Effect of Hyperthermia on AKR Lymphoma Variants Differing in Degree of Malignancy

The effect of hyperthermic treatment on AKR lymphoma cells of varying malignancy was investigated. Tumor cells were pretreated at 37 or 43°C and then injected to mice. The effect on the highly malignant variant, TAU-38, was compared to that on the low-malignancy variant, TAU-39, following both subcutaneous (s.c.) and intravenous (i.v.) inoculation. Hyperthermia showed no effect on the TAU-39 variant following s.c. inoculation on the primary tumors or mice survival, but the TAU-38 variant exhibited a significant delay of tumor appearance following treatment, namely, decreased tumor size and increased life span. Following i.v. inoculation, in both variants, hyperthermia caused a significant decrease in metastatic spread and an increased life span. We conclude that hyperthermia, in addition to exerting a greater effect on the high-malignancy variant, acts at the late phases of metastasis. Hyperthermia might therefore have a place in the management of cancer in its advanced disseminated phase.     

Eardrum perforation in explosion survivors: is it a marker of pulmonary blast injury?

STUDY OBJECTIVES: To determine whether isolated eardrum perforation is a marker for concealed blast lung injury in survivors of terrorist bombings. METHODS: Survivors who arrived at hospitals after 11 terrorist bombings in Israel between April 6, 1994, and March 4, 1996, were examined otoscopically by ear, nose, and throat specialists. All patients with eardrum perforation underwent chest radiography and were hospitalized for at least 24 hours for observation. The clinical course and final outcome of patients with isolated perforation of the eardrums and of those with other blast injuries were surveyed. RESULTS: A total of 647 survivors were examined; 193 (29.8%) of them sustained primary blast injuries, including 142 with isolated eardrum perforation and 51 with other forms of blast injuries (18 with isolated pulmonary blast injury, 31 with combined otic and pulmonary injuries, and 2 with intestinal blast injury). Blast lung injury was promptly diagnosed on admission by physical examination and chest radiography. No patient presenting with isolated eardrum perforation developed later signs of pulmonary or intestinal blast injury (mean 0%; 95% confidence interval, 0% to 2.7%). CONCLUSION: Isolated eardrum perforation in survivors of explosions does not appear to be a marker of concealed pulmonary blast injury nor of a poor prognosis. Therefore, in a mass casualty event, persons who have sustained isolated eardrum perforation from explosions may safely be discharged from the emergency department after chest radiography and a brief observation period.     

Increased glucose improves recovery of neuronal function after cerebral hypoxia in vitro

The rat hippocampal slice preparation was used to evaluate the effect of increasing glucose levels in the perfusion medium on the recovery of synaptic function after a standardized hypoxic insult. Slices exposed to low glucose (5 mM) did not recover from a standard hypoxic insult (10 min of 95% N₂/5% CO₂ atmosphere). Following the same insult, 39% of the control (10 mM glucose) slices recovered their synaptic function, while 93% of the slices provided with high glucose level (20 mM) exhibited recovery of synaptic function. Thus, a dose-dependent effect of glucose on recovery of neuronal function following an intermediate period (10 min) of oxygen deprivation was found. The high-glucose-treated slices could tolerate a severe hypoxic insult of 15 min or even 20 min from which 94% and 81% of them recovered, respectively. Only 21% of the control (10 mM glucose) slices recovered their synaptic activity following 15 min of hypoxia, and none survived 20 min of that insult.The adverse effects of hyperglycemia reported in vivo were not seen in our study. This may be due to the sustained perfusion of the brain slice preparation, which could limit accumulation of lactic acid during hypoxia. However, treatment of slices with lactic acid prior to and during the hypoxic insult did not worsen the outcome. Alternatively, glucose may protect against the damaging effects of oxygen free radicals formed during reoxygenation. Nevertheless, the antihypoxic effect of glucose appears to be a metabolic one, since l-glucose (the non-metabolic analog of d-glucose) was innocuous in this respect.     

Prediction of specific pathogens in patients with sepsis: evaluation of TREAT, a computerized decision support system

BACKGROUND: Prediction of bacterial infections and their pathogens allows for early, directed investigation and treatment. We assessed the ability of TREAT, a computerized decision support system, to predict specific pathogens. METHODS: TREAT uses data available within the first few hours of infection presentation in a causal probabilistic network to predict sites of infection and specific pathogens. We included 3529 patients (920 with microbiologically documented infections) participating in the observational and interventional trials of the TREAT system in Israel, Germany and Italy. Discriminatory performance of TREAT to predict individual pathogens was expressed by the AUC with 95% confidence intervals. Calibration was assessed using the Hosmer-Lemeshow goodness-of-fit statistic. RESULTS: The AUCs for Gram-negative bacteria, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella spp. and Escherichia coli, ranged between 0.70 and 0.80 (all significant). Adequate calibration was demonstrated for any Gram-negative infection and individual bacteria, except for E. coli. Discrimination and calibration were acceptable for Enterococcus spp. (AUC 0.71, 0.65-0.78), but not for Staphylococcus aureus (AUC 0.63, 0.55-0.71). The few infections caused by Candida spp. and Clostridium difficile were well predicted (AUCs 0.74, 0.54-0.95; and 0.94, 0.88-1.00, respectively). The coverage with TREAT's recommendation exceeded that observed with physicians' treatment for all pathogens, except Candida spp. CONCLUSIONS: TREAT predicted individual pathogens causing infection well. Prediction of S. aureus was inferior to that observed with other pathogens. TREAT can be used to triage patients by the risk for specific pathogens. The system's predictions enable it to prescribe appropriate antibiotic treatment prior to pathogen identification.     

Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials

OBJECTIVES: This study sought to compare the efficacy and adverse effects of any aminoglycoside as a single antibiotic with other antibiotics for the treatment of patients with infection. METHODS: Systematic review of the literature and meta-analysis. We searched for randomized controlled trials comparing the efficacy of single aminoglycoside antibiotic treatment with one or more non-aminoglycoside antibiotic for patients with infection in the Cochrane Library, MEDLINE, EMBASE, LILACS, databases of ongoing trials and conference proceedings. Two reviewers assessed trial eligibility, quality and extracted data. Pooled relative risks (RR) with 95% confidence intervals (CI) were calculated for dichotomous data. RESULTS: The search yielded 37 trials of which 26 included patients with urinary tract infection. Aminoglycosides were equally effective as comparators in the analysis of the primary outcomes, all-cause mortality (RR 1.11, 95% CI 0.68, 1.81, 9 trials, 503 patients) and treatment failure (RR 1.10, 95% CI 0.96, 1.27, 32 trials, 1890 patients). Aminoglycosides were associated with a significantly higher rate of bacteriological failure at end of therapy (RR 1.44, 95% CI 1.21, 1.72, 27 trials, 1668 patients). Subgroup analyses according to quality of trial, type of antibiotics, source of infection and rate of clinical sepsis did not alter the outcomes. Less adverse effects in total but more nephrotoxic effects were observed in patients treated with aminoglycosides. CONCLUSIONS: The present data support the use of aminoglycosides for urinary tract infections. The paucity of trials including patients with sepsis or reporting on mortality precludes firm recommendations for patients with infections other than of the urinary tract.     

Anti-inflammatory effects of moxifloxacin on activated human monocytic cells: inhibition of NF-kappaB and mitogen-activated protein kinase activation and of synthesis of proinflammatory cytokines

We previously showed that moxifloxacin (MXF) exerts protective anti-inflammatory effects in immunosuppressed mice infected with Candida albicans by inhibiting interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) production in the lung. Immunohistochemistry demonstrated inhibition of nuclear factor (NF)-kappaB translocation in lung epithelium and macrophages in MXF-treated mice. In the present study we investigated the effects of MXF on the production of proinflammatory cytokines (i.e., IL-8, TNF-alpha, and IL-1beta) by activated human peripheral blood monocytes and THP-1 cells and analyzed the effects of the drug on the major signal transduction pathways associated with inflammation: NF-kappaB and the mitogen-activated protein kinases ERK and c-Jun N-terminal kinase (JNK). The levels of IL-8, TNF-alpha, and IL-1beta secretion rose 20- and 6.7-fold in lipopolysaccharide (LPS)-activated monocytes and THP-1 cells, respectively. MXF (5 to 20 microg/ml) significantly inhibited cytokine production by 14 to 80% and 15 to 73% in monocytes and THP-1 cells, respectively. In THP-1 cells, the level of NF-kappaB nuclear translocation increased fourfold following stimulation with LPS-phorbol myristate acetate (PMA), and this was inhibited (38%) by 10 microg of MXF per ml. We then assayed the degradation of inhibitor (I)-kappaB by Western blotting. LPS-PMA induced degradation of I-kappaB by 73%, while addition of MXF (5 microg/ml) inhibited I-kappaB degradation by 49%. Activation of ERK1/2 and the 46-kDa p-JNK protein was enhanced by LPS and LPS-PMA and was significantly inhibited by MXF (54 and 42%, respectively, with MXF at 10 microg/ml). We conclude that MXF suppresses the secretion of proinflammatory cytokines in human monocytes and THP-1 cells and that it exerts its anti-inflammatory effects in THP-1 cells by inhibiting NF-kappaB, ERK, and JNK activation. Its anti-inflammatory properties should be further assessed in clinical settings.     

Oral versus intravenous antibiotic treatment for febrile neutropenia in cancer patients: a systematic review and meta-analysis of randomized trials

CONTEXT: Neutropenia is one of the grave consequences of cancer chemotherapy, and the treatment of neutropenic febrile patients with intravenous (iv) antibiotics has been shown to reduce mortality. Oral therapy could be an alternative approach for selected patients. OBJECTIVES: To compare the efficacy of oral antibiotics versus iv antibiotic therapy in febrile neutropenic cancer patients. DATA SOURCES: The Cochrane Library, the Cochrane Cancer Network Register of trials, EMBASE, LILACS and MEDLINE, databases for ongoing trials and the conference proceedings of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). STUDY SELECTION: Randomized controlled trials comparing oral antibiotic/s and iv antibiotic/s for the treatment of neutropenic cancer patients with fever. DATA COLLECTION: Two reviewers independently assessed trial eligibility, methodological quality and extracted all data. Data concerning mortality, treatment failures and adverse events were drawn from included studies assuming an 'intention-to-treat' and 'per-protocol' basis for the outcome measures whenever possible. Relative risks (RR) with their 95% confidence intervals (CI) for dichotomous data were estimated. MAIN RESULTS: Fifteen trials (median mortality 0, range 0%-8.8%) were included in the analyses. The mortality rate was similar comparing oral and iv antibiotic treatment (RR 0.83, 95% CI 0.49-1.41, 2224 patients). Treatment failure rates were also similar (RR 0.94, 95% CI 0.84-1.05, 15 trials). No significant heterogeneity was shown for the primary outcomes. This effect was stable in a wide range of patients. Quinolones alone or combined with other antibiotics were used with comparable results. Adverse reactions, mostly gastrointestinal, were more common with oral antibiotics. CONCLUSIONS: Oral antibiotics may be safely offered to neutropenic patients with fever who are at low risk for mortality.     

Departmental consumption of antibiotic drugs and subsequent resistance: a quantitative link

OBJECTIVE: To look for a quantitative model linking departmental consumption of antibiotic drugs to the subsequent isolation of resistant hospital-acquired coliform pathogens. MATERIALS AND METHODS: Included in the study were all patients with hospital-acquired bloodstream infections caused by a coliform pathogen, detected in six departments of internal medicine of one university hospital during the period 1991-1996, who had not been hospitalized in the month before the infection (n = 394). Departmental consumption of antibiotics in the year before the infection [expressed as defined daily dosages (DDD)/100 patient days], antibiotic treatment given to the individual patient before the infection, the day of hospital stay on which the infection occurred, and the department and the calendar year were all included in a logistic model to predict the isolation of a resistant pathogen. We looked at five drugs: gentamicin, amikacin, cefuroxime, ceftazidime and ciprofloxacin. RESULTS: Five logistic models were fitted for the resistance to each of the antibiotic drugs. The multivariable-adjusted odds ratios for a pathogen resistant to the specific antibiotic were 1.03 [95% confidence interval (CI) 0.70-1.50] for gentamicin, 1.80 (95% CI 1.00-3.24) for amikacin, 1.12 (95% CI 1.02-1.23) for cefuroxime, 1.45 (95% CI 1.19-1.76) for ceftazidime and 1.06 (95% CI 0.57-1.97) for ciprofloxacin, per 1 DDD/100 patient days. CONCLUSIONS: The departmental consumption of cephalosporin drugs and amikacin in six autonomous departments of medicine in the same hospital was associated with a measurable and statistically significant increase in the probability of infection caused by a resistant pathogen.