Jean-Louis Guéant

Incidence of and impact of medications on colectomy in newly diagnosed ulcerative colitis in the era of biologics

Background: The cumulative incidence of colectomy and the impact of 5‐aminosalicylates (5‐ASA), azathioprine, and antitumor necrosis factor (TNF) treatment on the long‐term need for surgery are unknown in ulcerative colitis (UC) in the era of biologics. Methods: This was an observational study of a referral center cohort. The cumulative incidence of UC‐related colectomy was estimated using the Kaplan–Meier method. Independent predictors of surgery were identified using Cox proportional hazards regression with propensity scores adjustment. The electronic charts of 151 incident cases of UC from Nancy University Hospital, France, diagnosed between 2000 and 2008, were reviewed through January 2010. Results: The median follow‐up time per patient was 58 months. Twenty‐one (14%) underwent surgery. The cumulative probabilities of colectomy were respectively 1.3% and 13.5% at 1 and 5 years from the time of diagnosis. The probability of receiving oral mesalamine at 5 years was 68.1%. The corresponding figures were 48.9% for azathioprine and 29.0% for infliximab. For corticosteroids, methotrexate, and cyclosporin these figures were 75%, 8.8%, and 11.5%, respectively. Using multivariate Cox proportional hazards regression analysis after propensity score adjustment, previous use of cyclosporin was the only independent predictor for colectomy (hazard ratio = 4.41; 95% confidence interval 1.75–1.13). Conclusions: About one‐tenth of patients still require colectomy for UC at 5 years in the era of biologics. Oral 5‐ASA, azathioprine, and anti‐TNF therapy are not associated with a reduced need for colectomy. (Inflamm Bowel Dis 2012)

Vascular and cellular stress in inflammatory bowel disease: revisiting the role of homocysteine.

Moderate hyperhomocysteinemia is a complex trait commonly associated with inflammatory bowel disease (IBD). Nutritional deficiencies and genetic determinants have been identified as risk factors for moderate hyperhomocysteinemia, such as folate and vitamin B12 deprivation and polymorphisms in the 5,10 methylenetetrahydrofolate reductase (MTHFR) encoding gene, respectively. Homocysteine has a crucial role in cellular stress, epigenetic events, inflammatory processes, and host-microbial interactions. Hyperhomocysteinemia might therefore influence the clinical history of IBD, including disease severity, susceptibility to particular enteric infections, and the risk for the development of colorectal cancer. In contrast, homocysteine metabolism does not seem to contribute to the greater risk of thrombosis in IBD subjects. Herein, we review the evidence linking homocysteine metabolism to the pathophysiology of IBD. Furthermore, we discuss the relevance of screening and treating folate and vitamin B12 deficiencies in IBD subjects. Given the peculiar frequency of such deficiencies in IBD, normalizing vitamin levels should be an integral part of the management of these patients, especially those with active disease, history of intestinal resection, and/or treated with methotrexate.

Colorectal cancer in inflammatory bowel diseases: A population-based study (1976–2008)

Background: Few data are available on the incidence, characteristics, treatment, and prognosis of inflammatory bowel disease (IBD)‐associated colorectal cancer (CRC) in population‐based cohorts. Methods: Among the 19,451 new cases of CRC recorded in the Burgundy digestive cancer registry between 1976 and 2008, all cases of IBD‐associated CRC were identified. Incidence rates were age‐standardized according to the world standard population. Prognosis was determined using univariate and multivariate relative survival. Results: Thirty‐eight IBD‐associated CRC were identified (ulcerative colitis, n = 29; Crohns disease, n = 9). The mean age at CRC diagnosis was greater for patients without IBD than those with IBD (70.9 vs. 56.9 years, respectively; P < 0.001). Distributions of gender, stage at presentation, location, and histological type of CRC did not differ from those of sporadic cases. The overall world age‐standardized incidence of IBD‐associated CRC per 100,000 was 0.11 (standard deviation [SD]: 0.03) for men and 0.06 (SD: 0.02) for women. Only age was independently associated with IBD‐associated CRC (odds ratio [OR]: 0.22; 95% confidence interval [CI]: 0.12–0.43; P < 0.001). Treatment modalities did not differ between IBD and non‐IBD patients. Five‐year relative survival was 51.9% (95% CI: 51.1–52.8%) in non‐IBD patients and 41.3% (95% CI: 24.6–57.2%) in IBD patients (P = 0.201). After adjustment for age, gender, and stage at diagnosis, the excess hazard of death was 1.46 times higher in IBD than in non‐IBD patients (95% CI: 0.94–2.27; P = 0.070). Conclusions: Apart from age, the characteristics of IBD‐associated CRC were similar to those of non‐IBD CRC. The prognosis of CRC may be poorer in patients with IBD than in those without IBD. (Inflamm Bowel Dis 2012;)

Vitamin B12-Impaired Metabolism Produces Apoptosis and Parkinson Phenotype in Rats Expressing the Transcobalamin-Oleosin Chimera in Substantia Nigra

Background Vitamin B12 is indispensable for proper brain functioning and cytosolic synthesis of S-adenosylmethionine. Whether its deficiency produces effects on viability and apoptosis of neurons remains unknown. There is a particular interest in investigating these effects in Parkinson disease where Levodopa treatment is known to increase the consumption of S-adenosylmethionine. To cause deprivation of vitamin B12, we have recently developed a cell model that produces decreased synthesis of S-adenosylmethionine by anchoring transcobalamin (TCII) to the reticulum through its fusion with Oleosin (OLEO). Methodology Gene constructs including transcobalamin-oleosin (TCII-OLEO) and control constructs, green fluorescent protein-transcobalamin-oleosin (GFP-TCII-OLEO), oleosin-transcobalamin (OLEO-TCII), TCII and OLEO were used for expression in N1E-115 cells (mouse neuroblastoma) and in substantia nigra of adult rats, using a targeted transfection with a Neurotensin polyplex system. We studied the viability and the apoptosis in the transfected cells and targeted tissue. The turning behavior was evaluated in the rats transfected with the different plasmids. Principal Findings The transfection of N1E-115 cells by the TCII-OLEO-expressing plasmid significantly affected cell viability and increased immunoreactivity of cleaved Caspase-3. No change in propidium iodide uptake (used as a necrosis marker) was observed. The transfected rats lost neurons immunoreactive to tyrosine hydroxylase. The expression of TCII-OLEO was observed in cells immunoreactive to tyrosine hydroxylase of the substantia nigra, with a superimposed expression of cleaved Caspase-3. These cellular and tissular effects were not observed with the control plasmids. Rats transfected with TCII-OLEO expressing plasmid presented with a significantly higher number of turns, compared with those transfected with the other plasmids. Conclusions/Significance In conclusion, the TCII-OLEO transfection was responsible for apoptosis in N1E-115 cells and rat substantia nigra and for Parkinson-like phenotype. This suggests evaluating whether vitamin B12 deficit could aggravate the PD in patients under Levodopa therapy by impairing S-adenosylmethionine synthesis in substantia nigra.

Methotrexate for psoriasiform lesions associated with anti- tumour necrosis factor therapy in inflammatory bowel disease

Psoriasiform lesions associated with anti‐tumour necrosis factor (TNF) therapy are frequent in patients with inflammatory bowel disease (IBD). While methotrexate is the most frequently used systemic treatment for psoriasis, its efficacy for psoriasiform lesions related to anti‐TNF therapy remains unknown.

Methyl deficient diet aggravates experimental colitis in rats

Inflammatory bowel diseases (IBD) result from complex interactions between environmental and genetic factors. Low blood levels of vitamin B12 and folate and genetic variants of related target enzymes are associated with IBD risk, in population studies. To investigate the underlying mechanisms, we evaluated the effects of a methyl‐deficient diet (MDD, folate, vitamin B12 and choline) in an experimental model of colitis induced by dextran sodium sulphate (DSS), in rat pups from dams subjected to the MDD during gestation and lactation. Four groups were considered (n= 12–16 per group): C DSS− (control/DSS−), D DSS− (deficient/DSS−), C DSS+ (control/DSS+) and D DSS+ (deficient/DSS+). Changes in apoptosis, oxidant stress and pro‐inflammatory pathways were studied within colonic mucosa. In rat pups, the MDD produced a decreased plasma concentration of vitamin B12 and folate and an increased homocysteine (7.8 ± 0.9 versus 22.6 ± 1.2 μmol/l, P < 0.001). The DSS‐induced colitis was dramatically more severe in the D DSS+ group compared with each other group, with no change in superoxide dismutase and glutathione peroxidase activity, but decreased expression of caspase‐3 and Bax, and increased Bcl‐2 levels. The mRNA levels of tumour necrosis factor (TNF)‐α and protein levels of p38, cytosolic phospolipase A2 and cyclooxygenase 2 were significantly increased in the D DSS+ pups and were accompanied by a decrease in the protein level of tissue inhibitor of metalloproteinases (TIMP)3, a negative regulator of TNF‐α. MDD may cause an overexpression of pro‐inflammatory pathways, indicating an aggravating effect of folate and/or vitamin B12 deficiency in experimental IBD. These findings suggest paying attention to vitamin B12 and folate deficits, frequently reported in IBD patients.

Microscopic features for initial diagnosis and disease activity evaluation in inflammatory bowel disease.

Abstract: Inflammatory bowel disease is characterized by 2 major entities: Crohn’s disease (CD) and ulcerative colitis (UC). In clinical practice, separation of UC and CD has been based on a variety of clinical features, symptoms, endoscopic and radiological, gross and microscopic characteristics. The microscopic diagnosis of inflammatory bowel disease is based on a combination of 2 types of lesions: architectural abnormalities and inflammatory features. However, microscopic distinction between these 2 entities can be difficult and often results in an interim diagnosis of “indeterminate colitis.” Recommendations are made to encourage pathologists to give an indication of the activity of the disease: in UC, biopsies are used to discriminate between quiescent disease, inactive disease, and different grades of activity; in CD, evaluation of disease activity is limited and inactivity in the biopsy may not reflect inactivity in the patient. The aim of this review was to summarize microscopic features of inflammatory bowel disease for initial diagnosis and evaluation of disease activity in both CD and UC.

Methyl donor deficiency affects small-intestinal differentiation and barrier function in rats.

Dietary methyl donors and their genetic determinants are associated with Crohns disease risk. We investigated whether a methyl-deficient diet (MDD) may affect development and functions of the small intestine in rat pups from dams subjected to the MDD during gestation and lactation. At 1 month before pregnancy, adult females were fed with either a standard food or a diet without vitamin B12, folate and choline. A global wall hypotrophy was observed in the distal small bowel (MDD animals 0·30 mm v. controls 0·58 mm; P< 0·001) with increased crypt apoptosis (3·37 v. 0·4%; P< 0·001), loss of enterocyte differentiation in the villus and a reduction in intestinal alkaline phosphatase production. Cleaved caspase-3 immunostaining (MDD animals 3·37% v. controls 0·4%, P< 0·001) and the Apostain labelling index showed increased crypt apoptosis (3·5 v. 1·4%; P= 0·018). Decreased proliferation was observed in crypts of the proximal small bowel with a reduced number of minichromosome maintenance 6 (MDD animals 52·83% v. controls 83·17%; P= 0·048) and proliferating cell nuclear antigen-positive cells (46·25 v. 59 %; P= 0·05). This lack of enterocyte differentiation in the distal small bowel was associated with an impaired expression of β-catenin and a decreased β-catenin-E-cadherin interaction. The MDD affected the intestinal barrier in the proximal small bowel by decreasing Paneth cell number after immunostaining for lysosyme (MDD animals 8·66% v. controls 21·66%) and by reducing goblet cell number and mucus production after immunostaining for mucin-2 (crypts 8·66 v. 15·33%; villus 7 v. 17%). The MDD has dual effects on the small intestine by producing dramatic effects on enterocyte differentiation and barrier function in rats.

Conditioning-like Brief Neonatal Hypoxia Improves Cognitive Function and Brain Tissue Properties with Marked Gender Dimorphism in Adult Rats

Although recent studies have documented compensatory generation of neurons in adult brains in response to various insults, a noninjurious short episode of hypoxia in rat neonates has been shown to trigger neurogenesis within the ensuing weeks, without apparent brain lesions. Very little is known of the long-term consequences. We therefore investigated the effects of such a conditioning-like hypoxia (100% N(2), 5 min) on the brain and the cognitive outcomes of rats at 40 to 100 days of age. Control and posthypoxic rats developed similar learning capacities over postnatal days 14 to 18, but hypoxia was associated with enhanced scores in a test used to evaluate memory retrieval between 40 and 100 days. A striking sexual dimorphism was observed, with an earlier functional gain observed in female (40 days) compared with male (100 days) rats; gains were associated with matching structural changes in areas involved in cognition, including the hippocampus and frontal cortex. Therefore, it is proposed that brief neonatal hypoxia may exert long-term beneficial effects through neurogenesis stimulation.

Fumonisin FB1 treatment acts synergistically with methyl donor deficiency during rat pregnancy to produce alterations of H3‐ and H4‐histone methylation patterns in fetuses

SCOPE Prenatal folate and methyl donor malnutrition lead to epigenetic alterations that could enhance susceptibility to disease. Methyl-deficient diet (MDD) and fumonisin FB1 are risk factors for neural tube defects and cancers. Evidence indicates that FB1 impairs folate metabolism. METHODS AND RESULTS Folate receptors and four heterochromatin markers were investigated in rat fetuses liver derived from dams exposed to MDD and/or FB1 administered at a dose twice higher than the provisional maximum tolerable daily intake (PMTDI = 2 μg/kg/day). Even though folate receptors transcription seemed up-regulated by methyl depletion regardless of FB1 treatment, combined MDD/FB1 exposure might reverse this up-regulation since folate receptors transcripts were lower in the MDD/FB1 versus MDD group. Methyl depletion decreased H4K20me3. Combined MDD/FB1 decreased H4K20me3 even more and increased H3K9me3. The elevated H3K9me3 can be viewed as a defense mechanism inciting the cell to resist heterochromatin disorganization. H3R2me2 and H4K16Ac varied according to this mechanism even though statistical significance was not consistent. CONCLUSION Considering that humans are exposed to FB1 levels above the PMTDI, this study is relevant because it suggests that low doses of FB1 interact with MDD thus contributing to disrupt the epigenetic landscape.