Clinical research in the lay press: irresponsible journalism raises a huge dose of doubt.
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Antifungal Agents↗
Biomedical subjects
Joseph S Solomkin
Publications and source records attributed to Joseph S Solomkin.
Formation of focal adhesion-like structures in circulating human neutrophils after severe injury: triggering of a tissue-phase response in the vascular space.
Neutrophils play a key role in injury to the lung, kidney, liver, and gastrointestinal tract, often seen after major trauma. We evaluated the role of integrin-linked focal adhesions in the primed state, previously identified in peripheral blood neutrophils from severely injured patients. Immunoblot analysis of Triton-insoluble cell fractions revealed that total paxillin content was unchanged in comparison with that found in neutrophils from healthy volunteers, but phosphorylation of paxillin on tyrosine residue 118 was increased by more than 2-fold. Immunoprecipitation with antipaxillin and immunoblotting for proline-rich tyrosine kinase 2 (Pyk2) and for fgr showed significantly more colocalization. Densitometric analysis of total phosphotyrosine profiles also demonstrated significantly more in patient cells as compared with healthy cells. When allowed to adhere to fibronectin-coated plates, healthy and patient cells demonstrate a significant increase in tyrosine phosphorylation from that found in suspension-phase cells. Differential interference contrast microscopy of healthy neutrophils adherent to fibronectin matrices demonstrated rounded cells, without evidence of spreading; spreading was induced by addition of TNF-alpha. Patient neutrophils spread spontaneously, a response not further enhanced by TNF-alpha. Confocal imaging using anti-Pyk2 demonstrated aggregation of Pyk2 into punctate structures in patient but not in healthy cells. We conclude that neutrophils from severely injured patients are in a primed state, characterized by formation of focal adhesion-like structures. The identification of such structures in a clinical disease setting where they likely participate in unwanted consequences provides a novel area for study of regulation of neutrophil function.
Adult↗
Ventilator-associated pulmonary infection: the germ theory of disease remains viable.
Pulmonary infection complicating mechanical ventilation is a major problem in critical care. The key issues surrounding care of patients suspected of having this disease are 1) appropriate diagnostic criteria; 2) when antibiotic therapy should be started; and 3) what constitutes adequate antibiotic therapy. Current data support use of quantitative cultures obtained by either bronchoscopic or blind catheter lavage or mini-brushing. Antibiotic therapy should be guided by duration of hospitalization prior to presumed infection and local predominating nosocomial organisms and their microbial resistance patterns. The key issue with timing of therapy now centers around early termination of therapy if quantitative cultures are negative.
Anti-Bacterial Agents↗
Interleukin 8 dimerization as a mechanism for regulation of neutrophil adherence-dependent oxidant production.
Interleukin 8 (IL-8), a member of the CXC subfamily of chemoattractant cytokines, induces a range of functional responses in human neutrophils via its interactions with two high-affinity cell-surface receptors, CXCR1 and CXCR2. Like other CXC chemokines, IL-8 forms homodimers at physiologic concentrations. Monomers and dimers bind to CXC receptors with high affinity and induce various functions. Binding to glycosaminoglycans decreases the dimerization constant, enhancing surface-bound dimer formation. However, a specific role for IL-8 dimerization has not been identified. We explored the hypothesis that certain neutrophil responses to IL-8 were induced primarily by the IL-8 dimers. To this end, two dimerization-deficient IL-8 mutant proteins, M3 and M4, were used in various functional assays. In contrast to native IL-8, these proteins existed primarily as monomers at micromolar concentrations. The mutants retained high-affinity binding to both CXC receptors and potently induced neutrophil calcium flux, chemotaxis, and elastase release. In contrast to native IL-8, neither mutant inhibited tumor necrosis factor alpha-induced oxidant production. Additionally, M4 was less effective than native IL-8 at desensitizing neutrophil migration. These data suggest that although IL-8 dimers or monomers are sufficient for several neutrophil functions, dimers may participate in suppression of specific surface-dependent neutrophil responses.
Binding, Competitive↗
Age-dependent responses to hepatic ischemia/reperfusion injury.
The current study explored the concept that adult and pediatric populations differ in their response to major injury. Male C57BL/6 mice of a "young adult" (8-12 weeks) or "mature adult" (12-13 months) age were subjected to partial hepatic ischemia and reperfusion. Mature adult mice displayed significantly more liver injury than young adult mice as assessed histologically and by serum levels of alanine aminotransferase. Interestingly, there was far less neutrophil accumulation in the livers of mature adult mice. However, liver-recruited neutrophils from mature adult mice had a higher activation state than those from young adult mice. Activation of the inflammatory transcription factor, NF-kappaB, was suppressed in whole livers from mature adult mice. In isolated liver cells, Kupffer cells showed no difference in NF-kappaB activation, but hepatocytes from mature adult mice had delayed NF-kappaB activation in response to TNF. Furthermore, isolated hepatocytes from young adult mice produced abundant amounts of the chemokine, macrophage inflammatory protein-2, whereas hepatocytes from mature adult mice produced little, if any macrophage inflammatory protein-2. Mature adult mice had much lower hepatic expression of the cytoprotective protein, heat shock protein 70, than did young adult mice. In contrast, serum heat shock protein 70 levels, which has been linked to subsequent tissue injury, were higher in mature adult mice than in young adult mice. These data suggest that there are multiple alterations at the cellular and molecular levels that contribute to enhanced postischemic liver injury in mature adult mice.
Age Factors↗
Cost-effectiveness issues in ventilator-associated pneumonia.
Ventilator-associated pneumonia has attracted considerable interest as a subject of clinical efficacy assessment research. This article summarizes recommendations made by the United States Public Health Service Panel on Cost-Effectiveness in Health and Medicine and by a panel convened by the American Thoracic Society to address economic analyses in critical care. The following recommendations are made for the performance of cost-efficacy studies in ventilator-associated pneumonia. For mortality-based studies, only data from prospective and blinded randomized trials are suitable for analysis. For cost-minimization studies, observational studies may be useful but should use rigorous matching schemes. Estimates for the quality of life of patients surviving an episode of ventilator-associated pneumonia should be based on the disease that required mechanical ventilation or compared to data available for survivors of the respiratory distress syndrome, whichever diagnosis provides a lessened quality of life. Within an individual intensive care unit the greatest cost savings come from constructing a cohesive and unified approach to many issues seen in the unit.
Clinical Protocols↗
A consensus statement on empiric therapy for suspected gram-positive infections in surgical patients.
BACKGROUND: Multidrug resistance among gram-positive pathogens in tertiary and other care centers is common. A systematic decision pathway to help select empiric antibiotic therapy for suspected gram-positive postsurgical infections is presented. DATA SOURCES: A Medline search with regard to empiric antibiotic therapy was performed and assessed by the 15-member expert panel. Two separate panel meetings were convened and followed by a writing, editorial, and review process. CONCLUSIONS: The main goal of empiric treatment in postsurgical patients with suspected gram-positive infections is to improve clinical status. Empiric therapy should be initiated at the earliest sign of infection in all critically ill patients. The choice of therapy should flow from beta-lactams to vancomycin to parenteral linezolid or quinupristin-dalfopristin. In patients likely to be discharged, oral linezolid is an option. Antibiotic resistance is an important issue, and in developing treatment algorithms for reduction of resistance, the utility of these new antibiotics may be extended and reduce morbidity and mortality.
Anti-Bacterial Agents↗
Guidelines for the selection of anti-infective agents for complicated intra-abdominal infections.
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Abdominal Abscess↗
A severity score for complicated skin and soft tissue infections derived from phase III studies of linezolid.
BACKGROUND: Severity scoring systems are useful for assessing patient risk and predicting prognosis. METHODS: We developed a scoring system using data from a phase III study comparing antibiotics in hospitalized patients with complicated skin and soft tissue infections (study A), and used logistic regression analysis to identify factors contributing to treatment failure. We tested this system using data from a similar study (study B). RESULTS: In study A (n = 682), cure rates were lower in patients with at least 1 comorbid condition (P <0.05) and in the highest risk class (P = 0.05); elevated blood urea nitrogen, hyponatremia, anemia, lesion size, and surgical wound infection were independent predictors of failure (P <0.05). In study B (n = 166), findings were similar and significant for risk class (P <0.05). In the combined analysis (n = 848), cure rates were higher for linezolid than for the comparator in all patients (85% versus 77%; P <0.01) and in subanalyses by comorbid conditions, median score, and risk class (P <0.05). CONCLUSIONS: We developed and validated a scoring system in which baseline variables predicted outcome. Patients with higher severity scores generally had poorer outcomes regardless of treatment group. Our finding that linezolid was an independent predictor of cure merits further evaluation.
Acetamides↗
NADPH oxidase activation in fibronectin adherent human neutrophils: A potential role for beta1 integrin ligation.
BACKGROUND: Hydrogen peroxide production by human neutrophils is tightly coupled to integrin ligation. This provides a means for spatial localization of oxidant production. However, integrin specificity and consequent signaling mechanisms for this process remain undefined. In the present study we demonstrate that otherwise unstimulated neutrophils adherent to fibronectin, a beta(1) ligand, but not fibrinogen, a beta(2) ligand, produce hydrogen peroxide in a time-dependent fashion. We hypothesized that signaling proceeded through focal, adhesionlike structures. METHODS: Triton-X insoluble (actin cytoskeleton) fractions from suspension phase cells and cells adherent to the beta(1) integrin ligand fibronectin were assessed for the presence of the integrin-associated kinase Pyk2, the scaffolding protein paxillin, and the downstream Src family kinase Lyn. Lysates were subjected to immunoprecipitation with anti-phosphotyrosine and probed for Pyk2, paxillin, and Lyn. Associations between focal adhesion kinase (FAK) and paxillin were determined by immunoprecipitation with anti-FAK and probing with anti-paxillin antibody. Activation of NADPH oxidase was determined by demonstration of redistribution of p47(phox) in Triton-X insoluble fractions. RESULTS: NADPH oxidase activation, as judged by H(2)O(2) production, occurred with fibronectin-, but not in suspension or fibrinogen-adherent cells. Cells adherent to fibronectin for 20 minutes demonstrated marked increases in Pyk2, paxillin, and Lyn activation in comparison to fibronectin-adherent and suspension phase cells. CONCLUSIONS: This study demonstrates that fibronectin adherence is a significant initiating factor for NADPH oxidase assembly in human neutrophils. This appears to be mediated by beta(1) integrins. We demonstrate formation of focal adhesions containing Pyk2/FAK, paxillin, and Lyn, and translocation of p47(phox).
Cell Adhesion↗
Intraabdominal sepsis: newer interventional and antimicrobial therapies for infected necrotizing pancreatitis.
PURPOSE OF REVIEW: Recent advances in interventional techniques and antimicrobial therapy have significantly affected the morbidity and mortality of infected pancreatic necrosis. This review describes elements of this progress. RECENT FINDINGS: Operative management of infected pancreatic necrosis has consisted of formal laparotomy and debridement of the pancreatic necrosis/infection. Typically, the abdominal wound has been left open and the pancreatic bed has been reexplored at frequent intervals. This staged approach has been replaced by a single definitive operative procedure. More recently, laparoscopic techniques have been used, and provide the possibility of substantially lessened morbidity. The benefits of antimicrobial prophylaxis, typically with carbapenems, have been demonstrated in several clinical trials. The use of such broad-spectrum therapy has complicated the antimicrobial management of prophylaxis failures. A resistant flora is encountered in such patients, including gram-positive cocci, yeast, and gram-negative bacilli. This has been shown to mandate empiric therapy with combination regimens based on agents not used for prophylaxis. SUMMARY: These findings recommend the practice of routine antibacterial prophylaxis with systemic agents. Patients receiving such treatment should be monitored for colonization by yeast; surveillance cultures do not appear to be necessary because these critically ill patients have an inflammatory disease and frequently experience temperature elevations warranting cultures to rule out infection. If infection is documented by aspiration or intervention, aggressive antimicrobial therapy directed at organisms identified by Gram stain should be started. Classes of antimicrobial agents other than those used for prophylaxis should be used.
Abdominal Cavity↗
Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial.
OBJECTIVE: To examine the clinical efficacy and safety of ertapenem, a novel beta-lactam agent with wide activity against common pathogens encountered in intraabdominal infection. SUMMARY BACKGROUND DATA: Ertapenem has a pharmacokinetic profile and antimicrobial spectrum that support the potential for use as a once-a-day agent for the treatment of common mixed aerobic and anaerobic infections. METHODS This prospective, randomized, controlled, and double-blind trial was conducted to compare the safety and efficacy of ertapenem with piperacillin/tazobactam as therapy following adequate surgical management of complicated intraabdominal infections. RESULTS: Six hundred thirty-three patients were included in the modified intent-to-treat population, with 396 meeting all criteria for the evaluable population. Patients with a wide range of infections were enrolled; perforated or abscessed appendicitis was most common (approximately 60% in microbiologically evaluable population). A prospective, expert panel review was conducted to assess the adequacy of surgical source control in patients who were failures as a component of evaluability. For the modified intent-to-treat groups, 245 of 311 patients treated with ertapenem (79.3%) were cured, as were 232 of 304 (76.2) treated with piperacillin/tazobactam. One hundred seventy-six of 203 microbiologically evaluable patients treated with ertapenem (86.7%) were cured, as were 157 of the 193 (81.2%) treated with piperacillin/tazobactam. CONCLUSIONS: In this study, the efficacy of ertapenem 1 g once a day was equivalent to piperacillin/tazobactam 3.375 g every 6 hours in the treatment of a range of intraabdominal infections. Ertapenem was generally well tolerated and had a similar safety and tolerability profile to piperacillin/tazobactam. A formal process for review of adequacy of source control was found to be of benefit. The results of this trial suggest that ertapenem may be a useful option that could eliminate the need for combination and/or multidosed antibiotic regimens for the empiric treatment of intraabdominal infections.
Abdominal Abscess↗
Molecular mechanisms of slime production: a transferable operon explains how a saprophyte finds a home.
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Biofilms↗