Biomedical subjects
Publications and source records attributed to A Schaffner.
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Because of the toxicity of amphotericin B-desoxycholate (AmB-d) during systemic therapy, less toxic forms of AmB, which promise to have a broader therapeutic index, are under investigation. There is, however, no convincing explanation of how such preparations might be made less toxic yet retain their antifungal efficacy. In this study, the antifungal activity of a less toxic, unilamellar liposomal (1) preparation of AmB (AmBisome), which is commercially available in some countries, was compared with conventional AmB-d in vitro and in models of systemic and localized candidiasis in immunosuppressed mice. Results indicate that 1AmB has four to eight times less antifungal activity than AmB-d in all experimental settings tested. Because 1AmB is significantly less active, the therapeutic index of such preparations must be tested clinically before their use can be recommended solely on the basis of toxicity data.
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CMV disease (CMVD) is a recognized problem of the early post-transplant period (PTP) in renal transplant recipients. Information on CMVD in the late (> or = 2 years) PTP is scarce. We have observed 5 cases of CMVD during late (3-8 years) PTP during the last 15 years. Three of these patients died from CMVD. One of the patients with late-onset CMVD recovered spontaneously from mild pneumonitis, 1 patient with severe CMVD after therapy with ganciclovir/anti-CMV-IgG. CMVD was ascribed to primary infection in 4/5 patients, and transmission was attributed to blood products in 2 cases. At the time of CMVD, 4/5 patients were on stable immunosuppression with azathioprine/prednisone; 1 patient who died had received prednisone pulses 1 month prior to CMVD. Late onset CMVD is an underreported disease in renal transplant recipients, which warrants preventive measures and consideration of antiviral therapy.
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Endothelial cells, through soluble mediators, play an important role in the regulation of the vascular tone. In the present paper we investigated whether endothelial tetrahydrobiopterin (BH4), an obligatory cofactor of nitric oxide (NO) synthase, could serve as such a regulatory mediator. By studying the human vascular endothelial hybrid cells EA hy 926, we found that 1) BH4 biosynthesis is highly regulated (70-fold) by activating and deactivating cytokines; that 2) up to 90% of the induced BH4 is released by activated endothelium, and 3) while intracellular BH4 could be related to cyclic GMP concentrations within the endothelial cells, the bulk of BH4 (up to 90 pmol/10(6) cells) appears not to serve endothelial cell requirements. Activation and deactivation of BH4 synthesis by cytokines was paralleled by other endothelial cell responses reflecting their activity. We propose that BH4 serves as an endothelial mediator augmenting the activity of cytokine-inducible NO synthase in vascular smooth muscle cells. BH4 could thereby account for endothelium-derived relaxing factor activity.
A 67-year old male patient was admitted to our clinic because of slowly developing dementia. Severe dysfunction of memory, confusional states and urinary incontinence were observed. A diagnosis of general paresis was made by positive serology for syphilis and CSF examination. The patient's condition improved markedly after high-dose penicillin G treatment.
At early developmental stages in the rat spinal cord (embryonic day 13), when neuronal progenitors are still proliferating, most differentiating neurons express truncated forms of glutamic acid decarboxylase (GAD) (approximately 25 kDa) which are the products of alternative splicing of the GAD67 gene. These truncated proteins do not appear to synthesize gamma-aminobutyric acid (GABA). The amino acid is detected in cells only after alternative splicing of the GAD67 gene generates a full-length, 67 kDa enzymatically active form of GAD. Both the 67 kDa GAD and GABA colocalize and appear diffusely distributed in the cytoplasm of embryonic neurons. GABA does not appear associated with synaptic vesicles until after birth, when its intracellular distribution becomes punctate and it colocalizes with synaptophysin. At this time, it also colocalizes with an immunologically distinct 65 kDa GAD protein encoded by a second GAD gene (GAD65). Expression of different GAD-related proteins with distinct intracellular distributions during development suggests that GABA, the product of these enzymes, may have trophic or metabolic roles during spinal cord differentiation.
Nitric oxide is a recently discovered biomolecule with a broad range of actions. The present study investigated the regulation of nitric oxide synthase activity by dexamethasone and the cofactor tetrahydrobiopterin in murine macrophages. The influence of the tetrahydrobiopterin biosynthesis inhibitors 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP cyclohydrolase I, and phenprocoumon, an inhibitor of sepiapterin reductase, on the synthesis of nitric oxide was investigated. Dexamethasone decreased the nitric oxide production due to direct inhibition of the induction of nitric oxide synthase and of GTP cyclohydrolase. Substitution of tetrahydrobiopterin via sepiapterin could not overcome the dexamethasone-mediated inhibition. 2,4-Diamino-6-hydroxypyrimidine abolished nitric oxide synthesis and synergized with dexamethasone, completely eliminating nitric oxide production. Phenprocoumon inhibited production of nitric oxide via interference with later steps of tetrahydrobiopterin biosynthesis. An exogenous supply of tetrahydrobiopterin through sepiapterin led to a further increase of nitric oxide production, even in fully activated macrophages. The amount of nitric oxide produced by murine macrophages is therefore limited by the amount of tetrahydrobiopterin present in the cells. Inhibitors of tetrahydrobiopterin biosynthesis could provide a novel approach for therapy of pathological conditions mediated by nitric oxide, such as septic shock.
The intravascular oxygenator (IVOX) is a new device which is implanted in the vena cava sup. and inf. where it oxygenates the blood and removes CO2. We report on its successful use in a young patient with severe pneumonia. This 21-year-old female was admitted to hospital with acute respiratory distress due to pneumococcal pneumonia and sepsis following chickenpox. Considering the rapidly progressive course with severe hypoxia and shock, PaO2/PaCO2 values of 6.5/6.4 kPa on mechanical ventilation with an FiO2 of 1.0 and a PEEP of 13 mbar, we decided to implant an intravascular oxygenator. Besides rapid improvement of oxygenation, we observed remarkable recovery of cardiovascular function such as an increase in mean arterial pressure and mixed-venous saturation, while the dose of vasopressors could be decreased. The intravascular oxygenator was removed without problems after 29 days of continuous use, when pulmonary function allowed an FiO2 of 0.45. The patient was discharged from the intensive care unit after 99 days in a good neurological and stable cardiovascular state.
One susceptible and two multiply resistant isolates of Listeria monocytogenes from a patient suffering from prosthetic valve endocarditis are described. They could not be distinguished by several typing methods. Two isolates were resistant to chloramphenicol, macrolide/lincosamide/streptogramin antibiotics and tetracycline. The resistance determinants were located on a 39 kb plasmid pWDB100 that was transferable by filter mating to several gram-positive bacteria. Evidence was obtained to support the hypothesis that the resistant variant had primarily infected the patient's blood and prosthetic valve, and later lost the resistance plasmid. The three resistance determinants showed homology to other known markers, cat221/cat223, ermB and tetM, which are frequently found in different gram-positive genera. Plasmid pWDB100 showed extensive homology to the Streptococcus agalactiae broad-host-range plasmid pIP501. It was also very similar to two listerial plasmids found in France. Thus, plasmid pWDB100 and the homologous plasmids from France, although isolated in geographically distant regions, may illustrate spread of a plasmid and its relatives.
A murine endothelial cell line, send1, was found to produce substantial amounts of nitric oxide, particularly after activation with cytokines. The endothelial cell activation paralleled that of macrophages. Macrophage deactivation opposing activation has recently been brought into focus. We therefore studied the cytokine-mediated deactivation of endothelial cells in send1 and vascular strips. Our observations document that activation of nitric oxide synthase of endothelial cells can be counterbalanced by deactivating cytokines such as interleukin-4, interleukin-8, interleukin-10 and transforming growth factor-beta. Deactivation of nitric oxide synthase in endothelial cells might be an essential mechanism for the control of immune-mediated vasodilatation or septic shock and represents a novel mechanism of communication between the immune and the vascular systems.
Nitric oxide synthase (NOS) has received immense interest as an antimicrobial and antitumoral effector system of mononuclear phagocytes from rodents. Because there is increasing doubt that an analogous system exists in human macrophages, NOS was reexamined in these cells. Under tightly controlled conditions, with murine macrophages as positive controls, human macrophages failed to secrete nitric oxide (< 0.1 mumol/10(6) cells/24 h), even after activation with endotoxin, interferon-gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, bacteria, or proliferating lymphocytes. The discrepancy between murine and human macrophages depended on neither the anatomic source (blood, peritoneum), the agent used for activation, nor the duration of activation. NOS activity was paralleled by metabolization of L-arginine to L-citrulline. Exogenous tetrahydrobiopterin, an essential cofactor of NOS not synthesized by human macrophages, did not support NOS activity in human macrophages. Also, no NOS activity was found in cellular subfractions of human macrophages. It appears that in humans, the inducible high-output NOS is not conserved as an antimicrobial system of macrophages.
The incidence of infective endocarditis in drug addicts is increasing with the spreading of intravenous drug abuse. The tricuspid valve is the most commonly involved valve followed by the mitral valve. We evaluated prospectively 22 patients with a mean age of 23 years, presenting with addiction-associated endocarditis endocarditis and referred to our institution during a three-year period. The tricuspid valve was involved in 13 instances, mitral valve in 4, mitral plus tricuspid valve in 5 patients and aortic valve in 1 case. Staphylococcus aureus was the most frequent infective organism (15x), followed by Streptococci (4x), Corynebacteria (2x) and one case with a mixed infection. Six patients were positive for an HIV-infection and 17 had evidence for a chronic viral hepatitis. Ten patients (3 of them HIV-seropositive) were treated surgically. Resection of the tricuspid valve with (1x) or without replacement (4x), resection of vegetations and valve repair (2x), mitral valve replacement (2x), aortic valve replacement (1x) were performed. In case of tricuspid endocarditis, the decision whether to proceed with resection, repair or replacement with a bioprosthesis was taken according to valve pathology and the psycho-social situation of the patient. When the vegetations involved only one leaflet and could be removed easily, vegetectomy with annuloplasty or with repair using autologous pericardium was performed. Valvulectomy without replacement was the chosen method for those where persistent or recurrent drug abuse could not be excluded. A bioprosthesis was inserted when the tricuspid valve was completely destroyed and there was a proven abstinence from drugs over a period of several weeks preoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)
The incidence of infective endocarditis in drug addicts is increasing with the spread of intravenous drug abuse. The tricuspid valve is involved most commonly, followed by the mitral. We evaluated 22 patients prospectively with a mean age of 23 years, presenting with addiction-associated endocarditis and referred to our institution during a three-year period. The tricuspid valve was involved in 13 instances, the mitral in four, mitral plus tricuspid valves in five patients and the aortic valve in one. Staphylococcus aureus was the most frequent infective organism (15 cases), followed by streptococci (4 cases), corynebacteria (2 cases) and one case with a mixed infection. Six patients were HIV positive and 17 had evidence of chronic viral hepatitis. Ten patients (three of them HIV positive) were treated surgically. Resection of the tricuspid valve with (one case) or without replacement (four cases), resection of vegetations and tricuspid repair (two cases), mitral valve replacement (2 cases) and aortic valve replacement (one case) were performed. Operative mortality (< 30 days) was high (2/10, 20%); one patient died from cerebral hemorrhage and another from multi-organ failure. Another three patients died after a mean follow up of 10 months. In 12 patients, surgery was not attempted because of still existing intravenous drug abuse or renal and liver failure. Five of these patients died after a mean follow up of 13 months, two from septicemia, two from AIDS-related complications and one from drug overdose. The prognosis of drug-associated endocarditis treated with antibiotics is generally good.(ABSTRACT TRUNCATED AT 250 WORDS)
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The co-localization of activated macrophages and damaged neurons observed in brain injury and degenerative brain diseases may hint to macrophage-induced neuronal cytotoxicity. Recently, macrophages have been found to secrete neurotoxic molecules such as radical oxygen intermediates and glutamate, the latter interacting with N-methyl-D-aspartate (NMDA) receptors. As shown in the present study, brain macrophages termed microglial cells co-cultured with differentiated cerebellar neurons excert potent neurotoxic effects. Neurotoxicity is unlikely to be due to cytokines since tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6 and interferon (IFN)-alpha/IFN-beta/IFN-gamma had no such effects. In contrast, when treating neurons with H2O2 or oxygen radical-generating systems cytotoxicity was induced. Furthermore, microglia were found to produce O2- and H2O2 when triggered with phorbol 12-myristate 13-acetate. However, in co-cultures of neurons and microglia, oxygen-radical scavengers catalase and superoxide dismutase, failed to protect neurons from microglia-induced killing. Moreover, when using undifferentiated neurons which are susceptible to H2O2 but not to NMDA receptor-dependent killing, microglia did not destroy the neurons. Thus, the amount of reactive oxygen intermediates produced by microglia in co-culture do not reach the critical concentrations required for neurotoxicity. As dibenzocyclohepteneimide, an antagonist to NMDA receptors neutralized neurotoxicity in microglia-neuronal co-cultures, excitatory amino acids released by microglia are suggested to compose the major determinant of neurotoxicity.