With an incidence of 15/10(5) in the general population, brain metastases constitute a serious, debilitating complication in cancer patients. The majority of those patients suffer from more than one metastasis, but up to 30% to 40% present with a solitary lesion. Whole-brain radiotherapy (WBRT) extends median survival from 1 to 2 months for treatment with steroids only, to 4 to 6 months in most series. However, long-term survival (>1-2 years) is observed in up to 10% of patients with favorable prognostic factors, such as solitary lesions, good Karnofsky performance status, and absence of extracranial disease. For those patients, individually optimized treatment is worthwhile. For good-prognosis patients with controlled extracranial disease, surgery in combination with postoperative WBRT should be considered, especially when fast relief of symptoms is mandated. For surgically inaccessible solitary lesions below a size threshold of approximately 30 ccm, stereotactic radiosurgery (RS), although never compared to surgery in a randomized fashion, seems to yield comparable results and is the treatment of choice for more than one lesion in appropriately selected patients. Nevertheless, a number of questions concerning the optimal treatment regimens for brain metastases remain. These mainly concern the radiation dose, need for a combination of RS and WBRT, relative timing of different treatment modalities, and maximum number of brain metastases that can reasonably be treated with RS when long-term progression-free survival is the goal. However, RS is definitely an excellent option for salvage and palliation in patients with short life expectancy, as it is simultaneously noninvasive and cost-effective, with short hospitalization times.

Brain Neoplasms↗

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Antibacterial effects of niridazole: its effect on microaerophilic campylobacter.

Niridazole, a nitrothiazole derivative, exhibited marked antimicrobial activity against a group of microaerophilic campylobacter. MICs ranged from 0.0037 to 2.0 mg/l, with an average of 0.25 mg/l. The activity of niridazole was compared to that of chemically related compounds (metronidazole, ornidazole, tinidazole). Although their activities ran parallel, niridazole was found to be markedly more potent. Thirteen other common antibiotics were also inferior to niridazole with respect to their inhibitory effect. The antibacterial activity of niridazole was bactericidal. Its in vivo activity was also tested in mice infected orally with campylobacter. The organisms, which caused a chronic colonization of the gut in untreated animals, disappeared rapidly from the faeces after treatment with niridazole, at least in the case of a highly susceptible campylobacter strain.

Animals↗

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Comparative therapeutic activities of ciprofloxacin, amoxicillin, ceftriaxone and co-trimoxazole in a new model of experimental infection with Escherichia coli.

A new mouse model for systemic infection with Escherichia coli is presented. Whereas in other models 10(7)-10(8) bacteria have to be injected into an animal to induce toxic effects resulting in death within 24 hours, now, only 10(3)-10(4) bacteria of an appropriate strain are required to produce a genuine infection characterized by an increase in the bacterial load over several days. The quantitative determination of bacterial counts per liver allows a more sensitive measurement than recording death rates. Furthermore, few animals are required for a definite result in contrast to the LD50 determination of other models. The salient point regarding this new model is that conditioning of animals has to be achieved by incorporating the inoculum into agar which is injected subcutaneously. The resulting infection is completely dependent on the E. coli strain used. Whereas a hemolytic, uropathogenic strain is so virulent that an overwhelming infection develops within 48 hours after the injection of 10(3) bacterial cells, a non-hemolytic variant of this strain is completely avirulent, being unable to multiply in spite of the potentiating agar. The hemolytic E. coli strain ATCC 25922 is intermediate in virulence. The bacterial counts per liver increase steadily until death occurs five to seven days after the injection of 10(4) bacteria. This bacterial infection can be therapeutically influenced by daily treatment with various drugs. Ciprofloxacin, ceftriaxone and co-trimoxazole are able to cure the infection, whereas amoxicillin given orally is only moderately active against this ATCC strain, which is relatively resistant to amoxicillin.

Amoxicillin↗

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Lack of synergism of ampicillin and gentamicin in experimental listeriosis.

Strain SLCC 4013 of Listeria monocytogenes is susceptible in vitro to ampicillin (MIC 0.5 mg/l) as well as to gentamicin (MIC 0.5 mg/l). Whereas treatment of mice infected with this virulent strain with 0.5 mg ampicillin twice a day resulted in a marked decrease in bacterial counts per spleen, the administration of 2 mg gentamicin twice a day hardly reduced bacterial multiplication. The combination of both drugs was not much more effective than ampicillin alone. Thus, a synergistic effect of both these antibiotics on intracellularly growing bacteria could not be demonstrated.

Ampicillin↗

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Listeriosis--a puzzling disease.

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Aged↗

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The role of macrophages in primary and secondary infection of mice with Salmonella typhimurium.

Elimination of macrophages with high-molecular dextran sulphate (DS) markedly impairs resistance of mice to primary infection with smooth, virulent strains of Salmonella typhimurium, whereas stimulation of this system by killed Bordetella pertussis organisms increases resistance. In infection with rough, avirulent strains of S. typhimurium the elimination of macrophages was not followed by an essential loss of resistance, and it appears that other non-specific defence mechanisms, for example the complement system, may have compensated for the lack of macrophages. Macrophages, therefore, play an important role in defence during primary infection with virulent strains. In immunity to challenge infection with S. typhimurium, macrophages play an even more significant role. Treatment with DS completely removes immunity, and both humoral and cell-mediated immune mechanisms seem to require the participation of macrophages.

Animals↗

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Salmonella typhimurium strains carrying haemolysin plasmids and cloned haemolysin genes from Escherichia coli.

Like all other Salmonella typhimurium strains examined, the smooth variants SF1397 (LT2) and 1366 and also their semi-rough and rough derivatives are non-haemolytic. Nevertheless, two haemolysin (Hly) plasmids of E. coli belonging to the inc groups incFIII,IV (pSU316) and incI2 (pHly152) were able to be introduced into these strains by conjugation and stably maintained. A considerable percentage of the Hly+ transconjugants obtained had lost parts of their O-side chains, a result of selection for the better recipient capability of "semi-rough" variants rather than the direct influence of the Hly+ plasmids themselves. In contrast to the incFIII,IV plasmid pSU316, which exhibited higher conjugation rates with rough recipients, the incI2 plasmid pHly152 was accepted best by smooth strains. Transformation with cloned E. coli haemolysin (hly) determinant was inefficient (less than 10(-6)) for smooth strains, but 10(2) - 10(3) times higher for rough recipients, and was increased by the use of Salmonella-modified DNA. The transformants and transconjugants were relatively stable and showed the same haemolytic activity as the E. coli donor strains. The virulence of the Hly+ smooth, semi-rough and rough S. typhimurium strains was tested in two mouse models, and neither the mortality rate nor the ability to multiply within the mouse spleen was influenced by the hly determinants.

Animals↗

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Molecular analysis of bacterial cytolysins.

Results of molecular and pathogenic studies of three different bacterial hemolysins (cytolysins) are presented. These exoproteins derive from the two gram-negative bacteria Escherichia coli and Aeromonas hydrophila and from the gram-positive pathogen Listeria monocytogenes. The hemolysin of E. coli is determined by an 8-kilobase (kb) region that includes four clustered genes (hlyC, hlyA, hlyB, and hlyD). This hemolysin determinant is part either of large transmissible plasmids or of the chromosome. The genes located chromosomally are found predominantly in E. coli strains that can cause pyelonephritis and/or other extraintestinal infections. A detailed analysis of the chromosomal hyl determinants of one nephropathogenic E. coli strain revealed the existence of specific, large chromosomal insertions 75 kb and 100 kb in size that carry the hly genes but that also influence the expression of other virulence properties, i.e., adhesion and serum resistance. The direct involvement of E. coli hemolysin in virulence could be demonstrated in several model systems. The genetic determinants for hemolysin (cytolysin) formation in A. hydrophila (aerolysin) and L. monocytogenes (listeriolysin) are less complex. Both cytolysins seem to be encoded by single genes, although two loci (aerB and aerC) that affect the expression and activity of aerolysin have been identified distal and proximal to the structural gene for aerolysin (aerA). Cytolysin-negative mutants of both bacteria were obtained by site-specific deletion and/or transposon mutagenesis. These mutants show a drastic reduction in the virulence of the respective bacteria.

Aeromonas↗

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Fungicidal effect of tyrothricin on Candida albicans.

Tyrothricin, a polypeptide antibiotic, is active against yeast cells. Tyrothricin was rapidly fungicidal towards Candida albicans. Concentration of four times the minimum inhibitory (25 mg l-1) reduced the yeast numbers by more than 3 log10 within 1 h. Similar results were obtained in a flow cytometric antifungal activity assay using the new two-colour probe for yeast viability, FUN-1, which measures impairment of metabolic activity. The respiratory activity of Candida albicans, measured in a XTT kinetic assay, was significantly reduced in comparison with controls by 3.12 mg l-1 of the substance. Because fungicidal concentrations of tyrothricin are locally achievable in patients, an evaluation of the local effect of tyrothricin in patients suffering from mucosal infections with Candida species should be considered.

Antifungal Agents↗

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Activated CD8+ T cells are involved in elimination of Candida albicans from the livers of mice.

We have investigated the course of infection of Balb/c mice with Candida albicans. After intravenous infection of mice, the yeasts were evenly distributed in the liver sections. There was a 90% reduction in the yeasts found within 7 days after infection. This reduction was accompanied by an increase in the number of phagocytic cells (Mac-1+, Gr-1+) in cellular infiltrates around the yeast cells. Furthermore, both CD4+ and CD8+ T lymphocytes were found in these pseudogranulomata, with the CD8+ cells in the periphery. Peak amounts of the cell types investigated were found at days 5 and 6 post infection, with an increased expression of receptors for interleukin 2 (IL-2R) on the surface of CD8+ cells. At day 14 of infection, the same levels as those in control mice were reached. At this time, the yeasts were virtually eliminated from the liver. By using simultaneous detection of cell surface markers and yeast cells in immunohistology, these data demonstrate the close association of fungal cells, phagocytes, TH and TC cells in pseudogranulomata during elimination of Candida albicans from the livers of mice.

Animals↗

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Infection of congenitally athymic (nude) mice with Toxoplasma gondii.

Nude mice, congenitally lacking most thymus-derived lymphocytes, are neither more susceptible nor more resistant against primary infection with virulent T. gondii cells than normal control mice. Both mouse groups died at the same time after intraperitoneal infection. Treatment with sulfadiazine protected both mouse groups against acute fatal disease. After termination of treatment with sulfadiazine the Nude mice gradually died, whereas the normal hairy mice survived. The latter had developed high amounts of antibodies and protective immunity to an otherwise lethal challenge infection. In the serum of Nude mice no antibodies could be detected. Pathologic alterations existed in the livers of Nude mice at the time of death.

Animals↗