Prolonged allogeneic islet graft survival by protoporphyrins

Transplantation of islets of Langerhans in patients with type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein heme-oxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrin-treated animals.     

Control of lead and trail limbs during obstacle crossing following stroke

BACKGROUND AND PURPOSE: Obstacle crossing is compromised following stroke. The purpose of this study was to quantify modifications during obstacle clearance following stroke. SUBJECTS: Twelve subjects with stroke and 12 subjects without stroke participated in the study. METHODS: Kinematic variables were measured while participants crossed a 4-cm-high obstacle. Subjects with stroke walked at a self-selected speed; subjects without stroke walked at a comparable speed and at a self-selected speed. RESULTS: Several modifications were observed following stroke with both groups walking at self-selected speeds. The affected lead limb was positioned closer to the obstacle before crossing. Affected trail-limb clearance over the obstacle was reduced. Both affected and unaffected lead and trail limbs landed closer to the obstacle after clearance. Swing time was increased in the affected lead limb after obstacle clearance. Fewer modifications were detected at matched walking speed; the trail limb still landed closer to the obstacle. DISCUSSION AND CONCLUSION: Modifications during obstacle crossing following stroke may be partly related to walking speed. The findings raise issues of safety because people with stroke demonstrated reduced clearance of a 4-cm obstacle and limb placement closer to the obstacle after clearance.     

Use of shopping centres in screening for hypertension

In two Edmonton shopping centres 9591 people were screened for hypertension: 3.3% were found to be normotensive but taking antihypertensive medication and another 8.8% were found to have elevated blood pressure. Systolic hypertension alone accounted for 45.3% of the hypertensive cases and diastolic hypertension, with or without systolic, for 54%. Of the group with elevated blood pressure 34.5% had been previously unaware of their condition, 18.7% had never received medication for it, 18.2% had received medication in the past but had discontinued it, 26.1% were still on medication and 2.5% were not taking antihypertensive medication and were uncertain if they had ever done so in the past. Eighty-eight percent of the hypertensives who were receiving no medication went to their physician; 41% were prescribed antihypertensive medication, and 87% were still on treatment three months later and 74% one year after detection. Eighteen percent of those started on treatment had their medication discontinued by their doctor over the next year and 8% stopped treatment on their own. Of those hypertensives already receiving medication 88% went to their doctor and 33% had their medication altered.

Physician measurements of blood pressure tended to be lower than those recorded at the screening. At least part of the explanation for this discrepancy is that physicians often used blood pressure cuffs that were too wide for the patient's arm; 25% of the people screened required cuffs narrower than the standard cuff used by most physicians.

The prevalence of hypertension was similar among women taking oral contraceptives and women not taking these agents.

     

Dexamethasone inhibits maturation and alters function of monocyte-derived dendritic cells from cord blood

Critically ill infants are treated with dexamethasone (Dx) and other glucocorticoids to reduce inflammation and to promote lung and cardiac function. The neonatal immune system is immature, so neonatal dendritic cells (DCs) might be especially sensitive to glucocorticoid-mediated immunosuppression. To test this, we compared Dx treatment of monocyte-derived DCs from cord (CB) and adult blood (AB). Dx decreased CD1a levels on both AB and CB DCs. CB-treated cells also exhibited decreased expression of CD83 and increased expression of CD14, alterations not observed in AB DCs. Characteristic immature endocytic activity was sustained and enhanced in Dx-treated CB DCs, whereas AB DCs matured normally. Maintenance of endocytosis corresponded with CD14 expression. Dx markedly increased CB DC IL-10, a T cell helper 2 (Th2)-preferential cytokine, while reducing IL-12, a counterbalancing Th1 cytokine. AB DCs were also affected, but increases in IL-10 and decreases in IL-12 were more modest. Dx treatment also inhibited DC-induced T cell proliferation, but CB DCs were inhibited more. In short, neonatal DCs seemed to be especially sensitive to the immunosuppressive effects of Dx as indicated by altered phenotype, endocytic function, ability to stimulate T cells, and cytokine shift favoring Th2. These alterations in DC function are consistent with an increased risk for certain infections and atopic diseases.