Biomedical subjects

M A West

Publications and source records attributed to M A West.

At least 19 recordsLinked to original sources

PubMed2003

Creation versus destruction of T cell epitopes in the class II MHC pathway.

Proteases perform two key roles in the class II MHC antigen processing pathway. They initiate removal of the invariant chain chaperone for class II MHC and they generate peptides from foreign and self proteins for eventual capture and display to T cells. How a balance is achieved between generation of suitable peptides versus their complete destruction in an aggressive proteolytic environment is not known. Nor is it known in most cases which proteases are actually involved in antigen processing. Our recent studies have identified asparagine endopeptidase (AEP or legumain) as an enzyme that contributes to both productive and destructive antigen processing in the class II MHC pathway. The emerging consensus seems to be that individual proteolytic enzymes make clear and non-redundant contributions to antigen processing.

Animals↗

PubMed2001

Minority dissent and team innovation: the importance of participation in decision making.

This study integrates research on minority dissent and individual creativity, as well as team diversity and the quality of group decision making, with research on team participation in decision making. From these lines of research, it was proposed that minority dissent would predict innovation in teams but only when teams have high levels of participation in decision making. This hypothesis was tested in 2 studies, 1 involving a homogeneous sample of self-managed teams and 1 involving a heterogeneous sample of cross-functional teams. Study 1 suggested that a newly developed scale to measure minority dissent has discriminant validity. Both Study 1 and Study 2 showed more innovations under high rather than low levels of minority dissent but only when there was a high degree of participation in team decision making. It is concluded that minority dissent stimulates creativity and divergent thought, which, through participation, manifest as innovation.

Adult↗

PubMed2001

The impact of managed care and current governmental policies on an urban academic health care center.

BACKGROUND: Managed care and governmental policies have restructured hospital reimbursement. We examined reimbursement trends in trauma care to assess the impact of this market driven change on an urban academic health center. METHODS: Patients injured between January 1997 and December 1999 were analyzed for Injury Severity Score (ISS), length of hospital stay, hospital cost, payer, and reimbursement. RESULTS: Between 1997 and 1999, the volume of patients with an ISS less than 9 increased and length of stay decreased. In addition, overall cost, payment, and profit margin increased. Commercially insured patients accounted for this margin increase, because the margins of managed care and government insured patients experienced double-digit decreases. Patients with ISS of 9 or greater also experienced a volume increase and a reduction in length of stay; however, costs within this group increased greater than payments, thereby reducing profit margin. Whereas commercially insured patients maintained their margin, managed care and government insured patients did not (double- and triple-digit decreases). CONCLUSIONS: Managed care and current governmental policies have a negative impact on urban academic health center reimbursement. Commercial insurers subsidize not only the uninsured but also the government insured and managed care patients as well. National awareness of this issue and policy action are paramount to urban academic health centers and may also benefit commercial insurers.

Academic Medical Centers↗

PubMed2001

Cytokines and the pathogenesis of nosocomial pneumonia.

BACKGROUND: Nosocomial pneumonia (NP) in injured patients is a significant clinical problem. We hypothesize that the pathogenesis of NP in injured patients involves an imbalanced cytokine response within the alveolar airspace that may inhibit effector cell function. METHODS: Proinflammatory (IL-8) and anti-inflammatory (IL-10) levels were measured in bronchoalveolar lavage (BAL) fluid from multitrauma patients on admission, 24, 48, and 72 hours post-injury and following lipopolysaccharide (LPS) induction of alveolar cells. Patients were compared based on IL-8 levels and the development of NP. RESULTS: A high level of IL-8 on admission was associated with the development of NP. In addition, levels of IL-8 were significantly greater in NP-positive patients at all time points. The IL-10 levels decreased from admission values in NP-negative patients but increased in NP-positive patients. Furthermore, a high level of IL-10 ( > 120 pg/mL) at 72 hours post-injury was associated with the development of NP. Alveolar cells from NP-positive patients produced significantly more IL-10 in response to LPS than cells from NP-negative patients. CONCLUSIONS: The pathogenesis of NP in injured patients involves an early and severe IL-8 process within the lung followed by an exaggerated IL-10 response that may inhibit effector cell function.

Adult↗

PubMed2001

Abdominal compartment syndrome in the intensive care unit.

The abdominal compartment syndrome is an increasingly recognized complication of both medical and surgical patients in the ICU setting. This syndrome has been described in a wide variety of clinical scenarios and results from a persistent elevation in intra-abdominal pressure characterized by graded organ system dysfunction. Manifestations of abdominal compartment syndrome include cardiovascular, pulmonary, renal, splanchnic, and neurologic impairment. The diagnosis of abdominal compartment syndrome requires a high level of clinical suspicion combined with an increased intra-abdominal pressure, usually obtained via urinary bladder pressure measurement. Patients at risk for abdominal compartment syndrome warrant close monitoring and we recommend prompt abdominal decompression following documentation of increased intra-abdominal pressure in the setting of physiologic compromise. Abdominal compartment syndrome can significantly contribute to the morbidity and mortality of both medical and surgical patients alike in the ICU. The signs and symptoms of abdominal compartment syndrome should become familiar to all critical care practitioners.

Abdomen↗

PubMed2001

Recent developments in clinical management of surgical sepsis.

The current clinical management of surgical patients with sepsis is governed by two principles: control of the source of infection and supportive management of the patient until recovery. Recently, there has been renewed interest in the concept of source control-in particular, its importance for evaluating and comparing clinical trials. This brief review highlights some of the developments in the surgical literature. Important recent publications center on source control, the management of systemic inflammatory response syndrome, necrotizing pancreatitis, acute diverticulitis, gastrointestinal fistulas, and the role of laparoscopy in surgical infections. Novel interventions in supportive care are being developed, and their clinical applicability and effectiveness will be improved with increased understanding of the pathophysiology of systemic inflammation.

Acute Disease↗

PubMed2000

Rac is required for constitutive macropinocytosis by dendritic cells but does not control its downregulation.

BACKGROUND: Dendritic cells use constitutive macropinocytosis to capture exogenous antigens for presentation on MHC molecules. Upon exposure to inflammatory stimuli or bacterial products such as lipopolysaccharide (LPS), macropinocytosis is dramatically downregulated as part of a developmental programme leading to dendritic cell maturation, migration and activation of T cells. It is not known, however, how macropinocytosis is sustained in dendritic cells in the absence of exogenous stimuli, nor how it is downregulated upon maturation. We have tested the possibility that one or more members of the Rho family of GTPases are involved in and control pinocytosis in dendritic cells. RESULTS: We established dendritic cell populations that show constitutive macropinocytosis that was downregulated by LPS treatment. Microinjection of immature cells with dominant-negative Rac (N17Rac1) or treatment with Clostridium difficile toxin B, the phosphoinositide 3-kinase (PI3-K) inhibitor wortmannin, or LPS all inhibited the formation of macropinosomes but, surprisingly, did not eliminate membrane ruffling. Microinjection of N17Cdc42 or the Rho inhibitor C3 transferase eliminated actin plaques/podosomes and actin cables, respectively, but had little effect on the formation of macropinosomes. Surprisingly, dendritic cells matured with LPS had equivalent or even somewhat higher levels of active Rac than immature cells. Moreover, microinjection of a constitutively active form of Rac (V12Rac1) into mature dendritic cells did not reactivate macropinocytosis. CONCLUSIONS: Rac has an important role in the constitutive formation of macropinosomes in dendritic cells but may be required downstream of membrane ruffling. Furthermore, regulation of Rac activity does not appear to be the control point in the physiological downregulation of dendritic cell pinocytosis. Instead, one or more downstream effectors may be modulated to allow Rac to continue to regulate other cellular functions.

Animals↗

PubMed2000

Academic practice groups: strategy for survival.

BACKGROUND: The mission of public academic health centers (puAHC) and their affiliated practice groups (APG) focuses on teaching, research, and the clinical care of at-risk populations. Resources to accomplish this mission, however, are becoming scarce. For puAHC to survive and remain competitive, innovative strategies will need to be developed by the APG. We hypothesized that the integration of a surgical academic practice of the APG with a nonacademic integrated health care delivery system (NAIDS) in a managed care environment would benefit all involved. METHODS: A surgical academic practice was integrated with a NAIDS in a 95% managed care market. Faculty alone provided care the first year, and third-year residents were added the following year. To assess outcome, we collected benefit and cost data for the 1-year period before integration and compared them with the two, 1-year periods after integration. RESULTS: In the second year of integration, revenues from the NAIDS referrals to the puAHC and APG increased 89% and 150%, respectively. The NAIDS' general surgical and endoscopy caseload increased by 25%. Additionally, there was a 92% reduction in operating room technician cost with no increase in operating time per case. Finally, the third-year resident experienced a caseload increase of 163%. CONCLUSIONS: In an environment where resources are diminishing and managed care consists of many large NAIDS that drive referrals and revenue, the integration of a surgical academic practice with a NAIDS benefits all shareholders. Academic practice groups that develop strategies that leverage their competitive advantage will have the best chance of surviving in today's turbulent health care market.

Academic Medical Centers↗

PubMed2000

Abdominal vena caval injuries: outcomes remain dismal.

BACKGROUND: The mortality rate for abdominal vena caval injuries remains high. We examined the experience of a level I trauma center to determine factors significant to the outcome in these injuries. METHODS: Forty-seven patients were identified in a retrospective review (1989 to 1999) of patients were identified with abdominal vena caval injury. Data were analyzed by uni- and multivariate methods, including logistic regression. RESULTS: Most of the individuals with abdominal vena caval injuries were young male patients who were injured by penetrating trauma and who were hypotensive on arrival. The severity of injury and the number of organs injured was high. The overall mortality rate was 55%. Nonsurvivors were more often hypotensive in the field with physiologic derangement consistent with hemorrhagic shock. Type and location of injury as well as method of repair were associated with death. Multiple regression analysis revealed that prehospital initial systolic blood pressure and intraoperative bicarbonate levels were independent predictors of survival. CONCLUSIONS: We identified factors related to poor outcome, including suprarenal and retrohepatic location of injury and variables that reflected the evolution of shock. Management should include appropriate resuscitation and ultimately may require novel operative techniques.

Abdominal Injuries↗

PubMed2000

Endotoxin tolerance from lipopolysaccharide pretreatment induces nuclear factor-kappaB alterations not present in C3H/HeJ mice.

BACKGROUND: Lipopolysaccharide (LPS) activation of macrophage (MO) cytokine secretion requires activation and translocation of nuclear factor-kappaB (NF-kappaB). Endotoxin tolerance induced in LPS-responsive C3H/HeN MOs by LPS pretreatment results in decreased tumor necrosis factor (TNF) secretion and altered NF-kappaB activation. C3H/HeJ MOs have a genetic defect that renders them tolerant to LPS activation. We hypothesized that the alterations of NF-kappaB activation seen with LPS tolerance in HeN MOs would be present in HeJ mice. METHODS: MOs from C3H/HeJ and C3H/HeN mice were cultured with +/- 10 ng/mL LPS pretreatment for 24 hours and then stimulated with 1 to 1,000 ng/mL LPS. Activation of NF-kappaB was assayed by gel shift using a 32P-labeled specific oligonucleotide 30 minutes after LPS activation. TNF secretion 6 hours after LPS stimulation was measured by bioassay. RESULTS: LPS stimulation activated NF-kappaB in both HeN and HeJ MOs. We observed decreased NF-kappaB activation and a characteristic mobility shift in endotoxin-tolerant MOs from HeN mice that were not present in HeJ MOs. In contrast with the results in HeN mice, LPS pretreatment did not induce any alterations in NF-kappaB activation in HeJ MOs. LPS-stimulated TNF secretion was decreased in HeN MOs after LPS pretreatment. There was no change in TNF secretion in HeJ MOs, but, overall, TNF secretion by these cells was much less than that seen in HeN cells. CONCLUSION: MOs from C3H/HeN mice rendered LPS-tolerant by low-dose LPS pretreatment have alterations in activation of NF-kappaB not present in LPS-hyporesponsive C3H/HeJ mice.

Animals↗

PubMed2000

Stapled versus hand sewn anastomoses in patients with small bowel injury: a changing perspective.

INTRODUCTION: Recent studies indicate that trauma patients with hollow viscus injuries requiring anastomosis who are managed with stapling have a higher rate of complications than do those in whom a hand-sewn anastomosis is used. We undertook this study to determine whether this finding applied to patients with small bowel trauma at our institution. METHODS: Records of patients with small bowel injuries were retrospectively reviewed. Demographics, severity of injury, injury management, and outcome data were collected. RESULTS: Patients who had their small bowel injuries managed by hand-sewn repair versus resection and stapled anastomosis demonstrated a nonsignificant decrease in overall complication rate (35% vs. 44%) and rate of intra-abdominal complication (10% vs. 18%). Yet the rate of intra-abdominal abscess formation was significantly lower with hand-sewn repair than with resection and stapled anastomosis (4% vs. 13%). However, when hand-sewn primary repairs were excluded from the analysis and injuries that required resection and either stapled or hand-sewn anastomosis were compared, there was a similar overall complication rate (41% vs. 41%) and rate of intra-abdominal complications (17% vs. 21%). CONCLUSION: The rate of intra-abdominal complications did not differ significantly between patients requiring small bowel resection and reanastomosis managed by either a stapled or hand-sewn technique. In our experience, surgical stapling devices appear to be safe for use in repairing traumatic small bowel injury.

Abdominal Injuries↗

PubMed2000

Impaired mitogen-activated protein kinase activation and altered cytokine secretion in endotoxin-tolerant human monocytes.

BACKGROUND: Dysregulation of monocyte/macrophage cytokine production after exposure to multiple inflammatory stimuli may contribute to multiple organ failure and sepsis. Endotoxin (lipopolysaccharide [LPS]) activation of murine macrophage results in the phosphorylation of kinases in the mitogen-activated protein kinase cascade. Pretreatment of murine macrophages with LPS induces LPS-tolerance, with inhibition of LPS-stimulated activation of kinases (ERK1/2 and p38) and diminished release of tumor necrosis factor (TNF). We sought to determine whether similar alterations in LPS-dependent signal transduction are present in LPS-tolerant human peripheral blood monocytes. METHODS: Human peripheral blood monocytes from healthy volunteer donors (n = 12) were incubated in RPMI 1640 culture medium +/- 10 ng/mL of LPS for 18 hours, then stimulated with 0 to 1,000 ng/mL of LPS. Supernatant TNF and interleukin-1 (IL-1) levels were measured after 5 hours by enzyme-linked immunosorbent assay. Activation of the p42/p44 kinases (ERK1/2) was measured 15 minutes after LPS with monoclonal antibodies to diphosphorylated (active) ERK1/2 using novel flow cytometric methods. RESULTS: LPS-tolerant (10 ng/mL LPS pretreatment) human monocytes had significant inhibition of LPS-stimulated TNF secretion but augmented IL-1 release (p < 0.05). Nontolerant human monocytes had a dramatic increase in the percentage of ERK1/2-positive cells in response to an initial stimulation with LPS. This did not occur in the LPS-tolerant cells. Phorbol-12-myristate-13 acetate restored ERK1/2 activation in LPS-tolerant human monocytes. CONCLUSION: LPS-tolerance in human monocytes is associated with inhibition of LPS-stimulated TNF secretion, augmented release of IL-1, and defective activation of mitogen-activated protein kinase cascade (ERK1/2). These results suggest a method of identifying LPS-tolerance and monocyte dysfunction in patients with sepsis.

Cytokines↗

PubMed2000

Defective lipopolysaccharide-dependent ERK 1/2 activation in endotoxin tolerant murine macrophages is reversed by direct protein kinase C stimulation.

Lipopolysaccharide (LPSp) pretreatment inhibits TNF secretion in endotoxin-tolerant macrophages via alterations in signal transduction pathways of LPS activation (LPSa). Protein kinase C inhibitors prevent TNF release in response to LPSa and direct protein kinase C activation with phorbol myristate acetate (PMA) restores TNF secretion after LPSp. In the current experiments the effect of protein kinase C modulation on LPSa-stimulated ERK 1/2 activation was investigated. Murine macrophage TNF production was determined after stimulation with 100 ng/mL of LPSa, +/- 24 h pretreatment with 10 ng/mL of LPSp. Direct protein kinase C activators (PMA or indolactam) or inhibitors (H7 or bisindolylmaleimide) were added 1 h before LPSa. Diphosphorylated ERK 1/2 was assayed after LPSa stimulation by Western blot. LPS tolerance after LPSp was characterized by inhibition of LPSa-stimulated TNF and accompanied by impaired ERK 1/2 activation by LPSa. Protein kinase C activation with PMA or indolactam restored ERK 1/2 activation and TNF secretion. Inhibition of protein kinase C with H7 or bisindolylmaleimide prevented TNF secretion and ERK 1/2 activation by LPSa. These findings suggest that both ERK 1/2 and protein kinase C are required for TNF production in nontolerant macrophages and that LPS tolerance may be associated with an inability to phosphorylate ERK 1/2.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed2000

Impaired ex vivo lipopolysaccharide-stimulated whole blood tumor necrosis factor production may identify "septic" intensive care unit patients.

Currently, there is no reliable diagnostic test to identify septic intensive care unit (ICU) patients. We initiated studies to test the hypothesis that in sepsis, the in vivo exposure to endotoxin is detectable by the ex vivo analysis of lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production. We obtained heparinized whole blood (WB) from 58 ICU patients and 14 healthy controls. The samples were incubated +/-10 ng/mL of LPS at 37 degrees C for 3 h. Plasma TNF levels were measured using enzyme-linked immunoassay (mean +/- standard error of the mean). Clinical data, including ICU length of stay (LOS), ventilator days (VentD), WBC, and positive cultures (Clt+), were obtained retrospectively. A wide range of LPS-stimulated WB TNF production (pg/mL) was observed in ICU patients (4481+/-469) and controls (6706+/-715). Patients were stratified into quartiles (I-IV) on the basis of the distribution of plotted LPS-stimulated TNF values (pg/mL). Patients in quartile I (N = 14) had significantly lower TNF production (< 2000 pg/mL, P < 0.05) and required increased VentD (16 vs. 10 days, P < 0.05) compared to quartiles II-IV (N = 44). Patients in quartile I also had a higher incidence of infection (79 vs. 50%) and longer LOS (18 vs. 13 d) compared to quartiles II-IV. Impaired TNF release may be a manifestation of monocyte endotoxin tolerance and may be useful to diagnose sepsis.

Adult↗

PubMed2000

Trauma in cirrhotics: survival and hospital sequelae in patients requiring abdominal exploration.

Hepatic cirrhosis significantly increases the mortality and morbidity of elective surgery; therefore we hypothesized that cirrhosis would adversely impact outcome after abdominal trauma. We used the trauma registry to identify 17 patients with cirrhosis who sustained trauma injuries requiring emergent exploratory laparotomy. Patients were characterized with respect to age, sex, hospital days, intensive care unit days, and trauma scores. A control group (n = 73) was constructed from the registry by matching age, sex, Injury Severity Score (ISS) and Abbreviated Injury score. Mortality rates were compared by Fisher's exact test and age, ISS, Revised Trauma Score 2, and hospital and intensive care unit days were compared by Student's t test. Despite similar ISS between cirrhotic patients and controls, patients with cirrhosis had a fourfold increase in mortality (mortality odds ratio = 7.2; 95% confidence interval = 2.2-24.0). Cirrhotic trauma patients had a complication rate of 71 per cent and a mortality of 44 per cent. We conclude that cirrhosis is a major independent risk factor for mortality in trauma patients with injuries that require emergent abdominal surgery.

APACHE↗

PubMed1999

Macrophage TNF secretion in endotoxin tolerance: role of SAPK, p38, and MAPK.

PURPOSE: Endotoxin (LPS) activation of macrophages results in phosphorylation of mitogen-activated protein kinases (MAPK), stress-activated protein kinases (SAPK), and p38 kinase. LPS pretreatment inhibits subsequent LPS-stimulated MAPK activation and TNF release and both were reversed if macrophages were treated with phorbol myristate acetate (PMA) before LPS stimulation. In this study we sought to determine if SAPK and p38 tyrosine kinases are required for TNF production and if LPS pretreatment alters their activation. METHODS: TNF production by murine peritoneal exudate macrophages was determined 6 h after stimulation with 100 ng/mL of LPS +/- 24 h pretreatment with 10 ng/mL of LPS. The active, diphosphorylated forms of MAPK (p42, p44), SAPK (p46, p54), and p38 were assayed 30 min after LPS stimulation by Western immunoblot using specific antibodies. In some experiments a p38 kinase inhibitor (SB202190) or the protein kinase C activator (PMA) was added 1 h before LPS stimulation. RESULTS: LPS activated MAPK, SAPK, and p38. LPS pretreatment significantly inhibited MAPK, SAPK, and p38 activation by LPS stimulation. TNF protein secretion and MAPK activation in tolerant macrophages were restored by PMA treatment, but this did not restore SAPK activation. The p38 inhibitor SB202190 blocked LPS-stimulated TNF production. CONCLUSION: LPS pretreatment-induced tolerance decreased LPS-stimulated MAP, SAP, and p38 kinase activation. LPS tolerance in murine macrophages appears to be associated with specific, PMA-reversible defects in MAPK and p38 kinase activation.

Animals↗

PubMed1999

Membrane ruffling, macropinocytosis and antigen presentation in the absence of gelsolin in murine dendritic cells.

Previous studies have shown that mice lacking the actin-severing and capping protein gelsolin have defects in leukocyte and platelet function. Moreover, dermal fibroblasts from gelsolin knockout (Gsn(-)) mice showed substantially reduced motility, membrane ruffling and pinocytosis. We have generated dendritic cells (DC) from spleens of Gsn(-) mice to investigate the importance of gelsolin in antigen endocytosis and processing. We show here that Gsn(-) DC produce apparently normal membrane ruffles which can resolve to form large macropinosomes. Moreover, presentation of exogenous antigens on both MHC class II and class I molecules was equivalent in Gsn(-) and wild-type DC. Thus the major rearrangements of the actin cytoskeleton needed for DC antigen uptake and presentation can proceed in the absence of a major actin filament regulatory protein.

Amino Acid Sequence↗

PubMed1999

Trauma faculty and trauma team activation: impact on trauma system function and patient outcome.

OBJECTIVE: To determine the impact of the presence of an attending trauma surgeon during trauma team activation on system function and patient outcome. METHODS: After a retrospective review of medical records and trauma registry, a comparative study between two American College of Surgeons Committee on Trauma Level I trauma centers was performed. One center (Hennepin County Medical Center) required a chief surgical resident, two junior residents, and a board-certified emergency medicine faculty to be present in the emergency department for all trauma team activations. The attending trauma surgeon was notified at the time of trauma team activation and was neither required to be present in the emergency department at time of patient arrival nor in the hospital 24 h/day. The other center (St. Paul Ramsey Medical Center) required a chief surgical resident, two junior residents, a board-certified emergency medicine faculty member, and an attending trauma surgeon to be present in the emergency department for all trauma activations and in hospital 24 hours/day. Over a 21-month period, all major trauma patients (Injury Severity Score > 15 or emergent operation within 4 hours of admission and any Injury Severity Score) that triggered trauma team activation were examined. Resuscitation time, time to incision, probability of survival, and mortality were analyzed. RESULTS: Resuscitation time was shorter at St. Paul Ramsey Medical Center when compared with Hennepin County Medical Center. Analysis by mechanism of injury demonstrates that this was true for blunt trauma (39+/-13 vs. 27+/-12 minutes, p = 0.001) and for penetrating trauma (28+/-14 vs. 24+/-17 minutes, p = 0.01). Subgroup analysis of penetrating trauma victims demonstrated that there was a significant difference in resuscitation times for gunshot wounds but not for stabs. There was no difference in how quickly operations could be initiated for blunt trauma patients. However, in penetrating cases, time to incision was significantly shorter at St. Paul Ramsey Medical Center (50+/-29 vs. 66+/-43 minutes, p = 0.01). There was no significant difference in mortality for any category of Trauma and Injury Severity Score probability of survival in blunt or penetrating trauma. Analysis of "in-house" and "out-house" time intervals demonstrated no difference in survival in any mechanism of injury, nor was there a difference in overall mortality. CONCLUSION: The presence of a trauma surgeon on the trauma team reduced resuscitation time and reduced time to incision for emergent operations, particularly in penetrating trauma. However, it had no measurable impact on mortality based on Trauma and Injury Severity Score probability of survival. Attending trauma surgeon presence on the trauma team improves in-hospital trauma system function without affecting patient outcome.

Adult↗