05) and reached a steady level thereafter. In contrast, a continued increase in peak VO(2) was noted from the early to the late phase (16.9 (4.1) to 21.1 (5.0) ml/kg/min, p < 0.05). The decrease in the VE-VCO(2) slope from baseline to the early phase, but not the increase in peak VO(2), correlated strongly with the decrease in pulmonary vascular resistance after surgery (r = 0.75, p < 0.01). CONCLUSIONS: Thromboendarterectomy may cause an immediate improvement in ventilatory efficiency, possibly through its beneficial haemodynamic effects. In contrast, exercise capacity may continue to improve towards the late phase, reflecting peripheral adaptation to exercise.

K(ATP) channels predominantly regulate conduit vessel tone in normoxic cat pulmonary arteries in vivo.

Through our investigations of the intact pulmonary circulation, we aimed to find out whether K(ATP) channels contribute to regulating basal vascular tone and to clarify which vascular segments dilate during K(ATP) channel activation under basal tone conditions. Using an X-ray television system on anesthetized cat lungs, we measured internal diameter (ID) responses to two K(ATP) channel inhibitors (glibenclamide and 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydrochloride (U-37883A)) and to an activator (levcromakalim) in normoxic pulmonary arteries. In conduit arteries (800-3000 microm ID), the inhibitors and activator induced larger ID constrictions (14-17%) and dilatations (29-32%), respectively. However, in resistance arteries (<500 microm), the constriction response was negligible and the dilatation response relatively small (5-10%). The data suggest that K(ATP) channels are active and capable of regulating basal vascular tone primarily within conduit pulmonary arteries even though these channels are present in all pulmonary arteries.

[Primary pulmonary hypertension].

Primary pulmonary hypertension is a rare and poor prognostic disease. This disease has a pulmonary arteriopathy that is due to unknown cause. Histological study shows medial hypertrophy and fibrosis. Plexogenic arteriopathy is usually observed, but not always. Recently gene mutation was discovered in familial primary pulmonary hypertension. Differential diagnosis is very important because therapies are much different among pulmonary hypertensions due to other causes. In the near future, the mechanism of the disease will be apparent, and therapy must be improved.

Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension.

We sought to assess the effects of oral supplementation of L-arginine, the precursor of nitric oxide (NO), on hemodynamics and exercise capacity in patients with pulmonary hypertension. Acute hemodynamic responses to oral L-arginine (0.5 g/10 kg body weight) or placebo were examined in 19 patients with primary or precapillary secondary pulmonary hypertension. Cardiopulmonary exercise tests were performed to measure peak oxygen consumption (peak V O(2)) and the ventilatory response to carbon dioxide production (V E-V CO(2) slope) before and 1 wk after treatment with L-arginine (1.5 g/10 kg body weight/d) or placebo. Oral supplementation of L-arginine significantly increased plasma L-citrulline, which indicated enhancement of NO production. Supplemental L-arginine produced a 9% decrease in mean pulmonary arterial pressure (53 +/- 4 to 48 +/- 4 mm Hg, p < 0.05) and a 16% decrease in pulmonary vascular resistance (14.8 +/- 1.5 to 12.4 +/- 1.4 Wood units, p < 0.05). L-arginine modestly decreased mean systemic arterial pressure (92 +/- 4 to 87 +/- 3 mm Hg, p < 0.05). A 1-wk supplementation of L-arginine resulted in a slight increase in peak V O(2) (831 +/- 88 to 896 +/- 92 ml/min, p < 0.05) and a significant decrease in the V E- V CO(2) slope (43 +/- 4 to 37 +/- 3, p < 0.05) without significant systemic hypotension. Hemodynamics and exercise capacity remained unchanged during placebo administration. These results suggest that oral supplementation of L-arginine may have beneficial effects on hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension.

[Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension].

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension. METHODS AND RESULTS: Plasma BNP was measured in 60 patients with primary pulmonary hypertension at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (> or = 150 pg/ml) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (p < 0.05). Plasma BNP in survivors decreased significantly during the follow-up (217 +/- 38 to 149 +/- 30 pg/ml, p < 0.05), whereas that in nonsurvivors increased (365 +/- 77 to 544 +/- 68 pg/ml, p < 0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (> or = 180 pg/ml) than for those with an inframedian value (p < 0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality in patients with primary pulmonary hypertension.

Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy.

BACKGROUND: Thrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. METHODS AND RESULTS: To assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (P<0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (P<0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (P<0.05). CONCLUSIONS: Decreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury.

Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension.

OBJECTIVE: To investigate whether infusion of adrenomedullin, a potent vasorelaxant peptide, has beneficial haemodynamic and hormonal effects in patients with pulmonary hypertension. PATIENTS AND DESIGN: The haemodynamic and hormonal responses to intravenous infusion of adrenomedullin (0.05 microgram/kg/min) or placebo were examined in 13 patients with precapillary pulmonary hypertension. RESULTS: Infusion of adrenomedullin produced a 44% increase in cardiac index (mean (SD) 1.8 (0.2) to 2.6 (0.3) l/min/m(2), p < 0. 05) and a 32% decrease in pulmonary vascular resistance (19.7 (1.4) to 13.4 (1.3) units, p < 0.05), with a 4% reduction in mean pulmonary arterial pressure (62 (4) to 59 (4) mm Hg, NS). Adrenomedullin also decreased mean systemic arterial pressure (81 (3) to 72 (4) mm Hg, p < 0.05) and increased heart rate (73 (4) to 79 (4) beats/min, p < 0.05). Adrenomedullin decreased plasma aldosterone (9.8 (2.5) to 7.1 (1.5) ng/dl, p < 0.05) without significant changes in plasma renin activity. Plasma atrial and brain natriuretic peptides tended to decrease with adrenomedullin, although these changes did not reach significance. The haemodynamic and hormonal variables remained unchanged during placebo infusion. CONCLUSIONS: Intravenous adrenomedullin has beneficial haemodynamic and hormonal effects in patients with precapillary pulmonary hypertension.

Gene transfer of human prostacyclin synthase ameliorates monocrotaline-induced pulmonary hypertension in rats.

BACKGROUND: Prostacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. METHODS AND RESULTS: The cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan-liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene-transfected rats compared with controls [mean pulmonary arterial pressure, 31+/-1 versus 35+/-1 mm Hg (-12%); total pulmonary resistance, 0.087+/-0.01 versus 0.113+/-0.01 mm Hg x mL x min(-1) x kg(-1) (-23%), both P:<0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, were significantly increased for >/=1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, P:<0.01). CONCLUSIONS: Intratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.

Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (>/=150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P<0.05). Plasma BNP in survivors decreased significantly during the follow-up (217+/-38 to 149+/-30 pg/mL, P<0. 05), whereas that in nonsurvivors increased (365+/-77 to 544+/-68 pg/mL, P<0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (>/=180 pg/mL) than for those with an inframedian value (P<0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.

Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging.

UNLABELLED: It remains unclear whether cardiac sympathetic nervous function is disturbed in patients with pulmonary arterial hypertension (PH) and how sympathetic dysfunction is related to PH. METHODS: In this study, (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart, which reveals the sympathetic innervation of the left ventricle, was performed in 7 healthy volunteers without cardiopulmonary disease (control subjects); 55 patients with PH, including 27 with chronic thromboembolic pulmonary hypertension (CTEPH) of major vessels; and 28 patients with primary pulmonary hypertension (PPH). RESULTS: Cardiac (123)I-MIBG uptake, assessed as the heart-to-mediastinum activity ratio (H/M), was significantly lower in the CTEPH and PPH groups compared with that in the control group (P < 0.01). Myocardial MIBG turnover, expressed as the washout rate (WR [%]) from 15 to 240 min, was significantly higher in the CTEPH and PPH groups than that in the control group (P < 0.01). In the PPH group, H/M and WR values of MIBG correlated with the severity of pulmonary hypertension (represented by total pulmonary vascular resistance determined by right heart catheterization), the right ventricular ejection fraction determined by electron beam CT, and other variables but did not correlate well in the CTEPH group. In both groups, patients with H/M > or = 2.0 showed better cumulative survival than did those with H/M < 2.0 (P < 0.05). CONCLUSION: Patients with PH have significant left ventricular myocardial sympathetic nervous alteration. (123)I-MIBG imaging of the heart is useful for assessing the severity of pulmonary hypertension caused by PPH or CTEPH.

Haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome.

OBJECTIVE: To assess haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome. DESIGN: Retrospective observational study. SETTING: Tertiary referral centre. PATIENTS: 94 adult patients with Eisenmenger syndrome who were diagnosed between September 1982 and July 1998. MAIN OUTCOME MEASURES: Serum uric acid was measured in all patients, together with clinical and haemodynamic variables related to mortality. RESULTS: Serum uric acid was raised in patients with Eisenmenger syndrome compared with age and sex matched control subjects (7.0 v 4.7 mg/dl, p < 0.0001) and increased in proportion to the severity of New York Heart Association functional class. Serum uric acid was positively correlated with mean pulmonary arterial pressure (r = 0.30, p = 0.0052) and total pulmonary resistance index (r = 0.55, p < 0.0001), and negatively correlated with cardiac index (r = -0.50, p < 0.0001). During a mean follow up period of 97 months, 38 patients died of cardiopulmonary causes. Among various clinical, echocardiographic, and laboratory variables, serum uric acid remained predictive in multivariate analysis. Kaplan-Meier survival curves based on median serum uric acid showed that patients with high values had a significantly worse survival rate than those with low values (log-lank test: p = 0.0014 in male patients, p = 0.0034 in female patients). CONCLUSIONS: Serum uric acid increases in proportion to haemodynamic severity in adult patients with Eisenmenger syndrome and is independently associated with long term mortality.

Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH. METHODS AND RESULTS: On 2 separate days, 3 days apart, 14 patients with precapillary PH (10 primary PH, 4 residual PH after correction of an intracardiac shunt; age, 40+/-12 years; mean pulmonary artery pressure, 60+/-23 mm Hg) performed exercise, with and without inhalation of 20 ppm NO, on a cycle ergometer. The work rate was increased 15 W/min until their symptom-limited maximum, with breath-by-breath gas analysis. Patients were randomly and blindly selected to inhale NO on either their first or second test. Peak exercise load and anaerobic threshold tended to increase, but not significantly. Peak oxygen consumption (f1.gif" BORDER="0">O(2)) and Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio increased significantly, by 18% and 22%, respectively (peak f1.gif" BORDER="0">O(2), 13.6+/-3.6 to 16.0+/-4. 1 mL. kg(-1). min(-1); Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio, 5. 8+/-2.4 to 7.1+/-2.3 mL. kg(-1). min(-1). W(-1); both P<0.01). Peak f1.gif" BORDER="0">O(2) increased >10% in 12 of the 14 patients. However, respiratory quotient at peak exercise decreased from 1. 22+/-0.15 to 1.09+/-0.15 (P<0.01). CONCLUSIONS: Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.

Effect of Sho-saiko-to extract on HGF and TGF-beta levels of intraorgans in liver-injured rats after partial hepatectomy.

To examine the effects of Sho-saiko-to extract on liver regeneration, Sho-saiko-to extract (0.75%, 1.5% or 3%) was administered to 70% partial hepatectomized rats with dimethylnitrosamine-induced liver-injury. S phase cell number, liver retinoid levels, hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-beta) levels in each intraorgan were measured as indicators of liver regeneration. Three to seven days after hepatectomy, HGF and TGF-beta levels of the liver and spleen of the Sho-saiko-to extract groups were significantly different from the levels of the ordinary food group (P < 0.05-0.1). HGF levels in the Sho-saiko-to extract groups were approximately 1.3-1.8 times higher in the liver and approximately 1.8-2.1 times higher in the spleen compared with the levels found in the ordinary food group. TGF-beta levels in the Sho-saiko-to extract groups were approximately 0.38-0.47 times the level in the liver and 0.58-0.77 times the level in the spleen of the ordinary food group. There was no difference in HGF and TGF-beta levels of the kidney and lung between the Sho-saiko-to extract group and the ordinary food group. There was a significant and positive correlation between HGF level and S phase cell number in the liver (r = 0.826, P < 0.01). There was a significant and negative correlation between TGF-beta level and the retinoid level in the liver (r = -0.696, P < 0.01). In addition, the levels of the active constituents of Sho-saiko-to extract (glycyrrhetic acid, baicalin and baicalein) showed high values in the liver and spleen of partial hepatectomized rats, and increased from the third day after partial hepatectomy. These results show that Sho-saiko-to extract induces liver regeneration by increasing the production of HGF and suppressing the production of TGF-beta in the liver and spleen of partial hepatectomized rats. It was considered that the increase in the Sho-saiko-to extract active constituent levels in the liver and spleen greatly influences this action.

Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure.

BACKGROUND: Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown. METHODS AND RESULTS: Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo. CONCLUSIONS: Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing.

The six-minute walk test is a submaximal exercise test that can be performed even by a patient with heart failure not tolerating maximal exercise testing. To elucidate the clinical significance and prognostic value of the six-minute walk test in patients with primary pulmonary hypertension (PPH), we sought (1) to assess the relation between distance walked during the six-minute walk test and exercise capacity determined by maximal cardiopulmonary exercise testing, and (2) to investigate the prognostic value of the six-minute walk test in comparison with other noninvasive parameters. The six-minute walk test was performed in 43 patients with PPH, together with echocardiography, right heart catheterization, and measurement of plasma epinephrine and norepinephrine. Symptom-limited cardiopulmonary exercise testing was performed in a subsample of patients (n = 27). Distance walked in 6 min was significantly shorter in patients with PPH than in age- and sex-matched healthy subjects (297 +/- 188 versus 655 +/- 91 m, p < 0. 001). The distance significantly decreased in proportion to the severity of New York Heart Association functional class. The distance walked correlated modestly with baseline cardiac output (r = 0.48, p < 0.05) and total pulmonary resistance (r = -0.49, p < 0. 05), but not significantly with mean pulmonary arterial pressure. In contrast, the distance walked correlated strongly with peak V O(2) (r = 0.70, p < 0.001), oxygen pulse (r = 0.57, p < 0.01), and V E-VCO(2) slope (r = -0.66, p < 0.001) determined by cardiopulmonary exercise testing. During a mean follow-up period of 21 +/- 16 mo, 12 patients died of cardiopulmonary causes. Among noninvasive parameters including clinical, echocardiographic, and neurohumoral parameters, only the distance walked in 6 min was independently related to mortality in PPH by multivariate analysis. Patients walking < 332 m had a significantly lower survival rate than those walking farther, assessed by Kaplan-Meier survival curves (log-rank test, p < 0.01). These results suggest that the six-minute walk test, a submaximal exercise test, reflects exercise capacity determined by maximal cardiopulmonary exercise testing in patients with PPH, and it is the distance walked in 6 min that has a strong, independent association with mortality.

[Pulmonary thromboendarterectomy for chronic pulmonary thromboembolism in three patients with systemic lupus erythematosus and antiphospholipid syndrome].

Pulmonary hypertension (PH) is a serious and often fatal complication of systemic lupus erythematosus (SLE). Several potential mechanisms have been postulated for narrowing of vessels as a result of pulmonary vasculitis and pulmonary thromboembolism caused by antiphospholipid antibodies. Pulmonary thromboendarterectomy for chronic pulmonary thromboembolism is performed to alleviate pulmonary hypertension. We report three rare cases of SLE with antiphospholipid syndrome in patients who presented with PH secondary to chronic pulmonary thromboembolism. Pulmonary thromboendarterectomy was performed, and all patients remained well without deterioration of PH after surgery. Pulmonary thromboendarterectomy should be considered as an effective method of treatment for this disease.