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Biomedical subjects

D C Winter

Publications and source records attributed to D C Winter.

At least 19 recordsLinked to original sources
PubMed2003

Sentinel lymph node mapping in colorectal cancer.

BACKGROUND: Ultrastaging, by serial sectioning combined with immunohistochemical techniques, improves detection of lymph node micrometastases. Sentinel lymph node mapping and retrieval provides a representative node(s) to facilitate ultrastaging. The impact on staging of carcinoma of the colon and rectum in all series emphasizes the importance of this technique in cancer management. Now the challenge is to determine the biological relevance and prognostic implications. METHODS: The electronic literature (1966 to present) on sentinel node mapping in carcinoma of the colon and rectum was reviewed. Further references were obtained by cross-referencing from key articles. RESULTS: Lymphatic mapping appears to be readily applicable to colorectal cancer and identifies those lymph nodes most likely to harbour metastases. Sentinel node mapping carries a false-negative rate of approximately 10 per cent in larger studies, but will also potentially upstage a proportion of patients from node negative to node positive following the detection of micrometastases. The prognostic implication of these micrometastases requires further evaluation. CONCLUSION: Further follow-up to assess the prognostic significance of micrometastases in colorectal cancer is required before the staging benefits of sentinel node mapping can have therapeutic implications.

Colorectal Neoplasms↗
PubMed2002

Soluble interleukin 6 receptor (sIL-6R) mediates colonic tumor cell adherence to the vascular endothelium: a mechanism for metastatic initiation?

The mechanisms by which surgery increases metastatic proliferation remain poorly characterized, although endotoxin and immunocytes play a role. Recent evidence suggests that endothelial adherence of tumor cells may be important in the formation of metastases. Soluble receptors of interleukin-6 (sIL-6R) shed by activated neutrophils exert IL-6 effects on endothelial cells, which are unresponsive under normal circumstances. This study examined the hypothesis that sIL-6R released by surgical stress increases tumor cell adherence to the endothelium. Neutrophils (PMN) were stimulated with lipopolysaccharide, C-reactive protein (CRP), and tumor necrosis factor-alpha. Soluble IL-6R release was measured by enzyme-linked immunosorbent assay. Colonic tumor cells transfected with green fluorescent protein and endothelial cells were exposed to sIL-6R, and tumor cell adherence and transmigration were measured by fluorescence microscopy. Basal release of sIL-6R from PMN was 44.7 +/- 8.2 pg/ml at 60 min. This was significantly increased by endotoxin and CRP (131 +/- 16.8 and 84.1 +/- 5.3, respectively; both P < 0.05). However, tumor necrosis factor-alpha did not significantly alter sIL-6R release. Endothelial and tumor cell exposure to sIL-6R increased tumor cell adherence by 71.3% within 2 h but did not significantly increase transmigration, even at 6 h. Mediators of surgical stress induce neutrophil release of a soluble receptor for IL-6 that enhances colon cancer cell endothelial adherence. Since adherence to the endothelium is now considered to be a key event in metastatic genesis, these findings have important implications for colon cancer treatment strategies.

Cell Adhesion↗
PubMed2002

Inosine modulates gut barrier dysfunction and end organ damage in a model of ischemia-reperfusion injury.

INTRODUCTION: Gut barrier failure is an important source of morbidity in critically ill patients, and patients undergoing aortic cross-clamp. Inosine, an endogenous purine nucleoside without known side effects, formed from the breakdown of adenosine by adenosine deaminase, has been shown to modify the effects of hypoxia on various tissues, including the heart and the brain. MATERIALS AND METHODS: This study examined the effect of inosine on ischemia-reperfusion-induced gut barrier dysfunction and on the associated lung injury. Twenty-four male Sprague-Dawley rats were divided into three groups. Eight were subjected to 60 min of superior mesenteric artery occlusion followed by 4 h of reperfusion. Eight had 100 mg/kg inosine prior to ischemia-reperfusion and 8 had sham laparotomy with encircling but not occlusion of the superior mesenteric artery. RESULTS: Rats treated with inosine had significantly less gut barrier dysfunction. Rats subjected to SMAO sustained a substantial lung injury and this was attenuated by inosine treatment. Serum cytokine levels were also significantly lower. CONCLUSIONS: We conclude that inosine has a beneficial effect in modulating both gut barrier dysfunction and distant organ injury in response to gut ischemia-reperfusion.

Animals↗
PubMed2002

Quality of life after ileal pouch-anal anastomosis: an evaluation of diet and other factors using the Cleveland Global Quality of Life instrument.

PURPOSE: Although functional results after ileal pouch-anal anastomosis are excellent, imperfections of function do occur. In this setting, quality-of-life assessment is an invaluable tool in determining overall therapeutic efficacy. We evaluated the impact of dietary restrictions, preoperative diagnosis (ulcerative colitis vs. familial adenomatous polyposis), and pregnancy (after pouch insertion) on quality of life. METHODS: After ethical approval, 64 patients were reviewed (mean age, 31 (range, 15-54) years). Long-term quality of life in patients after ileal pouch-anal anastomosis was assessed using the Cleveland Global Quality of Life instrument or Fazio score. The Cleveland Global Quality of Life score is a novel quality-of-life instrument specifically designed for patients with ileal pouches. Stool frequency and continence were recorded to establish the functional status of this group. RESULTS: Sixty-one patients (95.3 percent) complained of some form of dietary restriction and adopted a fixed dietary regimen. All such patients felt that a breach of this regimen would impinge significantly on their quality of life. Late eating and alcohol were associated with diarrhea, whereas smoking was not. Constipation was infrequently reported. The mean Cleveland Global Quality of Life score of patients with ulcerative colitis (0.81 +/- 0.13) was greater than that of patients with ulcerative colitis and a background of pouchitis (0.78 +/- 0.16; P = 0.042). Whereas postoperative stool frequency in patients with familial adenomatous polyposis was always higher than the preoperative level (4 vs. 2 movements per day; P = 0.04), the Cleveland Global Quality of Life score of this group was lower than that of ulcerative colitis patients (0.77 vs. 0.81; P = 0.047). The Cleveland Global Quality of Life score of females who had had pregnancies after pouch formation was 0.70, significantly lower (P = 0.039) than that of ulcerative colitis patients, although pouch function was similar to the general group (7 vs. 6 daily bowel movements with full continence in all parous patients). CONCLUSIONS: Most patients suffered dietary restrictions, forcing them to adopt a fixed dietary regimen. Breach of this regimen would impact on their quality of life. Hence composition of diet and timing of intake are important determinants of quality of life after ileal pouch formation. Patients with familial adenomatous polyposis and those with a history of pouchitis had poorer Cleveland Global Quality of Life scores than ulcerative colitis patients without a background of pouchitis. This indicates that they also had poorer quality of life. Parous patients had the lowest Cleveland Global Quality of Life scores, indicating the poorest quality of life. These differences did not correlate with poorer pouch function, highlighting the influence of non-pouch-related factors in quality of life after ileal pouch formation.

Adenomatous Polyposis Coli↗
PubMed2001

Structure of Arp2/3 complex in its activated state and in actin filament branch junctions.

The seven-subunit Arp2/3 complex choreographs the formation of branched actin networks at the leading edge of migrating cells. When activated by Wiskott-Aldrich Syndrome protein (WASp), the Arp2/3 complex initiates actin filament branches from the sides of existing filaments. Electron cryomicroscopy and three-dimensional reconstruction of Acanthamoeba castellanii and Saccharomyces cerevisiae Arp2/3 complexes bound to the WASp carboxy-terminal domain reveal asymmetric, oblate ellipsoids. Image analysis of actin branches indicates that the complex binds the side of the mother filament, and Arp2 and Arp3 (for actin-related protein) are the first two subunits of the daughter filament. Comparison to the actin-free, WASp-activated complexes suggests that branch initiation involves large-scale structural rearrangements within Arp2/3.

Acanthamoeba↗
PubMed2001

Tumor cell adhesion to endothelial cells is increased by endotoxin via an upregulation of beta-1 integrin expression.

BACKGROUND: Recent studies have demonstrated that metastatic disease develops from tumor cells that adhere to endothelial cells and proliferate intravascularly. The beta-1 integrin family and its ligand laminin have been shown to be important in tumor-to-endothelial cell adhesion. Lipopolysaccharide (LPS) has been implicated in the increased metastatic tumor growth that is seen postoperatively. We postulated that LPS increases tumor cell expression of beta-1 integrins and that this leads to increased adhesion. METHODS: The human metastatic colon cancer cell line LS174T was labeled with an enhanced green fluorescent protein (eGFP) using retroviral transfection. Cell cultures were treated with LPS for 1, 2, and 4 h (n = 6 each) and were subsequently cocultured for 30 or 120 min with confluent human umbilical vein endothelial cells (HUVECs), to allow adherence. Adherent tumor cells were counted using fluorescence microscopy. These experiments were carried out in the presence or absence of a functional blocking beta-1 integrin monoclonal antibody (4B4). Expression of beta-1 integrin and laminin on tumor and HUVECs was assessed using flow cytometric analysis. Tumor cell NF-kappaB activation after incubation with LPS was measured. RESULTS: Tumor cell and HUVEC beta-1 integrin expression and HUVEC expression of laminin were significantly (P < 0.05) enhanced after incubation with LPS. Tumor cell adhesion to HUVECs was significantly increased. Addition of the beta-1 integrin blocking antibody reduced tumor cell adhesion to control levels. LPS increased tumor cell NF-kappaB activation. CONCLUSIONS: Exposure to LPS increases tumor cell adhesion to the endothelium through a beta-1 integrin-mediated pathway that is NF-kappaB dependent. This may provide a target for immunotherapy directed at reducing postoperative metastatic tumor growth.

Cell Adhesion↗
PubMed2001

Inosine attenuates tourniquet-induced skeletal muscle reperfusion injury.

BACKGROUND: Adenosine attenuates skeletal muscle reperfusion injury, but its short half-life in vivo limits potential therapeutic benefits. The aim of this study was to ascertain whether inosine, a stable adenosine metabolite, modulates skeletal muscle reperfusion injury. MATERIALS AND METHODS: C57BL/6 mice were randomized (8-10 per group) to six groups: time controls; inosine (100 mg/kg) before anesthesia; 2 h of bilateral tourniquet hindlimb ischemia; I/R (2 h of bilateral tourniquet hindlimb ischemia, 3 h of reperfusion); inosine (100 mg/kg) before I/R; drug vehicle before I/R. Serum tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 were measured before ischemia and at the end of reperfusion. Tissue edema was determined by wet/dry weight ratios. Tissue leucosequestration was assessed by the myeloperoxidase (MPO) content. RESULTS: At the end of reperfusion, inosine pretreatment resulted in lower MPO levels in muscle (P = 0.02) and lung (P = 0.0002) than saline pretreatment. Similarly, muscle (P = 0.04) and lung (P = 0.02) wet/dry ratios were significantly reduced with inosine but not with saline pretreatment. At the end of reperfusion, serum proinflammatory cytokine levels (TNF-alpha and MIP-2) were significantly reduced (P < 0.05) compared to preischemia levels following inosine pretreatment but not saline pretreatment. Ischemia alone did not alter any of the parameters assessed. CONCLUSIONS: These findings demonstrate that pretreatment with inosine attenuates the local and systemic proinflammatory responses associated with skeletal muscle reperfusion injury.

Animals↗
PubMed2001

Minimally invasive, radioguided surgery for primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism affects 1 in 700 individuals in the United States. A single adenoma is responsible in over 85% of cases. Surgery remains the most effective treatment. This study was designed to assess the feasibility of minimally invasive radioguided parathyroidectomy (MIRP) with confirmation of excision by ex vivo radioactivity alone. METHODS: Seventy-five consecutive patients with primary hyperparathyroidism were prospectively studied. Following sestamibi scan, patients underwent unilateral neck exploration guided by a handheld gamma probe, which was also used to measure ex vivo radioactivity of excised tissue. RESULTS: The sestamibi scan was positive in 88% of the patients. A small incision (mean, 3.2+/-0.3 cm) was sufficient. Ectopic gland sites were localized in five patients with positive scans and single adenomas. Mean operative time was 48 minutes (range, 15-125 minutes), with shorter procedures after the initial 20 cases (mean, 24 vs. 72 minutes; P < .01). Radioguided parathyroidectomy was successful in 97%, with a mean follow-up of 11 months (range, 1-26 months). As noted previously, adenomatous parathyroid glands contained more than 20% of the background radioactivity. CONCLUSIONS: MIRP is a feasible alternative to bilateral dissection with the advantages of guided dissection and rapid confirmation, and may become the procedure of choice for primary hyperparathyroidism.

Adenoma↗
PubMed2001

Helicobacter pylori and tonsillectomy.

Tonsillar tissue is a component of mucosa-associated lymphoid tissue (MALT), which has evolved to protect vulnerable mucosal surfaces. Helicobacter pylori, implicated as an aetiological factor in duodenal ulcers and gastritis, induces the appearance of lymphoid aggregates (MALT) in the stomach. This organism is cytotoxic via a nitric oxide synthase cascade. The possibility that tonsillar tissue processes Helicobacter pylori or that Helicobacter pylori can colonize the palatine tonsils is explored. The study design was that of a prospective study. We determined if Helicobacter pylori (i) forms part of the normal microenvironment of the tonsil, (ii) plays a role in the pathogenesis of tonsillitis and (iii) is associated with increased expression of inducible nitric oxide synthase (iNOS) in macrophages of the tonsil. Serology for Helicobacter pylori was performed on 50 patients undergoing tonsillectomy. Tonsillar specimens were monitored for urease activity by CLO test (a sealed plastic slide holding an agar gel, which contains urea and detects the urease enzyme of Helicobacter pylori), and immunocytochemically probed for Helicobacter pylori and iNOS expression. The mean age of this patient group was 17.2 years (3-36 years). Fourteen (28%) were sero-positive for Helicobacter pylori but no evidence of this pathogen was found in any tonsillar specimen. The number of macrophages staining for iNOS, per field, under a magnification of x40, was increased in sero-positive patients (13.3 +/- 1.3 versus 9.9 +/- 0.7; P = 0.01). Helicobacter pylori does not appear to colonize the tonsil. We believe that Helicobacter pylori primes the tonsils by inducing macrophage iNOS expression. The higher expression in sero-positive patients is a reflection of a pro-inflammatory reaction to Helicobacter pylori that is both local and systemic.

Adolescent↗
PubMed2001

Desmoid tumours.

Desmoid tumours exhibit fibroblastic proliferation and arise from fascial or musculoaponeurotic structures. Despite their benign microscopic appearance, and their negligible metastatic potential, the propensity of desmoid tumours for local infiltration is potentially significant in terms of deformity, morbidity and mortality due to pressure effects and obstruction of vital structures and organs. The rarity of desmoid tumours, coupled with the variability in their clinical course, renders these lesions a vexing entity, and makes demonstration of the efficacy of any specific intervention difficult. Failure to recognize the potential for malignant behaviour in this tumour renders desmoids susceptible to inadequate treatment. This distinct pathological entity is reviewed with a specific focus on aetiology and treatment.

Antineoplastic Agents, Hormonal↗
PubMed2001

Nasogastric intubation causes gastroesophageal reflux in patients undergoing elective laparotomy.

BACKGROUND: The routine use of nasogastric tubes in patients undergoing elective abdominal operation is associated with an increased incidence of postoperative fever, atelectasis, and pneumonia. Previous studies have shown that nasogastric tubes have no significant effect on the incidence of gastroesophageal reflux or on lower esophageal sphincter pressure in healthy volunteers. We hypothesized that nasogastric intubation in patients undergoing laparotomy reduces lower esophageal sphincter pressure and promotes gastroesophageal reflux in the perioperative period. METHODS: A prospective randomized case-control study was undertaken in which 15 consenting patients, admitted electively for bowel surgery, were randomized into 2 groups. Group 1 underwent nasogastric intubation after induction of anesthesia, and Group 2 did not. All patients had manometry and pH probes placed with the aid of endoscopic vision at the lower esophageal sphincter and distal esophagus, respectively. Nasogastric tubes, where present, were left on free drainage, and sphincter pressures and pH were recorded continuously during a 24-hour period. Data were analyzed with 1-way analysis of variance. RESULTS: The mean number of reflux episodes (defined as pH < 4) in the nasogastric tube group was 137 compared with a median of 8 episodes in the group managed without nasogastric tubes (P =.006). The median duration of the longest episode of reflux was 132 minutes in Group 1 and 1 minute in Group 2 (P =.001). A mean of 13.3 episodes of reflux lasted longer than 5 minutes in Group 1, with pH less than 4 for 37.4% of the 24 hours. This was in contrast to Group 2 where a mean of 0.13 episodes lasted longer than 5 minutes (P =.001) and pH less than 4 for 0.2% of total time (P =.001). The mean lower esophageal sphincter pressures were lower in Group 1. CONCLUSIONS. These findings demonstrate that patients undergoing elective laparotomy with routine nasogastric tube placement have significant gastroesophageal reflux in the perioperative period and a reduced ability to clear refluxed acid from the distal esophagus. Due to the associated risk of postoperative pulmonary complications, we recommend that nasogastric intubation be performed on a selective rather than routine basis.

Case-Control Studies↗
PubMed2001

Attenuation of pancreatitis-induced pulmonary injury by aerosolized hypertonic saline.

BACKGROUND: The immunomodulatory effects of hypertonic saline (HTS) provide potential strategies to attenuate inappropriate inflammatory reactions. This study tested the hypothesis that administration of intratracheal aerosolized HTS modulates the development of lung injury in pancreatitis. METHODS: Pancreatitis was induced in 24 male Sprague-Dawley rats by intraperitoneal injection of 20% L-arginine (500 mg/100 g body weight). At 24 and 48 h, intratracheal aerosolized HTS (7.5% NaCl, 0.5 mL) was administered to 8 rats, while a further 8 received 0.5 mL of aerosolized normal saline (NS). At 72 hours, pulmonary neutrophil infiltration (myeloperoxidase activity) and endothelial permeability (bronchoalveolar lavage and wet:dry weight ratios) were assessed. In addition, histological assessment of representative lung tissue was performed by a blinded assessor. In a separate experiment, polymorphonucleocytes (PMN) were isolated from human donors, and exposed to increments of HTS. Neutrophil transmigration across an endothelial cell layer, VEGF release, and apoptosis at 1, 6, 12, 18, and 24 h were assessed. RESULTS: Histopathological lung injury scores were significantly reduced in the HTS group (4.78 +/- 1.43 vs. 8.64 +/- 0.86); p < 0.001). Pulmonary neutrophil sequestration (1.40 +/- 0.2) and increased endothelial permeability (6.77 +/- 1.14) were evident in the animals resuscitated with normal saline when compared with HTS (0.70 +/- 0.1 and 3.57 +/- 1.32), respectively; p < 0.04). HTS significantly reduced PMN transmigration (by 97.1, p = 0.002, and induced PMN apoptosis (p < 0.03). HTS did not impact significantly upon neutrophil VEGF release (p > 0.05). CONCLUSIONS: Intratracheal aerosolized HTS attenuates the neutrophil-mediated pulmonary insult subsequent to pancreatitis. This may represent a novel therapeutic strategy.

Acute Disease↗
PubMed2001

Tourniquet-induced systemic inflammatory response in extremity surgery.

BACKGROUND: Tourniquet-induced reperfusion injury in animals produces significant systemic inflammatory effects. This study investigated whether a biologic response occurs in a clinically relevant model of tourniquet-induced reperfusion injury. METHODS: Patients undergoing elective knee arthroscopy were prospectively randomized into controls (no tourniquet) and subjects (tourniquet-controlled). The effects of tourniquet-induced reperfusion on monocyte activation state, neutrophil activation state, and transendothelial migration (TEM) were studied. Changes in the cytokines implicated in reperfusion injury, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-10 were also determined. RESULTS: After 15 minutes of reperfusion, neutrophil and monocyte activation were significantly increased. Pretreatment of neutrophils with pooled subject (ischemia-primed) plasma significantly increased TEM. In contrast, TEM was not significantly altered by ischemia-primed plasma pretreatment of the endothelial monolayer. Significant elevation of tumor necrosis factor-alpha and IL-1beta were observed in subjects compared with controls after 15 minutes of reperfusion. There was no significant difference in serum IL-10 levels between the groups at all the time points studied. CONCLUSION: These results indicate a transient neutrophil and monocyte activation after tourniquet-ischemia that translates into enhanced neutrophil transendothelial migration with potential for tissue injury.

Adult↗
PubMed2001

Adenosine inhibits neutrophil vascular endothelial growth factor release and transendothelial migration via A2B receptor activation.

The effects of adenosine on neutrophil (polymorphonuclear neutrophils; PMN)-directed changes in vascular permeability are poorly characterized. This study investigated whether adenosine modulates activated PMN vascular endothelial growth factor (vascular permeability factor; VEGF) release and transendothelial migration. PMN activated with tumour necrosis factor-alpha (TNF-alpha, 10 ng/mL) were incubated with adenosine and its receptor-specific analogues. Culture supernatants were assayed for VEGF. PMN transendothelial migration across human umbilical vein endothelial cell (HUVEC) monolayers was assessed in vitro. Adhesion molecule receptor expression was assessed flow cytometrically. Adenosine and some of its receptor-specific analogues dose-dependently inhibited activated PMN VEGF release. The rank order of potency was consistent with the affinity profile of human A2B receptors. The inhibitory effect of adenosine was reversed by 3,7-dimethyl-1-propargylxanthine, an A2 receptor antagonist. Adenosine (100 microM) or the A2B receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA, 100 microM) significantly reduced PMN transendothelial migration. However, expression of activated PMN beta2 integrins and HUVEC ICAM-1 were not significantly altered by adenosine or NECA. Adenosine attenuates human PMN VEGF release and transendothelial migration via the A2B receptor. This provides a novel target for the modulation of PMN-directed vascular hyperpermeability in conditions such as the capillary leak syndrome.

Adenosine↗
PubMed2000

Rapid activation of basolateral potassium transport in human colon by oestradiol.

1. We investigated the effect of oestradiol on basolateral potassium channels in human colonic epithelium. 2. Ion transport was quantified using short circuit current (I:(sc)) measurements of samples mounted in Ussing chambers. Serosal K transport was studied using nystatin permeabilization of the apical membrane. Intracellular pH changes were quantified using spectroflouresence techniques. 3. Experiments were performed with either 10 nM or 1 microM Ca(2+) in the apical bathing solution. With 10 nM Ca(2+) in the apical bathing solution addition of oestradiol (1 nM) to the basolateral bath produced a rapid increase in current (delta I(K)=11.2+/-1.2 microA.cm(-2), n=6). This response was prevented by treatment of the serosal membrane with tolbutamide (1 microM). With 1 microM Ca(2+) in the apical bathing solution addition of oestradiol produced a rapid fall in current (delta I(K)=-12.8+/-1.4 microA.cm(-2)), this response was prevented by treatment of the basolateral membrane with tetra-pentyl-ammonium (TPeA). These responses were rapid and occurred independently of protein synthesis. 4. Inhibition of basolateral Na(+)/H(+) exchange with either amiloride or a low sodium bathing solution prevented this response. These responses were prevented by inhibition of protein kinase C (PKC) with bis-indolyl-maleimide. 5. Oestradiol (1 nM) produced a rapid intracellular alkanization (mean increase=0.11 pH units; n=6; P<0.01). 6. These results suggest that oestradiol rapidly modulates serosal K transport in human colon. These effects depend upon intact Na(+)/H(+) exchange and protein kinase C. We propose a non-classical, possibly membrane linked, mechanism for oestradiol action in human colonic epithelium.

Calcium↗