Staphylococcus aureus meningitis: experience with cefuroxime treatment during a 16 year period in a Danish region

Staphylococcus aureus is a rare cause of bacterial meningitis and there is no consensus on antibiotic treatment. Nafcillin is a common choice in countries where it is approved and marketed. High-dose cefuroxime has been the systemic treatment used in the study region, and a retrospective record review was conducted to determine its clinical efficacy. Cases of bacterial meningitis during 1984-1999 in the County of North Jutland, Denmark (approx. 490000 inhabitants), were identified in a regional bacteriology register. Inclusion of a case required either growth of S. aureus from > or = 2 specimens of cerebrospinal fluid (CSF), 1 positive CSF specimen with a CSF leucocyte count > 10(8)/l or 1 positive CSF specimen with a concurrent positive blood culture. A diagnosis of brain abscess required growth of S. aureus from aspirated pus. Staphylococcus aureus meningitis was confirmed in 45 patients, and 5 additional patients had a brain abscess. 44 cases were nosocomial (mortality 16%) and 6 were community acquired (mortality 83%). None of the isolates was methicillin resistant and 6 were penicillin susceptible. Intraventricular antibiotic treatment was given to 28 patients, systemic therapy included cefuroxime in 32 patients (64%) as either a primary or secondary choice, 6 (12%) were treated with penicillin G, 10 (20%) with penicillinase-resistant penicillin and 2 (4%) with cephalothin. Among 31 nosocomial cases treated systemically with cefuroxime the mortality was 10% (95% exact confidence limits 2-26%). In conclusion, cefuroxime seems to be a valid choice for S. aureus meningitis in the nosocomial setting.     

alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

Determinants for an impaired quality of life 10 years after coronary artery bypass surgery

OBJECTIVE: To identify determinants of an inferior quality of life (QoL) 10 years after coronary artery bypass grafting (CABG). SETTING: Sahlgrenska University Hospital, G?teborg, Sweden. PARTICIPANTS: All patients from Western Sweden who underwent CABG between 1988 and 1991 without simultaneous valve surgery and no previous CABG. MAIN OUTCOME MEASURES: Questionnaires for evaluating QoL 10 years after the operation. Three different instruments were used: The Nottingham health profile (NHP), the psychological general wellbeing index (PGWI), and the Physical Activity Score (PAS). RESULTS: 2000 patients underwent CABG, of whom 633 died during 10 years of follow-up. Information on QoL at 10 years was available in 976 patients (71% of survivors). A history of diabetes and chronic obstructive pulmonary disease were the two independent predictors for an inferior QoL with all three instruments. Furthermore, there were three predictors of an inferior QoL with two of the instruments: high age, female sex and a history of hypertension. A number of factors predicted an inferior QoL with one of the instruments. These were the duration of angina pectoris and functional class prior to CABG, renal dysfunction, a history of cerebrovascular disease, obesity, height, duration of respirator treatment and requirement of inotropic drugs postoperatively. In addition, when introducing preoperative QoL into the model a low QoL before surgery was a strong independent predictor also of an inferior QoL 10 years after CABG. CONCLUSION: Variables independently predictive of an impaired QoL 10 years after CABG, irrespective of the instrument used, were an impaired QoL prior to surgery, chronic obstructive pulmonary disease and a history of diabetes. However, other factors reflecting gender, the previous history as well as postoperative complications were also associated with the QoL 10 years later in at least one of these instruments.     

Evaluation of left ventricular dimensions and function in Marfan's syndrome without significant valvular regurgitation

Left ventricular dimensions and systolic function were studied using echocardiography in 234 patients with Marfan's syndrome without significant valvular regurgitation. Left ventricular dimensions and systolic function were found to be normal in most patients with Marfan's syndrome. Some involvement of the left ventricle may have been present in a small group of these patients. No patients, however, fulfilled the criteria for dilated cardiomyopathy.     

Antipsychotics and the risk of sudden cardiac death

BACKGROUND: Antipsychotics have been associated with prolongation of the corrected QT interval and sudden cardiac death. Only a few epidemiological studies have investigated this association. We performed a case-control study to investigate the association between use of antipsychotics and sudden cardiac death in a well-defined community-dwelling population. METHODS: We performed a population-based case-control study in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from 150 general practitioners. All instances of death between January 1, 1995, and April 1, 2001, were reviewed. Sudden cardiac death was classified based on time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, sex, date of sudden death, and practice. Exposure at the index date was categorized as 3 mutually exclusive groups of current use, past use, and nonuse. RESULTS: The study population comprised 554 cases of sudden cardiac death. Current use of antipsychotics was associated with a 3-fold increase in risk of sudden cardiac death. The risk of sudden cardiac death was highest among those using butyrophenone antipsychotics, those with a defined daily dose equivalent of more than 0.5 and short-term (相似文献   

Atrophic gastritis is associated with increased sucrose permeability related to chronic inflammation

BACKGROUND: Different theories have been presented to explain how atrophic gastritis may lead to gastric cancer development. One contributing factor could be impaired function of the gastric mucosal barrier. The aim of this study was to investigate if there are changes in gastric mucosal permeability to sucrose in atrophic gastritis. METHODS: The study comprised 22 patients with atrophic gastritis and 21 normal controls. Gastritis was classified according to the Sydney system from endoscopic biopsies of the gastric corpus and antrum. All subjects were exposed to oral sucrose load (100 g), and the fraction of sucrose excreted in urine was measured by gas chromatography-mass spectrometry. RESULTS: The fraction of sucrose excreted in urine after oral load was significantly increased in atrophic gastritis compared with controls (median 0.08 vs. 0.04%; p = 0.003). Sucrose excretion was positively related to the degree of chronic inflammation (median fraction excreted: mild inflammation 0.06%, moderate inflammation 0.08%, severe inflammation 0.18%; p = 0.04) rather than to the degree of atrophy in the gastric mucosa. Occurrence of intestinal metaplasia was also associated with significantly higher sucrose excretion. However, in multivariate analysis, including intestinal metaplasia, only the degree of inflammation was positively related to sucrose excretion. CONCLUSION: Atrophic gastritis is associated with increased sucrose permeability, suggesting paracellular leakage of the gastric mucosa. This leakage seems to be related to the degree of inflammation rather than the degree of atrophy. The findings may have implications for the diseases and complications associated with atrophic gastritis.     

Sensitivity and reproducibility of chemical tests for fecal occult blood with an emphasis on false-positive reactions

In 20 healthy volunteers ingesting 5 to 50 ml of⁵¹Cr-red cells, reaction intensities obtained with four chemical methods for fecal occult blood were compared with the “true” blood loss simultaneously determined by radioassay of each stool. Dilute tincture of guaiac reagent was found to have the same sensitivity and high frequency of false-positive reactions as the saturated guaiac reagent, but was more reproducible. Hematest^TM was slightly less sensitive but was poorly reproducible and yielded frequent false-negative as well as false-positive reactions. False-positive reactions by both methods were not eliminated by a meat-free diet; they were increased with guaiac reagents if stools were stored for 3 or more days. A new guaiac method (Hemoccult^TM) was found to be one-fourth as sensitive as the older tests, but was virtually free from false-positive reactions, even on an unrestricted diet and after storage of the stool specimens. It is recommended that the use of Hematest be abandoned and that Hemoccult be used preferentially if future studies confirm that its sensitivity is sufficient to detect most gastrointestinal lesions which are yielding occult blood.     

The use of methotrexate in rheumatoid arthritis

OBJECTIVE: To address the long-term efficacy and toxicity issues related to methotrexate (MTX) and compare it with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Review of the international literature on the clinical use of MTX in rheumatoid arthritis (RA) disease. RESULTS: MTX has emerged as a relatively safe and effective treatment for RA that compares favorably with other therapies, particularly because of its considerably longer median drug survival. The toxicity profile of MTX is well established and includes serious and sometimes fatal liver disease, pneumonitis, and cytopenias. Hence, regular and careful monitoring of patients taking MTX is essential, particularly when MTX is combined with other DMARDs. Folate supplementation can reduce some of the most common side effects of MTX, but it has not yet been established whether this translates into a reduced risk of serious disease. Another potential approach to reducing the toxicity of MTX is therapeutic drug monitoring and dose individualization. However, correlations between pharmacokinetics and clinical response have been addressed in only a few studies and with conflicting results. CONCLUSIONS: MTX is an effective DMARD with a relatively safe profile compared with other therapies. Folate supplementation can significantly reduce the risk of MTX toxicity. Finally, it is essential that patients be monitored carefully to reduce the potential serious toxicities of MTX.     

ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin

Vascular endothelial (VE)-cadherin is the major adhesion molecule of endothelial adherens junctions. It plays an essential role in controlling endothelial permeability, vascular integrity, leukocyte transmigration, and angiogenesis. Elevated levels of soluble VE-cadherin are associated with diseases like coronary atherosclerosis. Previous data showed that the extracellular domain of VE-cadherin is released by an unknown metalloprotease activity during apoptosis. In this study, we used gain-of-function analyses, inhibitor studies, and RNA interference experiments to analyze the proteolytic release of VE-cadherin in human umbilical vein endothelial cells (HUVECs). We found that VE-cadherin is specifically cleaved by the disintegrin and metalloprotease ADAM10 in its ectodomain, releasing a soluble fragment and generating a carboxyl-terminal membrane-bound stub, which is a substrate for a subsequent gamma-secretase cleavage. This ADAM10-mediated proteolysis could be induced by Ca(2+) influx and staurosporine treatment, indicating that ADAM10-mediated VE-cadherin cleavage contributes to the dissolution of adherens junctions during endothelial cell activation and apoptosis, respectively. In contrast, protein kinase C activation or inhibition did not modulate VE-cadherin processing. Increased ADAM10 expression was functionally associated with an increase in endothelial permeability. Remarkably, our data indicate that ADAM10 activity also contributes to the thrombin-induced decrease of endothelial cell-cell adhesion. Moreover, knockdown of ADAM10 in HUVECs as well as in T cells by small interfering RNA impaired T-cell transmigration. Taken together, our data identify ADAM10 as a novel regulator of vascular permeability and demonstrate a hitherto unknown function of ADAM10 in the regulation of VE-cadherin-dependent endothelial cell functions and leukocyte transendothelial migration.