The ACS National Surgical Quality Improvement Program-Inflammatory Bowel Disease Collaborative: Design, Implementation, and Validation of a Disease-specific Module.

BACKGROUND: Surgery for inflammatory bowel disease (IBD) involves a complex interplay between disease, surgery, and medications, exposing patients to increased risk of postoperative complications. Surgical best practices have been largely based on single-institution results and meta-analyses, with multicenter clinical data lacking. The American College of Surgeons National Surgical Quality Improvement Project (ACS-NSQIP) has revolutionized the way in which large-volume surgical outcomes data have been collected. Our aim was to employ the ACS-NSQIP to collect disease-specific variables relevant to surgical outcomes in IBD. STUDY DESIGN: A collaborative of 13 high-volume IBD surgery centers was convened to collect 5 IBD-specific variables in NSQIP. Variables included biologic and immunomodulator medications usage, ileostomy utilization, ileal pouch anastomotic technique, and colonic dysplasia/neoplasia. A sample of the Surgical Clinical Reviewer collected data was validated by a colorectal surgeon at each institution, and kappa's agreement statistics generated. RESULTS: Over 1 year, data were collected on a total of 956 cases. Overall, 41.4% of patients had taken a biologic agent in the 60 days before surgery. The 2 most commonly performed procedures were laparoscopic ileocolic resections (159 cases) and subtotal colectomies (151 cases). Overall, 56.8% of cases employed an ileostomy, and 134 ileal pouches were constructed, of which 92.4% used stapled technique. A sample of 214 (22.4%) consecutive cases was validated from 8 institutions. All 5 novel variables were shown to be reliably collected, with excellent agreement for 4 variables (kappa ≥ 0.70) and very good agreement for the presence of colonic dysplasia (kappa = 0.68). CONCLUSION: We report the results of the initial year of implementation of the first disease-specific collaborative within NSQIP. The selected variables were demonstrated to be reliably collected, and this collaborative will facilitate high-quality, large case-volume research specific to the IBD patient population.

Structural studies of some push-pull N-arylbenzazoles.

X-Ray crystal structures, and calculated structures (at B3LYP/6-31G level) are reported for seven N-arylbenzazoles (two carbazoles, indoles and benzimidazoles, and one indazole) bearing electron withdrawing groups in the 2-position of the N-aryl ring. The structures are markedly non-planar by rotation around the N-aryl bond, with the substituent in most cases lying s-E in relation to the N-aryl bond; intermolecular electrostatic interactions in the crystal rationalise the two examples in which an s-Z conformation is observed. A large interplanar angle between the benzazole and the N-aryl planes is associated with a small interplanar angle between the planes of the N-aryl group and the substituent and vice versa.

Thermal ring contraction of dibenz[b,f]azepin-5-yl radicals: new routes to pyrrolo[3,2,1-jk]carbazoles.

Flash vacuum pyrolysis (FVP) of N-allyl- or N-benzyldibenz[b,f]azepine at temperatures from 750 to 950 degrees C gives pyrrolo[3,2,1-jk]carbazole as the major product. The mechanism of the ring contraction involves dibenzazepin-1-yl radical formation, followed by transannular attack and formation of a 2-(indol-1-yl)phenyl radical which cyclizes. The mechanism is supported by independent generation of 2-(indol-1-yl)phenyl radicals by two different methods, and the use of 1-(2-nitrophenyl)indole as a radical generator gives an optimized synthetic route to pyrrolo[3,2,1-jk]carbazole (54% overall yield in two steps from indole). The first substituted pyrrolo[3,2,1-jk]carbazoles have been synthesized by FVP methods and also by reactions of the parent compound with electrophiles, leading to a range of 4-substituted pyrrolocarbazoles.

Isoindolo[2,1-a]indol-6-one--a new pyrolytic synthesis and some unexpected chemical properties.

Isoindolo[2,1-a]indol-6-one 1 is formed by a sigmatropic shift-elimination-cyclisation cascade by flash vacuum pyrolysis (FVP) of methyl 2-(indol-1-yl)benzoate 7 at 950 degrees C. The dihydro compound 16 is easily obtained by catalytic reduction of 1, but the reaction is very sensitive to steric effects at the 11-position. Attempted ring-opening of 1 in basic methanol provides an equilibrium of isoindolo[2,1-a]indol-6-one 1 and the ester 19. Lithium aluminium hydride reduction of 1 provides the alcohol 22 which can be dehydrated to a mixture of 23 and 24 by FVP at 800-950 degrees C.

Divergent metabolic and vascular phenotypes in pre-eclampsia and intrauterine growth restriction: relevance of adiposity.

OBJECTIVE: Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) may both arise secondary to inadequate trophoblast invasion. Maternal vascular disease is evident only in PE. Little mechanistic evidence exists to explain this dichotomy. METHODS: We employed laser Doppler imaging (LDI) to examine microvascular function in 15 women with PE and 30 healthy pregnant women matched for body mass index (BMI). We also examined 16 women with IUGR. Other factors examined included indices of inflammation, lipoproteins, leptin and insulin concentrations. RESULTS: Women with PE had double the concentration of leptin and 30% higher triglyceride than controls. Vascular cell adhesion molecule (VCAM)-1 and interleukin (IL)-6 were also higher in women with PE, with both factors correlating with leptin independently of BMI. No difference in microvascular reactivity was observed between controls and women with PE. Women with IUGR had a four-unit smaller BMI than women with PE. When compared with controls, they also had lower low-density lipoprotein cholesterol (LDL-C) concentrations and systemic inflammatory measures were not elevated. CONCLUSIONS: The technique of LDI is not sensitive to the vascular dysfunction of PE. However, circulating endothelial-derived factors are elevated in association with markedly elevated leptin levels. Therefore, women with IUGR may demonstrate a protective role for their 'leanness' with regard to maternal systemic inflammatory effect.

Serum C-reactive protein and lipids in ultra-Marathon runners.

In this investigation, we compared lipid and inflammatory parameters in regular long distance runners with matched sedentary controls. Long distance runners had significantly lower low-density lipoprotein cholesterol and C-reactive protein levels than the control group. This exercise-induced reduction in low-density lipoprotein cholesterol was independent of the decrease in C-reactive protein levels.

Strikingly low circulating CRP concentrations in ultramarathon runners independent of markers of adiposity: how low can you go?

OBJECTIVE: This study was undertaken to evaluate to what extent C-reactive protein (CRP) can be reduced by exercise by examining its circulating concentrations in male ultramarathon runners and to determine if low leptin as a robust circulating marker of fat mass could account for low CRP in such men. METHODS AND RESULTS: Sixty-seven male ultramarathon runners and 63 sedentary male controls of similar age and body mass index were recruited. CRP and leptin were measured by ELISA and radioimmunoassay, respectively. Median CRP concentration in lean (body mass index <25 kg/m2) marathon runners was less than half control median (0.4 [0.2 to 0.9] mg/L versus 0.9 [0.5 to 2.7] mg/L, P=0.0013) and, more strikingly, in nonlean runners was approximately 26% of control median (0.4 [0.3 to 0.8] mg/L versus 1.5 [0.9 to 2.5] mg/L, P=0.0002). Circulating leptin levels were also substantially lower in lean (45% less) and nonlean (63% less, both P<0.0001) ultramarathon runners. However, interleukin-6 levels were not different. Furthermore, leptin adjustment only minimally attenuated the case-control difference in CRP, suggesting that mechanisms other than fat mass reduction contribute to low concentrations of CRP in marathon runners. CONCLUSIONS: This study suggests that circulating CRP concentrations can be markedly suppressed, independently of total adiposity or indeed fat mass, by intense regular physical exercise.

Classic and novel risk factor parameters in women with a history of preeclampsia.

Epidemiological studies demonstrate a relation between preeclampsia (PE) and an increased risk of maternal coronary heart disease (CHD) in later life. However, there are few data available to explain any underlying mechanism. We recruited 40 primigravid women with a history of proteinuric PE delivering between 1975 and 1985 and 40 controls, matched as a group for time of index pregnancy, smoking, and current body mass index to assess classic (lipids, blood pressure) and novel (adhesion molecules, insulin, leptin) risk factor pathways. Women with a history of PE had higher diastolic blood pressure compared with controls (83 vs 76 mm Hg, P<0.05), but there were no significant differences in fasting lipoprotein concentrations (P>0.20). However, concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) in particular were higher in the PE group by 14% (P=0.038) and 44% (P=0.002), respectively. The cases also demonstrated a tendency toward higher fasting insulin (P=0.08) concentrations and had higher glycosylated hemoglobin levels (P=0.004). Leptin concentrations were not significantly elevated. Interestingly, significantly more of the women with history of PE were classified as menopausal (37.55% vs 17.5%, P=0.045). The differences in ICAM-1 concentration persisted (P=0.010) after adjustment for potential confounders, including hormonal use/menopausal status, antihypertensive or lipid-lowering therapy, and social class. We conclude that classic risk factors alone cannot fully explain the elevated CHD risk in women with a history of PE. Rather markedly elevated ICAM-1 concentrations and specific but subtle features of the metabolic syndrome (glucose, blood pressure) are likely to be involved.

Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

BACKGROUND: Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C-reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk. OBJECTIVE: To assess the metabolic effects of a continuous combined HRT containing 1 mg oestradiol and 0.5 mg norethisterone or matching placebo. DESIGN: Double-blind, randomized placebo-controlled trial. PATIENTS: Fifty women with type 2 diabetes. MEASUREMENTS: Classical and novel risk factors for vascular disease. RESULTS: Triglyceride concentration was not altered (P = 0.31, change in active arm relative to placebo) and low-density lipoprotein (LDL) cholesterol concentration declined 13% (P = 0.018). IL-6 concentration (mean difference -1.42 pg/ml, 95% CI: -2-55 to -0-29 IU/dl, P = 0.015), Factor VII (-32 IU/dl, -43 to -21 IU/l, P < 0.001) and tissue plasminogen activator antigen (by 13%, P = 0.005) concentrations fell, but CRP was not significantly altered (P = 0.62). Fasting glucose (P = 0.026) also declined significantly, but there are no significant effects on HBA1c, Factor IX or APC resistance. CONCLUSIONS: HRT containing 1 mg oestradiol and 0.5 mg norethisterone may avoid the adverse metabolic effects potentially implicated in the elevated CHD and stroke risk induced by conventional higher dose HRT. This type of preparation may therefore be more suitable than conventional HRT for women at elevated CHD risk such as those with type 2 diabetes. Large randomized controlled trials of such low dose preparations, powered for cardiovascular end points, are now needed.

Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways.

Obesity is increasing in prevalence worldwide and in all age groups. In nonpregnant individuals, obesity is associated with dyslipidemia; hyperinsulinemia; vascular dysfunction; and, more recently, low-grade chronic inflammation. However, whether such effects are sustained during pregnancy has been sparsely investigated but is important to establish, given the association of maternal obesity with numerous adverse metabolic and vascular consequences. We consecutively recruited 47 healthy women in the third trimester of pregnancy and divided the participants into 2 groups, lean [n = 24; median body mass index (BMI), 22.1 kg/m(2)] and obese (n = 23; median BMI, 31.0 kg/m(2)) around the median first trimester BMI. The age, parity, and smoking history were comparable in both groups. A detailed panel of metabolic and inflammatory parameters was measured and an in vivo assessment of endothelial-dependent and -independent microvascular function made using laser doppler imaging. Although low-density lipoprotein cholesterol and glycosylated hemoglobin were similar, fasting triglyceride concentrations were higher [2.70 (interquartile range, 2.3-3.21) vs. 2.20 (IQ range, 2.0-2.6) mmol/liter, P = 0.02] and high-density lipoprotein concentrations were lower [1.55 (IQ range, 1.1-1.7) vs. 1.72 (IQ range, 1.4-2.0) mmol/liter, P = 0.02] in the obese group. Leptin [55.6 (range, 45-64.4) ng/ml vs. 23.8 (range, 13.2-35.2) ng/ml, P < 0.0001] and fasting insulin [14.5 (range, 11.4-27.3) vs. 6.5 (range, 4.6-9.7) mU/liter, P < 0.0001] levels were more than double. Similarly, levels of inflammatory parameters, IL-6 [3.15 (range, 2.4-3.5) vs. 2.1 (range, 1.73-2.85) pg/ml, P = 0.003], and sensitive C-reactive protein [4.45 (range, 2.9-6.6) vs. 2.25 (range, 0.92-3.65) mg/ml, P = 0.0015] were also substantially elevated. Both endothelial-dependent and -independent vasodilatory responses were significantly reduced in the obese group (P = 0.0003 and P = 0.02, respectively, ANOVA) and systolic blood pressure was higher (P = 0.01). Metabolic factors, C-reactive protein (r = 0.289, P = 0.049), and insulin (r = 0.339, P = 0.02) were related inversely to endothelial-dependent function. These comprehensive data demonstrate that, as in nonpregnant obese individuals, obesity in pregnancy is associated not only with marked hyperinsulinemia (without necessarily glucose dysregulation) and dyslipidemia but also impaired endothelial function, higher blood pressure, and inflammatory up-regulation. Such a spectrum of risk factors may contribute to maternal complications in obese women and, as a result, influence fetal programming of adult vascular disease. Clearly, these data provide further rationale to examine the potential benefits of preconceptual weight loss and antenatal exercise.