Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group.

BACKGROUND. Intravenous amphotericin B, with or without flucytosine, is usually standard therapy for cryptococcal meningitis in patients with the acquired immunodeficiency syndrome (AIDS). Fluconazole, an oral triazole agent, represents a promising new approach to the treatment of cryptococcal disease. METHODS. In a randomized multicenter trial, we compared intravenous amphotericin B with oral fluconazole as primary therapy for AIDS-associated acute cryptococcal meningitis. Eligible patients, in all of whom the diagnosis had been confirmed by culture, were randomly assigned in a 2:1 ratio to receive either fluconazole (200 mg per day) or amphotericin B. Treatment was considered successful if the patient had had two consecutive negative cerebrospinal fluid cultures by the end of the 10-week treatment period. RESULTS. Of the 194 eligible patients, 131 received fluconazole and 63 received amphotericin B (mean daily dose, 0.4 mg per kilogram of body weight in patients with successful treatment and 0.5 mg per kilogram in patients with treatment failure; P = 0.34). Treatment was successful in 25 of the 63 amphotericin B recipients (40 percent; 95 percent confidence interval, 26 percent to 53 percent) and in 44 of the 131 fluconazole recipients (34 percent; 95 percent confidence interval, 25 percent to 42 percent) (P = 0.40). There was no significant difference between the groups in overall mortality due to cryptococcosis (amphotericin vs. fluconazole, 9 of 63 [14 percent] vs. 24 of 131 [18 percent]; P = 0.48); however, mortality during the first two weeks of therapy was higher in the fluconazole group (15 percent vs. 8 percent; P = 0.25). The median length of time to the first negative cerebrospinal fluid culture was 42 days (95 percent confidence interval, 28 to 71) in the amphotericin B group and 64 days (95 percent confidence interval, 53 to 67) in the fluconazole group (P = 0.25). Multivariate analyses identified abnormal mental status (lethargy, somnolence, or obtundation) as the most important predictive factor of a high risk of death during therapy (P less than 0.0001). CONCLUSIONS. Fluconazole is an effective alternative to amphotericin B as primary treatment of cryptococcal meningitis in patients with AIDS. Single-drug therapy with either drug is most effective in patients who are at low risk for treatment failure. The optimal therapy for patients at high risk remains to be determined.     

Release of histamine in whole blood by oxygen radicals: Division between specific and unspecific processes

Oxygen derived free radicals are involved in many pathological processes such as postischemic reperfusion injuries, hepatotoxicity of drugs and inflammatory processes. Thereby these oxygen radicals induce lipid peroxidation and perturbation of cellular membranes. The aim of our present study was to determine whether oxygen radicals generated by the xanthine oxidase/hypoxanthine system cause a release of histamine in human blood cell cultures. Stimulation of blood cell cultures with oxygen radicals induced a histamine liberation which was mainly due to calcium independent processes during the first 30 min, whereas then calcium requiring processes took part in the release of histamine. The regulation of the leukocyte selectin LECAM-1 was altered by oxygen radicals whereas histamine, which is known to modulate vascular selectin expression, did not affect the expression of LECAM-1. Our data indicate that oxygen radicals induce a direct calcium independent release of histamine which is due to membrane pertubating processes during the first phase but also induce a specific reaction leading to a further indirect histamine liberation which is probably mediated by PAF.accepted by W. LorenzThe first two authors contributed equally to this paper.     

Genotoxicity testing of antiparasitic nitrofurans in the Drosophila wing somatic mutation and recombination test

Nifurtimox and eight structurally related 5-nitrofuran compounds active against Trypanosoma cruzi were tested for genotoxicity in the wing somatic mutation and recombination test in Drosophila melanogaster. Nifurtimox, compound ada and compound 1B were clearly mutagenic and recombinogenic whereas the remaining six compounds were negative. In contrast to the situation in bacterial mutagenicity tests, nitroreductase activity is probably not decisive for the genotoxicity of these compounds in Drosophila. The three non-genotoxic nitrofurans with high antiparasitic activity are promising candidates for the replacement of nifurtimox. However, these compounds require further genotoxicity testing in eukaryotic assay systems for a final evaluation.     

Body awareness group therapy for patients with personality disorders. 2. Evaluation of the Body Awareness Rating Scale

The Body Awareness Rating Scale (BARS) was developed to evaluate the treatment process of the Body Awareness Group Therapy. The BARS subscales proved to have high interrater reliability. A factor analysis revealed two factors which seemed to measure one awareness and one movement dimension. The BARS was sensitive to change. As hypothesized, the BARS improvement enlarged with increasing duration of treatment. At discharge the good BARS outcome patients had improved significantly more than the poor BARS outcome ones, both concerning symptoms and global psychopathology.     

Clostridium difficile toxins A and B inhibit human immune response in vitro.

Two Clostridium difficile toxins isolated from strain VPI 10463 were tested for their effect on different human T-cell proliferation systems. In mitogen- and antigen-driven T-cell proliferation systems, toxins inhibited the proliferative response in a dose-dependent fashion. In interleukin-2-driven culture systems, no effect of toxins could be found on preactivated T cells. We suspected that monocytes were the influenced cells, since in antigen- and mitogen-driven systems monocytes were necessary for the proliferative response, whereas the interleukin-2-driven system was independent of monocytes. To prove this concept, purified monocytes were treated with toxins. The treatment was found to markedly reduce the capacity of monocytes to stimulate T-cell proliferation. No inhibition of the proliferative response was measured when, instead of monocytes, resting or preactivated T cells were treated with toxins. These experiments clearly show that C. difficile toxins interact with monocytes and not with T cells. The effect of toxins on cells of the immune system might be one factor in the development of pseudomembranous colitis.     

Left heart function in chronic obstructive lung disease

Summary In patients with varying degrees of chronic obstructive pulmonary disease (COPD), simultaneous measurements of central hemodynamics and left ventricular radionuclide ventriculograms at rest and during exercise were made. In 21 of these patients, satisfactory echocardiograms could be performed. In seven of the patients, arterial blood pressure at rest was increased. Decreased compliance of the left ventricle was thought to be present in patients with COPD and additional arterial hypertension. The left ventricular ejection fraction (LVEF) at rest was in the high normal range in all patients. During exercise, no further increase was observed. This pattern of LVEF response seems to be typical in patients with COPD. Because the highest values were observed in the more severe COPD and right ventricular hypertrophy, it is unlikely that an impairment of left ventricular function is caused by COPD. In five of 27 patients, an abnormal decrease of LVEF and regional hypokinesis occurred during exercise, thus suggesting additional coronary heart disease. The fact that at least 30% of the patients with COPD suffered from arterial hypertension and 20% of the patients exhibited unexpected ischemia detected by regional hypokinesis in RNV during exercise, but not in the ECG, may be of practical relevance. Coronary angiography was not indicated because most of these patients were over 65 and the factor limiting the working capacity was ventilatory impairment and not angina pectoris, in all patients. For this reason, a diagnostic uncertainty remains with regard to additional coronary heart disease in the older patients with advanced chronic obstructive pulmonary disease.Lung Function Parameters VC (1) inspiratory vital capacity - FEV1 (1) forced exspiratory volume in 1 sec - Raw (cmH20/l/s) airways resistance - RV/TLC (%) residual volume/total lung capacity - paO₂ (mm Hg) O₂ partial pressure Hemodynamic Parameters CI (1/min/sqm) cardiac index - SVI (ml/sqm) stroke volume index - PAP (mm Hg) pulmonary artery mean pressure - PwP (mm Hg) pulmonary capillary wedge pressure - RRs (mm Hg) systolic arterial pressure - RRd (mm Hg) diastolic arterial pressure (at the time of catheterization) - RR(WHO) (mm Hg) mean values measured at different days (at least 3 values). Parameters Derived from Combined Radionuclide Ventriculography and Central Hemodynamics LVEF (%) left ventricular ejection fraction - LVESVI (ml/sqm) left ventricular endsystolic volume index - P/V (mm Hg/ml/sqm) peak systolic pressure/endsystolic volume index - PFR (1/sec) peak filling rate: endsystolic volume/sec Echocardiographic Parameters RV d wth (mm) right ventricular enddiastolic wall thickness - LV d wth (mm) left ventricular enddiastolic wall thickness In honor to Prof. W.E. Adam's 60th birthday     

Epstein-Barr virus-specific serum immunoglobulin A as an acute-phase antibody in infectious mononucleosis.

Immunoglobulin A (IgA) antibodies to Epstein-Barr virus viral capsid antigen were assayed serially in 19 patients with infectious mononucleosis and in 38 controls. Seventy-four percent of infectious mononucleosis patients demonstrated IgA antibody, whereas this was found in 13% of controls. This antibody appeared early in infectious mononucleosis and was virtually gone 10 weeks after onset. Comparison of IgA antibody kinetics was made with IgG and IgM antibodies to viral capsid antigen, heterophile antibody, and antibody to Epstein-Barr virus early antigen and nuclear antigen. Failure to demonstrate IgA antibody was associated with severe illness, prolonged illness, delay in IgG and anti-Epstein-Barr virus nuclear antigen antibody, and low or absent heterophile and anti-early antigen antibody. Assay of IgA antibody to viral capsid antigen is a potentially useful adjunct in the serodiagnosis of infectious mononucleosis or recent Epstein-Barr virus infection, as are the other antibodies tested, but in this study IgM viral capsid antigen antibody was the only acute-phase antibody present in all patients.     

Liver-specific and shared cell membrane antigens. Studies by light- and electron microscopy.

Liver-specific and shared saline-insoluble cell surface antigens were localized by immunofluorescence as well as by light- and electron microscopic immunoenzyme techniques. Antisera against purified mouse liver cell membranes were surface membrane but not organ-specific. Variable quantities of shared antigens were present in endoderm- and mesoderm-derived organs but not in ectodermal nerve tissue. Species crossreactivity was observed for the rat. Repeated absorption produced liver-specific antisera that reacted with antigenic sites distributed along the entire hepatocyte and sinusoidal cell surfaces. For the precise localization as well as the detection of low concentrations of both liver-specific and nonspecific antigens, the ultrastructural visualization of reactive sites proved essential.     

Insoluble polyanions as activators of both pathways of complement

Soluble polyanions, e.g. dextran sulphate, are known to interact with components of the classical pathway of complement and also to activate the alternative pathway (APC).† Insoluble polyanions offer the opportunity to isolate and to characterize intermediates of the reaction sequence. Sephadex, an insoluble, crosslinked dextran, was substituted with sulphate groups using chlorosulphonic acid. The sulphated Sephadex (SS) activated the APC in normal and in C4-deficient-guinea-pig serum as shown by haemolytic and immunochemical methods. After incubation of SS with normal guinea-pig serum, a C3-cleaving enzyme bound to the SS particles was present. This enzyme was inhibited by antisera against the components C2 and C4. Anti-serum against factor B or anti-C3-Fab had no inhibitory effect. Incubation at 37° inactivated the enzyme; activity was restored by incubation with C2, but not with factors B and D of the APC. These results suggest the presence of the C[unk]42-enzyme bound to the SS particles after incubation with normal serum. However, preincubation of SS with C4 deficient serum did not yield an enzyme which could act on purified C3, but enzymatic activity cleaving C4 and C2 was present, indicating that binding and activation of C1 had occurred. Utilizing purified C[unk]1, it was shown that SS binds purified C[unk]1 in a functionally active state. These data indicate that the polyanion SS has a dual function: SS activates both the APC and the classical sequence. Thus, the chemically simple, ester-linked, anionic sulphate groups, distributed along crosslinked polysaccharide chains, are sufficient to be recognized as initiating signal for both pathways of complement.