Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.     

Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial

The primary objective of this phase 3 study was to determine whether postconsolidation immunotherapy with interleukin-2 (IL-2) and histamine dihydrochloride (HDC) improved the leukemia-free survival (LFS) of adult patients with acute myeloid leukemia (AML) in complete remission (CR). Three hundred twenty patients with AML (median age, 57 years; range, 18-84 years) were stratified by CR1 or subsequent CR (CR > 1) and randomly assigned to treatment with HDC/IL-2 or no treatment (control). Treatment comprised 10 21-day cycles with IL-2 (16 400 U/kg) plus HDC (0.5 mg); both compounds were administered by subcutaneous injection twice daily. Study arms were balanced for age, sex, previous treatment, leukemic karyotypes, time from CR to inclusion, and frequency of secondary leukemia. Three years after enrollment of the last patient, treatment with HDC/IL-2 was found to improve LFS over control in the study population (CR1 + CR > 1, n = 320; P < .01, log-rank test). For patients in CR1 (n = 261), treatment significantly improved LFS (P = .01) with 3-year LFS estimates of 40% (HDC/IL-2) compared with 26% (control). Side effects were typically mild to moderate. These results indicate that HDC/IL-2 treatment offers an efficacious and tolerable treatment for patients with AML in remission.     

Notch signaling in blood vessels: who is talking to whom about what?

It has become increasingly clear that the Notch signaling pathway plays a critical role in the development and homeostasis of the cardiovascular system. This notion has emerged from loss- and gain-of-function analysis and from the realization that several hereditary cardiovascular disorders originate from gene mutations that have a direct impact on Notch signaling. Current research efforts are focused on determining the specific cellular and molecular effects of Notch signaling. The rationale for this has stemmed from the clinical importance and therapeutic potential of modulating vascular formation during various disease states. A more complete appreciation of Notch signaling, as it relates to vascular morphogenesis, requires an in-depth knowledge of expression patterns of the various signaling components and a comprehensive understanding of downstream targets. The goal of this review is to summarize current knowledge regarding Notch signaling during vascular development and within the adult vascular wall. Our focus is on the genetic analysis and cellular experiments that have been performed with Notch ligands, receptors, and downstream targets. We also highlight questions and controversies regarding the contribution of this pathway to vascular development.     

Topography of human uterine prostaglandin E and F2 alpha receptors and their profiles during pathological states

The topography of prostaglandin (PG) E and F2 alpha receptors in uteri of premenopausal women was investigated by dividing uteri into six equal longitudinal strips and further dividing each strip into approximately 1-cm segments. Tissue for determination of smooth muscle content using the Trichrome stain was taken from each section, and the remainder was homogenized for binding studies with 3H-labeled PGs. The [3H] PGE1 binding (mean, 41.5 fmol/mg protein; range, 23.1-58.3) was about 8-fold greater in the fundus than [3H]PGF2 alpha binding (mean, 4.8 fmol/mg protein; range, 1.3-13.0), and this trend was found in most uterine sections. The binding of both 3H-labeled PGs decreased from fundus to cervix, and this decrease was similar to the decrease in smooth muscle content. Scatchard analysis revealed apparent dissociation constants (Kds) of 1.4 and 76 nM and apparent specific binding capacities (Ns) of 25 and 488 fmol/mg protein for [3H]PGE2, and Kd values of 11.5 and 81 nM and Ns values of 19.4 and 58 fmol/mg protein for [3H]PGF2 alpha in the uterine fundus. The Kd values for [3H]PGE2 were similar in other sections of the uterus, but the Ns values were smaller in the lower uterine body and cervical end. While the phase of the menstrual cycle did not influence [3H]PG binding, the diagnosis of abnormal uterine bleeding compared to dysmenorrhea was associated with an increase in [3H]PGE1 binding (P less than 0.05).     

Echocardiographic aortic to mitral valve opening area ratio for determining the presence and severity of mitral regurgitation

A simple and accurate noninvasive method to quantify the degree of mitral regurgitation (MR) is lacking. Therefore, the ratio of the aortic (AVO) to mitral valve opening area (MVO) from 2-dimensionally guided M-mode echocardiographic tracings was examined as an estimate for the presence and severity of MR. Seventy-two patients who had undergone catheterization were studied: 49 with idiopathic dilated cardiomyopathy, 7 with coronary artery disease and 16 with organic MR. Twenty-eight patients had no MR (group I), 23 had mild/moderate MR (group II) and 21 had severe MR (group III). The AVO/MVO ratio was 0.86 +/- 0.2 in group I, 0.53 +/- 0.1 in group II and 0.31 +/- 0.1 in group III (p less than 0.001). An AVO/MVO ratio of 0.65 or less predicted MR with a sensitivity of 98% and a specificity of 86%. Furthermore, a strong relation was found between the ratio and the angiographic severity of MR. Thus, the AVO/MVO ratio is a simple echocardiographic parameter for detecting the presence and severity of MR.     

Biliary secretion and hepatic metabolism of taurine-conjugated 7 alpha-hydroxy and 7 beta-hydroxy bile acids in the dog. Defective hepatic transport and bile hyposecretion

Experiments were carried out using chronic bile fistula dogs to define the physiologic properties and metabolism of two unnatural epimeric monohydroxy conjugated bile acids, 7 alpha-hydroxy cholanoyltaurine and 7 beta-hydroxy cholanoyltaurine. The compounds, labeled with 14C, were infused intravenously at a rate of 1 mumol/kg X min; effects on bile flow and biliary lipid secretion as well as hepatic biotransformation were defined. The 7-monohydroxy bile acids were secreted quite slowly in bile: recovery during the 90-min infusion interval averaged 16% for the 7 alpha compound and 23% for the 7 beta compound, and after 6 h was only about 60% for the 7 alpha compound and 80% for the 7 beta compound. Uptake by tissues, presumably the liver, appeared to be efficient, as the level of radioactivity in peripheral blood remained quite low. Both bile acids failed to induce the anticipated increase in bile flow; canalicular bile flow, which was assessed using erythritol clearance, was about half the value observed when cholyltaurine was infused at a similar rate. The "hyposecretion" of bile, which was thought likely to be caused by impaired canalicular transport of the monohydroxy conjugates, was fully reversible, as a subsequent cholyltaurine infusion at a rate of 1 mumol/min X kg immediately restored bile flow and the infused cholyltaurine was secreted normally. Each compound was partly 3-hydroxylated during hepatic passage: the 7 alpha compound, about 36% (to form chenodeoxycholyltaurine); the 7 beta compound, about 23% (to form ursodeoxycholyltaurine). No other biotransformation occurred. Each compound induced phospholipid and cholesterol secretion, but compared to the effects of cholyltaurine, the amount of phospholipid secretion induced (per micromole of secreted bile acid) was less, and that of cholesterol, greater. Thus, the two 7-monohydroxy taurine-conjugated bile acids caused a striking dissociation of induced phospholipid and cholesterol secretion. The results indicate that taurine-conjugated 7-monohydroxy bile acids are poorly secreted by the liver and that their impaired transport is associated with bile hyposecretion, possibly reflecting decreased bile acid-dependent flow; the configuration of their 7-hydroxy group influences their rate of secretion into bile. The results also establish a novel type of bile acid biotransformation (3-hydroxylation) in the dog.     

Proximal left anterior descending coronary heart disease and complex ventricular arrhythmias

In this study, 87 consecutive patients with angiographically proven coronary artery disease (CAD, stenosis >75%) underwent 24-h Holter monitoring, 76 of them having had transmural myocardial infarction, a mean of five months before evaluation. Of the total, 51 patients showed single-vessel disease, in 31 (61%) of them with involvement of the left anterior descending (LAD) artery. In 26 patients with proximal LAD stenosis or occlusion and usually large aneurysms and subsequently impaired left ventricular function relatively low prevalence of significant ventricular premature contraction (VPC, Lown (III) was seen. On the contrary in 19 patients with multivessel disease and proximal LAD stenosis advanced forms of VPCs were present in 63% (p<0.01). Further both groups differed significantly in the frequency of postinfarction angina (30% vs. 100%; p<0.001) and their incidence in positive exercise stress tests (15% vs. 84%; p<0.001). Ejection fractions were comparable in both groups (mean 45% vs. 52%). Finally 17 patients with multivessel disease but without proximal LAD lesion did not differ in any of the above mentioned parameters, when compared to the patients with single-vessel disease and proximal LAD stenosis. We conclude that impaired left ventricular function does not sufficiently explain the high risk of sudden death in postmyocardial infarction patients. The coronary and functional status of the surviving myocardium has to be taken into consideration as well.     

Diagnostic value of transesophageal echocardiography in atrial septal aneurysm

Transthoracic and transesophageal echocardiography was performed in 40 consecutive adult patients with an atrial septal aneurysm. In 11 (27%) of 40 patients transthoracic echocardiography failed to demonstrate the lesion and the diagnosis was established by the transesophageal approach only. Interatrial shunting, assessed by echocardiographic contrast study and/or color flow mapping, was detected in 13 (54%) of 24 patients on transthoracic imaging and in 29 (76%) of 38 patients during transesophageal echocardiography. Identification of multiple fenestrations (n=9) and thrombi within the aneurysm (n=2) could be achieved only by transesophageal ultrasound. A cerebrovascular event of suspected embolic origin occurred in 20 (50%) of 40 patients; 11 (55%) of the 20 patients had repeated cerebral events. Except for mitral valve prolapse in 2 patients and spontaneous left atrial contrast phenomenon in 1 patient no other potential cardiac source of embolism could be identified by transesophageal echocardiography. A marked thickening of the aneurysm was present in 14 (70%) of 20 patients with a cerebrovascular event versus only 4 (20%) of 20 patients without a cerebrovascular event (p<0,01). The mechanism of embolization may be both primary thrombus formation within the aneurysm and paradoxical embolization through an interatrial communication as suggested by the findings on transesophageal ultrasound in 2 patients. Although the patients of this study represent a highly selected group it may be concluded that atrial septal aneurysm is a cardiac abnormality with embolic potential. Transesophageal echocardiography has to be regarded the imaging method of choice for evaluation of this lesion.     

Niedermolekulares Heparin (Fragmin®) in der Therapie der Sepsis mit Gerinnungsstörungen – vergleichende Untersuchung zweier Dosierungsschemata

Zusammenfassung 30 Patienten einer internistischen Intensivstation mit dem Krankheitsbild einer Sepsis und einer beginnenden Verbrauchskoagulopathie wurden über 7 Tage mit dem niedermolekularen Heparin Fragmin behandelt: 15 Patienten erhielten nach randomisierter Gruppenzuteilung niedermolekulares Heparin in einer Dosis von 1,5–5 E pro Kilogramm K?rpergewicht/h (Low dose-Gruppe). 15 Patienten der High dose-Gruppe wurden 8–15 E niedermolekularen Heparins pro Kilogramm K?rpergewicht/h infundiert. Ein Vergleich der beiden Dosierungsschemata wurde anhand verschiedener Laborparameter durchgeführt, wobei besonders das Prothrombinfragment 1 + 2, das D-Dimer und der Thrombin-Antithrombin III-Komplex berücksichtigt wurden. Bei allen Patienten, die in die Studie aufgenommen wurden, zeigten die drei molekularen Marker bei Therapiebeginn eine Aktivierung des Gerinnung- und Fibrinolysesystems an. Keine Gruppenunterschiede waren zu erheben für die Indikatoren einer Entzündungsreaktion wie Temperatur, Leukozyten-Zahlen, CRP und Elastase. Auch hinsichtlich der (bei allen Patienten eingeschr?nkten) Nieren- oder Leberfunktion waren die beiden Gruppen gleich. In der High dose-Gruppe stellte sich ein schnellerer und st?rkerer Konzentrationsabfall von prim?r erh?htem Prothrombinfragment 1 + 2, D-Dimer und Thrombin-Antithrombin III ein. Blutungskomplikationen beobachteten wir in keinem Fall. Nach unseren Ergebnissen ist insbesondere die hochdosierte Therapie mit niedermolekularem Heparin geeignet, die im Rahmen einer Sepsis aktivierte Gerinnung zu inhibieren, ohne Blutungskomplikationen herbeizuführen. Eingegangen: 16. Juli 1996 Akzeptiert: 4. Dezember 1996