Hypertension management in patients with renal cell cancer treated with anti-angiogenic agents.

Inhibitors of the vascular endothelial growth factor (vegf-is) signalling pathway have fundamentally changed the treatment of metastatic renal cell carcinoma (mrcc). Hypertension is one of the most common side effects of vegf-is and has been reported with almost every vegf-i used for treatment to date. The exact mechanism of vegf-i-induced hypertension appears complex and multifactorial, and it remains to be fully explained. No randomized clinical trials are available to guide the management of hypertension during vegf-i treatment in mrcc patients. The guiding principles suggested here summarize the consensus of opinions on the diagnosis and management of vegf-i-induced hypertension during treatment of mrcc obtained from an expert working group composed of 4 Canadian medical oncologists and 5 Canadian hypertension specialists. The Canadian Hypertension Education Program guidelines, available literature, and expert opinion were used to develop the guiding principles.

Health and nutrition promotion program for patients with dementia (NutriAlz): cluster randomized trial.

OBJECTIVE: To assess the effectiveness of health and nutrition program (NutriAlz) versus usual care on functional level in elderly people with dementia living at home, as well as on clinical practice related to nutrition and on the caregiver's burden. DESIGN: Cluster randomized multi-centre study with one-year follow-up. SETTING: 11 Alzheimer outpatients and day care centres (Barcelona, Spain). PARTICIPANTS: Nine hundred and forty six home-living Alzheimer patients with identified caregiver were consecutively recruited (intervention group: 6 centres, 448 patients vs control group: 5 centres, 498 patients). INTERVENTION: The intervention was a teaching and training intervention on health and nutrition program, NutriAlz, directed both to physician and main caregiver, as well as persons affected by Alzheimer's disease or other dementias, including a standardised protocol for feeding and nutrition. MAIN OUTCOME MEASURES: The main outcome measure was the reduction in the loss of autonomy (Activities of daily living (ADL/IADL) scales) assessed at 6 and 12 months. Secondary outcomes measures were Improvement in nutritional status (Mini Nutritional Assessment (MNA), BMI, and weight changes), and caregiver burden (Zarit scale). RESULTS: The one-year assessment was completed for 293 patients (65.4%) in the intervention group and 363 patients (72.9%) in the control group (usual care). The annual rate of ADL change was -0.83 vs -0.62 (p=0.984), and the caregiver's subjective burden 0.59 vs 2.36 (p=0.681) in intervention and control group, respectively. MNA, however, showed an improvement (+0.46 vs -0.66, p=0.028), suggesting an effective nutritional behaviour. CONCLUSION: The NutriAlz program had no effect on functional decline in Alzheimer disease patients living at home over one year, but reduced the risk for malnutrition, as recommendations concerning diet and exercise were provided.

Interleukin-2 enhances angiogenesis and preserves cardiac function following myocardial infarction.

We previously demonstrated that injection of IL-2-activated natural killer (NK) cells contribute to vascular remodeling via a4b7 integrin and killer cell lectin-like receptor (KLRG) 1 and promote cardiac repair following myocardial infarction (MI). The aim of the present study is to test the hypothesis that injection of recombinant human interleukin (rhIL)-2 improves angiogenesis and preserves heart function after MI. A single IV injection of rhIL-2 two days following MI improved by 27.7% the left ventricular (LV) fractional shortening of immune competent (C57Bl6) mice, but had no effect on cardiac function of immune-deficient (NOD-SCID IL2Rγnull) mice. Immunohistochemical analysis of C57Bl6 cross sections of heart revealed that collagen deposition was reduced by 23.1% and that capillary density was enhanced in the scar area and the border zone of the infarct respectively by 22.4% and 33.6% following rhIL-2 injection. In addition, rhIL-2 enhanced 1.6-fold the in vivo endothelial cell proliferation index and 1.8-fold the number of NK cell infiltrating the infarcted heart, but had no effect on the number of cardiac CD4 and CD8 cells. In vitro, rhIL-2 activated NK cells enhanced cardiac endothelial cell proliferation by 17.2%. Here we show that a single IV injection of rhIL-2 positively impacted cardiac function by improving angiogenesis through a process involving NK cells.

A novel and simplified method of culture of human blood-derived early endothelial progenitor cells for the treatment of ischemic vascular disease.

Endothelial progenitor cells (EPCs) consist of two different subpopulations named early (eEPCs) and late EPCs (lEPCs) that are derived from CD14(+) and CD14(-) circulating cells, respectively. These cells are regularly cultured over fibronectin-coated surfaces in endothelial basal medium (EBM)-2 supplemented with insulin-like growth factor (IGF-1), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF). We have developed a new and simplified method for culturing human EPCs obtained from peripheral blood and tested their ability to preserve cardiac function following infarction. We first demonstrated that eEPCs derived from human peripheral blood mononuclear cells (PBMCs) and cultured in EBM-2 medium supplemented with autologous serum (10%) over fibronectin-coated surfaces (10 µg/ml) in the presence of IGF-1 (50 ng/ml) only, have a secretome similar to eEPCs cultured under regular conditions with IGF-1, VEGF, EGF, and FGF. Our data also indicate that IGF-1 modulates PBMC secretome in a dose-dependent manner. In another series of experiments, we showed that PBMCs cultured in suspension in bags (S-PBMCs) in basal medium supplemented with fibronectin and IGF-1 secrete significant amounts of stem cell factor (SCF, 31.3 ± 3.1 pg/ml)), hepatocyte growth factor (HGF, 438.6 ± 41.4 pg/ml), soluble tumor necrosis factor receptor 1 (sTNFR1, 127.1 ± 9.9 pg/ml), VEGF (139.3 ± 9.6 pg/ml), and IGF-1 (147.2 ± 46.1 pg/ml) but very low levels of TNF-α (13.4 ± 2.5 pg/ml). S-PBMCs injected intravenously into NOD SCID mice migrated to the injured myocardium, reduced cardiac fibrosis, enhanced angiogenesis, and preserved cardiac function after myocardial infarction (MI) in a manner similar to eEPCs cultured under standard conditions. In conclusion, we show in this study a refined and optimized method for culturing eEPCs. Our data indicate that S-PBMCs are composed of several cell populations including eEPCs and that they secrete high amounts of antiapoptotic, anti-inflammatory, and proangiogenic factors capable of preserving cardiac function following MI.

Monocyte derivatives promote angiogenesis and myocyte survival in a model of myocardial infarction.

In this study, we have investigated the hypothesis that previously reported beneficial effect of peripheral blood mononuclear cells cultured under angiogenic conditions on cardiovascular function following ischemia is not limited to EPCs but also to monocytes contained therein. We first purified and analyzed the phenotype and secretome of human and murine blood monocytes cultured under angiogenic conditions (named MDs for monocyte derivatives) and tested their effect in a mouse model of myocardial infarction (MI). FACS analysis of MDs shows that these cells express mature endothelial cell markers and that their proliferative capacity is virtually absent, consistent with their end-differentiated monocytic ontogeny. MDs secreted significant levels of HGF, IGF-1, MCP-1, and sTNFR-1 relative to their monocyte precursors. MDs were unable to form vascular networks in vitro when cultured on matrix coated flasks. Treatment of murine HL-1 cardiomyocyte cell line with MD-conditioned medium reduced their death induced by TNF-alpha, staurosporine, and oxidative stress, and this effect was dependent upon MD-derived sTNFR-1, HGF, and IGF-1. We further demonstrate that MD secretome promoted endothelial cell proliferation and capacity to form vessels in vitro and this was dependent upon MD-derived MCP-1, HGF, and IGF-1. Echocardiography analysis showed that MD myocardial implantation improved left ventricle fractional shortening of mouse hearts following MI and was associated with reduced myocardial fibrosis and enhancement of angiogenesis. Transplanted MDs and their secretome participate in preserving functional myocardium after ischemic insult and attenuate pathological remodeling.

Health and nutritional promotion program for patients with dementia (NutriAlz Study): design and baseline data.

BACKGROUND: There is a lack of data on global weight loss prevention programs for patients with dementia or clear evidence about their impact on a functional level, caregiver burden or the use of healthcare and social resources. NutriAlz is a socio-educative and nutritional intervention program to prevent weight loss and loss of function in dementia patients. STUDY DESIGN AND METHODS: A cluster randomized multi-centre study, which will allow the comparison of a group benefiting from the intervention with a control group after a year of monitoring. Patients were recruited from 11 hospitals in the ambulatory diagnostic units and day care centres. The baseline interview include: sociodemographic and socioeconomic variables (age, gender, educational level, marital status); diagnostic, treatments, MMS, a list of comorbid conditions; activities of daily living (ADL, IADL), Zarit Scale, brief-NPI, Cornell scale and nutritional status as measured by the Mini Nutritional Assessment. All participants or their family signed the inform consent form. BASELINE CHARACTERISTICS: Total of 946 patients were included, with a mean (+/- SD) of 79 +/- 7.3 year of age; 68,1 % were women; 44,9% lives with their partner, only 3% lives alone; 79.8% had Alzheimer's dementia, 5.25 +/- 3.0 years since symptoms of dementia and 2.8 +/- 2.11 years since diagnosis. Mean MMSE score was 15.4 +/- 6.2; mean weight was 64.4 +/- 12.5 kg; mean BMI was 27.0 +/- 4.5 (with 3% below 19, 5% between 19-21, 10% between 21-23, and 82% above 23). Mean ADL without difficulties was 3.2 +/- 2.1; mean IADL without difficulties was 0.7 +/- 1.6; mean number of symptoms in the NPI was 4.4 +/- 2.59, with severity score of 7.9 +/- 5.9 and distress score of 11.3 +/- 9.0; mean Zarit scale was 27.4 +/- 15.5; mean MNA was 23.2 +/- 3.5 with 5 % as malnourished, 32 % at risk of malnutrition, and 63 % with adequate nutritional status.

Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways.

OBJECTIVE: Synergistic interactions between aldosterone (Aldo) and angiotensin II (Ang II) have been implicated in vascular inflammation, fibrosis, and remodeling. Molecular mechanisms underlying this are unclear. We tested the hypothesis that c-Src activation, through receptor tyrosine kinase transactivation, is critically involved in synergistic interactions between Aldo and Ang II and that it is upstream of promigratory signaling pathways in vascular smooth muscle cells (VSMCs). METHODS AND RESULTS: VSMCs from WKY rats were studied. At low concentrations (10(-10) mol/L) Aldo and Ang II alone did not influence c-Src activation, whereas in combination they rapidly increased phosphorylation (P<0.01), an effect blocked by eplerenone (Aldo receptor antagonist) and irbesartan (AT1R blocker). This synergism was attenuated by AG1478 and AG1296 (inhibitors of EGFR and PDGFR, respectively), but not by AG1024 (IGFR inhibitor). Aldo and Ang II costimulation induced c-Src-dependent activation of NAD(P)H oxidase and c-Src-independent activation of ERK1/2 (P<0.05), without effect on ERK5, p38MAPK, or JNK. Aldo/Ang II synergistically activated RhoA/Rho kinase and VSMC migration, effects blocked by PP2, apocynin, and fasudil, inhibitors of c-Src, NADPH oxidase, and Rho kinase, respectively. CONCLUSIONS: Aldo/Ang II synergistically activate c-Src, an immediate signaling response, through EGFR and PDGFR, but not IGFR transactivation. This is associated with activation of redox-regulated RhoA/Rho kinase, which controls VSMC migration. Although Aldo and Ang II interact to stimulate ERK1/2, such effects are c-Src-independent. These findings indicate differential signaling in Aldo-Ang II crosstalk and highlight the importance of c-Src in redox-sensitive RhoA, but not ERK1/2 signaling. Blockade of Aldo/Ang II may be therapeutically useful in vascular remodeling associated with abnormal VSMC migration.

[Chronic kidney disease and the cardiovascular system]. / Chronische Nierenerkrankungen und kardiovaskuläres System.

Depending on the reduction in glomerular filtration rate (GFR) as a measure of renal insufficiency and depending on their age, patients with chronic kidney disease have a 1.5 to 1,000-fold higher cardiovascular risk. Renal insufficiency is inherently an independent risk factor for cardiovascular events, which is likewise the case for patients also presenting with hypertension or diabetes mellitus. When cardiac insufficiency or coronary heart disease is already manifest, the GFR is the most important predictive factor for the patients' further survival. Proteinuria or albuminuria as signs of kidney disease are also important markers and correlate with the cardiovascular risk in the range of both macro- and microalbuminuria. Endothelial dysfunction, oxidative stress, dyslipidemia, and increased atherosclerosis are being discussed as pathophysiological mechanisms of elevated cardiovascular risk.

Achieving blood pressure goals globally: five core actions for health-care professionals. A worldwide call to action.

The prevalence of hypertension continues to rise across the world, and most patients who receive medical intervention are not adequately treated to goal. A Working Group including representatives of nine international health-care organizations was convened to review the barriers to more effective blood pressure control and propose actions to address them. The group concluded that tackling the global challenge of hypertension will require partnerships among multiple constituencies, including patients, health-care professionals, industry, media, health-care educators, health planners and governments. Additionally, health-care professionals will need to act locally with renewed impetus to improve blood pressure goal rates. The Working Group identified five core actions, which should be rigorously implemented by practitioners and targeted by health systems throughout the world: (1) detect and prevent high blood pressure; (2) assess total cardiovascular risk; (3) form an active partnership with the patient; (4) treat hypertension to goal and (5) create a supportive environment. These actions should be pursued with vigour in accordance with current clinical guidelines, with the details of implementation adapted to the economic and cultural setting.

Systemic inflammatory markers in older persons: the effect of oral nutritional supplementation with prebiotics.

OBJECTIVE: To evaluate the effect of oral nutritional supplementation with and without oligosaccharides on gut bacteriology, in particular the bifidogenic flora, and on immunology and inflammatory parameters in older persons at risk of malnutrition. DESIGN: Prospective, randomized, double-blind, controlled study. SETTING: Division of Geriatric Medicine, St. Louis University, Missouri, United States. PARTICIPANTS: Seventy-four community dwelling elderly and/or nursing home subjects (age superior 70 y; 84 +/- 7 years) either undernourished or at risk of undernutrition. INTERVENTION: Daily liquid supplements, with (1.3 g/250 ml) and without oligosaccharides (OS) for 12 weeks. MEASUREMENTS: Nutritional evaluation, serum immunoglobulins, lymphocyte subsets, various cytokines and the endotoxin soluble receptor CD14 (sCD14) in serum, and cytokines specific mRNA in peripheral blood mononuclear cells at baseline and 12 weeks, and fecal bacteriologicy. RESULTS: Specific mRNA extracted from blood leucocytes showed a different level of pro-inflammatory gene activation: TNF-alpha mRNA and IL-6 mRNA diminished in the OS group after 12 weeks, while no changes were detected in the control group (P=0.05 and P=0.04 respectively). Serum levels of sCD14, a product shed by activated macrophages, decreased only in the OS group without reaching statistical significance (P=0.08). No significant differences were detected in the fecal gut flora or in the nutritional parameters. CONCLUSIONS: This study shows that the administration of supplements in older persons at risk of malnutrition may benefit from the addition of prebiotics that can improve the low noise inflammatory process frequently observed in this population.

Endothelin-1, but not Ang II, activates MAP kinases through c-Src independent Ras-Raf dependent pathways in vascular smooth muscle cells.

OBJECTIVE: Endothelin-1 (ET-1) and angiotensin II (Ang II) activate common signaling pathways to promote changes in vascular reactivity, remodeling, inflammation, and oxidative stress. Here we sought to determine whether upstream regulators of mitogen-activated protein kinases (MAPKs) are differentially regulated by ET-1 and Ang II focusing on the role of c-Src and the small GTPase Ras. METHODS AND RESULTS: Mesenteric vascular smooth muscle cells (VSMCs) from mice with different disruption levels in the c-Src gene (c-Src(+/-) and c-Src(-/-)) and wild-type (c-Src(+/+)) were used. ET-1 and Ang II induced extracellular signal-regulated kinase (ERK) 1/2, SAPK/JNK, and p38MAPK phosphorylation in c-Src(+/+) VSMCs. In VSMCs from c-Src(+/-) and c-Src(-/-), Ang II effects were blunted, whereas c-Src deficiency had no effect in ET-1-induced MAPK activation. Ang II but not ET-1 induced c-Src phosphorylation in c-Src(+/+) VSMCs. Activation of c-Raf, an effector of Ras, was significantly increased by ET-1 and Ang II in c-Src(+/+) VSMCs. Ang II but not ET-1-mediated c-Raf phosphorylation was inhibited by c-Src deficiency. Knockdown of Ras by siRNA inhibited both ET-1 and Ang II-induced MAPK phosphorylation. CONCLUSIONS: Our data indicate differential regulation of MAPKs by distinct G protein-coupled receptors. Whereas Ang II has an obligatory need for c-Src, ET-1 mediates its actions through a c-Src-independent Ras-Raf-dependent pathway for MAPK activation. These findings suggest that Ang II and ET-1 can activate similar signaling pathways through unrelated mechanisms. MAP kinases are an important point of convergence for Ang II and ET-1.

Synergistic vascular protective effects of combined low doses of PPARalpha and PPARgamma activators in angiotensin II-induced hypertension in rats.

BACKGROUND AND PURPOSE: Protective cardiovascular effects of peroxisome proliferator activated receptor (PPAR)alpha and PPARgamma activators have been demonstrated. If used as vasoprotective agents in high risk vascular patients rather than for their metabolic benefits, these agents could be associated with unwanted side effects. As a proof of concept to support the use of combined low doses of PPARalpha and PPARgamma as vascular protective agents in high risk vascular patients, we tested the hypothesis that combined low doses of PPARalpha (fenofibrate) and PPARgamma (rosiglitazone) activators would provide vascular protective benefits similar to full individual doses of these PPAR agonists. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats infused with Ang II (120 ng kg(-1) min(-1)) were treated with rosiglitazone (1 or 2 mg kg(-1) day(-1)) alone or concomitantly with fenofibrate (30 mg kg(-1) day(-1)) for 7 days. Thereafter, vessels was assessed on a pressurized myograph, while NAD(P)H oxidase activity was determined by lucigenin chemiluminescence. Inflammation was evaluated using ELISA for NFkappaB and Western blotting for adhesion molecules. KEY RESULTS: Ang II-induced blood pressure increase, impaired acetylcholine-induced vasorelaxation, altered vascular structure, and enhanced vascular NAD(P)H oxidase activity and inflammation were significantly reduced by low dose rosiglitazone+fenofibrate. CONCLUSIONS AND IMPLICATIONS: Combined low doses of PPARalpha and PPARgamma activators attenuated development of hypertension, corrected vascular structural abnormalities, improved endothelial function, oxidative stress, and vascular inflammation. These agents used in low-dose combination have synergistic vascular protective effects. The clinical effects of combined low-dose PPARalpha and PPARgamma activators as vascular protective therapy, potentially with reduced side-effects and drug interactions, should be assessed.

Ontogeny of intestinal epithelium immune functions: developmental and environmental regulation.

Intestinal mucosa integrates primary digestive functions with immune functions such as pathogen surveillance, antigen transport and induction of mucosal immunity and tolerance. Intestinal adaptive immunity is elicited in organized mucosa-associated lymphoid tissue (O-MALT) that is composed of antigen-presenting cells and lymphocytes and achieved by effector cells widely distributed in mucosa (diffuse MALT or D-MALT). Interaction between the intestinal epithelium, the O-MALT and the diffuse MALT plays a critical role in establishing an adequate immune response. In regions associated to O-MALT, lympho-epithelial cross-talks lead to acquisition of a specific epithelial phenotype that contributes to O-MALT organization and functionality. Beyond the expression of several innate immune functions, the intestinal epithelium may directly take up and present antigens due to the expression of major histocompatibility complex (MHC) and MHC-related molecules. A complex genetic program that will be outlined in the present review controls the development of immune functions of the intestinal epithelium. The effect of environmental signals on the modulation of this ontogenetic program during development and neonatal life, from bioactive components of amniotic fluid to lactation and bacterial colonization, will be discussed.

Enterococcus faecium SF68 enhances the immune response to Giardia intestinalis in mice.

We studied the ability of the probiotic organism Enterococcus faecium SF68 to antagonize Giardia intestinalis infection in mice. Oral feeding of E. faecium strain SF68 starting 7 d before inoculation with Giardia trophozoites significantly increased the production of specific anti-Giardia intestinal IgA and blood IgG. This humoral response was mirrored at the cellular level by an increased percentage of CD4(+) T cells in the Peyer's patches and in the spleens of SF68-fed mice. The improvement of specific immune responses in probiotic-fed mice was associated with a diminution in the number of active trophozoites in the small intestine as well as decreased shedding of fecal Giardia antigens (GSA65 protein). The ability of SF68 to stimulate the immune system at both mucosal and systemic levels highlights mechanisms by which this probiotic might antagonize pathogens in vivo. Taken together, the data demonstrate the strong potential of strain SF68 to prevent protozoa from causing intestinal infections.

p47phox associates with the cytoskeleton through cortactin in human vascular smooth muscle cells: role in NAD(P)H oxidase regulation by angiotensin II.

OBJECTIVE: We tested the hypothesis that p47phox associates with the actin cytoskeleton, enabling site-directed activation of NAD(P)H oxidase, and assessed whether these actions influence reactive oxygen species (ROS) generation and signaling by angiotensin II (Ang II) in vascular smooth muscle cells (VSMCs) from human resistance and coronary arteries. METHODS AND RESULTS: Electroporation of anti-p47phox antibody into VSMCs abrogated Ang II-mediated O2 generation, establishing the requirement for p47phox in this response. Immunfluorescence confocal microscopy demonstrated a cytosolic distribution of p47phox in basal conditions. After Ang II stimulation, p47phox rearranged in a linear fashion, colocalizing with F-actin. Co-immunoprecipitation studies confirmed an association between p47phox and actin and demonstrated an interaction with the actin-binding protein cortactin. Cytoskeletal disruption with cytochalasin prevented p47phox:actin interaction and attenuated ROS formation and p38MAP kinase and Akt phosphorylation by Ang II. Intracellular ROS generation in response to LY83583 (O2 generator) or exogenous H2O2 and Ang II-induced ERK1/2 activation were unaltered by cytochalasin. CONCLUSIONS: The p47phox:actin interaction, through cortactin, plays an important role in Ang II-mediated site-directed assembly of functionally active NAD(P)H oxidase, ROS generation, and activation of redox-sensitive p38MAP kinase and Akt, but not ERK1/2. These findings demonstrate the importance of an intact actin-cytoskeleton in NAD(P)H oxidase regulation and redox signaling by Ang II in human VSMCs.

Reactive oxygen species in vascular biology: implications in hypertension.

Reactive oxygen species (ROS), including superoxide (*O2-), hydrogen peroxide (H2O2), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO-), are biologically important O2 derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven *O2- production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.

The chronic colitis developed by HLA-B27 transgenic rats is associated with altered in vivo mucin synthesis.

HLA-B27 transgenic rats spontaneously developing a chronic inflammation mainly involving the colon are recognized as a powerful animal model for IBD. We investigated the mucin production in 6-month-old HLA-B27 rats by measuring in vivo fractional synthesis rate (FSR) and expression of mucins. In the inflamed colon of HLA-B27 rats, the mucin FSR was stimulated by 75% compared to F-344 controls, while MUC2,3 mRNA expression was unchanged. A local depletion in mucus-containing goblet cells was observed, suggesting a rapid mucin production/release and/or a real global decrease in goblet cell number. In the noninflamed jejunum of HLA-B27 rats, the mucin FSR was reduced by 35% compared to controls, while MUC2,3 mRNA expression was unchanged. Different alterations in mucin metabolism and expression are observed between HLA-B27 rats and a model of chemically induced chronic colitis (DSS-treated rats), suggesting that mucin alterations may be dependent on the animal model and colitis underlying mechanism.

Oligofructose does not affect the development of type 1 diabetes mellitus induced by dietary proteins in the diabetes-prone BB rat model.

BACKGROUND: Prevention of Type 1 diabetes mellitus (T1DM), a major childhood chronic disease with rapidly increasing incidence, is an urgent topic of research. We investigated whether 5% oligofructose (OF) as compared to 5% cellulose had a protective effect against diet-induced T1DM in the diabetes-prone BioBreeding (BB) rat model. METHODS: Groups of BB rats were fed the experimental diets from weaning. The diets were a cereal-based rodent diet (diabetogenic, positive control) and semi-synthetic rodent diets containing hydrolysed casein (non-diabetogenic, negative control), soy or whey as the sole protein source and 5% cellulose as fibre source. In additional groups fed soy and whey protein, the fibre source was 5% OF. T1DM incidence up to the age of 160 days was recorded applying biochemical and morphological criteria. Physiological effects of fibre were assessed through the analysis of biochemical parameters in plasma and of the protein/DNA ratio in intestinal mucosa. RESULTS: T1DM incidence was diet-dependent. Cereal-, soy- and whey-based diets were significantly more diabetogenic than the hydrolysed casein-based diet. Five per cent OF did not affect the incidence of T1DM induced by either soy or whey proteins as compared to cellulose, nor induce any of the biological effects attributed to a fermentable fibre. CONCLUSIONS: In the BB rat model, 5% OF in the diet did not have any protective effects against diet-induced T1DM. The present data do not suggest dietary OF as a promising approach for the dietary prevention of T1DM.