Signal transduction pathways of IL-1beta-mediated iNOS in pulmonary vascular smooth muscle cells.

Interleukin (IL)-1beta is an important early mediator of inflammation in pulmonary artery smooth muscle cells. We previously reported that a geranylgeranyltransferase inhibitor elevated basal levels of inducible nitric oxide synthase (iNOS) and enhanced IL-1beta-mediated induction, suggesting that Rac or Rho small G proteins are candidates for antagonism of such induction. In this study, overexpression of constitutively active Rac1 or its dominant negative mutant did not affect IL-1beta induction of iNOS. Alternatively, treatment with Clostridium botulinum C3 exoenzyme, which ADP-ribosylates Rho, was associated with superinduction of iNOS, suggesting an inhibitory role for Rho. IL-1beta activated the three mitogen-activated protein kinase (extracellular signal-regulated kinases 1 and 2, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38) and the Janus kinase (JAK)-signal transducer and activator of transcription pathways. The former two pathways were not associated with IL-1beta-mediated iNOS induction, whereas the latter two appeared to have inhibitory roles in iNOS expression. These data suggest that a broad intracellular signaling response to IL-1beta in rat pulmonary artery smooth muscle cells results in elevated levels of iNOS that is opposed by the geranylgeranylated small G protein Rho as well as the p38 and JAK2 pathways.

Colonic adenomas: prevalence and incidence rates, growth rates, and miss rates at colonoscopy.

Cost-effective use of colonic imaging studies can be achieved through an understanding of the prevalence, incidence, growth, and miss rates of colon adenomas. High adenoma prevalence rates are associated with increasing age, male gender, and a family history of colorectal cancer or multiple first-degree relatives with colorectal neoplasia or neoplasia diagnosed at a young age. The incidence rate of advanced adenomas is higher in patients with multiple adenomas and is likely also associated with a family history of colorectal cancer, increased age, and large adenoma size at the index examination. Direct observational data on growth rates suggests that adenomas <1 cm in size have a fairly stable size over a 3-year interval. Although colonoscopy is the most sensitive colonic imaging study, substantial miss rates for small adenomas are inherent to the procedure. Advancements in endoscopic technology should lead to reduced miss rates, allowing expansion of intervals between examinations while reducing negative outcomes of fatal interval cancers.

Induced nitric oxide inhibits IL-6-induced stat3 activation and type II acute phase mRNA expression.

Inducible nitric oxide synthase (iNOS) can be coexpressed with acute phase reactants in hepatocytes; however, it is unknown if NO can regulate the acute phase response. We tested the hypothesis that iNOS-derived nitric oxide (NO) attenuates the acute phase response by inhibiting IL-6-enhanced Stat3 DNA-binding activity and type II acute phase mRNA expression. iNOS was overexpressed in cultured rat hepatocytes via transduction with a replication defective adenovirus containing cDNA for human iNOS (AdiNOS), and Stat3 DNA-binding activity was determined by electrophoretic mobility shift assay (EMSA). EMSAs demonstrated that AdiNOS inhibits IL-6-induced Stat3 activation and that this inhibition is reversible in the presence of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMA). The induction of beta-fibrinogen mRNA by IL-6, a Stat3 dependent process, is attenuated in AdiNOS-transduced cells and partially reversed by L-NMA. Thus, iNOS overexpression suppresses IL-6-induced Stat3 activation and type II acute phase mRNA expression in cultured hepatocytes. This suppression may represent a mechanism by which NO down-regulates the acute phase response.

Outcome analysis of external coloanal anastomosis.

BACKGROUND: To evaluate the safety and efficacy of treating low-lying rectal lesions with resection and primary repair using a pull-through technique with rectal stump eversion and external coloanal anastomosis with immediate reintroduction into the pelvis. METHODS: All coloanal anastomoses with the above technique on the Gastrointestinal Surgery Service at the University of Pittsburgh from March 1990 to September 1995 were evaluated. RESULTS: Fifty-two patients underwent coloanal anastomoses with the above technique, and follow-up was available for 96% (50 of 52) of patients. Rectal lesions in the 50 patients included cancer (n = 34), rectal adenomas (n = 13), and other lesions (n = 3). Mean follow-up period was 29.6 +/- 21.8 months (28.5 months for patients with carcinoma). Fecal continence was normal or good in 88% (44 of 50) of patients. Moderate or complete incontinence was present in 12% (6 of 50) of patients. The local recurrence rate of rectal cancer was 0%. Morbidity occurred in 22% (11 of 50) of patients. Survival was 90% (45 of 50 patients). CONCLUSIONS: Coloanal anastomosis with this technique provides effective treatment for low-lying malignant or benign rectal lesions and has an acceptable complication rate.

Analysis of laparoscopy in trauma.

BACKGROUND: The optimum roles for laparoscopy in trauma have yet to be established. To date, reviews of laparoscopy in trauma have been primarily descriptive rather than analytic. This article analyzes the results of laparoscopy in trauma. STUDY DESIGN: Outcome analysis was done by reviewing 37 studies with more than 1,900 trauma patients, and laparoscopy was analyzed as a screening, diagnostic, or therapeutic tool. Laparoscopy was regarded as a screening tool if it was used to detect or exclude a positive finding (eg, hemoperitoneum, organ injury, gastrointestinal spillage, peritoneal penetration) that required operative exploration or repair. Laparoscopy was regarded as a diagnostic tool when it was used to identify all injuries, rather than as a screening tool to identify the first indication for a laparotomy. It was regarded as a diagnostic tool only in studies that mandated a laparotomy (gold standard) after laparoscopy to confirm the diagnostic accuracy of laparoscopic findings. Costs and charges for using laparoscopy in trauma were analyzed when feasible. RESULTS: As a screening tool, laparoscopy missed 1% of injuries and helped prevent 63% of patients from having a trauma laparotomy. When used as a diagnostic tool, laparoscopy had a 41% to 77% missed injury rate per patient. Overall, laparoscopy carried a 1% procedure-related complication rate. Cost-effectiveness has not been uniformly proved in studies comparing laparoscopy and laparotomy. CONCLUSIONS: Laparoscopy has been applied safely and effectively as a screening tool in stable patients with acute trauma. Because of the large number of missed injuries when used as a diagnostic tool, its value in this context is limited. Laparoscopy has been reported infrequently as a therapeutic tool in selected patients, and its use in this context requires further study.

The role of protein phosphatases in the expression of inducible nitric oxide synthase in the rat hepatocyte.

Previously, we demonstrated that nuclear factor-kappaB (NF-kappaB) mediates cytokine-induced hepatic inducible nitric oxide synthase (iNOS) expression. NF-kappaB activation is regulated by kinases and phosphatases whose function is only beginning to be understood. Therefore, experiments were performed to determine the role of protein phosphatases (PPase) in cytokine-induced iNOS expression. Hepatocytes were stimulated with cytokines in the presence or absence of tyrosine phosphatase inhibitors (pervanadate [PV], phenylarsine oxide [PAO]) and a serine-threonine phosphatase inhibitor (okadaic acid [OA]). Cytokines induced hepatocyte iNOS mRNA, protein, and NO2- production that was substantially decreased by the addition of the tyrosine phosphatase inhibitors (PAO and PV). The serine-threonine phosphatase inhibitor (OA) decreased NO release and protein levels in a concentration-dependent fashion; however, iNOS mRNA levels were not significantly reduced. Nuclear run-on experiments demonstrated that protein tyrosine phosphatases (PTPases) are required for iNOS transcription, while the serine-threonine phosphatase inhibitor (OA) had no effect on iNOS transcription. Electromobility shift assays (EMSAs) revealed that the tyrosine-phosphatase inhibitors blocked cytokine-induced NF-kappaB activation, while OA did not have a significant effect on NF-kappaB DNA binding activity. Therefore, tyrosine phosphatases are involved in the regulation of cytokine-induced activation of NF-kappaB, while serine-threonine phosphatases posttranscriptionally regulate iNOS translation. These results identify the regulatory role of specific protein phosphatases (PPases) in hepatic iNOS expression.

Analysis of thoracoscopy in trauma.

BACKGROUND: The role of video-assisted thoracic surgery (VATS) in trauma has yet to be established. Up to the time of this writing, reviews of thoracoscopy in trauma have been primarily descriptive rather than analytic. This article analyzes the results of thoracoscopy (nonvideo and VATS) in trauma. METHODS: Analysis was done by reviewing 28 nonoverlapping studies since the introduction of thoracoscopy in 1910, with a combined total of more than 500 patients. RESULTS: Diagnostically, thoracoscopy has been used primarily to evaluate diaphragmatic injury, continued chest tube bleeding, and suspected cardiac injury. Thoracoscopy has a 98% (188/191 patients) accuracy rate in diagnosing diaphragmatic injuries. Therapeutically, thoracoscopy has been used primarily to control chest tube bleeding, evacuate retained hemothoraces, and evacuate empyemas. Thoracoscopy is 90% (89/99 patients) effective in evacuating retained hemothoraces, 86% (19/22 patients) effective in evacuating empyemas, and 82% (33/40 patients) effective in controlling chest tube bleeding. Thoracoscopy benefits include preventing 62% (323/514) of trauma patients from having a thoracotomy or laparotomy. Risks include a 2% (11/534 patients) procedure-related complication rate and a 0.8% (4/471 patients) missed injury rate. Technical failure rates are 10% (10/99 patients) and 4% (7/199 patients) in evacuation of retained hemothoraces and evaluation of diaphragmatic injuries, respectively. CONCLUSIONS: Analysis suggests that thoracoscopy (nonvideo and VATS) can be applied safely and effectively in the care of the injured patient.

Pulmonary tractotomy as an abbreviated thoracotomy technique.

BACKGROUND: Operative abbreviated thoracotomy techniques in thoracic trauma include emergency center thoracotomy, ligation of major arterial branches, packing the thoracic cavity for diffuse bleeding, towel clip or Bogota bag closure of the chest, and pulmonary tractotomy. Pulmonary tractotomy with selective vascular ligation was originally described for deep through-and-through lung injuries that did not involve hilar vessels or airways. Pulmonary tractotomy has evolved into use as an abbreviated thoracotomy technique in patients with severe thoracic or multivisceral trauma. As with any operative technique in high-risk patients, specific procedure-related complications may occur and are analyzed herein. The objective of this manuscript is to review the indications, techniques, and results for pulmonary tractotomy in trauma patients requiring abbreviated thoracotomy. METHODS: Medical records were retrospectively reviewed for 30 of 32 consecutive tractotomy patients treated at Ben Taub General Hospital, during a 3-year period. By using a model for logistic regression analysis, the characteristics of each patient and their clinical course were tested for impact on mortality. RESULTS: Seventy percent of patients had at least one intraoperative parameter indicative of acidosis (pH < 7.2), coagulopathy (prothrombin time > 13.8 or partial thromboplastin time > 38.0 seconds), or hypothermia (core temperature < 34 degrees C), and 50% of patients manifested two of these three parameters. The mortality rate among the 30 patients was 17%. Three of the five patients who died were noted to be acidotic, coagulopathic, and hypothermic. Twelve of 25 patients who survived more than 1 day had at least one thoracic complication. There were no late deaths. There was one failed tractotomy and one missed injury. A second thoracotomy was not required for control of a lung injury in any patient. Logistic regression analysis showed that intraoperative blood loss was the only predictive factor for mortality. CONCLUSION: Pulmonary tractotomy is a simple and effective technique in injured patients who require an abbreviated thoracotomy and has an acceptable mortality and complication rate. This follow-up report notes that as definitive therapy, tractotomy continues to allow for direct control of bleeding and air leak and obviates the need for formal resection.

The pathogenesis of Staphylococcus aureus in the trauma patient and potential future therapies.

BACKGROUND: Staphylococcus aureus is the most frequently isolated pathogen in the trauma patient and uses multiple virulent factors to cause infection. At the cellular level, infection begins with the prokaryotic bacterial cell manipulating the eukaryotic host cell through its virulent factors. Researching this cellular interaction by describing the mechanisms of actions of various virulent factors may lead to new preventive therapies which will make the trauma patient less susceptible to S aureus infections. METHODS: Surgical, medical, and microbial literature was reviewed to provide an update on S aureus pathogenesis. RESULTS: Novel future therapies, in addition to antibiotics, are being devised based on understanding the molecular nature of S aureus pathogenesis. CONCLUSION: The impact of S aureus on trauma will increase as S aureus develops more antibiotic resistance and as the trauma population becomes older and includes an increasing proportion of immunocompromised patients. To meet the challenge of increased virulence, trauma surgeons should be directly involved in the research of microbial pathogenesis.