Local resection versus radical surgery for parathyroid carcinoma: A National Cancer Database analysis.

INTRODUCTION: Parathyroid carcinoma (PC) is rare and often diagnosed incidentally after local resection (LR) for other indications. Although recommended treatment has traditionally been radical surgery (RS), more recent guidelines suggest that LR alone may be adequate. We sought to further investigate outcomes of RS versus LR for localized PC. MATERIALS AND METHODS: PC patients from 2004 to 2015 with localized disease were identified from the National Cancer Database, then stratified by surgical therapy: LR or RS. Demographic and clinicopathologic data were compared. Cox proportional hazard models were constructed to estimate associations of variables with overall survival (OS). OS was estimated from time of diagnosis using Kaplan-Meier curves. RESULTS: A total of 555 patients were included (LR = 522, RS = 33). The groups were comparable aside from LR patients having higher rates of unknown nodal status (66.9% versus 39.4%; p = 0.003). By multivariable analysis, RS did not have a significant association with OS (hazard ratio (HR) = 0.43, 95% confidence interval (95%CI) = 0.10, 1.83; p = 0.255), nor did positive nodal status (HR = 0.66, 95%CI = 0.09, 5.03; p = 0.692) and unknown nodal status (HR = 1.30, 95%CI = 0.78, 2.17; p = 0.311). There was no difference in OS between the LR and RS groups, with median survival not reached by either group at 10 years (median follow-up = 60.4 months; p = 0.20). CONCLUSIONS: There was no difference in OS between LR and RS for localized PC. RS and nodal status may not impact survival as previously identified, and LR should remain a valid initial surgical approach. Future higher-powered studies are necessary to assess the effects of surgical approaches on morbidity and oncologic outcomes.

Selection bias: Examining the feasibility, utility, and participant receptivity to incorporating simulation into the general surgery residency selection process.

BACKGROUND: Opportunities exist to revise the current residency selection process to capture desirable candidate competencies. We examined the extent to which components of the American College of Surgeons/Association for Surgical Education simulation-based medical student curriculum combined with a teamwork activity could be used as potential screening method. METHODS: Students participated in a workshop consisting of training/evaluation of knot tying, suturing, airway management, gowning/gloving, and teamwork. Surveys were given to medical students (MS) and faculty/resident/staff (FRS) to examine their opinions about the residency screening process, the most critical competencies to assess, and the effectiveness of each station for candidate evaluation. RESULTS: Communication (FRS, 4.86 ± .35; MS, 4.93 ± .26), leadership (FRS, 4.41 ± .80; MS, 4.5 ± .76), judgment (FRS, 4.62 ± .74; MS, 4.67 ± .62), professionalism (FRS, 4.64 ± .73; MS, 5.00 ± .00), integrity (FRS, 4.71 ± .78; MS, 4.87 ± .35), and grit/resilience (FRS, 4.71 ± .78; MS, 4.53 ± .74) were considered most valuable for candidate screening. The simulation-based curriculum for evaluation of residency candidates was rated lowest by both groups. Open response comments indicated positive perceptions of this process. CONCLUSIONS: Employing simulation to assess candidates may be most beneficial for examining nontechnical attributes. Future work should continue to explore this area.

MicroRNA-101 inhibits growth of epithelial ovarian cancer by relieving chromatin-mediated transcriptional repression of p21(waf¹/cip¹).

PURPOSE: MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC). METHODS: In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21(waf1/cip1) and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH-2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells. RESULTS: ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re-expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21(waf1/cip1) promoter. CONCLUSIONS: MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC.

Ritonavir blocks AKT signaling, activates apoptosis and inhibits migration and invasion in ovarian cancer cells.

BACKGROUND: Ovarian cancer is the leading cause of mortality from gynecological malignancies, often undetectable in early stages. The difficulty of detecting the disease in its early stages and the propensity of ovarian cancer cells to develop resistance to known chemotherapeutic treatments dramatically decreases the 5-year survival rate. Chemotherapy with paclitaxel after surgery increases median survival only by 2 to 3 years in stage IV disease highlights the need for more effective drugs. The human immunodeficiency virus (HIV) infection is characterized by increased risk of several solid tumors due to its inherent nature of weakening of immune system. Recent observations point to a lower incidence of some cancers in patients treated with protease inhibitor (PI) cocktail treatment known as HAART (Highly Active Anti-Retroviral Therapy). RESULTS: Here we show that ritonavir, a HIV protease inhibitor effectively induced cell cycle arrest and apoptosis in ovarian cell lines MDH-2774 and SKOV-3 in a dose dependent manner. Over a 3 day period with 20 muM ritonavir resulted in the cell death of over 60% for MDAH-2774 compared with 55% in case of SKOV-3 cell line. Ritonavir caused G1 cell cycle arrest of the ovarian cancer cells, mediated by down modulating levels of RB phosphorylation and depleting the G1 cyclins, cyclin-dependent kinase and increasing their inhibitors as determined by gene profile analysis. Interestingly, the treatment of ritonavir decreased the amount of phosphorylated AKT in a dose-dependent manner. Furthermore, inhibition of AKT by specific siRNA synergistically increased the efficacy of the ritonavir-induced apoptosis. These results indicate that the addition of the AKT inhibitor may increase the therapeutic efficacy of ritonavir. CONCLUSION: Our results demonstrate a potential use of ritonavir for ovarian cancer with additive effects in conjunction with conventional chemotherapeutic regimens. Since ritonavir is clinically approved for human use for HIV, drug repositioning for ovarian cancer could accelerate the process of traditional drug development. This would reduce risks, limit the costs and decrease the time needed to bring the drug from bench to bedside.

Telomere maintenance in laser capture microdissection-purified Barrett's adenocarcinoma cells and effect of telomerase inhibition in vivo.

PURPOSE: The aims of this study were to investigate telomere function in normal and Barrett's esophageal adenocarcinoma (BEAC) cells purified by laser capture microdissection and to evaluate the effect of telomerase inhibition in cancer cells in vitro and in vivo. EXPERIMENTAL DESIGN: Epithelial cells were purified from surgically resected esophagi. Telomerase activity was measured by modified telomeric repeat amplification protocol and telomere length was determined by real-time PCR assay. To evaluate the effect of telomerase inhibition, adenocarcinoma cell lines were continuously treated with a specific telomerase inhibitor (GRN163L) and live cell number was determined weekly. Apoptosis was evaluated by Annexin labeling and senescence by beta-galactosidase staining. For in vivo studies, severe combined immunodeficient mice were s.c. inoculated with adenocarcinoma cells and following appearance of palpable tumors, injected i.p. with saline or GRN163L. RESULTS: Telomerase activity was significantly elevated whereas telomeres were shorter in BEAC cells relative to normal esophageal epithelial cells. The treatment of adenocarcinoma cells with telomerase inhibitor, GRN163L, led to loss of telomerase activity, reduction in telomere length, and growth arrest through induction of both the senescence and apoptosis. GRN163L-induced cell death could also be expedited by addition of the chemotherapeutic agents doxorubicin and ritonavir. Finally, the treatment with GRN163L led to a significant reduction in tumor volume in a subcutaneous tumor model. CONCLUSIONS: We show that telomerase activity is significantly elevated whereas telomeres are shorter in BEAC and suppression of telomerase inhibits proliferation of adenocarcinoma cells both in vitro and in vivo.

Lipopolysaccharide activation of pericyte's Toll-like receptor-4 regulates co-culture permeability.

BACKGROUND: Pericytes (PCs) have a synergistic relationship with endothelial cells (MVEC) in regulating capillary permeability. PCs express Toll-like receptor-4 (TLR-4). We hypothesize one mechanism of MVEC/PC co-culture permeability is regulated through lipopolysaccharide (LPS) activation of pericyte TLR-4. METHODS: Rat PCs were harvested and cultured. PCs were transfected with siRNA targeted to TLR-4. Western blotting was used to confirm gene silencing of TLR-4. A previously described co-culture permeability assay was performed after LPS treatment. RESULTS: Western blot confirmed successful silencing of TLR-4 in PCs, which was sustained for 7 days. A dose- and time-dependent effect of LPS on albumin clearance was seen in MVEC/PC co-cultures. Co-cultures with TLR-4 silenced in PCs eliminated the LPS dose-dependent increase in albumin clearance. CONCLUSIONS: TLR-4 regulates pericyte mediated capillary leak seen with LPS exposure. Our TLR-4 silencing model can be used to further investigate TLR-4's role in pericyte mediated capillary leak.

Lipopolysaccharide up-regulates heat shock protein expression in rat lung pericytes.

BACKGROUND: Heat shock proteins (HSP) function as molecular chaperones, participating in protein folding and maturation throughout the cell. Serum HSPs may correlate with acute lung injury. Pericytes are perivascular cells located abluminally from endothelial cells, and play a regulatory role in capillary leak. It is our hypothesis that pericytes express HSP 60 and HSP 70, and these HSPs are up-regulated in response to lipopolysaccharide (LPS). METHODS: Rat microvascular lung pericytes were isolated and cultured. Cells from passages three to five were used and treated with LPS (control, 10 ng/mL, and 100 ng/mL) for either 4 or 18 h. Immunoblotting and real-time PCR were used to analyze the presence and quantity of HSP 60 and HSP 70. RESULTS: Immunoblotting revealed the presence of HSP 60 and HSP 70 in control pericytes. After 4 h of treatment with LPS (10 ng/mL and 100 ng/mL), no increase in protein expression of HSP 60 or HSP 70 was seen. However, after 18 h an increase in protein expression of HSP 60 and HSP 70 was seen. Real-time PCR demonstrated the presence of HSP 60 mRNA and HSP 70 mRNA in control pericytes. An increase in mRNA was seen after 18 h of LPS treatment, but not after 4 h. CONCLUSIONS: This study provides the first in vitro evidence that rat lung pericytes express HSP 60 and HSP 70. HSP 60 and HSP 70 are up-regulated after 18 h of LPS exposure. Pericyte heat shock protein expression may contribute to the lung's response seen in sepsis.

Cytokine production in lipopolysaccharide-exposed rat lung pericytes.

BACKGROUND: Vessels of the pulmonary microvasculature are composed of two cell types: endothelial cells and pericytes. Pericytes are crucial to the development of capillary leak and pulmonary edema seen in acute respiratory distress syndrome (ARDS). Pericytes express toll-like receptor-4, and is upregulated in response to lipopolysaccharide (LPS). The objective of this study was to evaluate secretory cytokine production by rat microvascular pericytes. It is our hypothesis that pericytes secrete interleukin (IL)-1B, IL-6, and tumor necrosis factor (TNF)-A in response to LPS. METHODS: Rat lung pericytes (RLPs) were isolated and grown either alone or in coculture with rat endothelial cells. Cells from passages 3 to 5 were used and treated with LPS (control, 10 ng/mL, and 100 ng/mL) for varying amounts of time. Immunoblotting and reverse transcriptase polymerase chain reaction (RT-PCR) was used for detection and quantification of NF-kB. Enzyme-linked immunosorbent assay and RT-PCR were used for detection and quantification of cytokines. RESULTS: The protein and mRNA for NF-kB was detected in RLPs. Additionally, NF-kB mRNA increased with exposure to LPS. The supernatant of RLPs exposed to LPS contained IL-1B, and IL-1B increased in a time- and dose-dependant manner. An increase in mRNA for IL-1B, IL-6, and TNF-A was seen in a dose-dependant fashion. Cocultures produced significantly less IL-1B when exposed to similar concentrations of LPS. CONCLUSIONS: Pericytes contain the machinery necessary, and produce pro-inflammatory cytokines. Cocultures manufacture less IL-1B then pericytes alone, which is similar to previous coculture observations. Pericyte activation and cytokine production may play a role in capillary leak seen in gram-negative sepsis.

Solid-pseudopapillary tumors of the pancreas: case report and literature review.

Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms of low malignant potential that mostly affect young women. These tumors are of unclear pathogenesis, are slow growing, and can become considerably large before causing symptoms. Complete resection is curative in most cases. This is the case of a 39-year-old African-American woman undergoing evaluation for Roux-en-Y gastric bypass, who was found to have a pancreatic mass. Image-guided biopsy revealed SPT. The patient underwent complete excision of the tumor and had an open Roux-en-Y gastric bypass performed concurrently. The patient had an uneventful postoperative course. A review of the literature is presented.

Vascular endothelial growth factor modulates contractile response in microvascular lung pericytes.

BACKGROUND: Pericytes are capillary support cells that may play a role in regulating permeability by their contractile responses. Vascular endothelial growth factor (VEGF) may play a role in the increased permeability found in sepsis and other inflammatory conditions. The purpose of this study was to evaluate the role of VEGF in regulating pericyte contraction. METHODS: Rat microvascular lung pericytes were isolated according to previously described methods and cultured on collagen gel matrices. Cells were exposed to VEGF (10, 100, and 1000 pg/mL) for varying time periods (0, 10, 30, 60, and 120 minutes). The gels were released and their contractile responses digitally quantified. RESULTS: At all doses, VEGF induced initial pericyte relaxation (contraction 85% to 90% of controls; P < .001). This was followed-up by increased and sustained contraction (107% to 120% of controls; P < .01). CONCLUSIONS: VEGF modifies the contractile response of microvascular lung pericytes. This mechanism may play a role in the increased permeability demonstrated in inflammatory states.

TNF-alpha and IL-1beta increase pericyte/endothelial cell co-culture permeability.

BACKGROUND: Pericytes (PC) have a unique synergistic relationship with microvascular endothelial cells (MVEC) in the regulation of capillary permeability. This study investigates the effect of TNF-alpha, IL-1beta, and IL-6 on the microvasculature by measuring changes in PC contractility, and also, albumin permeability across MVEC/PC co-cultures. MATERIALS AND METHODS: Semi-permeable inserts were plated first with rat lung MVEC and then PCs (on the fourth day) at a ratio of 10:1 MVEC/PC. On day 5, 50 ng/ml of TNF-alpha, IL-1beta, and IL-6 were added with or without a secretory phospholipase A(2)-IIA (sPLA(2)-IIA) inhibitor for 24 h. After treatments, albumin clearances were quantified. For measuring contractility, PCs were cultured on collagen matrices and exposed for 24 h to TNF-alpha, IL-1beta, and IL-6 at 1 ng/ml, 10 ng/ml, and 50 ng/ml with/without inhibitors for sPLA(2)-IIA, phospholipase A(2) (PLA(2)), and cyclooxygenase-II (COX-II). After treatments, the surface area of the collagen disks was digitally quantified. RESULTS: TNF-alpha and IL-1beta significantly increased albumin clearance in MVEC/PC co-cultures (P < 0.05) and induced dose-dependent relaxation of PCs (P < 0.05). PC relaxation was completely attenuated with the sPLA(2)-IIA and pLA(2) inhibitors; the COX-II inhibitor provided partial blockade. IL-6 had no effect on PC contractility or permeability. CONCLUSION: TNF-alpha and IL-1beta directly increased microvascular permeability in co-cultures. They also induced relaxation of PCs through a sPLA(2)-IIA dependent mechanism. Interestingly, IL-6 had no effect, although its presence in high levels has been demonstrated in inflamed lungs. These findings may help elucidate the significance of PC in regulating the capillary response to various pro-inflammatory cytokines.

Endothelial cells protect against lipopolysaccharide-induced caspase-3-mediated pericyte apoptosis in a coculture system.

BACKGROUND: Cells that comprise the pulmonary capillary walls, the pericytes and endothelial cells, may undergo apoptosis in inflammatory states. This study examined the effects of lipopolysaccharide (LPS) on apoptosis in pericytes and endothelial cells, both individually and grown together in a coculture system. METHODS: Pericytes and endothelial cells were isolated and cultured separately and in coculture as previously described. The cells were subsequently exposed to LPS for 12, 24, 48, and 72 hours. The cellular contents were then examined by Western blot analysis for products of apoptosis. TUNEL staining was also performed to analyze for apoptosis. RESULTS: Pericytes alone exposed to LPS showed increased levels of p11 and p17, which are activated fragments of capase-3, a cysteine effector protease involved in cleaving cytoskeletal and nuclear proteins to induce apoptosis. When grown in coculture with endothelial cells and exposed to LPS in coculture but harvested independently, pericytes showed decreased levels of p11 and p17 and increased levels of Bcl-xL, an antiapoptotic protein that protects the integrity of mitochondria, and prevents cytochrome c release and subsequent caspase-9 activation. CONCLUSIONS: In response to LPS, pericytes undergo apoptosis involving the caspase-3 pathway. Endothelial cells may decrease this effect through the expression of a soluble mediator.

Prognostic determinants in duodenal injuries.

A retrospective review of 222 consecutive patients with duodenal injuries admitted to an urban Level 1 Trauma Center who subsequently underwent laparotomy during the period July 1980 to April 2002 was performed in an effort to elucidate factors associated with mortality, infectious morbidity, and length of stay in these patients. Predictably, the patients were predominantly male (92.7%) and young (mean age, 31.6 years). The overall mortality rate was 22.5 per cent, with a mortality rate of 18 per cent seen in the first 48 hours. Penetrating trauma was suffered by 88.3 per cent of the patients. Multivariate analysis revealed the performance of a thoracotomy, initial emergency department (ED) systolic blood pressure (SBP) <90 mm Hg, final operating room (OR) core body temperature less than 35 degrees C, and presence of a splenic injury to be the most important predictors of mortality (all P < 0.05). Mortality in the patients undergoing a resuscitative thoracotomy was 88.9 per cent versus 13.3 per cent in those patients not requiring thoracotomy. An initial SBP in the ED <90 was associated with a 46 per cent mortality rate, as compared with 4 per cent in those patients not in shock. A final OR core body temperature of less than 35 degrees C led to a 60 per cent mortality rate versus 8.3 per cent for warmer patients. Patients with a concomitant splenic injury were noted to have a 62.5 per cent mortality rate; those without had a 19.4 per cent mortality rate. The mean length of stay among survivors greater than 48 hours was 16.0 +/- 24.7 days. Univariate analyses revealed lowest OR core body temperature below 35 degrees C, initial OR SBP <90, presence of infection, >5 transfusions, initial ED SBP <90, final OR core temperature <35 degrees C, colon injury, spleen injury, and an injury severity score (ISS) >25 all to be significantly associated with increased length of stay. Multivariate analysis revealed an initial operating room blood pressure of less than 90 mm Hg systolic, the presence of an infection, and greater than 5 blood transfusions to be the factors most significantly correlated with increased length of stay (all P < 0.02). Of 182 patients surviving 48 hours, 98 (54%) developed an infection. Fifty-seven (31%) patients were noted to have wound-related infections, 92 (51%) patients had nosocomial infections, and 50 (27%) patients had both types. The presence of an abdominal arterial injury, an ISS >25, pancreatic injury, and lowest OR core body temperature <35 degrees C were the factors identified on multivariate analysis most significantly correlated with infectious morbidity (all P < 0.05). This data suggests that early efforts to prevent shock and rapidly control bleeding are the most likely efforts to reduce mortality rates in these patients. Those patients with duodenal injury presenting in shock or requiring a thoracotomy for resuscitation did poorly. Splenic injury was the associated injury found on multivariate analysis to be most closely associated with increased mortality. Early control of bleeding and the prevention of infection provide the most significant opportunity for decreasing length of stay. Infections are common with duodenal injuries, and aggressive surveillance should especially be performed in those patients with an abdominal arterial injury, an ISS >25, pancreatic injury, or lowest OR core body temperature <35 degrees C.

Inhibition of heme oxygenase-1 in microvascular lung pericytes diminishes at high concentrations of an inflammatory mediator.

Post-traumatic inflammation and sepsis induce changes in the lung microvasculature causing increased permeability. Pericytes, contractile cells positioned abluminally to endothelial cells, play a role in regulating this response. An in vitro model of microvascular lung pericytes (MLP) was used to investigate the effect of inhibiting heme oxygenase-1 (HO-1), a stress-induced enzyme, in the presence of varying levels of lipopolysaccharide (LPS), a mediator in the initiation of inflammation, on pericyte contractility. Rat MLP were cultured on collagen gel matrices. Cells were exposed to three concentrations of LPS in the presence of zinc protoporphyrin IX (ZnPP-9), a known inhibitor of HO-1. After 24 hours, the surface area of the collagen disks was quantified, thereby measuring pericyte contraction. ZnPP-9 caused a significant attenuation of the LPS-induced relaxation of the pericytes (P < or = 0.003). The effects of ZnPP-9, however, depended on the concentration of LPS to which the pericytes were exposed. Greater concentrations of LPS decrease the attenuating power of ZnPP-9. The inhibition of HO-1 diminished MLP relaxation triggered by LPS. The effect of ZnPP-9, however, is dependent on the concentration of LPS to which the MLP are exposed, indicating its saturation. ZnPP-9 may antagonize the microvascular response to trauma.

Predictors of mortality in patients with traumatic diaphragmatic rupture and associated thoracic and/or abdominal injuries.

This is a retrospective review of 731 patients sustaining diaphragmatic trauma over a 22 year period (1980-2002) at an urban level I trauma center. Patients had an average injury severity score (ISS) of 22 +/- 12. The mortality rate (MR) was 23 per cent (168/731). There were a total of 460 left-sided diaphragmatic injuries (L-TDR), 263 right-sided diaphragmatic injuries (R-TDR), and 8 bilateral diaphragmatic injuries (B-TDR). There were no significant differences in mortality with L-TDR versus R-TDR. Shotgun wounds had the highest MR (42%) (P = 0.0028). Emergency thoracotomies were performed in 31 per cent (225) with a 62 per cent (140) MR. Bilateral thoracotomies had a significantly higher MR of 85 per cent (33/39) compared to the 58 per cent (107/186) for unilateral thoracotomies (P = 0.0028). Multivariate analysis revealed the most significant independent predictors of mortality to be the revised trauma score, transfusion of pRBCs > 10 units, and need for thoracotomy (P < 0.0001). The infection rate was 41 per cent. Multivariate analysis revealed blunt trauma, blood transfusions, ISS, and pancreatic injury as the most significant independent predictors of infection (P < 0.001). The initial physiologic presentation of the patient and the severity of hemorrhagic shock are the primary determinants for survival. Prompt identification of associated injuries with rapid control of bleeding is paramount to survival.

The roles of cyclic adenosine monophosphate- and cyclic guanosine monophosphate-dependent protein kinase pathways in hydrogen peroxide-induced contractility of microvascular lung pericytes.

BACKGROUND: Sepsis and posttraumatic inflammatory processes are accompanied by definite changes in microvascular permeability, particularly in the lung. These permeability changes may occur because of damaged regulatory mechanisms at the level of the capillary wall. Pericytes are adventitial cells located within the basement membrane of capillaries. These cells contain multiple cytoplasmic processes that envelope endothelial cells, and are consequently thought to stabilize capillary walls and participate in microcirculation and endothelial cell permeability. Data from this laboratory and other laboratories have confirmed that pericytes are contractile cells, adding to the evidence that pericytes may influence or help regulate capillary permeability. We have already determined that hydrogen peroxide (H2O2) causes dose-dependent relaxation in microvascular lung pericytes (MLPs) at 10 minutes and, conversely, dose-dependent contraction at 30 minutes. It is the aim of this study to determine the mechanism of this biphasic contractile response. Specifically, we will determine whether cyclic adenosine monophosphate (cAMP)- or cyclic guanosine monophosphate (cGMP)-dependent protein kinase intracellular pathways are responsible for the hydrogen peroxide-induced contractility of MLPs. METHODS: Rat MLPs were isolated by previously published protocol and cultured on collagen gel matrices. MLPs were pretreated with either ODQ, a soluble guanylate cyclase inhibitor (100 mumol/L), for 15 minutes; GKIP, a protein kinase G inhibitor (100 mumol/L), for 1 hour; SQ22536, an adenylate cyclase inhibitor (100 mumol/L), for 15 minutes; or H89, a protein kinase A inhibitor (10 mumol/L), for 1 hour. Hydrogen peroxide was then introduced to each MLP culture at 10 mumol/L, 100 mumol/L, and 1 mmol/L. After each of these treatments, the surface area of the collagen gels was digitally quantified at 10 and 30 minutes. RESULTS: SQ22536 attenuated both relaxation at 10 minutes and the contraction seen at 30 minutes for all concentrations of H2O2. H89 caused a marked basal relaxation and prevented the cells from contracting at 30-minute exposures to all concentrations of H2O2. Both ODQ and GKIP attenuated the relaxation at 10 minutes but had no affect on the later contraction. CONCLUSION: The cGMP-dependent protein kinase pathway is a mechanism for H2O2-induced relaxation of MLPs. Up-regulation of cAMP and cGMP is responsible for early H2O2-induced relaxation and late contraction. Protein kinase A (cAMP-dependent protein kinase pathway) may be an important intracellular signaling protein in the H2O2-induced contraction of MLPs or may be unable to down-regulate cAMP once inhibited. This evidence further supports the concept that there are separate intracellular pathways that regulate divergent cellular responses. This idea parallels the clinical concept of reversible and irreversible dysfunction of cellular processes in shock, and that the cellular dysfunction is initiated by separate intracellular pathways.

End-tidal CO2-derived values during emergency trauma surgery correlated with outcome: a prospective study.

BACKGROUND: The purpose of this study was to determine whether end-tidal carbon dioxide (PETCO) derived variables assist in evaluating the adequacy of resuscitation during emergency surgery for trauma. METHODS: This was a prospective study of end-tidal derived variables and outcome in 106 trauma patients in an urban Level I trauma center. RESULTS: The patients who lived (compared with those who died) had higher final end-tidal Pco levels, lower arterial-end tidal CO differences (Pa-ET)CO, and a decreased alveolar dead space ratio (p < 0.001). The best survival rates were with a PETCO > 27 mm Hg, a (Pa-ET)CO < or = 9 mm Hg, and 96% (56 of 58) for an alveolar dead space ratio < or = 0.20 (p < 0.001). An inappropriately high or "excess Paco also correlated with a decreased (Pa-ET)CO and poorer prognosis. If, after the initial resuscitation, the PETCO -derived values did not achieve these "optimal" levels, survival was significantly reduced. CONCLUSION: During emergency trauma surgery, the PETCO and its derived values help to predict outcome and may be used to identify patients needing more aggressive resuscitation.