The cardiac conduction system is a network of cells responsible for the rhythmic and coordinated excitation of the heart. Components of the murine conduction system, including the peripheral Purkinje fibers, are morphologically indistinguishable from surrounding cardiomyocytes, and a paucity of molecular markers exists to identify these cells. The murine conduction system develops in close association with the endocardium. Using the recently identified CCS-lacZ line of reporter mice, in which lacZ expression delineates the embryonic and fully mature conduction system, we tested the ability of several endocardial-derived paracrine factors to convert contractile cardiomyocytes into conduction-system cells as measured by ectopic reporter gene expression in the heart. In this report we show that neuregulin-1, a growth and differentiation factor essential for ventricular trabeculation, is sufficient to induce ectopic expression of the lacZ conduction marker. This inductive effect of neuregulin-1 was restricted to a window of sensitivity between 8.5 and 10.5 days postcoitum. Using the whole mouse embryo culture system, neuregulin-1 was shown to regulate lacZ expression within the embryonic heart, whereas its expression in other tissues remained unaffected. We describe the electrical activation pattern of the 9.5-days postcoitum embryonic mouse heart and show that treatment with neuregulin-1 results in electrophysiological changes in the activation pattern consistent with a recruitment of cells to the conduction system. This study supports the hypothesis that endocardial-derived neuregulins may be the major endogenous ligands responsible for inducing murine embryonic cardiomyocytes to differentiate into cells of the conduction system.

OBJECTIVERenal insufficiency may increase the risk of hypoglycemia in hospitalized patients with diabetes who are treated with insulin. We randomized inpatients with type 2 diabetes and chronic renal failure to treatment with two different dose levels of insulin glargine and glulisine and studied control of hyperglycemia and the frequency of hypoglycemia.RESEARCH DESIGN AND METHODSWe conducted a multicenter, prospective, randomized trial to compare the efficacy of once-daily glargine and three-times daily glulisine at 0.5 vs. 0.25 units/kg/day. A total of 107 subjects had type 2 diabetes for >1 year, had a glomerular filtration rate <45 mL/min but did not require dialysis, and had an initial blood glucose (BG) >180 mg/dL. Doses were adjusted based on four-times daily BG measurements for 6 days.RESULTSMean BG on the first day was 196 ± 71 mg/dL in the group receiving 0.5 units/kg (0.5 group) and 197 ± 55 mg/dL in the group receiving 0.25 units/kg (0.25 group; P = 0.94). On days 2 to 6, mean BG was 174 ± 52 mg/dL in the 0.5 group and 174 ± 46 mg/dL in the 0.25 group (P = 0.96). There were no significant differences between groups in the percentage of BG values within the target range of 100 to 180 mg/dL on any of the 6 study days. In the 0.5 group, 30% experienced hypoglycemia (BG <70 mg/dL) compared with 15.8% of the 0.25 group (P = 0.08).CONCLUSIONSReduction of initial glargine/glulisine insulin weight-based dosing in hospitalized patients with diabetes and renal insufficiency reduced the frequency of hypoglycemia by 50% without compromising the control of hyperglycemia.

Injury and stress are accompanied by a characteristic hormonal response and altered energy utilisation. Hyperglycaemia and negative nitrogen (N) balance are the leading symptoms of the metabolic changes in the post-operative state. In a prospective, randomised study the efficacy and metabolic effects of glucose-xylitol (GX) 35% (1:1) versus glucose (G) 40% were investigated in patients undergoing major surgery. METHOD. Twenty-four patients undergoing abdomino-thoracic oesophageal cancer surgery were treated in a standardised manner. Total parenteral nutrition was administered over 6 days (kg body wt.-1/day): day of surgery 1-1.25 g carbohydrate (CH); 1st postoperative day (POD) 1.5 g CH, 1 g amino acids (AA); 2nd POD 3 g CH, 1.5 g AA, 1.0 g fat; from 3rd POD 3 g CH, 1.5 g AA, 1.5 g fat (CH GX35% (n = 12) or G40% (n = 12), AA Intrafusin 15%, fat Intralipid 20%). Daily and cumulative N balances, blood-G profiles, blood chemistry, and physical parameters were determined. Glucagon and insulin profiles, CH losses, and oxalic acid secretion were measured. RESULTS. Both groups were comparable for age, body mass index, clinical and physical parameters, and blood chemistry. Mean cumulative N balances after 6 days were -12.0 +/- 16.3 g N for GX35% and -5.6 +/- 19.4 g N for G40% (n.s.; Wilcoxon, P < 0.05). Blood G was similar for both groups with values ranging from 130 to 240 mg/dl on the day of surgery and below 150 mg/dl on the consecutive days. In each group 1 patient needed additional insulin therapy. Glucagon and insulin levels did not show a significant difference between the groups. CONCLUSION. No difference in tolerance and efficacy of nutritional support by GX versus G at a dose of 3 g.kg body wt.-1.d in oesophagectomised patients could be observed. Similar blood G profiles were in accordance with comparable glucagon and insulin levels. Because of the high standard deviations of N balances, differences in efficacy could not be proven. A significantly lower level of pseudocholinesterase (PCHE) for G40% on day 7 might indicate enhanced hepatic protein synthesis in the GX group.