Islet neogenesis: a potential therapeutic tool in type 1 diabetes.

Current therapies for type 1 diabetes, including fastidious blood glucose monitoring and multiple daily insulin injections, are not sufficient to prevent complications of the disease. Though pancreas and possibly islet transplantation can prevent the progression of complications, the scarcity of donor organs limits widespread application of these approaches. Understanding the mechanisms of beta-cell mass expansion as well as the means to exploit these pathways has enabled researchers to develop new strategies to expand and maintain islet cell mass. Potential new therapeutic avenues include ex vivo islet expansion and improved viability of islets prior to implantation, as well as the endogenous expansion of beta-cell mass within the diabetic patient. Islet neogenesis, through stem cell activation and/or transdifferentiation of mature fully differentiated cells, has been proposed as a means of beta-cell mass expansion. Finally, any successful new therapy for type 1 diabetes via beta-cell mass expansion will require prevention of beta-cell death and maintenance of long-term endocrine function.

Low postoperative hematocrit increases cerebrovascular damage after hypothermic circulatory arrest.

OBJECTIVE: The objective of this study was to evaluate the systemic and cerebral effects of different postoperative hematocrit management following cardiopulmonary bypass and deep hypothermic circulatory arrest. DESIGN: Animal case study. SETTING: Laboratory. SUBJECTS: Four-week-old Yorkshire piglets. INTERVENTIONS: Twelve piglets were subjected to cardiopulmonary bypass (hematocrit = 25%) and 100 mins of deep hypothermic circulatory arrest (15 degrees C). After weaning cardiopulmonary bypass, they were randomized to either group L or H, in which the postoperative hematocrit was maintained approximately 20% vs. approximately 30%, respectively, and survived for 6 hrs. MEASUREMENTS AND MAIN RESULTS: Changes in body weight, bioimpedance, and colloid oncotic pressure were assessed. Near-infrared spectroscopy and immunohistochemical assays for cerebral transforming growth factor-beta(1) and caspase-3 were performed. Postoperative weight gain (kg) and decreases in bioimpedance (ohms) were significantly less in group H (1.5 +/- 0.2 [H] vs. 2.4 +/- 0.6 [L], p = .01; 39.3 +/- 15.5 [H] vs. 89.1 +/- 29.6 [L], p = .01). Mean colloid oncotic pressure (mm Hg) was significantly higher in group H (10.8 +/- 1.6 [H] vs. 8.2 +/- 0.8 [L], p = .01) at 6 hrs postoperatively. Oxyhemoglobin, oxidized cytochrome aa(3) (muM x differential path-length factor), and tissue oxygenation index (%) were significantly better in group H (65.7 +/- 31.8 [H] vs. -104.7 +/- 55.2 [L], p = .0001; 0.52 +/- 4.1 [H] vs. -12.8 +/- 6.1 [L], p = .0001, and 55.7 +/- 4.6% [H] vs. 45.3 +/- 6.4% [L], p = .004, respectively). Cerebral transforming growth factor-beta(1) and caspase-3 scores were significantly better in group H (3.0 +/- 0.6 [H] vs. 1.9 +/- 0.9 [L], p = .04 and 1.8 +/- 0.5 [H] vs. 3.2 +/- 0.8 [L], p = .02, respectively). Mean arterial pressure (mm Hg) was consistently higher with group H (94.7 +/- 13.0 [H] vs. 78.3 +/- 11.5 [L], p = .003) despite comparable central venous pressure ( approximately 11 mm Hg). CONCLUSIONS: Lower postoperative hematocrit was associated with increased fluid retention, lower perfusion pressure, and worse cerebrovascular injury following deep hypothermic circulatory arrest. Postoperative hematocrit management may have profound systemic and cerebral effects after deep hypothermic circulatory arrest and merits further investigation.

Timing of steroid treatment is important for cerebral protection during cardiopulmonary bypass and circulatory arrest: minimal protection of pump prime methylprednisolone.

OBJECTIVES: The contact of cardiopulmonary bypass surface and patient's blood activates systemic inflammatory response which aggravates ischemia-reperfusion injury. This study evaluates the effects of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on cerebral protection using different steroid administration protocols. METHODS: Eighteen (n=6/group) 4 week-old piglets were divided in three groups. Methylprednisolone (30 mg/kg) was administered intravenously 4 h prior to CPB in Group I, or added in pump prime in group II. Group III received no steroid. All animals were cooled to 15 degrees C followed by 100 min of DHCA, then rewarmed over 40 min and sacrificed 6 h after CPB. Post-operative weight gain, bioelectrical impedance, colloid oncotic pressure (COP) and interleukin-6 (IL-6) were evaluated. Determination of cerebral trypan blue and immunohistochemical assays of transforming growth factor (TGF)-beta1 and caspase-3 activities were performed. RESULTS: Post-operative % weight gain (13.0+/-3.8 (I) versus 26.4+/-9.9 (II) versus 22.6+/-6.4 (III), P=0.02); % bioimpedance reduction (14.5+/-8.0 (I) versus 38.3+/-13.3 (II) versus 30.5+/-8.0 (III), P=0.003); mean COP (mmHg) (14.9+/-1.8 (I) versus 10.9+/-2.0 (II) versus 6.5+/-1.8 (III), P=0.0001) and systemic IL-6 levels (pg/ml) (208.2+/-353.0 (I) versus 1562.1+/-1111.4 (II) versus 1712.3+/-533.2 (III), P=0.01) were significantly different between the groups. Spectrophotometric analysis of cerebral trypan blue (ng/g dry weight) was significantly different between the groups (0.0053+/-0.0010 (I) versus 0.0096+/-0.0026 (II) versus 0.0090+/-0.0019 (III), P=0.004). TGF-beta1 scores were 3.3+/-0.8 (I) versus 1.5+/-0.8 (II) versus 1.5+/-0.5 (III), P<0.05, groups I versus II and I versus III. Remarkable perivascular caspase-3 activity was observed in groups II and III. CONCLUSION: Different timing of steroid administration results in different inflammatory mediator response. Steroid in CPB prime is not significantly better than no steroid treatment, while systemic steroid pre-treatment significantly decreases systemic manifestation of inflammatory response and brain damage.