Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium-induced colitis in rats

We have evaluated morphologic alterations and epithelial cell apoptosis and proliferation of colonic mucosa in the acute and chronic phases of DSS-induced colitis. Colitis was induced in Sprague-Dawley rats by 7 days of 4% DSS oral administration followed by 7 days of tap water for one, two, and three cycles. Control rats receved tap water only. Morphological changes in colonic mucosa were evaluated and scored by light and scanning electron microscopy. Apoptosis was studied by TUNEL assay and cell proliferation by Ki-67 immunoreaction. The expression of both proapoptotic (Fas, FasL, Bax, p53) and antiapoptotic (Bcl2) cellular proteins was determined by immunohistochemistry. Morphologic assessment showed the most severe colonic epithelial lesions and inflammation in the distal colon with a trend to increasing severity from the first to the third DSS cycle. In DSS rats, the epithelial apoptotic index increased 20-fold after the first cycle and 120-fold after the second and third cycles compared with the controls; in the same way, the expression index of proapoptotic proteins (Fas, FasL, Bax, p53) dramatically increased. The proliferative index increased about 40 to 60-fold compared to controls, with no difference among the three DSS cycles. In conclusion, DSS-induced colitis in rats, which has many structural and ultrastructural features similar to those seen in human ulcerative colitis, is a suitable model for studying increased epithelial apoptosis and proliferation. Further studies employing this model will permitt two hypotheses to be tested. (1) Increased apoptosis may lead to a breakdown of the epithelial barrier function and facilitate the mucosal invasion of intraluminal microorganisms and/or antigens. (2) Abnormal and persistent epithelial hyperproliferation could be causally related to the development of colorectal cancers in the setting of chronic colonic inflammation.     

Relationship of exercise volume to improvements of quality of life with supervised exercise training in patients with type 2 diabetes in a randomised controlled trial: the Italian Diabetes and Exercise Study (IDES)

Aims/hypothesis

A positive impact of exercise intervention programmes on quality of life (QoL) may be important for long-term patient compliance to exercise recommendations. We have previously shown that QoL improves significantly with supervised exercise, whereas it worsens with counselling alone, in patients with type 2 diabetes from the Italian Diabetes and Exercise Study (IDES). Here, we report data on the relationship between changes in QoL and volume of physical activity/exercise in these individuals.

Methods

This multicentre parallel randomised controlled, open-label, trial enrolled sedentary patients with type 2 diabetes (n?=?606 of 691 eligible) in 22 outpatient diabetes clinics. Patients were randomised by centre, age and diabetes treatment using a permuted-block design to twice-a-week supervised aerobic and resistance training plus exercise counselling (exercise group) versus counselling alone (control group) for 12?months. Health-related QoL was assessed by the 36-Item Short Form (SF-36) Health Survey.

Results

In the exercise group (n?=?268 of 303 randomised), there was a trend for increasing QoL with increasing exercise volume, with significant improvement of the physical component summary (PCS) measure only above 17.5 metabolic equivalents h^?1?week^?1 and a clear volume-relationship for the mental component summary (MCS) measure. A relationship with volume of physical activity also was observed in the control group (n?=?260 of 303 randomised), despite overall deterioration of all scores. Independent correlates of improvements in both PCS and MCS were exercise volume, study arm and, inversely, baseline score.

Conclusions/interpretation

This large trial shows a relationship between changes in physical and mental health-related QoL measures and volume of physical activity/exercise, with supervised exercise training also providing volume-independent benefits.

Trial registration:

ISRCTN-04252749

Funding:

The study was funded by Lifescan SrL, Novo Nordisk Ltd, Bristol Myers Squibb Italy, Technogym SpA and Cosmed SrL.     

Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.