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Papers by Richard Turnage

World Journal of Surgery, 2002

Even in the absence of inhalational injury, acute lung injury is a common cause of morbidity and ... more Even in the absence of inhalational injury, acute lung injury is a common cause of morbidity and mortality for patients sustaining severe burns. Other than general supportive measures, there are few therapeutic options for improving survival in these critically ill patients. Numerous clinical and laboratory studies have implicated tumor necrosis factor (TNF)-a and neutrophils as important participants in the pathogenesis of burn-induced lung injury. There is, however, little information regarding the mechanism by which these and other pro-inflammatory mediators affect the movement of fluid and protein across the microvascular barrier into the interstitium of the lung. In addition to reviewing the evidence implicating TNF-a and neutrophils in the pathophysiology of burn-induced lung injury, this report summarizes current theories regarding potential mechanisms by which these mediators may alter microvascular barrier function to lead ultimately to the development of pulmonary edema.

Surgery, 2000

This study examined the hypothesis that exposure of an endothelial cell (EC) monolayer to tumor n... more This study examined the hypothesis that exposure of an endothelial cell (EC) monolayer to tumor necrosis factor-alpha (TNF-alpha) and that burn-activated neutrophils alter EC actin cytoskeleton and enhance the permeability of the monolayer. Neutrophils were harvested from rats that had undergone a 45% surface area burn (BURN-neutrophil) or uninjured control rats. ECs were grown on polyester filters or fibronectin-coated glass slides and exposed for 4 hours to media, TNF-alpha (100 ng/mL), or TNF-alpha plus BURN-neutrophil or uninjured control rats (10(7) cells). Monolayer permeability was assessed by measuring the flux of albumin across the cells. EC surface area and microfilament number and length were determined by the staining of actin microfilaments with rhodamine phalloidin followed by fluorescent microscopy. The amount of albumin that moved across the monolayer in response to TNF-alpha plus BURN-neutrophil was twice that of media alone (P <.05) or TNF-alpha alone (P <.05). The number and length of actin microfilaments in ECs exposed to TNF-alpha plus BURN-neutrophil were significantly less than that of cells exposed to media alone or TNF-alpha alone. These data are consistent with a hypothesis that TNF-alpha plus BURN-neutrophil affect endothelial monolayer permeability by altering EC actin cytoskeletal organization.

Surgery, 2002

Adherens junctions (AJ), by their association with the endothelial cytoskeleton, maintain microva... more Adherens junctions (AJ), by their association with the endothelial cytoskeleton, maintain microvascular barrier integrity. Phosphorylation states of AJ proteins, such as vascular endothelial (VE) cadherin, can potentially alter the interactions between component AJ proteins. Furthermore, AJ protein phosphorylation is susceptible to regulation by inflammatory mediators. We previously demonstrated the importance of VE cadherin in tumor necrosis factor (TNF)-mediated endothelial permeability. We now postulate that TNF-induced endothelial permeability is associated with tyrosine phosphorylation of VE cadherin. Confluent monolayers of human umbilical vein endothelial cells were exposed to saline solution, TNF-alpha (100 U/mL) or TNF and the Src-tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Permeability was assessed by fluorescein isothiocyanate-dextran flux. VE-cadherin phosphorylation was determined by immunoprecipitation and immunoblotting with antiphosphotyrosine antibody. Data are expressed as mean +/- SEM and analyzed by analysis of variance. TNF-alpha-induced tyrosine phosphorylation of VE cadherin and increased intercellular gap formation. These changes were associated with increased endothelial-cell monolayer permeability, all of which were prevented by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Exposure to an inactive tyrphostin, AG9 (negative control), did not prevent TNF-induced endothelial permeability. We conclude that tyrosine phosphorylation of VE cadherin is an important regulatory pathway associated with TNF-induced endothelial barrier dysfunction. Modulating AJ protein phosphorylation may provide targets for therapy during inflammation.

Shock, 2002

The mechanism by which tumor necrosis factor alpha (TNFalpha) increases endothelial permeability ... more The mechanism by which tumor necrosis factor alpha (TNFalpha) increases endothelial permeability is unclear. Vascular endothelial (VE) cadherin (cadherin 5) is an important contributor to endothelial monolayer integrity. The purpose of our study was to determine the effect of TNFalpha on VE-cadherin cell-surface expression and to identify the signaling pathways involved in TNF-induced changes in cadherin expression. Human umbilical vein endothelial cell monolayer permeability was measured by enzyme-linked immunosorbent assay for biotin-labeled albumin. Immunofluorescence, laser confocal microscopy, and Western immunobloting were used to assess VE cadherin distribution. Mitogen-activated protein kinase (MAPK) activity was determined using functional kinase assays and was inhibited with the compounds SB202190 and PD98059. TNFalpha significantly increased permeability and induced p38 and ERK MAPK activation compared with controls (P < 0.05). These changes were associated with a loss of membrane-associated VE cadherin. Inhibition of p38 but not ERK MAPK significantly reduced the effect of TNFalpha on endothelial permeability and cell-surface VE cadherin expression. p38 MAP kinase activation appears to be an important upstream signaling event associated with increased endothelial permeability and vascular endothelial cadherin redistribution.

Shock, 2002

ABSTRACT This study examines the hypotheses that TNF-alpha causes a dose-dependent increase in th... more ABSTRACT This study examines the hypotheses that TNF-alpha causes a dose-dependent increase in the microvascular permeability of ex vivo buffer perfused lungs that is quantitatively similar to that caused by lipopolysaccharide (LPS) or thromboxane A2 (TxA2). We also postulated that TNF-alpha potentiates the effect of interleukin-1beta (IL-1beta) or TxA2 receptor activation on pulmonary microvascular permeability. Lungs harvested from Wistar rats were perfused ex vivo with Krebs-Henseleit buffer containing 0, 10, 100, or 1000 ng/mL recombinant rat TNF-alpha. Twenty minutes later pulmonary microvascular permeability was determined by measuring the capillary filtration coefficient (Kf) using a gravimetric technique. The effect of TNF-alpha (100 ng/mL) on pulmonary Kf was compared with that of lungs exposed to LPS (400 microg/mL; E. coli 0111:B4) or a TxA2 receptor agonist (U-46619; 7 x 10(-8)). In other experiments, perfused lungs were exposed to TNF-alpha plus IL-1beta (1 ng/mL) or TNF-alpha plus U-46619 after which Kf was measured. Exposure of ex vivo buffer perfused lungs to 10-1000 ng/mL TNF-alpha had no effect on Kf whereas LPS and U-46619 was associated with a two- and six-fold increase in Kf, respectively (P < 0.05). The Kf of lungs exposed to TNF-alpha plus IL-1 was similar to that of lungs exposed to TNF-alpha alone. Lastly, the Kf of lungs exposed to TNF-alpha plus U-46619 was not different than that of lungs exposed to U-46619 alone. In conclusion, TNF-alpha at least when administered for a relatively brief period of time does not affect microvascular permeability in an isolated, buffer-perfused lung model.

Journal of Surgical Oncology, 1997

Perianal mucinous adenocarcinoma is a rare variant of anal canal epithelioid tumors. Our objectiv... more Perianal mucinous adenocarcinoma is a rare variant of anal canal epithelioid tumors. Our objective in this report is to examine the clinical features, pathology, treatment, and outcome for patients with perianal mucinous adenocarcinoma. A retrospective review identified four patients with histologically proven perianal mucinous adenocarcinoma. The medical records of these patients were reviewed for presentation, therapy, and outcome. Pain and bleeding were present in all cases. In three of four patients, chronic perirectal disease was present, including two abscesses and one fistula. All patients had extensive local disease at presentation. One patient presented with bilateral inguinal nodal metastases. Two patients received neoadjuvant chemotherapy and radiation, with a third patient receiving radiation alone. Two of these three patients underwent abdominoperineal resection. Three patients subsequently died (all of progression and/or recurrence) 2-48 months after diagnosis. The fourth patient (who was treated with chemotherapy and radiation followed by abdominoperineal resection) is alive and disease free at 12 months. Perianal mucinous adenocarcinoma is a rare disease with a poor prognosis, mostly due to its advanced nature at the time of diagnosis. Chemoradiation followed by surgery may improve outcome in selected individuals.

Annals of Surgical Oncology, 2001

Little information is available on the impact that therapies used in the treatment of colorectal ... more Little information is available on the impact that therapies used in the treatment of colorectal cancer (CRC) have on long-term, health-related quality of life (HRQL). Knowledge of how HRQL is affected by these therapies is essential in properly selecting patients for treatment. The purpose of this study was to determine the long-term impact that surgical and adjuvant therapy for resectable CRC has on patient-reported HRQL in a male veteran population through a case-control design. All participating patients had completed therapy at least 6 months before enrollment. One hundred fifty-eight patients were accrued over a 3-year period (January 1, 1997 to December 31, 1999) at a single institution. The impact of CRC surgery on HRQL was measured by comparing a cohort of 61 patients undergoing surgery alone for the treatment of CRC (CRC-S group) with 44 patients undergoing surgery for benign colonic disease (BCD group). To study the effect of adjuvant therapy for CRC on HRQL, a third cohort of 53 patients undergoing both surgical and adjuvant treatment (CRC-S/A group) was compared with the CRC-S group. For each group, health status was measured by a health survey questionnaire, SHORT FORM 36 (SF36). For patients treated for CRC, an additional disease-specific supplemental questionnaire also was used. Self-reported health status, as measured by mean SF36 score, was significantly reduced for the BCD group compared with CRC-S patients on general health perception (41.9 +/- 3.9 vs. 52.2 +/- 3.0, P = .04) and the standardized physical component score (31.2 +/- 1.7 vs. 37.5 +/- 1.5, P < .005). Despite an increased number of distally located tumors, later stage cancers, and an increased number of recurrences in the CRC-S/A group compared with the CRC-S cohort, no significant differences were identified between these groups on any of the subscales or standardized scores of SF36. Using the supplemental questions, no differences were identified between the CRC groups with respect to appetite, weight, or gastrointestinal or urinary functioning. Surgical therapy for CRC probably has minimal impact on long-term HRQL when compared with surgery for benign colonic processes. Similarly, there does not appear to be a measurable, lasting impact of CRC adjuvant therapy on HRQL when compared with surgery alone. Although overall impact of therapies for CRC on HRQL appears to be limited, measurement of therapeutic influence on an individual level and identification of selection criteria based on estimated impact on HRQL for these therapies requires prospective validation.

Annals of Surgery, 2001

To determine whether the investment in postgraduate education and training places patients at ris... more To determine whether the investment in postgraduate education and training places patients at risk for worse outcomes and higher costs than if medical and surgical care was delivered in nonteaching settings. The Veterans Health Administration (VA) plays a major role in the training of medical students, residents, and fellows. The database of the VA National Surgical Quality Improvement Program was analyzed for all major noncardiac operations performed during fiscal years 1997, 1998, and 1999. Teaching status of a hospital was determined on the basis of a background and structure questionnaire that was independently verified by a research fellow. Stepwise logistic regression was used to construct separate models predictive of 30-day mortality and morbidity for each of seven surgical specialties and eight operations. Based on these models, a severity index for each patient was calculated. Hierarchical logistic regression models were then created to examine the relationship between teaching versus nonteaching hospitals and 30-day postoperative mortality and morbidity, after adjusting for patient severity. Teaching hospitals performed 81% of the total surgical workload and 90% of the major surgery workload. In most specialties in teaching hospitals, the residents were the primary surgeons in more than 90% of the operations. Compared with nonteaching hospitals, the patient populations in teaching hospitals had a higher prevalence of risk factors, underwent more complex operations, and had longer operation times. Risk-adjusted mortality rates were not different between the teaching and nonteaching hospitals in the specialties and operations studied. The unadjusted complication rate was higher in teaching hospitals in six of seven specialties and four of eight operations. Risk adjustment did not eliminate completely these differences, probably reflecting the relatively poor predictive validity of some of the risk adjustment models for morbidity. Length of stay after major operations was not consistently different between teaching and nonteaching hospitals. Compared with nonteaching hospitals, teaching hospitals in the VA perform the majority of complex and high-risk major procedures, with comparable risk-adjusted 30-day mortality rates. Risk-adjusted 30-day morbidity rates in teaching hospitals are higher in some specialties and operations than in nonteaching hospitals. Although this may reflect the weak predictive validity of some of the risk adjustment models for morbidity, it may also represent suboptimal processes and structures of care that are unique to teaching hospitals. Despite good quality of care in teaching hospitals, as evidenced by the 30-day mortality data, efforts should be made to examine further the structures and processes of surgical care prevailing in these hospitals.

Journal of applied physiology (Bethesda, Md. : 1985), 1997

This study examines the hypothesis that intestinal ischemia-reperfusion (I/R) injury contributes ... more This study examines the hypothesis that intestinal ischemia-reperfusion (I/R) injury contributes to renal dysfunction by altered renal eicosanoid release. Anesthetized Sprague-Dawley rats underwent 60 min of sham or superior mesenteric artery (SMA) occlusion with 60 min of reperfusion. The I/R groups received either allopurinol, pentoxifylline, 1-benzylimidazole, or carrier before SMA occlusion. In vivo renal artery blood flow was measured by Transonic flow probes, the kidneys were then perfused in vitro for 30 min, and the effluent was analyzed for eicosanoid release and renal function. Intestinal I/R caused a twofold increase in the ratio of renal release of thromboxane B2 to prostaglandin E2 and to 6-ketoprostaglandin F1alpha compared with the sham level, with a corresponding 25% decrease in renal sodium and inulin clearance and renal blood flow. Pentoxifylline or allopurinol pretreatment restored renal eicosanoid release and renal sodium and inulin clearance to the sham level bu...

Journal of Surgical Research, 2007

Introduction. CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal r... more Introduction. CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors.

Prostaglandins, 1995

This study examines the hypothesis that PAF stimulates release of PGI2 from inflamed rabbit gallb... more This study examines the hypothesis that PAF stimulates release of PGI2 from inflamed rabbit gallbladder explant cell cultures. New Zealand white rabbits underwent bile duct ligation for 72 h (72 h BDL), or sham operation, Sham and 72 h BDL gallbladder explants were placed in culture, and the cells grown to 75% confluence. The cells were exposed to increasing concentrations

World Journal of Surgery, 2000

The purpose of this study was to determine the influence of chronic illness, obesity, and type of... more The purpose of this study was to determine the influence of chronic illness, obesity, and type of repair on the likelihood of recurrence following incisional herniorrhaphy. The medical records of 77 patients who underwent elective repair of a midline incisional hernia at the Dallas Veterans Affairs Medical Center between 1991 and 1995 were reviewed. Demographic data, presence of chronic illnesses, type of repair, and presence of recurrence were noted. Ninety-six percent of the patients were men, with an average age of 59 years. More than 50% of the patients had chronic lung or cardiac diseases and more than 40% weighed >120% of their ideal body weight and had a body mass index (BMI) >30. Sixty-two percent of the patients underwent primary reapproximation of the fascia (tissue repair), whereas 38% underwent repair with prosthetic material (prosthetic repair). The overall recurrence rate was 45%, with a median follow-up of 45 months (range 6 -73). Seventy-four percent of the recurrences presented within 3 years of repair. The recurrence rate for those patients undergoing a tissue repair was 54%, whereas the recurrence rate following prosthetic repair was 29%. The incidence of recurrence for patients with pulmonary or cardiac disease or diabetes mellitus was similar to that of patients without these illnesses. The percent ideal body weight and BMI of patients who developed a recurrent hernia, particularly following a prosthetic repair, were significantly greater than those of patients whose repairs remained intact. These data strongly support the use of prosthetic repairs for incisional hernias, particularly in patients who are overweight.

World Journal of Surgery, 2006

Background: The role of whole-body fluorine-18-FDG positron emission tomography (FDG-PET) as an a... more Background: The role of whole-body fluorine-18-FDG positron emission tomography (FDG-PET) as an adjunct localize recurrence in stages II and III breast cancer patients who present with clinical suspicion for recurrence is not well established. We report our experience in such a patient population. Methods: A retrospective review of all patients with stages II and III breast cancer who had a whole-body FDG-PET scan was performed. Results: Of the 23 patients who fit the criteria, 9 had stage II and 14 had stage III breast cancer. Overall sensitivity, specificity, and accuracy were 81%, 100%, and 87%, respectively. Positive and negative predictive values for stages II and III were 100% and 83%, respectively, and 100% and 50%, respectively. FDG-PET detected two recurrences that were missed by conventional imagings, but such recurrences were local and amenable for biopsy. Conclusions: In patients with stages II and III breast cancer who present with a suspicion for recurrent disease, a whole-body FDG-PET scan may be a useful adjunct in the evaluation of recurrence. However, its added benefit over conventional imaging should be questioned.

The American Journal of Surgery, 2012

BACKGROUND: The purpose of this retrospective study was to characterize the presentation, treatme... more BACKGROUND: The purpose of this retrospective study was to characterize the presentation, treatment, and outcomes of patients with multiple myeloma requiring surgical evaluation for abdominal pain.

The American Journal of Surgery, 2001

The role of mammography in the evaluation of male patients presenting with breast disease is cont... more The role of mammography in the evaluation of male patients presenting with breast disease is controversial. This controversy is a function of the lack of specific data concerning the diagnostic accuracy of mammography when used in this clinical setting. The purpose of this study was to define the diagnostic accuracy of mammography in the evaluation of male breast disease. One hundred and four prebiopsy mammograms from 100 patients with tissue diagnoses were read blindly by two independent radiologists, and placed into one of five predetermined categories: definitely malignant, possibly malignant, gynecomastia, benign mass, and normal. Radiologic/pathologic correlation was performed and the sensitivity (Sn), specificity (Sp), positive (Ppv) and negative predictive value (Npv), and accuracy (Ac) for each of the mammographic diagnostic category determined. The pathologic diagnoses were 12 cancers, including 1 patient with bilateral breast cancer, 70 cases of gynecomastia, 16 benign masses, and 6 normals. The accuracy data for the mammographic diagnostic categories are as follows: malignant (combined definitely and possibly malignant), Sn 92%, Sp 90%, Ppv 55%, Npv 99%, Ac 90%; and overall benignity (combined gynecomastia, benign mass, and normal), Sn 90%, Sp 92%, Ppv 99%, Npv 55%, Ac 90%. Six cancers (50%) coexisted with gynecomastia. Mammography can accurately distinguish between malignant and benign male breast disease. Although not a replacement for clinical examination, its routine use could substantially reduce the need for biopsy in patients whose mammograms and clinical examination suggest benign disease.

Surgery, 1995

This study examines the hypothesis that pulmonary inducible nitric oxide synthase (iNOS) activity... more This study examines the hypothesis that pulmonary inducible nitric oxide synthase (iNOS) activity is up-regulated during intestinal reperfusion and that inhibition of NO generation exacerbates pulmonary microvascular dysfunction. Sprague-Dawley rats underwent intestinal ischemia and reperfusion (IIR) or sham operation (SHAM). Pulmonary iNOS activity was measured by quantitating the conversion of L-arginine (L-Arg) to L-citrulline. Another set of animals undergoing IIR or SHAM received an inhibitor of NOS (NG-nitro-L-arginine methylester; L-NAME; 20 mg/kg intravenously), substrate for NO generation (L-Arg; 300 mg/kg intravenously), or vehicle (normal saline solution; 3 ml). Pulmonary microvascular dysfunction was then quantitated by measuring the extravasation of Evans blue dye (EBD) into the lung. Inducible NOS activity was six times greater in the lungs of animals sustaining IIR when compared with SHAM (p = 0.0005). The concentration of EBD within the lungs of animals sustaining IIR was 30% greater than SHAM (p < 0.05). Inhibiting NOS with L-NAME significantly increased pulmonary EBD concentration of both IIR and SHAM groups when compared with normal saline solution-treated animals (p < 0.0001). Treatment with L-Arg prevented this IIR-induced increase in pulmonary dye extravasation. These data suggest that pulmonary iNOS activity is up-regulated in animals sustaining IIR and that this may serve as a compensatory protective response to remote organ injury.

Surgery, 1998

Background. This study examines the hypothesis that specific inhibition of the inducible isoform ... more Background. This study examines the hypothesis that specific inhibition of the inducible isoform of nitric oxide synthase (iNOS) will attenuate intestinal reperfusion-induced pulmonary microvascular dysfunction.

Surgery, 1996

Background. Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunctio... more Background. Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunction and thus has been used as a model of multiple organ failure syndrome. This study examines the hypothesis that hepatic blood flow is markedly reduced in this injury model. Methods. Sprague-Dawley rats underwent 120 minutes of intestinal ischemia and 60 minutes of repeorusion (IIR). Hepatic blood flow was measured with radiolabeled microspheres and Doppler flow probes. Hepatic dysfunction was quantitated by measuring bile flow and serum alanine aminotransferase and hepatic tissue adenosine triphosphate levels. Sham-operated animals served as controls.

Shock, 1994

This study examines the relationship between hypovolemia and remote organ injury following intest... more This study examines the relationship between hypovolemia and remote organ injury following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia (120 min) and reperfusion (90 min, IIR) or sham operation (CTL). The animals received normal saline (NS) at 0, 30, or 40 ml/kg/h intravenously. Lung and intestinal injury was quantitated using an edema index, and liver injury was assessed by measuring bile flow rates. The infusion of 40 ml/kg/h of NS attenuated the intestinal edema index of IIR animals nearly 50% (p < .05). Despite this improvement, this parameter remained nearly 10-fold greater than that of CTL (p < .05). The lung edema index was 70% greater in IIR animals receiving 30 and 40 ml/kg/h of NS than those not receiving NS. The infusion of 40 ml/kg/h of NS restored bile flow rates in IIR animals to that of CTL. These data suggest that hypovolemia may contribute to the intestinal and hepatic injury in this model. The lung injury is independent of hypovolemia.

Shock, 1994

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reper... more This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.

World Journal of Surgery, 2002

Even in the absence of inhalational injury, acute lung injury is a common cause of morbidity and ... more Even in the absence of inhalational injury, acute lung injury is a common cause of morbidity and mortality for patients sustaining severe burns. Other than general supportive measures, there are few therapeutic options for improving survival in these critically ill patients. Numerous clinical and laboratory studies have implicated tumor necrosis factor (TNF)-a and neutrophils as important participants in the pathogenesis of burn-induced lung injury. There is, however, little information regarding the mechanism by which these and other pro-inflammatory mediators affect the movement of fluid and protein across the microvascular barrier into the interstitium of the lung. In addition to reviewing the evidence implicating TNF-a and neutrophils in the pathophysiology of burn-induced lung injury, this report summarizes current theories regarding potential mechanisms by which these mediators may alter microvascular barrier function to lead ultimately to the development of pulmonary edema.

Surgery, 2000

This study examined the hypothesis that exposure of an endothelial cell (EC) monolayer to tumor n... more This study examined the hypothesis that exposure of an endothelial cell (EC) monolayer to tumor necrosis factor-alpha (TNF-alpha) and that burn-activated neutrophils alter EC actin cytoskeleton and enhance the permeability of the monolayer. Neutrophils were harvested from rats that had undergone a 45% surface area burn (BURN-neutrophil) or uninjured control rats. ECs were grown on polyester filters or fibronectin-coated glass slides and exposed for 4 hours to media, TNF-alpha (100 ng/mL), or TNF-alpha plus BURN-neutrophil or uninjured control rats (10(7) cells). Monolayer permeability was assessed by measuring the flux of albumin across the cells. EC surface area and microfilament number and length were determined by the staining of actin microfilaments with rhodamine phalloidin followed by fluorescent microscopy. The amount of albumin that moved across the monolayer in response to TNF-alpha plus BURN-neutrophil was twice that of media alone (P <.05) or TNF-alpha alone (P <.05). The number and length of actin microfilaments in ECs exposed to TNF-alpha plus BURN-neutrophil were significantly less than that of cells exposed to media alone or TNF-alpha alone. These data are consistent with a hypothesis that TNF-alpha plus BURN-neutrophil affect endothelial monolayer permeability by altering EC actin cytoskeletal organization.

Surgery, 2002

Adherens junctions (AJ), by their association with the endothelial cytoskeleton, maintain microva... more Adherens junctions (AJ), by their association with the endothelial cytoskeleton, maintain microvascular barrier integrity. Phosphorylation states of AJ proteins, such as vascular endothelial (VE) cadherin, can potentially alter the interactions between component AJ proteins. Furthermore, AJ protein phosphorylation is susceptible to regulation by inflammatory mediators. We previously demonstrated the importance of VE cadherin in tumor necrosis factor (TNF)-mediated endothelial permeability. We now postulate that TNF-induced endothelial permeability is associated with tyrosine phosphorylation of VE cadherin. Confluent monolayers of human umbilical vein endothelial cells were exposed to saline solution, TNF-alpha (100 U/mL) or TNF and the Src-tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Permeability was assessed by fluorescein isothiocyanate-dextran flux. VE-cadherin phosphorylation was determined by immunoprecipitation and immunoblotting with antiphosphotyrosine antibody. Data are expressed as mean +/- SEM and analyzed by analysis of variance. TNF-alpha-induced tyrosine phosphorylation of VE cadherin and increased intercellular gap formation. These changes were associated with increased endothelial-cell monolayer permeability, all of which were prevented by 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine. Exposure to an inactive tyrphostin, AG9 (negative control), did not prevent TNF-induced endothelial permeability. We conclude that tyrosine phosphorylation of VE cadherin is an important regulatory pathway associated with TNF-induced endothelial barrier dysfunction. Modulating AJ protein phosphorylation may provide targets for therapy during inflammation.

Shock, 2002

The mechanism by which tumor necrosis factor alpha (TNFalpha) increases endothelial permeability ... more The mechanism by which tumor necrosis factor alpha (TNFalpha) increases endothelial permeability is unclear. Vascular endothelial (VE) cadherin (cadherin 5) is an important contributor to endothelial monolayer integrity. The purpose of our study was to determine the effect of TNFalpha on VE-cadherin cell-surface expression and to identify the signaling pathways involved in TNF-induced changes in cadherin expression. Human umbilical vein endothelial cell monolayer permeability was measured by enzyme-linked immunosorbent assay for biotin-labeled albumin. Immunofluorescence, laser confocal microscopy, and Western immunobloting were used to assess VE cadherin distribution. Mitogen-activated protein kinase (MAPK) activity was determined using functional kinase assays and was inhibited with the compounds SB202190 and PD98059. TNFalpha significantly increased permeability and induced p38 and ERK MAPK activation compared with controls (P < 0.05). These changes were associated with a loss of membrane-associated VE cadherin. Inhibition of p38 but not ERK MAPK significantly reduced the effect of TNFalpha on endothelial permeability and cell-surface VE cadherin expression. p38 MAP kinase activation appears to be an important upstream signaling event associated with increased endothelial permeability and vascular endothelial cadherin redistribution.

Shock, 2002

ABSTRACT This study examines the hypotheses that TNF-alpha causes a dose-dependent increase in th... more ABSTRACT This study examines the hypotheses that TNF-alpha causes a dose-dependent increase in the microvascular permeability of ex vivo buffer perfused lungs that is quantitatively similar to that caused by lipopolysaccharide (LPS) or thromboxane A2 (TxA2). We also postulated that TNF-alpha potentiates the effect of interleukin-1beta (IL-1beta) or TxA2 receptor activation on pulmonary microvascular permeability. Lungs harvested from Wistar rats were perfused ex vivo with Krebs-Henseleit buffer containing 0, 10, 100, or 1000 ng/mL recombinant rat TNF-alpha. Twenty minutes later pulmonary microvascular permeability was determined by measuring the capillary filtration coefficient (Kf) using a gravimetric technique. The effect of TNF-alpha (100 ng/mL) on pulmonary Kf was compared with that of lungs exposed to LPS (400 microg/mL; E. coli 0111:B4) or a TxA2 receptor agonist (U-46619; 7 x 10(-8)). In other experiments, perfused lungs were exposed to TNF-alpha plus IL-1beta (1 ng/mL) or TNF-alpha plus U-46619 after which Kf was measured. Exposure of ex vivo buffer perfused lungs to 10-1000 ng/mL TNF-alpha had no effect on Kf whereas LPS and U-46619 was associated with a two- and six-fold increase in Kf, respectively (P < 0.05). The Kf of lungs exposed to TNF-alpha plus IL-1 was similar to that of lungs exposed to TNF-alpha alone. Lastly, the Kf of lungs exposed to TNF-alpha plus U-46619 was not different than that of lungs exposed to U-46619 alone. In conclusion, TNF-alpha at least when administered for a relatively brief period of time does not affect microvascular permeability in an isolated, buffer-perfused lung model.

Journal of Surgical Oncology, 1997

Perianal mucinous adenocarcinoma is a rare variant of anal canal epithelioid tumors. Our objectiv... more Perianal mucinous adenocarcinoma is a rare variant of anal canal epithelioid tumors. Our objective in this report is to examine the clinical features, pathology, treatment, and outcome for patients with perianal mucinous adenocarcinoma. A retrospective review identified four patients with histologically proven perianal mucinous adenocarcinoma. The medical records of these patients were reviewed for presentation, therapy, and outcome. Pain and bleeding were present in all cases. In three of four patients, chronic perirectal disease was present, including two abscesses and one fistula. All patients had extensive local disease at presentation. One patient presented with bilateral inguinal nodal metastases. Two patients received neoadjuvant chemotherapy and radiation, with a third patient receiving radiation alone. Two of these three patients underwent abdominoperineal resection. Three patients subsequently died (all of progression and/or recurrence) 2-48 months after diagnosis. The fourth patient (who was treated with chemotherapy and radiation followed by abdominoperineal resection) is alive and disease free at 12 months. Perianal mucinous adenocarcinoma is a rare disease with a poor prognosis, mostly due to its advanced nature at the time of diagnosis. Chemoradiation followed by surgery may improve outcome in selected individuals.

Annals of Surgical Oncology, 2001

Little information is available on the impact that therapies used in the treatment of colorectal ... more Little information is available on the impact that therapies used in the treatment of colorectal cancer (CRC) have on long-term, health-related quality of life (HRQL). Knowledge of how HRQL is affected by these therapies is essential in properly selecting patients for treatment. The purpose of this study was to determine the long-term impact that surgical and adjuvant therapy for resectable CRC has on patient-reported HRQL in a male veteran population through a case-control design. All participating patients had completed therapy at least 6 months before enrollment. One hundred fifty-eight patients were accrued over a 3-year period (January 1, 1997 to December 31, 1999) at a single institution. The impact of CRC surgery on HRQL was measured by comparing a cohort of 61 patients undergoing surgery alone for the treatment of CRC (CRC-S group) with 44 patients undergoing surgery for benign colonic disease (BCD group). To study the effect of adjuvant therapy for CRC on HRQL, a third cohort of 53 patients undergoing both surgical and adjuvant treatment (CRC-S/A group) was compared with the CRC-S group. For each group, health status was measured by a health survey questionnaire, SHORT FORM 36 (SF36). For patients treated for CRC, an additional disease-specific supplemental questionnaire also was used. Self-reported health status, as measured by mean SF36 score, was significantly reduced for the BCD group compared with CRC-S patients on general health perception (41.9 +/- 3.9 vs. 52.2 +/- 3.0, P = .04) and the standardized physical component score (31.2 +/- 1.7 vs. 37.5 +/- 1.5, P < .005). Despite an increased number of distally located tumors, later stage cancers, and an increased number of recurrences in the CRC-S/A group compared with the CRC-S cohort, no significant differences were identified between these groups on any of the subscales or standardized scores of SF36. Using the supplemental questions, no differences were identified between the CRC groups with respect to appetite, weight, or gastrointestinal or urinary functioning. Surgical therapy for CRC probably has minimal impact on long-term HRQL when compared with surgery for benign colonic processes. Similarly, there does not appear to be a measurable, lasting impact of CRC adjuvant therapy on HRQL when compared with surgery alone. Although overall impact of therapies for CRC on HRQL appears to be limited, measurement of therapeutic influence on an individual level and identification of selection criteria based on estimated impact on HRQL for these therapies requires prospective validation.

Annals of Surgery, 2001

To determine whether the investment in postgraduate education and training places patients at ris... more To determine whether the investment in postgraduate education and training places patients at risk for worse outcomes and higher costs than if medical and surgical care was delivered in nonteaching settings. The Veterans Health Administration (VA) plays a major role in the training of medical students, residents, and fellows. The database of the VA National Surgical Quality Improvement Program was analyzed for all major noncardiac operations performed during fiscal years 1997, 1998, and 1999. Teaching status of a hospital was determined on the basis of a background and structure questionnaire that was independently verified by a research fellow. Stepwise logistic regression was used to construct separate models predictive of 30-day mortality and morbidity for each of seven surgical specialties and eight operations. Based on these models, a severity index for each patient was calculated. Hierarchical logistic regression models were then created to examine the relationship between teaching versus nonteaching hospitals and 30-day postoperative mortality and morbidity, after adjusting for patient severity. Teaching hospitals performed 81% of the total surgical workload and 90% of the major surgery workload. In most specialties in teaching hospitals, the residents were the primary surgeons in more than 90% of the operations. Compared with nonteaching hospitals, the patient populations in teaching hospitals had a higher prevalence of risk factors, underwent more complex operations, and had longer operation times. Risk-adjusted mortality rates were not different between the teaching and nonteaching hospitals in the specialties and operations studied. The unadjusted complication rate was higher in teaching hospitals in six of seven specialties and four of eight operations. Risk adjustment did not eliminate completely these differences, probably reflecting the relatively poor predictive validity of some of the risk adjustment models for morbidity. Length of stay after major operations was not consistently different between teaching and nonteaching hospitals. Compared with nonteaching hospitals, teaching hospitals in the VA perform the majority of complex and high-risk major procedures, with comparable risk-adjusted 30-day mortality rates. Risk-adjusted 30-day morbidity rates in teaching hospitals are higher in some specialties and operations than in nonteaching hospitals. Although this may reflect the weak predictive validity of some of the risk adjustment models for morbidity, it may also represent suboptimal processes and structures of care that are unique to teaching hospitals. Despite good quality of care in teaching hospitals, as evidenced by the 30-day mortality data, efforts should be made to examine further the structures and processes of surgical care prevailing in these hospitals.

Journal of applied physiology (Bethesda, Md. : 1985), 1997

This study examines the hypothesis that intestinal ischemia-reperfusion (I/R) injury contributes ... more This study examines the hypothesis that intestinal ischemia-reperfusion (I/R) injury contributes to renal dysfunction by altered renal eicosanoid release. Anesthetized Sprague-Dawley rats underwent 60 min of sham or superior mesenteric artery (SMA) occlusion with 60 min of reperfusion. The I/R groups received either allopurinol, pentoxifylline, 1-benzylimidazole, or carrier before SMA occlusion. In vivo renal artery blood flow was measured by Transonic flow probes, the kidneys were then perfused in vitro for 30 min, and the effluent was analyzed for eicosanoid release and renal function. Intestinal I/R caused a twofold increase in the ratio of renal release of thromboxane B2 to prostaglandin E2 and to 6-ketoprostaglandin F1alpha compared with the sham level, with a corresponding 25% decrease in renal sodium and inulin clearance and renal blood flow. Pentoxifylline or allopurinol pretreatment restored renal eicosanoid release and renal sodium and inulin clearance to the sham level bu...

Journal of Surgical Research, 2007

Introduction. CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal r... more Introduction. CXCR4 is a chemokine receptor that has recently been implicated to play a pivotal role in breast cancer growth and metastasis. In animal models, reduction of CXCR4 expression significantly abrogated metastatic disease and prolonged survival. In human breast cancers, CXCR4 overexpression may portend a worse clinical course. Recent data suggest that HER-2 up-regulates CXCR4, but whether this is applicable in the clinical setting is not known. In this study, we evaluated the role of CXCR4 overexpression in breast cancer and determined whether it can serve as a potential marker of tumor recurrence in HER-2 negative tumors.

Prostaglandins, 1995

This study examines the hypothesis that PAF stimulates release of PGI2 from inflamed rabbit gallb... more This study examines the hypothesis that PAF stimulates release of PGI2 from inflamed rabbit gallbladder explant cell cultures. New Zealand white rabbits underwent bile duct ligation for 72 h (72 h BDL), or sham operation, Sham and 72 h BDL gallbladder explants were placed in culture, and the cells grown to 75% confluence. The cells were exposed to increasing concentrations

World Journal of Surgery, 2000

The purpose of this study was to determine the influence of chronic illness, obesity, and type of... more The purpose of this study was to determine the influence of chronic illness, obesity, and type of repair on the likelihood of recurrence following incisional herniorrhaphy. The medical records of 77 patients who underwent elective repair of a midline incisional hernia at the Dallas Veterans Affairs Medical Center between 1991 and 1995 were reviewed. Demographic data, presence of chronic illnesses, type of repair, and presence of recurrence were noted. Ninety-six percent of the patients were men, with an average age of 59 years. More than 50% of the patients had chronic lung or cardiac diseases and more than 40% weighed >120% of their ideal body weight and had a body mass index (BMI) >30. Sixty-two percent of the patients underwent primary reapproximation of the fascia (tissue repair), whereas 38% underwent repair with prosthetic material (prosthetic repair). The overall recurrence rate was 45%, with a median follow-up of 45 months (range 6 -73). Seventy-four percent of the recurrences presented within 3 years of repair. The recurrence rate for those patients undergoing a tissue repair was 54%, whereas the recurrence rate following prosthetic repair was 29%. The incidence of recurrence for patients with pulmonary or cardiac disease or diabetes mellitus was similar to that of patients without these illnesses. The percent ideal body weight and BMI of patients who developed a recurrent hernia, particularly following a prosthetic repair, were significantly greater than those of patients whose repairs remained intact. These data strongly support the use of prosthetic repairs for incisional hernias, particularly in patients who are overweight.

World Journal of Surgery, 2006

Background: The role of whole-body fluorine-18-FDG positron emission tomography (FDG-PET) as an a... more Background: The role of whole-body fluorine-18-FDG positron emission tomography (FDG-PET) as an adjunct localize recurrence in stages II and III breast cancer patients who present with clinical suspicion for recurrence is not well established. We report our experience in such a patient population. Methods: A retrospective review of all patients with stages II and III breast cancer who had a whole-body FDG-PET scan was performed. Results: Of the 23 patients who fit the criteria, 9 had stage II and 14 had stage III breast cancer. Overall sensitivity, specificity, and accuracy were 81%, 100%, and 87%, respectively. Positive and negative predictive values for stages II and III were 100% and 83%, respectively, and 100% and 50%, respectively. FDG-PET detected two recurrences that were missed by conventional imagings, but such recurrences were local and amenable for biopsy. Conclusions: In patients with stages II and III breast cancer who present with a suspicion for recurrent disease, a whole-body FDG-PET scan may be a useful adjunct in the evaluation of recurrence. However, its added benefit over conventional imaging should be questioned.

The American Journal of Surgery, 2012

BACKGROUND: The purpose of this retrospective study was to characterize the presentation, treatme... more BACKGROUND: The purpose of this retrospective study was to characterize the presentation, treatment, and outcomes of patients with multiple myeloma requiring surgical evaluation for abdominal pain.

The American Journal of Surgery, 2001

The role of mammography in the evaluation of male patients presenting with breast disease is cont... more The role of mammography in the evaluation of male patients presenting with breast disease is controversial. This controversy is a function of the lack of specific data concerning the diagnostic accuracy of mammography when used in this clinical setting. The purpose of this study was to define the diagnostic accuracy of mammography in the evaluation of male breast disease. One hundred and four prebiopsy mammograms from 100 patients with tissue diagnoses were read blindly by two independent radiologists, and placed into one of five predetermined categories: definitely malignant, possibly malignant, gynecomastia, benign mass, and normal. Radiologic/pathologic correlation was performed and the sensitivity (Sn), specificity (Sp), positive (Ppv) and negative predictive value (Npv), and accuracy (Ac) for each of the mammographic diagnostic category determined. The pathologic diagnoses were 12 cancers, including 1 patient with bilateral breast cancer, 70 cases of gynecomastia, 16 benign masses, and 6 normals. The accuracy data for the mammographic diagnostic categories are as follows: malignant (combined definitely and possibly malignant), Sn 92%, Sp 90%, Ppv 55%, Npv 99%, Ac 90%; and overall benignity (combined gynecomastia, benign mass, and normal), Sn 90%, Sp 92%, Ppv 99%, Npv 55%, Ac 90%. Six cancers (50%) coexisted with gynecomastia. Mammography can accurately distinguish between malignant and benign male breast disease. Although not a replacement for clinical examination, its routine use could substantially reduce the need for biopsy in patients whose mammograms and clinical examination suggest benign disease.

Surgery, 1995

This study examines the hypothesis that pulmonary inducible nitric oxide synthase (iNOS) activity... more This study examines the hypothesis that pulmonary inducible nitric oxide synthase (iNOS) activity is up-regulated during intestinal reperfusion and that inhibition of NO generation exacerbates pulmonary microvascular dysfunction. Sprague-Dawley rats underwent intestinal ischemia and reperfusion (IIR) or sham operation (SHAM). Pulmonary iNOS activity was measured by quantitating the conversion of L-arginine (L-Arg) to L-citrulline. Another set of animals undergoing IIR or SHAM received an inhibitor of NOS (NG-nitro-L-arginine methylester; L-NAME; 20 mg/kg intravenously), substrate for NO generation (L-Arg; 300 mg/kg intravenously), or vehicle (normal saline solution; 3 ml). Pulmonary microvascular dysfunction was then quantitated by measuring the extravasation of Evans blue dye (EBD) into the lung. Inducible NOS activity was six times greater in the lungs of animals sustaining IIR when compared with SHAM (p = 0.0005). The concentration of EBD within the lungs of animals sustaining IIR was 30% greater than SHAM (p < 0.05). Inhibiting NOS with L-NAME significantly increased pulmonary EBD concentration of both IIR and SHAM groups when compared with normal saline solution-treated animals (p < 0.0001). Treatment with L-Arg prevented this IIR-induced increase in pulmonary dye extravasation. These data suggest that pulmonary iNOS activity is up-regulated in animals sustaining IIR and that this may serve as a compensatory protective response to remote organ injury.

Surgery, 1998

Background. This study examines the hypothesis that specific inhibition of the inducible isoform ... more Background. This study examines the hypothesis that specific inhibition of the inducible isoform of nitric oxide synthase (iNOS) will attenuate intestinal reperfusion-induced pulmonary microvascular dysfunction.

Surgery, 1996

Background. Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunctio... more Background. Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunction and thus has been used as a model of multiple organ failure syndrome. This study examines the hypothesis that hepatic blood flow is markedly reduced in this injury model. Methods. Sprague-Dawley rats underwent 120 minutes of intestinal ischemia and 60 minutes of repeorusion (IIR). Hepatic blood flow was measured with radiolabeled microspheres and Doppler flow probes. Hepatic dysfunction was quantitated by measuring bile flow and serum alanine aminotransferase and hepatic tissue adenosine triphosphate levels. Sham-operated animals served as controls.

Shock, 1994

This study examines the relationship between hypovolemia and remote organ injury following intest... more This study examines the relationship between hypovolemia and remote organ injury following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia (120 min) and reperfusion (90 min, IIR) or sham operation (CTL). The animals received normal saline (NS) at 0, 30, or 40 ml/kg/h intravenously. Lung and intestinal injury was quantitated using an edema index, and liver injury was assessed by measuring bile flow rates. The infusion of 40 ml/kg/h of NS attenuated the intestinal edema index of IIR animals nearly 50% (p < .05). Despite this improvement, this parameter remained nearly 10-fold greater than that of CTL (p < .05). The lung edema index was 70% greater in IIR animals receiving 30 and 40 ml/kg/h of NS than those not receiving NS. The infusion of 40 ml/kg/h of NS restored bile flow rates in IIR animals to that of CTL. These data suggest that hypovolemia may contribute to the intestinal and hepatic injury in this model. The lung injury is independent of hypovolemia.

Shock, 1994

This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reper... more This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.