[New preventive antimalaria drug. 3 tables, 2 months of protection. Interview by Petra Eiden].
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Biomedical subjects
Publications and source records attributed to P Kremsner.
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In a prospective study, 17 Brazilian patients with parenchymatous neurocysticercosis were monitored for a period of 12 months after treatment with praziquantel. Taenia solium-specific IgG antibodies, interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha, neopterin, and soluble interleukin-2 receptor (sIL-2R) were measured in serum and CSF before starting the therapy, on the last day of treatment, 5 weeks after treatment, and 3, 6, and 12 months after treatment. The most common symptoms and signs found in patients before treatment were headache, neck stiffness, and seizures. Six months after commencement of therapy, 13 of the 17 patients were free of complaints. Clinical normalization was paralleled by a significant decrease (p < 0.05) in the amount of intrathecally produced anti-T solium IgG 1 year after treatment. IL-1 beta was undetectable in serum at all times, whereas in the CSF it was within the normal range during the whole study period. The mean concentration of sIL-2R in the CSF was 65 kU/l (normal, < 50 kU/l) 5 weeks after treatment, whereas in all subsequent investigations sIL-2R was undetectable. The median CSF neopterin level was slightly elevated before treatment (6.8 nmol/l). One year after treatment, it had dropped by 69% (p < 0.001) to a median value of 2.1 nmol/l. The size of planimetrically measured focal cystic brain lesions on CT correlated with the amount of intrathecally synthesized anti-T solium IgG at the end of the study (r = 0.89, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of tumour necrosis factor-alpha on malaria-infected mice was studied. C57Bl/6J mice infected with Plasmodium berghei K173 exhibited an increased sensitivity to exogenous TNF. Injection of 15 micrograms TNF was lethal to some of the animals when given 5-7 days after infection, while when given later on in the infection (i.e. days 8-10) amounts as low as 2.5 micrograms TNF appeared to be lethal in all mice. The pathology in infected mice treated with TNF resembled that found in the brains of infected mice dying with cerebral malaria. Infected mice treated with TNF, however, also developed severe pathological changes in other organs. On the contrary, treatment with sublethal amounts of TNF (1.0 micrograms or less) given on days 8 and 9 after infection, protected mice against the development of cerebral malaria. In addition, infected mice exhibited and enhanced sensitivity for treatment with lipopolysaccharide (LPS). Sublethal amounts of LPS, however, did not prevent mortality as in TNF-treated mice (LPS-treated mice died at about the same time as infected mice that developed cerebral malaria), but no cerebral haemorrhages were found in the majority of LPS treated, infected animals. Treatment with dexamethasone during infection protected mice against the development of cerebral malaria, but did not suppress their increased sensitivity to exogenous TNF. Treatment of mice with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP), used to eliminate macrophages (an important source of TNF), prevented the development of cerebral malaria, but only when given before day 5 of infection. Mice protected by treatment with lip-Cl2MDP, however, remained sensitive for LPS on the eighth day of infection.
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Elevated serum or plasma concentration of immunoreactive tumor necrosis factor (TNF) is consistently detected in patients with malaria. TNF levels correlate with high parasitemia and clinical severity but not always with outcome. Since the effects of TNF may be neutralized by soluble TNF receptors, sera of 30 nonimmune patients with malaria were analyzed before and during antimalarial therapy. High concentrations of receptors R1 (55 kDa) and R2 (75 kDa) were detected immunologically in all sera of untreated patients. Levels of immunoreactive TNF correlated closely with levels of soluble TNF R1 and R2 (r = .75 and .59, respectively). In contrast, sera lacked cytotoxic activity against target cells in the TNF bioassays. Soluble TNF receptor levels remained elevated for days after treatment. These results suggest that excessive release of TNF induced by the asexual stage of malaria parasites is controlled by a subsequent shedding of soluble TNF receptors that may bind and deactivate biologically functional TNF.
Immunohistological studies of tuberculoid leprosy lesions (TT-lesions) showed a dense, well organized granuloma consisting of a central area with epitheloid and giant cells containing interferon-gamma (IFN-Gamma) and CD3+, CD4+ T helper/inducer (Th/i) cells, a considerable proportion of which expressed the interleukin-2-receptor (IL-2 R). This central area was surrounded by round cells which consisted mainly of CD3+/CD8+ T cytotoxic/suppressor (Tc/s) lymphocytes. The overlying keratinocytes (KC) were strongly positive for HLA-DR antigens on the surface, indicating high intralesional IFN-Gamma activity. In contrast, lepromatous leprosy lesions (LL-lesions) showed a disorganized infiltrate composed by foamy cells and round cells, the latter mainly expressing the CD3+/CD8+ phenotype. IFN-Gamma activity could not be detected within the lesions. The KC overlying the infiltrate were consistently negative for HLA/DR reactivity pointing to a defective intralesional IFN-Gamma production in LL patients. Two out of four patients with LL leprosy could be sensitized with dinitrochlorobenzene (DNCB). The eliciting of DNCB skin reactions within the LL-lesion led to the recruitment of new infiltrating cells; the resulting infiltrate resembled a local reversal towards the tuberculoid pole of leprosy.
Gastroenteritis may be due to many agents, infectious or non infections. Most cases of infections diarrhea are selflimited--e.g. food born intoxications with 1 to 2 days duration or infections with enteropathogenic E. coli, Salmonella spp., Vibrio parahaemolyticus or rota virus. Even the majority of shigellosis, salmonella-gastroenteritis and infections with Campylobacter fetus cease without treatment within 4 days. Fever and diarrhea persisting for more than 4 days justify the use of antibiotics, favourably trimethoprim and quinolones. Fluid and electrolyte replacement is the mainstay of treatment. Antimotility agents worsen some forms of diarrhea (especially these due to enteroinvasic bacteria) by retarding the natural purgative effect of diarrhea.
A randomized double blind study in long term malaria chemoprophylaxis was performed to compare the tolerability of Fansimef (1 tablet containing 250 mg mefloquine + 500 mg sulfadoxine + 25 mg pyrimethamine per week) with chloroquine (300 mg per week). 211 Austrian industrial workers and their families in Warri, Nigeria, participated in this study; 101 received Fansimef and 110 chloroquine for 3-18 months (mean 41 weeks). Prophylaxis was discontinued because of adverse effects in 7 volunteers in the Fansimef group (mainly insomnia, palpitations, dizziness, nausea and headache) and in 2 volunteers of the chloroquine group (headache and loss of hair in one volunteer, nausea, dizziness and vomiting in the other). Most of the adverse effects could be due to the mefloquine component. A few minor complaints of burning eyes, nausea and gastric pain were reported in both groups. Laboratory checks performed at 3-monthly intervals showed a slight, transient and clinically irrelevant (but statistically significant) increase of serum glutamic-oxalacetic transaminase and gamma-glutamyl transpeptidase at month 3 in the Fansimef group. An attack of acute Plasmodium falciparum malaria occurred in one volunteer 6 weeks after discontinuation of prophylaxis with Fansimef. Antibodies against blood stage parasites could be demonstrated by the indirect immunofluorescence test at different stages of the study, indicating that these two antimalarials are not causal prophylactic agents.
Yeast-derived hepatitis B vaccines (partially purified or highly purified) at different dosages and a plasma-derived hepatitis B vaccine (control) were injected into 50 young volunteers 3 times at monthly intervals. Before and 4 weeks after this series of immunizations, blood samples were drawn and tested for presence of IgE and IgG antibodies against yeast antigens. No rise in IgE antibodies against Saccharomyces cerevisiae antigens nor in IgG antibodies against Candida albicans antigens was found. Together with former clinical results this underlines the experience that type I and type III reactions against putative yeast contaminants apparently play no major role after immunization with recombinant hepatitis B vaccines.
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Healthy young adult volunteers, 778 in number, without HBV markers were randomly distributed into groups and administered different lots of a yeast-derived hepatitis B vaccine (YDV) at different dose levels or a commercial plasma-derived vaccine (PDV), according to a 0, 1, 2, 12-month vaccination schedule. The YDV proved to be safe and well tolerated, even when partly purified lots were given. Reactions were mild and transient, comparable to those observed after PDV. One month after three YDV doses, 0-7% of subjects overall had failed to seroconvert; all those evaluated one month after the booster dose had seroconverted. No significant difference was found between the two vaccine types as far as seroconversion rates were concerned. Geometric mean anti-HBs levels following three vaccine doses were higher in seroconverters of the PDV groups. However, a booster dose of YDV resulted in high anti-HBs levels in all groups varying from 11,474 to 51,404 IU l-1 (purified YDV lot), 4915 to 18,832 IU l-1 (partly purified YDV lots) and 11,008 to 15,805 IU l-1 (PDV lots). Of seroconverters to the purified lots of YDV 93% attained 1000 IU l-1 after the booster dose, thus ensuring protection for a number of years. Dose-response studies provided a basis for the selection of 20 micrograms of highly purified YDV as the standard dose.
We report the case of a patient who acquired cutaneous leishmaniasis in Israel, with multiple lesions on the face and wrists. The diagnosis was made several months after the onset of disease. We observed large multiple ulcers, which at first responded to sodium stibogluconate (600 mg daily for 2 weeks). After initially decreasing in size, the lesions remained unchanged. Several weeks later clinical exacerbation of the cutaneous leishmaniasis was observed. Fearing late complications on the upper eyelid, we administered two 2-week courses of ketoconazole, 800 mg daily. The early and rapid improvement achieved indicates that ketoconazole was successful in this case of cutaneous leishmaniasis.
Several lots of a yeast-derived hepatitis B vaccine at different doses and a 20 micrograms dose of plasma-derived vaccine were tested in young healthy adults and compared with respect to risk of hypersensitivity reactions, reactogenicity, and immunogenicity. No signs of hypersensitivity either pre-existing or vaccine-induced were observed. Reactogenicity was low and similar in all vaccine groups. It was not dose related and unaffected by the number of injections. Immunogenicity was evaluated for a 0, 1, 2, and 12 month vaccination schedule. Seroconversion rates (greater than or equal to 10 IU/l) were not significantly different between the purified yeast- and plasma-derived vaccines one month after the second vaccination whereas the percentage of seroconversion was slightly lower in the groups receiving only partly purified recombinant vaccines. Although geometric mean titres induced by the plasma-derived vaccine were somewhat higher after the first months, the antibody titres induced by the recombinant vaccine were at least as high as those elicited by a plasma-derived vaccine following the booster dose.
Protection against hepatitis B virus infection can be achieved by the induction of neutralizing antibodies against the hepatitis B surface antigen (HBsAg). An antibody concentration of 10 IU/l, as measured by radioimmunoassay, is considered to be protective. HBsAg can be produced either from the plasma of chronic carriers or by DNA recombinant technology in yeast cells. Plasma- and yeast-derived vaccines have been compared in several studies and their immunological properties were found to be similar, including the persistence of antibodies induced by either type of vaccine. Finally, yeast-derived hepatitis B vaccine can boost anti-HBs responses initially elicited by either plasma- or yeast-derived vaccine equally and effectively. In order to maintain protective immunity after hepatitis B vaccination, antibody determination and, if necessary, booster vaccination should be performed, particularly in high-risk persons.
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