New perspectives on the long-term outcome of segmental colectomy for Crohn’s colitis: an observational study on 200 patients

Background and aims

Surgical management of Crohn’s colitis represents one of the most complex situations in colorectal surgery. Segmental colectomy (SC) and total abdominal colectomy with ileorectal anastomosis (TAC-IRA) are the most common procedures, but there are few available data on their long-term outcome. The aim of the present study was to analyze the long-term outcome of patients who underwent segmental colectomy for Crohn’s colitis, with regard to the risk for total abdominal colectomy.

Methods

In this observational, monocentric, retrospective analysis, we analyzed patients who received a segmental colectomy for Crohn’s colitis at our institution. The database was updated by asking patients to complete a questionnaire by telephone or at the outpatient clinic. Only patients followed up at our Hospital were included. Patients were followed up by a specialized multidisciplinary team (IBD Unit). The primary endpoint was the interval between segmental colectomy and, when performed, total abdominal colectomy.

Results

Between 1973 and 2014, 200 patients underwent segmental colectomy for Crohn’s colitis. The median follow-up was 13.5 years (interquartile range [IQR] 7.8–21.5). Overall, 62 patients (31%) had a surgical recurrence, of these, 42 (21%) received total abdominal colectomy. At multivariate analysis, the presence of ≥?3 sites (HR =?2.47; 95% CI 1.22–5.00; p?=?0.018) and perianal disease (HR =?3.23; 95% CI 1.29–8.07; p?=?0.006) proved to be risk factors for total abdominal colectomy.

Conclusions

The risk for surgical recurrence after SC for Crohn’s colitis is acceptable. We recommend a bowel-sparing policy for the treatment of Crohn’s colitis in any case in which the extent of the disease at the moment of surgery makes the conservative approach achievable.

     

Observer variability in the pulmonary examination

Observer variability in the pulmonary examination was assessed by having four blindfolded observers (two medical students and two pulmonary physicians) twice examine 31 patients with abnormal pulmonary findings. Examiners were consistent in the repetitive detection of pulmonary abnormalities in 74–89% of the examinations; conversely, 11–26% of the time they disagreed with themselves. Although pulmonary specialists recorded fewer (55% of observations) abnormal findings than did medical students (74%), they were significantly (p=0.008) less self-consistent than were the students. There was no clear trend in agreement between examiners (kappa=0.20−0.49). Each examiner’s findings were compared with those of physicians specially trained in pulmonary examination. Dichotomous variables (wheezes, crackles, rubs) were more reliably detected (kappa=0.30−0.70) than graded variables (tympany, dullness, breath sound intensity), where kappa=0.16−0.43. The authors suggest that dichotomous variables deserve greatest clinical reliance; that time in training, alone, does not improve clinical performance; and that there is a disconcertingly large amount of inter- and intraobserver disagreement in this fundamental clinical task. Received from the Division of General Internal Medicine, Department of Medicine; the Division of Biometry, Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina; and the Ambulatory Care Service and Health Services Research Field Program, Durham V.A. Medical Center, Durham, North Carolina.     

Deciphering TGF‐β3 function in medial edge epithelium specification and fusion during mouse secondary palate development

Background: Transforming growth factor‐β3 (TGF‐β3) plays a central role in mediating secondary palate fusion along the facial midline. However, the mechanisms by which TGF‐β3 functions during secondary palate fusion are still poorly understood. Results : We found that mouse cytokeratin 6α and 17 mRNAs were expressed exclusively in the palate medial edge epithelium on embryonic day 14.5, and this expression was completely abolished in Tgf‐β3 mutant embryos. In contrast, we found that Jagged2 was initially expressed throughout the palate epithelium, but was specifically down‐regulated in the medial edge epithelium during palatal fusion. Jagged2 down‐regulation was regulated by TGF‐β3, since Jagged2 was persistently expressed in palatal medial edge epithelium in Tgf‐β3 null mutant embryos. Moreover, addition of DAPT, a specific inhibitor of Notch signaling, partially rescued the fusion defects in Tgf‐β3 null mutant palatal shelves. Conclusions : Based on these results, together with the previous study indicating that the loss of Jagged2 function promotes embryonic oral epithelial fusion, we concluded that TGF‐β3 mediates palate fusion in part by down‐regulating Jagged2 expression in palatal medial edge epithelium. In addition, cytokeratin 6α and 17 are two TGF‐β3 downstream target genes in palate medial edge epithelium differentiation. Developmental Dynamics 243:1536–1543, 2014. © 2014 Wiley Periodicals, Inc.     

Testicular vasculitis: findings differentiating isolated disease from systemic disease in 72 patients

Testicular vasculitis (TV) may be part of systemic (testicular) vasculitis (STV) or may exist as single-organ/isolated (testicular) vasculitis (ITV). In the current study we sought to identify clinical and histologic features that distinguish STV from ITV. The distinction was deemed important because it is already well established that in other forms of single organ vasculitis, surgical therapy alone may be curative. We identified patients with biopsy-proven TV from pathology databases from our institution and from an English-language PubMed search. Patients were included if data were available to determine TV extent confidently. Data recorded included clinical, laboratory, and histologic features; treatment; and clinical follow-up. The study included 72 patients with TV (mean age, 42 yr; range, 4-78 yr) (7 from our institution). About 74% of patients presented with painful testicular swelling/mass, 10% with a painless testicular swelling/mass, and 4% with epididymal swelling/mass. Eleven percent had no testicular complaints and vasculitis was discovered at autopsy or in other surgical interventions. Vasculitis involved the testicle in 80.3% of cases, the epididymis in 44.6%, and the spermatic cord in 30.6%. Thirty-seven (51%) patients had ITV and 35 (49%) had STV. No differences between ITV and STV patients were found in regards to age, presenting testicular features, duration of testicular symptoms, and time of follow-up. Compared to ITV patients, STV patients presented more often with constitutional/musculoskeletal symptoms (74.3% vs. 8.3%, respectively; p = 0.0001), elevated erythrocyte sedimentation rate (94.7% vs. 16%; p = 0.0001), and anemia (50% vs. 0%; p = 0.0001). Neoplasm was more frequently suspected in ITV than in STV (74.2% vs. 31.6%; p = 0.001), but only occurred in 2 ITV patients. Long-term glucocorticoid therapy was given only to STV patients, and 59.1% of them also received cytotoxic agents. ITV was diagnosed more often by orchiectomy (81.1% vs. 42.9%; p = 0.001) and less frequently by testicular biopsy (2.7% vs. 28.6%; p = 0.003) than STV. Nongranulomatous inflammation affecting medium-sized vessels occurred in most patients with both ITV and STV. Among STV, polyarteritis nodosa was the most frequently diagnosed (63%), followed by Wegener granulomatosis (17%).In summary, TV occurs as ITV in men usually presenting with a testicular mass in the absence of systemic symptoms and normal laboratory results. In most ITV patients, a testicular neoplasm is initially suspected, and TV is an unexpected finding. After surgical removal, ITV does not require systemic therapy. Polyarteritis nodosa is the systemic vasculitis most frequently associated with testicular involvement.     

The role of macrophage colony-stimulating factor in patients with acute myocardial infarction: a pilot study

We assessed whether macrophage colony-stimulating factor (M-CSF) levels are associated with left ventricular systolic dysfunction (LVSD) in patients with acute myocardial infarction (AMI). We studied 56 patients with AMI (mean age: 67 ± 12 years) and identified those with clinical (Killip class >II) or echocardiographic signs (ejection fraction ≤45%) of LVSD. We evaluated the established cardiovascular risk factors and measured several cardiovascular biomarkers, including M-CSF. Serum M-CSF concentrations (pg/mL) were significantly increased in patients with both clinical and echocardiographic signs of LVSD (460 ± 265 vs 290 ± 210, P = .0103 and 493 ± 299 vs 287 ± 174, P = .0028, respectively). We found a significant inverse association between M-CSF and ejection fraction (r = -.351, P = .0079). Logistic regression analysis revealed that, among all evaluated clinical and biochemical parameters, the stronger predictor of LVSD was M-CSF (odds ratios 2.1, 95% confidence interval 1.1-2.9, P = .0168). This is the first study reporting plasma M-CSF levels as independent determinants of low LV ejection fraction and clinical LV dysfunction in patients with AMI.     

Cytotoxic effects of bortezomib in myelodysplastic syndrome/acute myeloid leukemia depend on autophagy-mediated lysosomal degradation of TRAF6 and repression of PSMA1

Bortezomib (Velcade) is used widely for the treatment of various human cancers; however, its mechanisms of action are not fully understood, particularly in myeloid malignancies. Bortezomib is a selective and reversible inhibitor of the proteasome. Paradoxically, we find that bortezomib induces proteasome-independent degradation of the TRAF6 protein, but not mRNA, in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) cell lines and primary cells. The reduction in TRAF6 protein coincides with bortezomib-induced autophagy, and subsequently with apoptosis in MDS/AML cells. RNAi-mediated knockdown of TRAF6 sensitized bortezomib-sensitive and -resistant cell lines, underscoring the importance of TRAF6 in bortezomib-induced cytotoxicity. Bortezomib-resistant cells expressing an shRNA targeting TRAF6 were resensitized to the cytotoxic effects of bortezomib due to down-regulation of the proteasomal subunit α-1 (PSMA1). To determine the molecular consequences of loss of TRAF6 in MDS/AML cells, in the present study, we applied gene-expression profiling and identified an apoptosis gene signature. Knockdown of TRAF6 in MDS/AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem/progenitor function. In summary, we describe herein novel mechanisms by which TRAF6 is regulated through bortezomib/autophagy-mediated degradation and by which it alters MDS/AML sensitivity to bortezomib by controlling PSMA1 expression.     

Hyperparathyroidism can be useful in the identification of primary aldosteronism due to aldosterone-producing adenoma

Type 1 diabetes triggers protein kinase C (PKC)-dependent NADPH oxidase activation in the renal medullary thick ascending limb (mTAL), resulting in accelerated superoxide production. As acute exposure to superoxide stimulates NaCl transport by the mTAL, we hypothesized that diabetes increases mTAL Na(+) transport through PKC-dependent and NADPH oxidase-dependent mechanisms. An O(2)-sensitive fluoroprobe was used to measure O(2) consumption by mTALs from rats with streptozotocin-induced diabetes and sham rats. In sham mTALs, total O(2) consumption was evident as a 0.34±0.03 U change in normalized relative fluorescence (ΔNRF)/min per mg protein. Ouabain (2 mmol/L) reduced O(2) consumption by 69±4% and 500 μmol/L furosemide reduced O(2) consumption by 58±8%. Total O(2) consumption was accelerated in mTAL from diabetic rats (0.74±0.07 ΔNRF/min/mg protein; P<0.05 versus sham), reflecting increases in ouabain- and furosemide-sensitive O(2) consumption. NADPH oxidase inhibition (100 μmol/L apocynin) reduced furosemide-sensitive O(2) consumption by mTAL from diabetic rats to values not different from sham. The PKC inhibitor calphostin C (1 μmol/L) or the PKCα/β inhibitor G?6976 (1 μmol/L) decreased furosemide-sensitive O(2) consumption in both groups, achieving values that did not differ between sham and diabetic. PKCβ inhibition had no effect in either group. Similar inhibitory patterns were evident with regard to ouabain-sensitive O(2) consumption. We conclude that NADPH oxidase and PKC (primarily PKCα) contribute to an increase in O(2) consumption by the mTAL during type 1 diabetes through effects on the ouabain-sensitive Na(+)-K(+)-ATPase and furosemide-sensitive Na(+)-K(+)-2Cl(-) cotransporter that are primarily responsible for active transport Na(+) reabsorption by this nephron segment.     

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment: The Cocoa, Cognition, and Aging (CoCoA) Study

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r(2)=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.