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OBJECTIVE: To provide reliable risk-adjusted morbidity and mortality rates after major surgery to the 123 Veterans Affairs Medical Centers (VAMCs) performing major surgery, and to use risk-adjusted outcomes in the monitoring and improvement of the quality of surgical care to all veterans. SUMMARY BACKGROUND DATA: Outcome-based comparative measures of the quality of surgical care among surgical services and surgical subspecialties have been elusive. METHODS: This study included prospective assessment of presurgical risk factors, process of care during surgery, and outcomes 30 days after surgery on veterans undergoing major surgery in 123 medical centers; development of multivariable risk-adjustment models; identification of high and low outlier facilities by observed-to-expected outcome ratios; and generation of annual reports of comparative outcomes to all surgical services in the Veterans Health Administration (VHA). RESULTS: The National VA Surgical Quality Improvement Program (NSQIP) data base includes 417,944 major surgical procedures performed between October 1, 1991, and September 30, 1997. In FY97, 11 VAMCs were low outliers for risk-adjusted observed-to-expected mortality ratios; 13 VAMCs were high outliers for risk-adjusted observed-to-expected mortality ratios. Identification of high and low outliers by unadjusted mortality rates would have ascribed an outlier status incorrectly to 25 of 39 hospitals, an error rate of 64%. Since 1994, the 30-day mortality and morbidity rates for major surgery have fallen 9% and 30%, respectively. CONCLUSIONS: Reliable, valid information on patient presurgical risk factors, process of care during surgery, and 30-day morbidity and mortality rates is available for all major surgical procedures in the 123 VAMCs performing surgery in the VHA. With this information, the VHA has established the first prospective outcome-based program for comparative assessment and enhancement of the quality of surgical care among multiple institutions for several surgical subspecialties. Key features to the success of the NSQIP are the support of the surgeons who practice in the VHA, consistent clinical definitions and data collection by dedicated nurses, a uniform nationwide informatics system, and the support of VHA administration and managerial staff.

Agmatine has been previously proposed to represent a novel neurotransmitter. One of the criteria required to test that hypothesis is that the exogenously administered chemical produces pharmacological effects similar to the physiological effects of the putative neurotransmitter. Since agmatine was first identified in brain, approximately sixty studies of the in vivo effects of exogenously administered agmatine have been reported. Despite the assertion that agmatine functions as a neuromodulator/neurotransmitter, the vast majority of experiments have administered agmatine through systemic (rather than central) routes of administration. Systemic delivery of agmatine for studies of centrally mediated phenomenona (e.g., pain, spinal cord injury, cardiovascular responses) relies on the presumption that agmatine (a polar compound) gains appreciable access to the CNS. The mechanism by which agmatine crosses the blood-brain barrier is not well understood. A number of studies have examined the in vivo effects of agmatine following central administration (e.g., intracerebroventricular and intrathecal). This paper summarizes and provides a comparison between the systemic versus central routes of administration for delivery of agmatine in experimental subjects.

Background Diverticular disease is a common entity. The presentation, investigations performed, and management are variable. Our objectives were to assess the presentation, extent of disease, and treatment of a cohort of patients with colonic diverticulitis. Methods All patients with a diagnosis of diverticulitis over a 9-year period were reviewed. Patients were assessed as to age, sex, presenting symptoms, diagnostic studies, extent of disease, treatment, and outcome. Results Over a 9-year period (1992 to 2001), 192 patients were admitted with a diagnosis of colonic diverticulitis. The mean age was 61 years (range 28 to 90); 113 of 192 (59%) were female. The mean duration of symptoms prior to presentation was 14 days (range 1 to 270 days). One hundred eighteen of 192 (61%) had a previous documented attack of diverticulitis. Of the investigations performed 128 of 192 (66.7%) had a computed tomography (CT) scan of the abdomen and pelvis, 37 of 192 (20%) underwent a contrast enema, 61 of 192 (32%) underwent colonoscopy and 2 of 192 (1%) underwent a small bowel series. The abnormal findings on the CT scan were as follows: diverticular abscess (16%), diverticulitis (37%), diverticulosis without inflammation (15%), free air (10%) and fistula (1%). The locations of the diverticular abscesses were: pelvic (36%), pericolic sigmoid (36%), and “other,” which included interloop (28%). Preoperative abscess drainage occurred in 10 of 192 (5%), which were either percutaneous, 6 of 192 (3%), or transrectal, 4 of 192 (2%). Nine of 192 (6%) presented with a fistula, colovesical fistulae (3%), colocutaneous (1%), enterocolic (1%), or colovaginal (1%). Overall, 73 of 192 (38%) underwent surgery. All patients undergoing surgery had a resection of their colon. The operative findings were localized abscess in 16 of 73 (22%), purulent/feculent peritonitis in 12 of 73 (17%), and phlegmon in 10 of 73 (14%). Sixty-seven of 73 (92%) had a primary resection with anastomosis; 38 of 67 (56%) had a protecting stoma. Five of 73 (7%) patients were found to have an unsuspected carcinoma. Overall, 29 of 192 (15%) developed a complication related to diverticulitis. Morbidity was 15.1%, of which 34% was infection related. Four of 192 patients (2%) died. Conclusions In our experience, most patients presented with abdominal pain predominantly in the left lower quadrant. The symptoms were present on average of 14 days, most were female (59%), and most patients had a previous attack of diverticulitis. The commonest investigation performed was a CT scan (66.7%); however, other investigations were performed, for example, barium enemas. The practice of resection and primary anastomosis for acute diverticulitis has an acceptable morbidity and mortality. For high-risk anastomoses, a covering loop ileostomy and not a Hartmann's procedure is preferred. Surgery remains safe for the majority of patients and is associated with resolution of symptoms. We believe that because of the high number of patients in our series who had a previous attack of diverticulitis, therapy should be focused on preventing recurrent and virulent attacks by earlier operative intervention.

Background: This is a retrospective study aimed to report short-term outcome among patients age ≥70 years surgically treated for colorectal cancer. Methods: All patients with the discharge diagnosis of colon and rectal cancer at St. Louis University Hospital from 1992 to 2002 were reviewed. Patients were assessed as to demographics, presenting symptoms, therapy, surgical morbidity and mortality. Results: One hundred eighty-one patients age ≥70 years with colorectal cancer were identified. The mean age was 78 years; 107/181 (59%) were females. Rectal bleeding and change in bowel habits were the most common presenting symptoms. Fifty-four out of 181 (30%) were asymptomatic at diagnosis. The diagnosis was made by colonoscopy in 75% of the patients. One hundred forty-three out of 181 (79%) had colon cancer; 38/181 (21%) had rectal cancer. Fourteen out of 181 (8%) did not undergo surgery. Twenty-two out of 181 (12%) were operated on as a surgical emergency. ASA classification was I–II in 52%, III in 34%, and IV–V in 14%. Nineteen out of 38 (50%) with rectal cancer underwent a sphincter-preserving procedure. Overall, there was a 29% major morbidity from surgery. Thirty-day mortality was 11% (21 deaths). Only the development of a postoperative complication predicted mortality. Conclusions: Elderly patients tolerate surgery well for colon and rectal cancer in the short-term. Many patients are asymptomatic at diagnosis. Surgical emergencies are few and patients have a favorable stage of disease. This data supports aggressive detection of colorectal cancer in asymptomatic elderly patients who may harbor occult colorectal cancer.

The present study explored the question of whether the grief process affects the characteristics of relationships within the family system or, alternatively, whether family characteristics affect the experience of grief symptoms. Sixty-one people who had recently experienced the death of a parent (82%) or spouse (18%) completed a questionnaire to assess their current grief symptomatology and characteristics of the relationships within their family 4-5 weeks after the death, and again six months later. Results from cross-lagged panel analyses suggested that increased expression of family affect, family cohesion, and both higher total Family Environment Scale and Family Assessment Measure Version III General scores were predictors of fewer grief symptoms over time. Overall, these results suggest that knowledge of a variety of aspects of a family's structure and process shortly after a death may help predict the later grief of the loss of a loved one.

Background:Interleukin-6 (IL-6), a pluripotent cytokine, has traditionally been considered the product of proinflammatory cells. However, many other cell types have been shown to produce IL-6. Since intestinal inflammation is commonly associated with a vigorous systemic inflammatory response, we hypothesized that intestinal epithelial and smooth muscle cells might contribute to that response by producing IL-6. We therefore studied the capacity of differentiated human intestinal epithelial and smooth muscle cell lines to produce IL-6 in response to various proinflammatory stimuli.Materials and methods:CCL-241, a human intestinal epithelial cell line, and HISM, a human intestinal muscle cell line, were grown to confluency and then treated for 24 h with various concentrations of lipopolysaccharide,Clostridium difficileculture extract containing both toxin A and toxin B, recombinant human tumor necrosis factor-alpha (TNF-α), or recombinant human interleukin-1 beta (IL-1β). Supernatants were then collected for IL-6 determination using an enzyme-linked immunosorbent assay. Cell numbers were determined using a Coulter counter. For comparison, parallel studies were performed using phorbol ester-primed U-937 and THP-1 human macrophage cell lines.Results:Both human intestinal epithelial and smooth muscle cells produced IL-6 under basal conditions. In HISM cells, but not in CCL-241 cells, IL-6 release was increased slightly by treatment withC. difficileculture extract containing both toxin A and toxin B and with lipopolysaccharide. In both cell lines, IL-6 production was profoundly stimulated by treatment with IL-1β and less so with TNF-α. Combinations of high-dose TNF-α and IL-1β may have a slightly additive, but not synergistic, effect on IL-6 release. The amount of IL-6 produced by IL-1-stimulated intestinal cell lines was 70-fold higher than that produced by stimulated macrophage cell lines.Conclusions:Both intestinal epithelial and smooth muscle cells demonstrate the ability to release significant amounts of IL-6. The profound response to IL-1β and TNF-α stimulation by both cell lines suggests that human intestinal parenchymal cells, influenced by paracrine mediators liberated from proinflammatory cells, might significantly contribute to the overall systemic inflammatory response by producing IL-6.

Plant bugs in the genus Lygus (Hahn) (Hemiptera: Miridae) are sporadic pests of canola, Brassica napus L. (Brassicaceae) and Brassica rapa L., in western Canada and infestations appear to have become increasingly common and severe in recent years. Surveys conducted from 1998 to 2000 identified a "northern" assemblage in the boreal ecoregion that was dominated by Lygus lineolaris (Palisot de Beauvois), with minor representation of Lygus borealis (Kelton), Lygus elisus (Van Duzee), and Lygus keltoni (Schwartz). A "southern" assemblage in the grassland ecoregions was dominated by L. keltoni, with a substantial abundance of L. elisus and L. borealis and with few L. lineolaris in the driest areas. The assemblage from the parkland ecoregion was variable but with few L. elisus. The boreal plains and parkland ecoregions of Alberta had the most serious and persistent infestations of Lygus spp. Relative species composition of the Lygus assemblage at the bolting stage was not related to the overall abundance of these bugs at the early pod stage. Lygus species assemblages were similar in terms of composition and relative abundance at the bolting and early pod stages of canola. A shift in species proportions in favour of L. lineolaris in the north and L. keltoni in the south and a decrease of L. elisus has taken place relative to studies conducted in the 1980's.

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25×10-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genome-wide significant associations with hyperopia. These regions overlapped with loci on 15q14 (minimum p value = 9.11×10-11) and 8q12 (minimum p value 1.82×10-11) previously reported for MSE and myopia age at onset. We also used an intermarker linkage- disequilibrium-based method for calculating the effective number of tests in targeted regional replication analyses. We analyzed myopia (which represents the closest phenotype in our data to the one used by Kiefer et al.) and showed replication of 10 additional loci associated with myopia previously reported by Kiefer et al. This is the first replication of these loci using myopia as the trait under analysis. "Replication-level" association was also seen between hyperopia and 12 of Kiefer et al.'s published loci. For the loci that show evidence of association to both myopia and hyperopia, the estimated effect of the risk alleles were in opposite directions for the two traits. This suggests that these loci are important contributors to variation of refractive error across the distribution.

The aim of this study was to determine the effects of diet and arginine (Arg) treatment on serum concentrations of selected metabolites and metabolic and reproductive hormones in nonpregnant ewes. Sixty days before the onset of estrus (Day 0), Rambouillet ewes were randomly assigned to one of three dietary groups: maintenance control (C; N = 16; 100% National Research Council requirements), overfed (O; N = 16; 2 × C), or underfed (U; N = 16, 0.6 × C) to achieve and maintain three different body conditions during their estrous cycle(s). At Day 0, ewes from each nutritional group were randomly assigned to receive one of two treatments: saline (Sal) or Arg (L-Arg-HCl; 155 μmol Arg per kg of body weight [BW]; intravenous), which was administered three times per day for 21 or 26 days. Blood samples were collected on Days 0, 6, 10, 12, 16, 21, and 26 of Sal or Arg treatment for evaluation of Arg, nitric oxide metabolite, cholesterol, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone. For a time-response trial, blood samples were collected at 0, 1, 2, 4, and 7 hours after Sal or Arg treatment at the mid-luteal phase to determine serum Arg concentrations. During the 11-week study, C maintained body weight, O gained 9.6 ± 0.7 kg, and U lost 13.9 ± 0.1 kg. Overall, serum concentrations of Arg, glucose, insulin, insulin-like growth factor 1, leptin, and progesterone were greater (P

The authors report results of modeling thermal fields by the method of finite elements under conditions of milling of 00H17N14M2A austenitic steel by a finger‐type cutter. A solution of the problem of unsteady nonlinear heat conduction has made it possible to find the temperature distribution in the surface layers of a workpiece as a function of the cutting rate and the position of the tip of the cutter edge.

Information suggests that the cyclooxygenase (COX) metabolites, the prostanoids, play a role in gall bladder physiology and disease. Non-steroidal anti-inflammatory drugs which inhibit COX enzymes have been shown in vivo and in vitro to alter the growth patterns of intestinal epithelial cells, and specific COX-2 inhibitors have been shown to decrease mitogenesis in intestinal epithelial cells. The present study was intended to evaluate the effect of specific COX inhibitors on the growth patterns of gall bladder cancer cells. Employing a human gall bladder cancer cell line, mitogenesis, apoptosis and prostaglandin E(2) (PGE(2)) formation were evaluated in response to serum and hepatocyte growth factor and transforming growth factor alpha stimulation in the presence and absence of specific COX-1 and -2 inhibitors. The effect of the mitogens on COX enzyme expression was also evaluated. Serum and the growth factors increased COX enzyme expression and mitogenesis, and decreased apoptosis as evaluated by the percentage of cells that were floating in culture media rather than attached. There was more DNA degradation in floating than in attached cells. The specific COX-2 inhibitor, but not the COX-1 inhibitor, decreased mitogenesis and increased gall bladder cell apoptosis as evaluated by the number of floating versus attached cells and the number of floating cells in the terminal phase of apoptosis or dead. The inhibition of mitogenesis and the increased apoptosis produced by the COX-2 inhibitor was associated with decreased PGE(2) production. The inhibition of replication of gall bladder cancer cells and the increase in apoptosis produced by the selective COX-2 inhibitor suggests that the COX enzymes and the prostanoids may play a role in the development of gall bladder cancer and that the COX-2 inhibitors may have a therapeutic role in the prevention of gall bladder neoplasms.

Absolute photoabsorption cross-sections at 195 +/- 3 K are reported for dinitrogen pentoxide, N2O5, between 150 and 240 nm. The spectrum consists of a broad intense band with a maximum at 160 nm. The lack of sharp features indicates that excitation of N2O5 results in dissociation over the whole of the spectral range studied. At wavelengths above 200 nm, our results are up to 30% smaller than the current NASA recommendation, but are in generally good agreement with a more recent measurement. Below 200 nm, there are no reported data with which to compare our work. (C) 1999 Elsevier Science Ltd. All rights reserved.

Beginning in the early 1990s investigations into the body image concerns of men have increased, and this study adds to extant research by examining correlates of more general body dissatisfaction (BD) and symptoms of muscle dysmorphia (MD) in particular. Three hundred four undergraduate men completed a broad-based symptom inventory, a self-concept questionnaire, and an instrument that assessed problematic body image, eating, and exercise patterns as well as specific symptoms of MD. Multiple regression analyses suggest that lower ratings of overall self-concept and higher levels of depression, anxiety, and interpersonal sensitivity are predictive of body image concerns in men. Furthermore, these variables accounted for almost twice the variance in general BD than they did for specific symptoms of MD. In addition, anorexic and bulimic behaviors, obsessive–compulsive symptoms, and risk factors for interpersonal problems were also associated with symptoms of MD, even when BD was controlled.

Background. Group II phospholipase A 2 (PLA 2 ) enzymes, the rate controlling enzymes in arachidonic acid metabolism, have been well characterized and subdivided into secretory 14-kDa PLA 2 (sPLA 2 ) and cytoplasmic 85-kDa PLA 2 (cPLA 2 ). Previous research has demonstrated increased PLA 2 in colorectal tumors. The present study was performed to determine the effect of specific PLA2 inhibitors on the proliferation and induction of apoptosis of intestinal epithelial cells. Methods. A continuously proliferating rat small intestinal cell line (IEC-18) and a mouse colon cancer cell line (WB-2054-M 4 ) were utilized for these experiments. The cells were placed in microwells with serum-free or serum-supplemented media. The effects of serum on proliferation were then evaluated in the presence of the cPLA 2 inhibitor, methylarachidonyl fluorophosphate (MAFP), or the sPLA 2 inhibitor p -bromophenacyl bromide (BPB). The sPLA 2 and cPLA 2 protein was estimated by Western blotting. Proliferation of intestinal cells was quantitated by incorporation of [ 3 H]thymidine into DNA and PLA 2 activity was evaluated by quantitating arachidonic acid formation and prostaglandin E 2 production. Results. Western blotting of IEC-18 and WB-2054 cell protein demonstrated sPLA 2 and cPLA 2 enzyme in cells incubated in media containing 10% serum. Spontaneous DNA synthesis was present in both cell lines and serum consistently increased proliferation. In IEC-18 cells [ 3 H]thymidine incorporation stimulated by serum was inhibited by MAFP and BPB, while in the malignant cell line, proliferation was inhibited only by BPB. BPB, but not MAFP, produced a dose-dependent increase in apoptotic ratios in both cell lines. Arachidonic acid and PGE 2 formation, stimulated by serum, was inhibited by MAFP and BPB. Conclusions. A differential effect on intestinal cell mitogenesis was seen with different PLA 2 inhibitors. The sPLA 2 inhibitor, but not the cPLA 2 inhibitor, significantly inhibited [ 3 H]thymidine incorporation in the malignant cell line. This occurred with an induction of apoptosis. sPLA 2 inhibitors may be specific inhibitors of growth of malignant cells. The inhibition of arachidonic acid and PGE 2 production did not correlate with the inhibition of proliferation, suggesting that the two processes may be unrelated.

Electronatom/molecule scattering has been the subject of intense research activity, both experimentally and theoretically, for nearly a century, yet particularly for electronmolecule scattering our...

Acute cholecystitis is associated with increased gallbladder prostanoid formation and the inflammatory changes and prostanoid increases can be inhibited by nonsteroidal anti-inflammatory agents. Recent information indicates that prostanoids are produced by two cyclooxygenase (COX) enzymes, COX-1 and COX-2. The purpose of this study was to determine the COX enzymatic pathway in gallbladder mucosal cells involved in the production of prostanoids stimulated by inflammatory agents. Human gallbladder mucosal cells were isolated from cholecystectomy specimens and maintained in cell culture and studied in comparison with cells from a well differentiated gallbladder mucosal carcinoma cell line. COX enzymes were evaluated by Western immunoblotting and prostanoids were measured by ELISA. Unstimulated and stimulated cells were exposed to specific COX-1 and COX-2 inhibitors. In both normal and transformed cells constitutive COX-1 was evident and in gallbladder cancer cells lysophosphatidyl choline (LPC) induced the formation of constitutive COX-1 enzyme. While not detected in unstimulated normal mucosal cells and cancer cells, COX-2 protein was induced by both lipopolysaccharide (LPS) and LPC. Unstimulated gallbladder mucosal cells and cancer cells produced prostaglandin E2 (PGE2) and prostacyclin (6-keto prostaglandin F1alpha, 6-keto PGF1alpha) continuously. In freshly isolated normal gallbladder mucosal cells, continuously produced 6 keto PGF1alpha was inhibited by both COX-1 and COX-2 inhibitors while PGE2 levels were not affected. Both LPS and LPC stimulated PGE2 and 6 keto PGF1alpha formation were blocked by COX-2 inhibitors in freshly isolated, normal human gallbladder mucosal cells and in the gallbladder cancer cells. The prostanoid response of gallbladder cells stimulated by proinflammatory agents is inhibited by COX-2 inhibitors suggesting that these agents may be effective in treating the pain and inflammation of gallbladder disease.

Discusses Connecticut's mandated health insurance benefits. Updates OLR research report 2014-R-0143 by incorporating laws enacted in 2015.

Discusses whether any state insurance departments have explicitly banned property and casualty insurers from using "price optimization" in the ratemaking process.

Discusses the number of dog-related claims made under property and casualty (e.g., homeowners and renters) insurance policies over a five-year period (2010 through 2014) and the types of dog breeds involved in claims.

Discusses regulatory review process for insurer acquisitions, such as the July announcement of Anthem, Inc.'s proposed acquisition of CIGNA Corporation.

Discusses whether any states have laws that prohibit a person from leaving an animal in an unattended motor vehicle.

Discusses new laws (public acts) affecting real estate enacted during the 2015 legislative session.

Discusses highlights of new laws (public acts) affecting animals and agriculture enacted during the 2015 legislative session.

Discusses Connecticut's fracking waste moratorium and related requirements of Public Act (PA) 14-200.

Discusses size by acreage, when it was built and last upgraded, and the cost of upgrades made in the past 10 years for gun ranges located on state-owned property.

Summarizes acts enacted since 2002 amending the Common Interest Ownership Act (CIOA) and the Condominium Act.

Background: Transmucosal chemoneurolytic injection of benzalkonium chloride (BAC) has previously been shown to duplicate operative proximal gastric vagotomy (PGV) in controlling gastric acid secretion. In this study, BAC was evaluated as to efficacious dose, methods of delivery, and systemic toxicities. Methods: Sham celiotomy, operative PGV controls, transmucosal injections through a gastrotomy, and transserosal injections of BAC (saline controls, 0.625, 1.25, 2.5, 5.0, 10 mg BAC/kg body wt) were administered to SpragueDawley rats. After 3 months the rats underwent Congo red testing (CRT), horseradish peroxidase (HRP) neuronal staining, and necropsy. The color density change of the gastric mucosa from basic to acidic demonstrated by the CRT at the time of necropsy was used to calculate the residual anatomic acid-secreting area. Prior to necropsy, subserosal HRP injections into the anterior and posterior stomach walls assayed vagal neuronal viability via retrograde axonal flow. Results were compared by an ANOVA. Results: The results demonstrated that 1.25‐10 mg/kg transmucosal BAC replicated the results of operative PGV; 2.5 mg/kg was found to be the most effective dose. All injection groups including saline controls demonstrated similar diminished vagal retrograde axonal flow by HRP testing consistent with local BAC chemoneurolytic effects. No systemic toxic symptoms were observed after tail vein intravenous BAC 1.25, 2.5, and 5.0 mg/kg. Conclusions: These efficacy studies have demonstrated BAC’s potential utility in the performance of endoscopic transmucosal chemoneurolytic PGV.

Intestinal smooth muscle plays a major role in the repair of injured intestine and contributes to the prostanoid pool during intestinal inflammatory states. Cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostanoids exists in two isoforms, COX-1 and COX-2. The purpose of this study was to determine the relative contributions of COX-1 and COX-2 in the production of prostanoids by human intestinal smooth muscle (HISM) cells when stimulated by interleukin-1β (IL-1β) and lipopolsaccharide (LPS). Furthermore the effects of specific COX-1 and COX-2 inhibitors on the proliferation of smooth muscle cells was also evaluated. Confluent monolayer cultures of HISM cells were incubated with IL-1β or LPS for 0-24 h while control cells received medium alone. PGE2and PGI2as 6-keto-PGF1α and LTB4were measured by a specific radioimmunoassay. COX enzymes were evaluated by Western immunoblotting. Unstimulated and stimulated cells were exposed to the specific COX-1 inhibitor valerylsalicylic acid (VSA) and the COX-2 inhibitors NS-398 and SC-58125. The effects of serum on proliferation were then evaluated in the presence of each of the specific COX inhibitors by incorporation of3H-thym idine into DNA. IL-1β and LPS increased both PGE2and 6-ketoPGF1α in a dose dependent fashion with enhanced production detected two hours following exposure. Neither stimulus stimulated LTB4release. Immunoblot analysis using isoform-specific antibodies showed that both COX-1 and COX-2 were present constitutively. Furthermore, COX-1 was upregulated by each inflammatory stimulus. In a separate set of experiments cells were pretreated with either the selective COX-1 inhibitor VSA or the selective COX-2 inhibitors NS-398 or SC-58125 prior to treatment with IL-1β or LPS. The COX-1 and COX-2 inhibitors decreased both basal and IL-1β and LPS stimulated prostanoid release. Spontaneous DNA synthesis was present and serum consistently increased proliferation.3H-thymidine incorporation, stimulated by serum, was inhibited by both COX-1 and COX-2 inhibitors. This study suggests that the prostanoid response stimulated by proinflammatory agents of gut-derived smooth muscle cells appears to be mediated by both COX-1 and COX-2 enzymes. Proliferation of smooth muscles cells also appears to be influenced by both COX-1 and COX-2.

Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1 β with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2, 6-keto prostaglandin F1α, prostaglandin D2and leukotriene B4levels were determined by radio immunoassay. Immunoblot analysis using isoformspecific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1β treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1β and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 μ M concentration, and VSA inhibited lipopolysaccharide and interleukin 1β stimulated prostaglandin E2, but not 6-keto prostaglandin F1αformation. SC-58125 inhibited lipopolysaccharide and interleukin-1β stimulated 6-keto prostaglandin F1αbut not prostaglandin E2release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2but not interleukin-1β stimulated prostaglandin D2While SC-58125 inhibited basal 6-keto prostaglandin-F1αformation it significantly increased basal prostaglandin E2and prostaglandin D2formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1β induced 6-keto prostaglandin F1αproduction but not prostaglandin E2production, it suggests that these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E2production occurs through a cyclooxygenase-1 mediated mechanism. Prostaglandin D2production appeared to be variably produced by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus.

PURPOSE: In this study, we sought to determine the outcome of patients with ischemic colitis, comparing patients with segmental disease with those with total colonic ischemia. METHODS: Patients with the diagnosis of ischemic colitis over the past six years were selected and reviewed for demographics, presenting symptoms, diagnosis, and treatment. RESULTS: Forty-three consecutive patients with ischemic colitis were identified and were grouped into those with segmentai ischemic colitis and total colonic ischemia. Mean age was 68.8 years; 28 of 43 patients (65 percent) were males. Diagnosis was established by colonoscopy in 31 of 43 patients (72 percent), whereas in the remainder, diagnosis was made in the operating room. Ischemic colitis developed in the hospital in 17 of 43 patients (40 percent) during admission for an unrelated illness. In 6 of 43 (14 percent) of these patients, ischemic colitis developed following surgery. Thirty-one of 43 patients (72 percent) were found to have segmental colitis; 11 of 31 patients (35 percent) were successfully managed nonoperatively. Segmental colitis was present in 31 of 43 patients (72 percent), and 12 of 31 (35 percent) of these patients were successfully managed nonoperatively. In the patients with segmental colitis who required surgery, the 30-day mortality rate was 22 percent. Among 12 of 17 patients (71 percent) with segmental ischemia treated by resection and stoma, 9 of 12 (75 percent) underwent eventual stoma closure. All 12 patients with total colonic ischemia required surgery, and 9 of 12 patients (75 percent) died. CONCLUSION: Ischemic colitis occurs commonly during an unrelated hospital admission and following previous surgery. Most patients treated by resection and stoma undergo stoma closure. Total colonic ischemia carries a worse prognosis than segmental colonic ischemia.

The VUV photoabsorption spectrum of dichlorine monoxide has been recorded between 6.5 and 9.7 eV photon energies using the UK Daresbury Synchrotron Radiation facility. The spectrum consists of a broad structureless band centred at 7.25 eV followed by several vibrationally resolved high-intensity bands. The 7.25 eV band has been interpreted in terms of the excitation of a dissociative valence excited state while the higher-energy electronic bands (above 7.5 eV) have been classified into several ( n = 3, 4) Rydberg states linked with the ionic ground state and its lowest-energy excited states. An analysis of the vibrational progressions associated with the excitation of the various Rydberg states has been completed.

To determine how exercise from mid to late (days 40–104) gestation impacts offspring body, uterine and ovarian weight, and ovarian cell proliferation at three different developmental stages, Yorkshire gilts were either exercised by walking (EX) or not exercised (CON). In parity 1, ovaries and uteri were collected from the heaviest (H) and lightest (L) neonates and adolescent (6 mo) offspring. In parity 2, mothers were assigned the same treatment groups, and ovaries and uteri were collected from H and L fetuses on day 94 of gestation. Body weight was greater (P < 0.02) for H than L fetuses and neonates but not affected by EX treatment at any developmental stage. Ovarian weight in L but not H neonates was greater (P < 0.02) in EX than CON. Labeling index (LI; percentage of proliferating cells) was greater (P < 0.01) in cortex than medulla regions of fetal and neonatal ovaries. In fetal ovaries, EX enhanced LI (P < 0.01), and LI was greater (P < 0.01) in H compared with L offspring. In adolescent ovaries, LI was greatest (P < 0.01) in healthy antral and least in atretic antral follicles, and LI was greater (P < 0.01) in granulosa than theca cells of healthy antral follicles. Thus, exercise increased LI in fetal but not neonatal or adolescent ovaries. Although maternal exercise during gestation influences fetal and neonatal ovarian development, impacts on fertility remain unknown.

BACKGROUND: Platelet-activating factor (PAF) and cytokines, such as interleukins, tumor necrosis factor, and others, are thought to play a role in the inflammatory process involving gastrointestinal disorders such as Crohn's disease, ulcerative colitis, ischemic colitis, or antibiotic-associated colitis. PURPOSE: This study was undertaken to review the latest literature on the role of PAF and cytokines in the genesis of inflammatory bowel disease and implications for therapy and management. RESULTS: PAF is an endogenous phospholipid involved in hypersensitivity and inflammatory reactions such as platelet and neutrophil aggregation, vasodilation, increased vascular permeability, and leukocyte adhesion, which have been associated with inflammatory processes. Cytokines are peptides that regulate and coordinate inflammatory and immunologic responses. Increased production of cytokines has been reported during Crohn's disease and ulcerative colitis and is correlated with disease activity. CONCLUSIONS: Because PAF and cytokines may have an important role in the pathogenesis of inflammatory bowel disease, their inhibition by specific antagonists, mediators, or other agents such as steroids may have a potential therapeutic benefit in treatment and management of these inflammatory diseases in the near future.

Twenty-nine college women evidencing low body esteem, repeated dieting efforts, and other dysfunctional eating behaviors or attitudes were randomly assigned to group treatment or control conditions. At posttest and follow-up, participants who received the intervention reported significantly improved levels of self-esteem and body satisfaction, as well as reductions in their reliance on potentially dangerous methods of weight management compared with controls. They also reported fewer fears of negative evaluation by others and endorsed fewer stereotypes about thinness and attractiveness. Finally, participants in the treatment condition showed significantly reduced levels of perfectionism at posttest, but this change was not maintained at follow-up. Clinical implications and research recommendations are discussed.

Background: During prolonged laparoscopic operations with carbon dioxide (CO 2 ) pneumoperitoneum (PP), hypercapnia with significant acidosis has been reported to occur in some patients with pulmonary dysfunction. An alternate inert insufflation gas like helium (He) could avoid this problem. Methods: This prospective, IRB-approved study compared the cardiopulmonary response in 20 patients with both CO 2 and He PP. With the minute ventilation held constant, baseline arterial blood gases and ventilatory and cardiac parameters were obtained after anesthetic induction but prior to CO 2 PP. All values were repeated at 20 to 30 and 40 to 60-minute intervals after the insufflation of CO 2 PP, then again during He PP. Values were compared by a paired t test analysis. Results: Patients experienced significant hypercapnia during CO 2 PP when compared with baseline arterial blood gases, but all values returned to baseline levels during He PP. Conclusions: He PP is an effective alternative to CO 2 PP for a laparoscopic cholecystectomy avoiding CO 2 retention and subsequent acidosis. Carbon dioxide retention may be dangerous in patients with pulmonary dysfunction who undergo laparoscopy. (Gastrointest Endosc (1996;43:38-41.)

Cytochrome P450 isozyme 3A4 (CYP3A4) is a major isozyme in the human liver and is known to metabolize a larger variety of xenobiotics and endogenous biochemicals. The identities of CYP3A4 substrates are summarized here. A total of 32 chemicals belonging to different structural classes have been evaluated and found to be substrates for CYP3A4. The metabolic pathways for these substrates include N-oxidation, C-oxidation, N-dealkylation, O-dealkylation, nitro-reduction, dehydration, and C-hydroxylation. While the major experimental system used to elucidate the role of CYP3A4 in the metabolic transformation of these substrates is the human liver microsome system, cultured human hepatocytes and yeast/cultured cells genetically engineered to express CYP3A4 are also employed by the different investigators. The common approaches to identify the role of CYP3A4 are also summarized, which include correlation of metabolic activity of the substrates studied with those for known CYP3A4-catalyzed substrates, correlation of activity with CYP3A4 content, inhibition of activity with CYP3A4 specific antibodies, inhibition of activity with known CYP3A4 substrates and inhibitors, induction of activity with CYP3A4 inducers and demonstration of activity with purified CYP3A4 enzyme.

In our laboratory, human cells and tissues are used as experimental models to understand the pathogenesis of human diseases. A reproducible method for the isolation and culturing of colonocytes from human surgical specimens has been developed. This method involves the dissection of the colon specimen to expose the mucosa, cleaning of the mucosa surface, and digestion of the mucosa with a mixture of pronase and collagenase. The dissociated colonocytes are then quantified and cultured on collagen-coated plastic. Our procedure yields approx. 30–40 million viable colonocytes per gram of tissue, with a viability of approx. 90%. We believe that the primary colonocyte cultures can be used to study important human diseases such as Crohn's disease and ulcerative colitis.

It has been demonstrated in experimental cholecystitis in cats produced by lysophosphatidylcholine that the development of inflammation is associated with the exsorption of a large amount of protein into the gallbladder lumen. It was subsequently demonstrated that in feline experimental cholecystitis the protein produced was albumin and that its production was decreased by vesicular transport inhibitors, suggesting an active secretory process. In the present study, the effect of lysophosphatidylcholine on protein production by fresh, isolated human gallbladder mucosal cells was evaluated. Isolated gallbladder mucosal cells were incubated with [14C]leucine for 24 hr in tissue culture medium. The cells readily incorporated the radioactive label into cellular protein, a process inhibited by cycloheximide. Exposure of the cells to lysophosphatidylcholine for 1 hr in buffer solution resulted in loss of intracellular protein into the buffer solution. Exposure of the cells for 1 hr prior to lysophosphatidylcholine administration to vesicular transport inhibitors, colchicine, and cytochalasin B and to 4 degrees C culture conditions failed to alter the lysophosphatidylcholine-produced passage of the 14C label extracellularly. SDS-PAGE evaluation of the protein produced demonstrated that human gallbladder mucosal cells continuously produced a 66-kDa protein that was not increased by increasing concentration of lysophosphatidylcholine and a 14-kDa protein that increased with increasing concentrations of lysophosphatidylcholine. Employing Western blotting with specific antibodies, the 66-kDa protein was demonstrated to not be albumin but a 66-kDa glycoprotein, and the 14-kDa protein was demonstrated to contain phospholipase A2. Human gallbladder mucosal cells produced a protein and glycoprotein in response to lysophosphatidylcholine by a mechanism not related to vesicular transport.

The development of experimental cholecystitis produced by lysophosphatidylcholine is associated with reversal of the normal absorptive characteristics of gallbladder mucosa, resulting in the intraluminal accumulation of water, glycoprotein, and protein. The purpose of the present study was to attempt to ascertain if the protein leaks into the lumen because of the cytolytic properties of lysophosphatidylcholine or if it is due to an active secretory process and to characterize the protein produced. Experiments were performed on anesthetized cats undergoing gallbladder perfusion with and without lysophosphatidylcholine. The amount of protein in the perfusate was measured and albumin clearance from blood to gallbladder lumen was calculated with and without the administration of vesicular transport inhibitors. In separate experiments, control and lysophosphatidylcholine (LPC) produced gallbladder perfusates were collected and the protein subjected to SDS-PAGE to ascertain the nature of the protein secreted. Inhibitors of both microtubular and microfilament activity decreased the protein accumulation and clearance produced by lysophosphatidylcholine. Gallbladder white blood cell accumulation and inflammation as evaluated by beta-glucuronidase and prostaglandin E levels were not significantly altered by cytochalasin or colchicine administration. Lysophosphatidylcholine also produced significant increases in perfusate LDH levels. The protein produced was primarily a 66-kDa protein. Transfer of the protein to a nitrocellulose membrane and immunoblotting with anti-albumin antibody demonstrated that the protein was albumin. The results suggest that during the development of cholecystitis, lysophosphatidylcholine produces albumin accumulation in the gallbladder primarily by inducing an active secretory process resulting in gallbladder distension.

The transport of L-glutamine was examined in isolated adult and fetal human hepatocytes as well as in the human hepatoma cell lines HepG2 and SK-Hep. In all cells studied, glutamine uptake was at least 85% Na(+)-dependent. Kinetic analysis of the Na(+)-dependent component indicated mediation by a single transporter in three human hepatocyte preparations and in SK-Hep cells, whereas two transporters appeared to be responsible for glutamine uptake in HepG2 cells and in hepatocytes from the liver of one male patient. Amino acid inhibition analysis showed primary mediation by System N in fetal and adult hepatocytes, whereas System ASC was principally responsible for glutamine uptake in transformed cells. Similar to the rat transporter, human System N was pH-sensitive, stereospecific, and responsive to treatment with steroid hormones. Although the human carrier was less tolerant of Li(+)- for Na+ substitution, glutamine transport in primary human hepatocytes was stimulated by treatment with hypotonic buffer (cell swelling), as reported in rat parenchymal cells. In contrast, glutamine transport in hepatoma cells was relatively insensitive to changes in extracellular pH and failed to show enhanced activity in response to hypoosmotic challenge. Collectively, the data suggest that markedly distinct plasma membrane transporters mediate the concentrative uptake of glutamine in normal and transformed human hepatocytes, and that the salient properties of System N have been largely conserved from rat to man.

It has been demonstrated that lysolecithin (lysophosphatidyl choline, LPC) produces experimental cholecystitis in cats mediated by arachidonic acid metabolites. LPC is a cytolytic agent that has been postulated as a contributing factor in the development of cholecystitis in humans. The purpose of this research was to evaluate the effect of LPC on human gall-bladder mucosal cell phospholipase A2and cyclooxygenase activity. Gall-bladder mucosal cells were isolated from the gall-bladders of patients undergoing routine cholecystectomy. Fresh, isolated cells were maintained in tissue culture and stimulated with varying doses of LPC. Platelet-activating factor concentration was quantitated as an index of phospholipase A2activity and prostanoids were measured as an index of cyclooxygenase activity. Also, the effect of LPC on cyclooxygenase 1 and 2 expression in microsomal protein was evaluated. LPC caused dose related increases in 6-keto-PGF1αand PAF produced by human gall-bladder mucosal cells. Exposure of human gall-bladder mucosal cells to LPC failed to elicit expression of constitutive cyclooxygenase-1, while the expression of inducible cyclooxygenase-2 was increased. The results of this study indicate that LPC induces the formation of prostanoids and PAF by human gall-bladder mucosal cells, suggesting that this substance may promote the development of gall-bladder inflammation.

We sought to determine the effect of exogenously administered platelet-activating factor (PAF) on eicosanoid release from the left colon of the rabbit. Using an isolated buffer-perfused rabbit left colon preparation, 1.0- or 5.0-μg doses of PAF were infused into the inferior mesenteric artery. Effluents from the inferior mesenteric vein and colonic lumen were collected and the concentrations of the eicosanoids, prostaglandin E, 6-ketoprostaglandin F 1α , thromboxane B 2 , and leukotriene B 4 (LTB 4 ), were measured by ELISA. During PAF infusion there was a significant increase of all prostanoids, but not LTB 4 into the venous effluent and colonic luminal perfusate when compared to control experiments. Additional studies were performed by pretreating the colons with the PAF antagonists WEB-2170 or alprazolam prior to PAF infusion. Both venous and luminal effluent prostanoid release was effectively blocked by WEB-2170, but not by alprazolam. Colons pretreated with WEB-2170 prior to PAF had markedly diminished tissue injury when compared to colons treated with PAF alone. Inhibition of PAF-stimulated prostanoid release by WEB-2170 suggests that a PAF-sensitive receptor is present in rabbit colonic tissue which may induce eicosanoid-mediated tissue injury.

Laparoscopic cholecystectomy (LC) may inhibit the discovery of unsuspected gallbladder cancer, and the effect of LC on the prognosis of gallbladder cancer is unknown. We present two cases of unsuspected gallbladder cancer removed laparoscopically and report the discovery of peritoneal tumor implantation at the umbilical port site 21 days after LC. Although gallbladder carcinoma flow cytometry has been reported to be of prognostic value by Japanese investigators, this technique did not distinguish herein between an invasive adenocarcinoma and carcinoma in situ. A cellular doubling time of 56 h was calculated from one tumor. When unsuspected invasive gallbladder cancer is found after LC, laparoscopic port sites should be inspected at reoperation and, at a minimum, the port site through which the gallbladder was removed should be widely excised. This demonstration of cancer recurrence in laparoscopic port sites may limit the application of laparoscopy to elective cancer resection.

Acute acalculous cholecystitis (AAC) is a severe inflammatory disorder of the gallbladder. It occurs primarily in patients acutely ill from other disorders and is related to sepsis and shock. We previously found that platelet-activating factor (PAF), a phospholipid autacoid purported to be a mediator of the shock response, produced AAC. This study was performed to determine the effect of intravenous lipopolysaccharide (LPS) on feline gallbladders. Anesthetized cats underwent LPS administration with and without administration of a cyclooxygenase inhibitor and PAF antagonist. Gallbladder inflammation was evaluated by quantitation of luminal water transport and tissue myeloperoxidase levels. In an attempt to understand the mechanisms of the response, gallbladder perfusate and tissue prostanoid and PAF levels were quantitated as were serum PAF levels. LPS administration resulted in alteration of the normal absorptive pattern of the gallbladder mucosa to exsorption of fluid into the gallbladder lumen, increased tissue myeloperoxidase levels and increased serum PAF levels. This was associated with increased gallbladder tissue and perfusate prostanoid levels and increased perfusate PAF levels. Indomethacin prevented the pro-inflammatory changes in the gallbladder produced by LPS. The PAF antagonist, alprazolam, increased gallbladder prostanoid production when administered alone and with LPS. The administration of LPS resulted in the production of acute changes in the gallbladder consistent with cholecystitis. These changes being prevented by a cyclooxygenase inhibitor suggests that development of AAC may be related to the release of systemic and local pro-inflammatory substances.

Physiological responses to hypoglycemia, hyperinsulinemia, and hyperglycemia include a critical adrenocortical component that is initiated by hypothalamic control of the anterior pituitary and adrenal cortex. These adrenocortical responses ensure appropriate long-term glucocorticoid-mediated modifications to metabolism. Despite the importance of these mechanisms to disease processes, how hypothalamic afferent pathways engage the intracellular mechanisms that initiate adrenocortical responses to glycemia-related challenges are unknown. This study explores these mechanisms using network- and cellular-level interventions inin vivoandex vivorat preparations. Results show that a hindbrain-originating catecholamine afferent system selectively engages a MAP kinase pathway in rat paraventricular hypothalamic CRH (corticotropin-releasing hormone) neuroendocrine neurons shortly after vascular insulin and 2-deoxyglucose challenges. In turn, this MAP kinase pathway can control both neuroendocrine neuronal firing rate and the state of CREB phosphorylation in a reducedex vivoparaventricular hypothalamic preparation, making this signaling pathway an ideal candidate for coordinating CRH synthesis and release. These results establish the first clear structural and functional relationships linking neurons in known nutrient-sensing regions with intracellular mechanisms in hypothalamic CRH neuroendocrine neurons that initiate the adrenocortical response to various glycemia-related challenges.

An instrument was developed to survey third-year medical students about their experience with 18 clinical skills that are generally recognized as required learning for the third-year surgical clerkship. The same instrument was adapted to ascertain which surgical skills 25 fourth-year medical students, 25 surgical residents, and 25 practicing surgeons thought should be acquired during the third-year surgical clerkship. None of these evaluators had completed medical school or residency at our institution. A remarkable degree of conformity was found in the rankings of the 18 clinical skills by senior students, surgical residents, and practicing surgeons; fourth-year students rated only central venous line placement and simple operative procedures as significantly more important than did more senior evaluators. The third-year medical students' actual surgical clerkship experience with 10 out of the 18 skills was significantly below the overall competency levels desired by the graduate groups. Our survey demonstrates that both students and graduates attach similar importance to the acquisition of clinical skills in the third-year surgical curriculum. The instrument utilized in this study to measure students' experience and satisfaction with this phase of their education was reliable, the measurements were consistent, and this information was useful in the evaluation and modification of the curriculum.