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H K Johansen

Publications and source records attributed to H K Johansen.

At least 19 recordsLinked to original sources
PubMed2006

Voriconazole versus amphotericin B in cancer patients with neutropenia.

BACKGROUND: Opportunistic fungal infections are a major cause of morbidity and mortality in neutropenic cancer patients and antifungal therapy are used both empirically and therapeutically in these patients. OBJECTIVES: To compare the benefits and harms of voriconazole with those of amphotericin B and fluconazole when used for prevention or treatment of invasive fungal infections in cancer patients with neutropenia. SEARCH STRATEGY: MEDLINE and the Cochrane Library (May 2005). Letters, abstracts and unpublished trials were accepted. Contact to authors and industry. SELECTION CRITERIA: Randomised trials comparing voriconazole with amphotericin B or fluconazole. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by two authors independently. MAIN RESULTS: Two trials were included. One trial compared voriconazole to liposomal amphotericin B as empirical treatment of fever of unknown origin (suspected fungal infections) in neutropenic cancer patients (849 patients, 58 deaths). The other trial compared voriconazole to amphotericin B deoxycholate in the treatment of confirmed and presumed invasive Aspergillus infections (391 patients, 98 deaths). In the first trial, voriconazole was significantly inferior to liposomal amphotericin B according to the authors' prespecified criteria. More patients died in the voriconazole group and a claimed significant reduction in the number of breakthrough fungal infections disappeared when patients arbitrarily excluded from analysis by the authors were included. In the second trial, the deoxycholate preparation of amphotericin B was used without any indication of the use of premedication and substitution with electrolytes and salt water to avoid handicapping this drug. This choice of comparator resulted in a marked difference in the duration of treatment on trial drugs (77 days with voriconazole versus 10 days with amphotericin B), and precludes meaningful comparisons of the benefits and harms of the two drugs. AUTHORS' CONCLUSIONS: Liposomal amphotericin B is significantly more effective than voriconazole for empirical therapy of neutropenic cancer patients and should be preferred. For treatment of aspergillosis, there are no trials that have compared voriconazole with amphotericin B given under optimal conditions.

Amphotericin B↗
PubMed2004

House dust mite control measures for asthma.

BACKGROUND: The major allergen in house dust comes from mites. Chemical, physical and combined methods of reducing mite allergen levels are intended to reduce asthma symptoms in people who are sensitive to house dust mites. OBJECTIVES: To assess the effects of reducing exposure to house dust mite antigens in the homes of people with mite-sensitive asthma. SEARCH STRATEGY: Cochrane Airways Group trials register, and PubMed and The Cochrane Library (last searches June 2004), reference lists. SELECTION CRITERIA: Randomised trials of mite control measures vs placebo or no treatment in asthmatic people known to be sensitive to house dust mites. DATA COLLECTION AND ANALYSIS: Two reviewers applied the trial inclusion criteria, assessed their quality and extracted the data independently. Study authors were contacted to clarify information. MAIN RESULTS: Forty-nine trials (2733 patients) were included; the number of patients has more than doubled since the last version of this review. Thirty-one trials assessed physical methods, ten assessed chemical methods, and eight a combination of chemical and physical methods. Despite the fact that many trials were of poor quality and would be expected to exaggerate the reported effect, we did not find an effect of the interventions. For the most frequently reported outcome, peak flow in the morning (1339 patients), the standardised mean difference was -0.02 (95% confidence interval (CI) -0.13 to 0.08). There were no statistically significant differences either in number of patients improved (relative risk 1.01, 95% CI 0.80 to 1.27), asthma symptom scores (standardised mean difference -0.01, 95% CI -0.10 to 0.13), or in medication usage (standardised mean difference -0.05, 95% CI -0.18 to 0.09). REVIEWERS' CONCLUSIONS: Chemical and physical methods aimed at reducing exposure to house dust mite allergens cannot be recommended. It is doubtful whether further studies, similar to the ones in our meta-analysis, are worthwhile. If other types of studies are considered, they should be methodologically rigorous and use other methods than those used so far, with careful monitoring of mite exposure and relevant clinical outcomes.

Allergens↗
PubMed2004

Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis.

BACKGROUND: The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs. OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and non-steroidal, anti-inflammatory drugs in patients with rheumatoid arthritis. SEARCH STRATEGY: PubMed, The Cochrane Central Register of Controlled Trials (CENTRAL ), reference lists were searched until February 2004. SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a non-steroidal, anti-inflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. For adverse effects, long-term trials and matched cohort studies were also selected. DATA COLLECTION AND ANALYSIS: Decisions on which trials to include were made independently by two observers based on the methods sections of the trials. Standardised mean difference (random effects model) was used for the statistical analyses. MAIN RESULTS: Ten studies, involving 320 patients, were included. Prednisolone had a marked effect over placebo on joint tenderness (standardised mean difference 1.30, 95% confidence interval 0.78 to 1.83), pain (1.75, 0.87 to 2.64) and grip strength (0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than non-steroidal, anti-inflammatory drugs on joint tenderness (0.63, 0.11 to 1.16) and pain (1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable. REVIEWERS' CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.

Anti-Inflammatory Agents↗
PubMed2001

Mechanisms of endothelin receptor subtype-specific targeting to distinct intracellular trafficking pathways.

We recently reported that the endothelin (ET) receptor subtypes ET(A) and ET(B) are targeted to distinct intracellular destinations upon agonist stimulation (Bremnes, T., Paasche, J. D., Mehlum, A., Sandberg, C., Bremnes, B., and Attramadal, H. (2000) J. Biol. Chem. 275, 17596-17604). The ET(A) receptor was shown to follow the recycling route of transferrin, whereas ET(B) is targeted to lysosomes for degradation. In the present study we have investigated the mechanisms of ET receptor subtype-specific targeting to distinct intracellular trafficking pathways. Truncation mutants of the ET(A) and ET(B) receptors with deletions of the cytoplasmic carboxyl-terminal tail distal to the palmitoylation site were found to mediate inositol phosphate accumulation and to internalize upon agonist stimulation, although internalization occurred at a slower rate as compared with the wild-type receptors. However, the truncated ET(A) receptor was no longer able to undergo recycling. Rather, both truncation mutants were recognized by beta-arrestin for recruitment to endocytosis and were sorted to lysosomes by a dynamin-dependent internalization pathway. Furthermore, studies of chimeric ET(A) and ET(B) receptors where the cytoplasmic tail of ET(A) was swapped with the corresponding domain of ET(B), and vice versa, revealed that the cytoplasmic tail of ET(B) is required for efficient lysosomal sorting and that signals for targeting to recycling reside in the cytoplasmic tail of the ET(A) receptor.

Animals↗
PubMed2001

Autoantibodies to pancreatic hsp60 precede the development of glucose intolerance in patients with cystic fibrosis.

Persons expressing the genetic disease cystic fibrosis (CF) suffer from a high risk of developing impaired glucose tolerance and diabetes. The development of diabetes in CF has been attributed, in the past, to the destruction of pancreatic islets and their resident beta-cells secondary to the destruction of the surrounding tissue by mechanical clogging of the pancreatic exocrine ducts. However, the discovery that autoimmunity to the 60-kDa heat shock protein (hsp60) may cause type I diabetes in NOD mice raises the possibility that hsp60 autoimmunity may be involved in CF diabetes too; could the hyperimmunization to bacterial hsp60 characteristic of CF spread to self-hsp60 and hence to autoimmune diabetes? We now report that rising levels of IgG autoantibodies to hsp60 do indeed precede the appearance of glucose intolerance and diabetes in CF patients. We produced a recombinant human pancreatic hsp60 protein and investigated the IgG antibody response to hsp60 in prediabetic and non-diabetic patients with CF. To detect hsp60 autoantibodies in the presence of high levels of antibodies to bacterial hsp60, we absorbed test sera with the 60-kDa GroEL of Pseudomonas aeruginosa and used an immunostaining technique. Using this technique, 32 prediabetic CF patients were evaluated over a five-year period, three years, on the average, before the onset of glucose intolerance. We found that a significant increase in hsp60 autoantibody preceded impaired glucose tolerance (P=0.042, n=17), diabetes (P=0.011, n=15) and glucose intolerance (P=0.005, n=32). As has been observed in NOD mice and in type I diabetic patients, the hsp60 autoantibodies decline at the outbreak of glucose intolerance in the CF patients. The association of CF diabetes with the rise and fall of hsp60 autoimmunity suggests that the pathogenesis of the diabetes may not be merely mechanical, but arise in the wake of bacterial hyperimmunisation.

Adolescent↗
PubMed2001

Relative increase in IgG antibodies to Pseudomonas aeruginosa 60-kDa GroEL in prediabetic patients with cystic fibrosis.

In recent years research has focused on a possible connection between bacterial infection and development of diabetes mellitus. In this study, serum antibody responses against bacterial antigens in diabetic and nondiabetic patients with cystic fibrosis (CF) were evaluated. The first part of the study included 252 CF patients of whom 46 (18 %) had diabetes. This study showed that precipitating antibodies (precipitins) against Pseudomonas aeruginosa and other bacteria in crossed immunoelectrophoresis, and IgG antibodies against a 60-kD GroEL of P. aeruginosa, were highly variable and positively correlated with age. Patient material matched for age and sex showed no significant difference between diabetic and nondiabetic CF patients in precipitins or IgG antibodies to P. aeruginosa GroEL. Two longitudinal studies of 9 and 5 y using retrospectively selected sera from 29 prediabetic and 29 cross-matched nondiabetic CF patients were performed. As to precipitins against P. aeruginosa, we found no difference between the prediabetic and the nondiabetic group of patients during the study period. The study revealed, however, a significant increase of 24.6 % (p = 0.008) of IgG antibodies against P. aeruginosa 60-kD GroEL, 3-12 mo before the onset of diabetes in patients with CF, compared with an overall increase of 5 % to 6 % per year in both groups during the observation period. This study shows that diabetes in CF appears after a peak of serum IgG antibodies against GroEL and indicates that development of diabetes in CF patients may not only be caused by a progressive fibrosis of the pancreatic tissue, but may be augmented by a short-term specific immunologic reaction, initially triggered by an ongoing and progressive pulmonary infection.

Adolescent↗
PubMed2000

Routine versus selective antifungal administration for control of fungal infections in patients with cancer.

BACKGROUND: Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever. OBJECTIVES: The objective of this review was to assess the effect of antifungal drugs in cancer patients with neutropenia. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register (October 1997), MEDLINE (to September 1997) and the reference lists of articles. We searched the proceedings of the ICAAC, General Meeting of the ASM (from 1990 to 1995), and the 7th European Congress of Clinical Microbiology and Infectious Diseases (1995) and contacted researchers in the field. SELECTION CRITERIA: Randomised trials of amphotericin B, AmBisome, fluconazole, ketoconazole, miconazole, or itraconazole compared with placebo or no treatment in cancer patients with neutropenia. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial eligibility, methodological quality and abstracted data. MAIN RESULTS: Twenty-five trials involving 2912 patients were included. In 19 trials, prophylactic or later treatment with antifungal drugs had no effect on mortality (odds ratio 0.92, 95% confidence interval 0.75 to 1.14). Only amphotericin showed a significant benefit (odds ratio 0.58, 95% confidence interval 0.37 to 0.93) based on seven trials, but the studies were small and the difference in number of deaths was only 15. Overall it would be necessary to treat 59 patients (95% confidence interval 37 to 131) with an antifungal drug to prevent one case of fungal invasion in surviving patients, although only amphotericin and fluconazole showed a clear beneficial effect. Antifungal treatment decreased fungal colonisation and the need for additional antifungal therapy, but there was heterogeneity across the trials. REVIEWER'S CONCLUSIONS: Routine prophylactic or later therapy with antifungal drugs in cancer patients with neutropenia does not appear to have a beneficial effect on mortality and only a modest effect on fungal invasion.

Antifungal Agents↗
PubMed2000

Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis.

BACKGROUND: The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We therefore performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs. OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and nonsteroidal, antiinflammatory drugs in patients with rheumatoid arthritis. SEARCH STRATEGY: Medline Silverplatter, The Cochrane Controlled Trials Register, reference lists and a personal archive. SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a nonsteroidal, antiinflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. DATA COLLECTION AND ANALYSIS: Decisions on which trials to include were made independently by two observers based on the methods sections of the trials only. Standardised effect measures were used for the statistical analyses; the random effects model was used if P<0.10 for the test of heterogeneity. MAIN RESULTS: Ten studies, involving 320 patients, were included in the meta-analysis. Prednisolone had a marked effect over placebo on joint tenderness (standardised effect size 1.31, 95% confidence interval 0.78 to 1.83), pain (standardised effect size 1.75, 0.87 to 2.64) and grip strength (standardised effect size 0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than nonsteroidal, antiinflammatory drugs on joint tenderness (standardised effect size 0.63, 0.11 to 1.16) and pain (standardised effect size 1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (standardised effect size 0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable. REVIEWER'S CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Amphotericin B vs fluconazole for controlling fungal infections in neutropenic cancer patients.

BACKGROUND: Systemic fungal infection is considered to be an important cause of morbidity and mortality in cancer patients, particularly those with neutropenia. Antifungal drugs are often given prophylactically, or to patients with persistent fever. OBJECTIVES: To compare the effect of fluconazole and amphotericin B on morbidity and mortality in patients with cancer complicated by neutropenia. SEARCH STRATEGY: MEDLINE and Cochrane Library (March 2000). Letters, abstracts, and unpublished trials. The industry and authors were contacted. SELECTION CRITERIA: Randomised trials comparing fluconazole with amphotericin B. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, colonisation, use of additional (escape) antifungal therapy and adverse effects leading to discontinuation of therapy were extracted by both authors independently. MAIN RESULTS: Thirteen trials (2977 patients) were included. In 3 large 3-armed trials, which comprised 43% of the patients, results for amphotericin B were combined with results for nystatin in a "polyene" group. Because nystatin is an ineffective drug in theses circumstances, this approach creates a bias in favour of fluconazole. Furthermore, 79% of the patients were randomised to oral amphotericin B, which is poorly absorbed and poorly documented. It was unclear whether there was overlap among the "polyene" trials. We were unable to obtain any information to clarify these issues from the trial authors or the manufacturer of fluconazole. There was no significant difference in effect between fluconazole and amphotericin B. Apart from the "polyene" trials, more patients dropped out of the study when they received amphotericin B. REVIEWER'S CONCLUSIONS: Amphotericin B had been disfavoured in most of the trials through their design or analysis. Since intravenous amphotericin B is the only antifungal agent with a documented effect on mortality and is considerably cheaper than fluconazole, it should be preferred.

Amphotericin B↗
PubMed2000

Amphotericin B lipid soluble formulations vs amphotericin B in cancer patients with neutropenia.

BACKGROUND: Patients with cancer who are treated with chemotherapy or receive a bone marrow transplant have an increased risk of acquiring fungal infections. Such infections can be life-threatening. Antifungal drugs are therefore often given prophylactically to such patients, or when they have a fever. OBJECTIVES: To compare the effect and adverse effects of AmBisome and other lipid soluble formulations of amphotericin B with conventional amphotericin B in cancer patients with neutropenia. SEARCH STRATEGY: MEDLINE and Cochrane Library. Unpublished trials from conference proceedings and contact to industry. SELECTION CRITERIA: Randomised trials comparing lipid soluble formulations of amphotericin B with conventional amphotericin B. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection, nephrotoxicity, serum creatinine and dropouts were extracted by both authors independently. MAIN RESULTS: AmBisome vs conventional amphotericin B (3 trials, 1149 patients): AmBisome tended to be more effective than conventional amphotericin B for invasive fungal infection (relative risk 0.63, 95% confidence interval 0.39 to 1.01, P=0.053) whereas there was no significant difference in mortality (relative risk 0.74, 95% CI 0.52 to 1.07). AmBisome decreased significantly the incidence of nephrotoxicity, defined as a 100% increase in serum creatinine (relative risk 0.51, 95% CI 0.40 to 0.64). Fewer patients dropped out on AmBisome but the difference was not significant (relative risk 0.78, 95% CI 0.56 to 1. 08). Amphotericin B in Intralipid vs conventional amphotericin B (4 trials, 145 patients): There were no significant differences in clinical effect whereas the patients treated with the lipid soluble formulation experienced significantly less nephrotoxicity (relative risk 0.34, 95% CI 0.15 to 0.75) and smaller increases in serum creatinine (weighted mean difference 32 micromol/l, 95% CI 21 to 43 micromol/l). Amphotericin B colloidal dispersion (ABCD) vs conventional amphotericin B (1 trial, 213 patients): There was lower nephrotoxicity with ABCD (relative risk 0.38, 95% CI 0.25 to 0.59). REVIEWER'S CONCLUSIONS: AmBisome is a better drug than conventional amphotericin B but its high cost prohibits routine use in most settings. Furthermore, the advantages of AmBisome may be smaller than indicated in our review if conventional amphotericin B is administered under optimal circumstances. It is not clear whether other lipid formulations of amphotericin B could offer a worthwhile advantage compared to conventional amphotericin B.

Amphotericin B↗
PubMed2000

House dust mite control measures for asthma.

BACKGROUND: The major allergen in house dust comes from mites. Chemical, physical and combined methods of reducing mite allergen levels are intended to reduce asthma symptoms in people who are sensitive to house dust mites. OBJECTIVES: The objective of this review was to assess the effects of reducing exposure to house dust mite antigens in the homes of mite-sensitive asthmatics. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register, checked reference lists of articles and hand-searched Respiration (1980 to 1996) and Clinical and Experimental Allergy (1980 to 1996). SELECTION CRITERIA: Randomised trials of mite control measures in asthmatic people known to be sensitive to house dust mites. DATA COLLECTION AND ANALYSIS: Two reviewers applied the trial inclusion criteria and extracted the data independently. One reviewer applied the trial quality assessment criteria. Study authors were contacted to clarify information. MAIN RESULTS: Twenty-three trials were included, with four trials awaiting assessment. There was little difference in improvement of asthma between people in experimental groups compared to control groups (odds ratio 1.2, 95% confidence interval 0.66 to 2.18). Asthma symptom scores were also similar for the experimental and control groups (standardised mean difference -0. 06, 95% confidence interval -0.54 to 0.41). These scores showed a high degree of heterogeneity. No significant difference was noted for medication usage (standardised mean difference -0.14, 95% confidence interval -0.43 to 0.15). Peak flow in the morning showed no significant difference between the experimental and the control groups (standardised mean difference -0.03, 95% confidence interval -0.25 to 0.19). REVIEWER'S CONCLUSIONS: Current chemical and physical methods aimed at reducing exposure to house dust mite allergens seem to be ineffective and cannot be recommended as prophylaxis for mite sensitive asthmatics.

Allergens↗
PubMed2000

Vaccines for preventing infection with Pseudomonas aeruginosa in people with cystic fibrosis.

OBJECTIVES: To assess the effectiveness of vaccination against Pseudomonas aeruginosa in patients with cystic fibrosis. SEARCH STRATEGY: The Cochrane Cystic Fibrosis and Genetic Disorders Group specialist trials register which comprises references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings. Date of the most recent search of the Group's specialised register: November 1999. SELECTION CRITERIA: All randomised or pseudorandomised trials (published or unpublished) comparing Pseudomonas aeruginosa vaccines (oral, parenteral or intranasal) with control vaccines or no intervention in patients with cystic fibrosis. DATA COLLECTION AND ANALYSIS: We planned to assess the following outcomes: time to infection with Pseudomonas aeruginosa, pulmonary function, body mass index, Schwachman score, frequency of pulmonary infective exacerbations, days of antibiotic usage, days unable to carry out normal daily activities, adverse events, mortality, antibody levels to Pseudomonas aeruginosa and T cell proliferation and cytokine production in response to Pseudomonas aeruginosa. MAIN RESULTS: One trial which included 17 vaccinated patients, with follow up reported to 10 years met the inclusion criteria. Finding only a single trial, and the lack of information on our predefined outcomes limited analysis. REVIEWER'S CONCLUSIONS: There is a paucity of randomised controlled trials assessing the effectiveness of vaccination against Pseudomonas aeruginosa in cystic fibrosis. Increased understanding of modulation of the immune response by vaccination has led to the development of alternative vaccines. We suggest that there is an urgent need for newer vaccines to be evaluated in adequately-powered, multicentre randomised controlled trials examining clinically relevant end-points in addition to immunological variables. Such a trial should assess effectiveness over several years, and include follow-up of vaccinees who become colonised with Pseudomonas aeruginosa.

Bacterial Vaccines↗
PubMed2000

Nystatin prophylaxis and treatment in severely immunodepressed patients.

BACKGROUND: Nystatin is sometimes used prophylactically in patients with severe immunodeficiency or in the treatment of fungal infection in such patients, although the effect seems to be equivocal. OBJECTIVES: To study whether nystatin decreases morbidity and mortality when given prophylactically or therapeutically to patients with severe immunodeficiency. SEARCH STRATEGY: MEDLINE and The Cochrane Library using a comprehensive search strategy. Contacted industry and scanned reference lists. SELECTION CRITERIA: Randomised trials comparing nystatin with placebo, an untreated control group, fluconazole or amphotericin B. DATA COLLECTION AND ANALYSIS: Data on mortality, invasive fungal infection and colonisation were extracted by both authors independently. The outcomes were weighted by the inverse variance. A random effects model was used unless p>0.10 for the test of heterogeneity. MAIN RESULTS: We included 10 trials (1, 122 patients). The drugs were given prophylactically in eight trials and as treatment in two. Six trials were in acute leukaemia, one mainly in cancer, one in liver transplant patients, one in critically ill surgical and trauma patients, and one in AIDS patients. Nystatin had been compared with placebo in three trials and with fluconazole in seven; the dose varied from 1.5 MIE to 72 MIE daily. The effect of nystatin was similar to that of placebo on fungal colonisation (relative risk 0.85, 95% confidence interval 0. 65 to 1.13). There was no difference between fluconazole and nystatin on mortality (relative risk 0.87, 0.52 to 1.44) whereas fluconazole was more effective in preventing invasive fungal infection (relative risk 0.42, 0.16 to 1.12) and colonisation (relative risk 0.50, 0.36 to 0.71). The results were very similar if the three studies which were not performed in cancer patients were excluded. REVIEWER'S CONCLUSIONS: Nystatin cannot be recommended for prophylaxis or treatment of Candida infections in immunodepressed patients.

Antibiotic Prophylaxis↗
PubMed2000

cAMP-dependent protein kinase (PKA) inhibits T cell activation by phosphorylating ser-43 of raf-1 in the MAPK/ERK pathway.

cAMP-dependent protein kinase (PKA) has been suggested to interfere with T-cell activation by inhibiting interleukin (IL-2) receptor alpha-chain (CD25) expression and IL-2 production. The Ras/MAP kinase pathway has been found to be necessary for induction of the IL-2 production. In this study, we have scrutinized the Ras/MAP kinase pathway in Jurkat T-cells to attempt to identify any sites for PKA-mediated regulatory phosphorylations. Here we unambiguously demonstrate that PKA directly inhibits anti-CD3-induced MAP kinase activation. In vitro phosphorylation experiments showed that Raf-1 was extensively phosphorylated by PKA, while ERK2 and MEK were not. Phosphopeptide mapping identified Ser-43 of Raf-1 as the only site phosphorylated by PKA in the Ras/MAPK pathway. Transient transfection experiments demonstrated that mutations of Ser-43 of the Raf-1 kinase were rendered insensitive to cAMP-mediated inhibition.

Cyclic AMP↗
PubMed2000

Antagonism between penicillin and erythromycin against Streptococcus pneumoniae in vitro and in vivo.

The combination of beta-lactam antibiotics and macrolides is often recommended for the initial empirical treatment of acute pneumonia in order to obtain activity against the most important pathogens. Theoretically, this combination may be inexpedient, as the bacteriostatic agent may antagonize the effect of the bactericidal agent. In this study, the possible interaction between penicillin and erythromycin was investigated in vitro and in vivo against four clinical isolates of Streptococcus pneumoniae with MICs of penicillin ranging from 0.016 to 0.5 mg/L and of erythromycin from 0. 25 to >128 mg/L. In vitro time-kill curves were generated with clinically relevant concentrations of penicillin (10 mg/L) and erythromycin (1 mg/L), either individually or in combination. Antagonism between penicillin and erythromycin was observed for the four isolates. In vivo interaction was investigated in the mouse peritonitis model. After intraperitoneal inoculation, penicillin and erythromycin were given either individually or in combination. For two of the four isolates, mortality was significantly higher in the groups treated with the combination of penicillin and erythromycin than in the groups treated with penicillin alone [32/36 (86%) vs. 3/12 (25%), P<0.05; and 24/36 (67%) vs. 3/12 (25%), P<0.05, respectively]. Using the mouse peritonitis model, in vivo time-kill curves showed that there was antagonism between erythromycin and penicillin for the examined isolate. The antagonism demonstrated in vitro and in vivo between penicillin and erythromycin suggests that ss-lactam antibiotics and macrolides should not be administered together unless pneumococcal infection is ruled out.

Animals↗
PubMed2000

Excretion of beta-lactam antibiotics in sweat--a neglected mechanism for development of antibiotic resistance?

The concentrations of beta-lactam antibiotics after standard doses were measured in blood and apocrine (axilla) and eccrine (forearm) sweat from six adult healthy persons. All persons had ceftazidime (axilla, 28.4 microg/ml; forearm, 11 microg/ml) and ceftriaxone (axilla, 8.9 microg/ml; forearm, 2.5 microg/ml) in sweat, and one person had cefuroxime in sweat (axilla, 7.8 microg/ml) (all data are mean peaks). Three persons had benzylpenicillin (axilla, 2.6 to 0.1 microg/ml) and one had phenoxymethylpenicillin (axilla, 0.4 microg/ml) in sweat. Excretion of beta-lactam antibiotics in the sweat may explain why staphylococci so rapidly become resistant to these drugs.

Administration, Oral↗