David A. Krusch

Synergies and Distinctions between Computational Disciplines in Biomedical Research: Perspective from the Clinical and Translational Science Award Programs

Clinical and translational research increasingly requires computation. Projects may involve multiple computationally oriented groups including information technology (IT) professionals, computer scientists, and biomedical informaticians. However, many biomedical researchers are not aware of the distinctions among these complementary groups, leading to confusion, delays, and suboptimal results. Although written from the perspective of Clinical and Translational Science Award (CTSA) programs within academic medical centers, this article addresses issues that extend beyond clinical and translational research. The authors describe the complementary but distinct roles of operational IT, research IT, computer science, and biomedical informatics using a clinical data warehouse as a running example. In general, IT professionals focus on technology. The authors distinguish between two types of IT groups within academic medical centers: central or administrative IT (supporting the administrative computing needs of large organizations) and research IT (supporting the computing needs of researchers). Computer scientists focus on general issues of computation such as designing faster computers or more efficient algorithms, rather than specific applications. In contrast, informaticians are concerned with data, information, and knowledge. Biomedical informaticians draw on a variety of tools, including but not limited to computers, to solve information problems in health care and biomedicine. The paper concludes with recommendations regarding administrative structures that can help to maximize the benefit of computation to biomedical research within academic health centers.

Effect of Endogenous Insulin on Pancreatic Exocrine Secretion in Perfused Dog Pancreas

Canine pancreas was perfused with an intraar-terial infusion of Krebs-Ringer bicarbonate solution containing 5% dog red blood cells, 0.1% bovine serum albumin, and 3% dextran at 15 ml/min, while portal effluent was continuously collected. Pancreatic juice was obtained in 15-min samples via main pancreatic duct cannulation. After a 1-h basal period, secretin and cholecys-tokinin-8 (CCK), at doses of 2.5 ng. min−1 each, were simultaneously infused for 10 min, with background infusion of a normal rabbit serum (NRS) or an antiinsulin serum (Anti-I) in 5 ml each via a sidearm of the intraar-terial catheter. The infusion of secretin and CCK resulted in a significant increase in pancreatic bicarbonate and protein secretion during the infusion of NRS, whereas the pancreatic secretory response of bicarbonate and protein was profoundly suppressed by the infusion of Anti-I in six pancreata so studied. This suppression by Anti-I coincided with significant increases in somatostatin and pancreatic polypeptide levels in portal venous effluent. In three additional pancreata, simultaneous infusions of Anti-I with antisomatostatin (5 ml) and antipancreatic polypeptide (5 ml) serum failed to inhibit the pancreatic exocrine secretion. These results indicate that secretin-and CCK-stimulated pancreatic secretion of bicarbonate and protein depends heavily on local action of insulin. The suppression by Anti-I of pancreatic secretion is mediated, in part, by local releases of somatostatin and pancreatic polypeptide. Thus, the insuloacinar axis plays an important regulatory role in pancreatic exocrine secretion in the dog, and it involves at least three islet hormones including insulin, somatostatin, and pancreatic polypeptide.

Evaluation of insulin secretion after pancreas autotransplantation by oral or intravenous glucose challenge

Segmental pancreatic autotransplantation is accompanied by surgical alterations to the pancreas that may have consequences for carbohydrate metabolism. Four mongrel dogs were evaluated before operation and sequentially until 40 weeks after total pancreatectomy and autotransplantation of the splenic lobe of the pancreas with bolus intravenous and oral administration. Intravenous glucose tolerance test (IVGTT) (0.5 g/kg) revealed maintenance of fasting euglycemia for as long as 40 weeks after operation. Peak glucose and integrated glucose values did not show significant changes as a result of autotransplantation. Following transplantation, a delayed peak insulin response was seen; however, basal, peak, and integrated insulin values were largely unaltered. Only K values, a measure of glucose disposal, showed severe alterations (2.44 +/- 0.21 before operation to 1.24 +/- 0.30 at 40 weeks after operation). Oral glucose tolerance tests (OGTT) (2.0 g/kg) demonstrated an increased peak hyperglycemic response after autotransplantation with increased integrated glucose responses. Insulin levels remained at those levels seen before operation, and glucose-dependent insulinotropic polypeptide (GIP) responses were unchanged during the OGTT as late as 20 weeks after operation. In conclusion, pancreas autotransplantation after total pancreatectomy results in significant metabolic alterations that the IVGTT fails to detect with absolute glucose or insulin levels. However, K values are significantly lowered, which indicates alterations in cellular glucose transport. The OGTT demonstrates hyperglycemia without increased insulin or GIP levels, which suggests an altered beta cell response to the enteric stimulus of insulin release. These changes are nonetheless well tolerated by animals that have remained clinically healthy and euglycemic in the basal state.

Experimental studies of biliary excretion of piperacillin.

The nonrecirculating isolated perfused rat liver was used to study biliary antibiotic excretion by the liver in a steady-state, controlled environment in which bile flow, bile salt output, and antibiotic delivery were maintained under constant conditions. The effects of piperacillin, ampicillin, and gentamicin on bile flow and bile salt output were analyzed; none altered bile salt output, and only high concentrations of piperacillin (100 μg/mL) increased bile flow. The ratio of antibiotic concentration in bile and perfusate depended on the type of antibiotic and perfusate concentration. Piperacillin infusions at perfusate concentrations of SO or 100 μg/mL (in the presence of 60 μM taurocholate) yielded bile to perfusate ratios of 112 ± 10 versus 49 ± 3, respectively. Using similar perfusate, the concentration ratios for ampicillin (20 Mg/mL) and gentamicin (10 fig/mL) were only 3.4 ± 0.5 and 0.5 ± 0.1, respectively. By altering the perfusate to contain either 60 MM or 240 μM taurocholate, we found variance in bile salt output from 27 ±1 to 115 ± 2μmol/h, yet this alteration had little effect on the output of ampicillin (perfusate concentration of 20 μg/mL), 73 ± 7 versus 74 ± 12 μg/h, or piperacillin (perfusate concentration 100 μg/mL), 10 ± 1 versus 11 ± 2 mg/h. Thus, it appears ampicillin and piperacillin are excreted into bile at high concentrations by bile salt-independent pathways. Partial biliary obstruction (6 cm H2O) results in significant decreases in bile volume. Infusion of 50 μg/mL of piperacillin resulted in increased biliary flow that approached non- obstructed values. Obstruction resulted in significant decreases in bile piperacillin concentration. Whether the choleretic effect of high concentrations of piperacillin has any clinical significance in nonobstructed or obstructed conditions remains to be established.

Hepatic insulin extraction after major hepatectomy

BACKGROUND After major hepatectomy, the remaining liver compensates for its reduced mass and maintains euglycemia through increased hepatic glucose output. The mechanism of this compensation may be a diminished hepatic extraction of portal insulin, which thereby decreases the suppressive effects of insulin on gluconeogenesis. METHODS Extraction of insulin by the liver was measured using the isolated perfused rat liver model. Fasted Sprague-Dawley rats were studied at 1, 2, 3, 4, 6, and 14 days after 70% hepatectomy. Control rats had no operation, and sham rats were studied 1 day after a sham laparotomy. The difference between portal and caval insulin concentrations was determined and reported as micromoles of insulin extracted per gram liver per minute. RESULTS Insulin extraction decreased from 191 +/- 22 microU/gm liver/min in control rats to 87 +/- 13.2 microU/gm liver/min at postoperative day 1 (p = 0.0001). Extraction normalized by postoperative day 6. Extraction rates in rats recovering from sham laparotomy were similar to control rats (p = 0.088), suggesting that decreased extraction in hepatectomized rats was not due to postoperative stress. CONCLUSIONS After 70% hepatectomy, the remaining liver extracts less insulin per gram. This may explain the ability of the reduced liver mass to maintain euglycemia after major hepatectomy.

Surgical alterations of the pancreas and insulin-independent glucose disposal☆

Systemic drainage of pancreatic venous effluent and denervation of the pancreas that follows pancreatic transplantation has been shown to alter postoperative glucose disposal despite elevated levels of peripheral insulin in response to a glucose challenge. Since an appreciable fraction of postprandial glucose disposal takes place in the absence of insulin (insulin-independent glucose disposal--IIGD), we have investigated potential changes in this aspect of carbohydrate metabolism before and after bladder-drained pancreatic auto-transplantation (PAT/B) as well as partial pancreatectomy (PPx). The hyperglycemic clamp protocol with a background infusion of somatostatin was performed on control (PREOP) dogs as well as PAT/B and PPx animals. The rate of glucose disposal (M Value) during the period of hypoinsulinemia induced by Somatostatin (SST) was measured and reported. Whereas glucose disposal during steady state hyperglycemia was significantly diminished for both PPx and PAT/B in the absence of SST, IIGD was unaltered across all three groups studied. We therefore conclude that surgical alteration of the pancreas results in abnormal glucose disposal during steady state hyperglycemia despite apparently normal to supranormal levels of peripheral insulin, and that alterations in IIGD are not responsible for these differences.

Effect of verapamil on insulin-stimulated choleresis

Insulin is one of several neurohumoral substances known to have a choleretic effect in vivo and in the isolated perfused rat liver. Infusion of insulin in the perfused rat liver preparation results in stimulation of bile acid-independent bile flow evidenced by increased bile flow, decreased bile acid concentration, and stable bile acid output. The mechanism of insulin-stimulated choleresis is unknown but may involve calcium as an intracellular second messenger. The present studies were performed to assess the role of membrane calcium channels in mediating choleresis and insulin-stimulated bile acid-independent bile flow in the in situ perfused rat liver. We have shown that verapamil, a specific calcium channel blocker, has no effect on bile flow, bile acid concentration, or bile acid output during bile acid-stimulated choleresis at a taurocholate infusion rate of 40 or 80 nmole/g liver/min. Insulin caused a significant increase in bile flow (18-30%) and a decrease in bile acid concentration (13-21%) without affecting bile acid output at a taurocholate infusion rate of 40 or 80 nmole/g liver/min. Verapamil failed to inhibit insulin-stimulated choleresis at a taurocholate infusion rate of 80 nmole/g liver/min. Although we observed an insulin-stimulated increase in bile flow and a decrease in bile acid concentration in the presence of verapamil at a taurocholate infusion rate of 40 nmole/g liver/min, these changes failed to reach statistical significance. We conclude that verapamil has no effect on choleresis or insulin-stimulated bile flow in the perfused rat liver and that the mechanism by which insulin promotes bile acid-independent bile flow is not mediated by verapamil-sensitive calcium channels.

Effect of glipizide on the surgically altered pancreas

Surgical alterations of the pancreas affect peripheral glucose, insulin, and glucagon levels with accompanying changes in carbohydrate metabolism. The sulfonylurea glipizide has been used to treat insulin-deficient states; however, its mechanism is not completely known. We hypothesized that glipizide would correct postoperative changes in glucose handling in a way that would allow more complete understanding of the drugs action. Two surgical groups (Group 1:80 percent proximal pancreatectomy; Group 2: proximal pancreatectomy plus splenocaval diversion) were compared with a healthy control group (Group 3). We have concluded that glipizide may have affected basal insulin sensitivity in the control group and Group 2 animals without affecting insulin secretion in response to oral or intravenous glucose stimulation. Glipizide does not correct the alterations in glucose handling or insulin secretion after reduction in beta-cell mass.