Systematic review and meta-analysis: Diagnostic performance of DNA alterations in pancreatic juice for the detection of pancreatic cancer.

BACKGROUND AND AIMS: Pancreatic cancer has a dismal prognosis. So far, imaging has been proven incapable of establishing an early enough diagnosis. Thus, biomarkers are urgently needed for early detection and improved survival. Our aim was to evaluate the pooled diagnostic performance of DNA alterations in pancreatic juice. METHODS: A systematic literature search was performed in EMBASE, MEDLINE Ovid, Cochrane CENTRAL and Web of Science for studies concerning the diagnostic performance of DNA alterations in pancreatic juice to differentiate patients with high-grade dysplasia or pancreatic cancer from controls. Study quality was assessed using QUADAS-2. The pooled prevalence, sensitivity, specificity and diagnostic odds ratio were calculated. RESULTS: Studies mostly concerned cell-free DNA mutations (32 studies: 939 cases, 1678 controls) and methylation patterns (14 studies: 579 cases, 467 controls). KRAS, TP53, CDKN2A, GNAS and SMAD4 mutations were evaluated most. Of these, TP53 had the highest diagnostic performance with a pooled sensitivity of 42% (95% CI: 31-54%), specificity of 98% (95%-CI: 92%-100%) and diagnostic odds ratio of 36 (95% CI: 9-133). Of DNA methylation patterns, hypermethylation of CDKN2A, NPTX2 and ppENK were studied most. Hypermethylation of NPTX2 performed best with a sensitivity of 39-70% and specificity of 94-100% for distinguishing pancreatic cancer from controls. CONCLUSIONS: This meta-analysis shows that, in pancreatic juice, the presence of distinct DNA mutations (TP53, SMAD4 or CDKN2A) and NPTX2 hypermethylation have a high specificity (close to 100%) for the presence of high-grade dysplasia or pancreatic cancer. However, the sensitivity of these DNA alterations is poor to moderate, yet may increase if they are combined in a panel.

Longitudinal changes of serum protein N-Glycan levels for earlier detection of pancreatic cancer in high-risk individuals.

BACKGROUND: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals. METHODS: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature. RESULTS: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%. CONCLUSION: Serum N-glycan monitoring may support early detection in a pancreas surveillance program.

The pursuit of stability in halide perovskites: the monovalent cation and the key for surface and bulk self-healing.

We find significant differences between degradation and healing at the surface or in the bulk for each of the different APbBr3 single crystals (A = CH3NH3+, methylammonium (MA); HC(NH2)2+, formamidinium (FA); and cesium, Cs+). Using 1- and 2-photon microscopy and photobleaching we conclude that kinetics dominate the surface and thermodynamics the bulk stability. Fluorescence-lifetime imaging microscopy, as well as results from several other methods, relate the (damaged) state of the halide perovskite (HaP) after photobleaching to its modified optical and electronic properties. The A cation type strongly influences both the kinetics and the thermodynamics of recovery and degradation: FA heals best the bulk material with faster self-healing; Cs+ protects the surface best, being the least volatile of the A cations and possibly through O-passivation; MA passivates defects via methylamine from photo-dissociation, which binds to Pb2+. DFT simulations provide insight into the passivating role of MA, and also indicate the importance of the Br3- defect as well as predicts its stability. The occurrence and rate of self-healing are suggested to explain the low effective defect density in the HaPs and through this, their excellent performance. These results rationalize the use of mixed A-cation materials for optimizing both solar cell stability and overall performance of HaP-based devices, and provide a basis for designing new HaP variants.

[Pancreatic cystic neoplasms: a clinical dilemma]. / Neoplastische cysten van het pancreas.

Pancreatic cystic neoplasms are increasingly detected in the general population. Although most of these lesions are benign, some are (pre)malignant and require follow-up or even surgical intervention. Three cases are presented and used to discuss the clinical implications of the renewed European Guideline on pancreatic cystic neoplasms in which relative and absolute indications for resection are proposed. In the first case, a pancreatic cystic lesion was found on abdominal ultrasound in a 77-year old female patient. After endoscopic ultrasound was performed, a serous cystic neoplasm was diagnosed without need for surveillance. In a 57-year old male, an abdominal MRI was performed to further assess an incidentally found pancreatic cystic lesion. Based on the MRI, a side-branch intraductal papillary mucinous neoplasm (SB-IPMN) was diagnosed and yearly surveillance was initiated. A 61-year old male underwent a laparoscopic distal pancreatectomy because of a mixed-type IPMN (MT-IPMN). The pathological results showed an IPMN with high-grade dysplasia.

Management of Intraductal Papillary Mucinous Neoplasms: Controversies in Guidelines and Future Perspectives.

PURPOSE OF REVIEW: Management of intraductal papillary mucinous neoplasm (IPMN) is currently based on consensus, in the absence of evidence-based guidelines. In recent years, several consensus guidelines have been published, with distinct management strategies. In this review, we will discuss these discrepancies, in order to guide treating physicians in clinical management. RECENT FINDINGS: The detection rate of pancreatic cysts has increased substantially with the expanded use of high-quality imaging techniques to up to 45%. Of these cysts, 24-82% are IPMNs, which harbour a malignant potential. Timely detection of high-risk lesions is therefore of great importance. Surgical management is based on the presence of clinical and morphological high-risk features, yet the majority of resected specimens appear to be low risk. International collaboration and incentive large-scale prospective registries of individuals undergoing cyst surveillance are needed to accumulate unbiased data and develop evidence-based guidelines. Additionally, development of non-invasive, accurate diagnostic tools (e.g. biomarkers) is needed to differentiate between neoplastic and non-neoplastic pancreatic cysts and detect malignant transformation at an early stage (i.e. high-grade dysplasia).

Gastrointestinal actions of glucagon-like peptide-1-based therapies: glycaemic control beyond the pancreas.

The gastrointestinal hormone glucagon-like peptide-1 (GLP-1) lowers postprandial glucose concentrations by regulating pancreatic islet-cell function, with stimulation of glucose-dependent insulin and suppression of glucagon secretion. In addition to endocrine pancreatic effects, mounting evidence suggests that several gastrointestinal actions of GLP-1 are at least as important for glucose-lowering. GLP-1 reduces gastric emptying rate and small bowel motility, thereby delaying glucose absorption and decreasing postprandial glucose excursions. Furthermore, it has been suggested that GLP-1 directly stimulates hepatic glucose uptake, and suppresses hepatic glucose production, thereby adding to reduction of fasting and postprandial glucose levels. GLP-1 receptor agonists, which mimic the effects of GLP-1, have been developed for the treatment of type 2 diabetes. Based on their pharmacokinetic profile, GLP-1 receptor agonists can be broadly categorized as short- or long-acting, with each having unique islet-cell and gastrointestinal effects that lower glucose levels. Short-acting agonists predominantly lower postprandial glucose excursions, by inhibiting gastric emptying and intestinal glucose uptake, with little effect on insulin secretion. By contrast, long-acting agonists mainly reduce fasting glucose levels, predominantly by increased insulin and reduced glucagon secretion, with potential additional direct inhibitory effects on hepatic glucose production. Understanding these pharmacokinetic and pharmacodynamic differences may allow personalized antihyperglycaemic therapy in type 2 diabetes. In addition, it may provide the rationale to explore treatment in patients with no or little residual ß-cell function.

Glucagon-like peptide-1 receptor agonist exenatide has no acute effect on MRI-measured exocrine pancreatic function in patients with type 2 diabetes: a randomized trial.

AIMS: To investigate the effect of infusion of the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide on exocrine pancreatic function. METHODS: This was a randomized, placebo-controlled, double-blind, crossover study in 12 male patients with type 2 diabetes, treated with oral glucose-lowering agents. On two separate occasions, exenatide or placebo (saline 0.9%) were administered intravenously, in randomized order. Exocrine pancreatic function was measured using secretin-enhanced magnetic resonance cholangiopancreatography. The primary outcome measure was defined as secretin-stimulated pancreatic excretion volume. Secondary outcome measures were maximum secretion speed and the time to reach this maximum. In addition, changes in pancreatic duct (PD) diameter were measured. RESULTS: Exenatide did not change secretin-stimulated pancreatic excretion volume, as compared with placebo (mean ± standard error of the mean 142.2 ± 15.6 ml vs 142.6 ± 8.5 ml, respectively; p = 0.590). Also, exenatide did not change the maximum secretion speed (33.1 ± 1.4 vs 36.9 ± 2.2; p = 0.221), nor the time to reach this maximum (both 4 min 30 s). No differences in PD diameter were observed between the two groups. CONCLUSIONS: Infusion of exenatide did not directly influence MRI-measured exocrine pancreatic excretion in patients with type 2 diabetes. Although long-term studies are warranted, these findings suggest that potential adverse pancreatic effects of GLP-1 receptor agonists are not mediated by changes in exocrine pancreatic secretion.

Prospective assessment of the influence of pancreatic cancer resection on exocrine pancreatic function.

BACKGROUND: Exocrine insufficiency frequently develops in patients with pancreatic cancer owing to tumour ingrowth and pancreatic duct obstruction. Surgery might restore this function by removing the primary disease and restoring duct patency, but it may also have the opposite effect, as a result of resection of functional parenchyma and anatomical changes. This study evaluated the course of pancreatic function, before and after pancreatic resection. METHODS: This prospective cohort study included patients with tumours in the pancreatic region requiring pancreatic resection in a tertiary referral centre between March 2010 and August 2012. Starting before surgery, exocrine function was determined monthly by measuring faecal elastase 1 levels (normal value over 0.200 µg per g faeces). Endocrine function, steatorrhoea-related symptoms and bodyweight were also evaluated before and after surgery. Subjects were followed from diagnosis until 6 months after surgery, or until death. RESULTS: Twenty-nine patients were included, 12 with pancreatic cancer, 14 with ampullary carcinoma and three with bile duct carcinoma (median tumour size 2.6 cm). Twenty-six patients underwent pancreaticoduodenectomy and three distal pancreatectomy. Thirteen patients had exocrine insufficiency at preoperative diagnosis. After a median follow-up of 6 months, this had increased to 24 patients. Diabetes was present in seven patients at diagnosis, and developed in one additional patient within 1 month after surgery. CONCLUSION: Most patients with tumours in the pancreatic region requiring pancreatic resection either had exocrine insufficiency at diagnosis or became exocrine-insufficient soon after surgical resection.

Surgical and endoscopic treatment of pain in chronic pancreatitis: a multidisciplinary update.

Chronic pancreatitis is an inflammatory disease of the pancreas with abdominal pain as the most prominent symptom. Adequate treatment of patients with chronic pancreatitis remains a major challenge, mainly because of the lack of evidence-based treatment protocols. The primary goal of treatment is to achieve long-term pain relief, control of the complications associated with the disease, and to restore the quality of life. Currently, a conservative step-up approach is often used for the treatment of pain; progression to severe and intractable pain is considered necessary before invasive treatment is considered. Recent studies, however, suggest that surgical intervention should not be considered only as last-resort treatment, since it can mitigate disease progression, achieve excellent pain control, and preserve pancreatic function. In this review, we present a state-of-the art overview of endoscopic and surgical treatment options for patients with painful chronic pancreatitis, and elaborate on the timing of surgery.

Benchmarking patient experiences in colonoscopy using the Global Rating Scale.

INTRODUCTION: The Global Rating Scale (GRS) is a quality assurance program that was developed in England to assess patient-centered care in endoscopy. The aim of the current study was to evaluate patient experiences of colonoscopy using the GRS in order to compare different departments and to provide benchmarks. The study also evaluated factors associated with patient satisfaction. METHODS: A GRS questionnaire was used both before and after the procedure in outpatients undergoing colonoscopy. The questionnaire assessed the processes associated with the colonoscopy, from making the appointment up until discharge. Mean values and ranges of 12 endoscopy departments were calculated together with P values in order to assess heterogeneity. RESULTS: In total, 1904 pre-procedure and 1532 (80 %) post-procedure questionnaires were returned from 12 endoscopy departments. The mean time patients had to wait for their procedure was 4.3 weeks (range 3.1 - 5.8 weeks), and 54 % (range 35 - 64 %; P < 0.001) reported being given a choice of appointment dates/times. Discomfort during colonoscopy was reported by 20 % (range 8 - 40 %; P < 0.001). Recovery room privacy was satisfactory for 76 % of patients (range 66 - 90 %; P < 0.05). The majority of patients reported being sufficiently informed about what to do in case of problems after discharge (79 %, range 43 - 98 %; P < 0.001), and 85 % of individuals stated that they would be willing to repeat the colonoscopy procedure (range 72 - 92 %; P < 0.001). Factors associated with a decreased willingness to return were the burdensome bowel preparation (odds ratio [OR] = 0.25; P < 0.001), "rushing staff" attitude (OR = 0.57; P < 0.05), low acceptance of the procedure (OR = 0.42; P < 0.01), and more discomfort than expected (OR = 0.54; P < 0.05). CONCLUSION: Overall patient experiences with colonoscopy were satisfactory, but they also showed considerable variation. This study shows that use of a GRS patient questionnaire is feasible in the Dutch endoscopy setting for the assessment of patient experience. The significant variability between endoscopy units can be used to benchmark services and enable shortcomings to be identified.

Porcine somatotropin alters insulin response in growing pigs by reducing insulin sensitivity rather than changing responsiveness.

Exogenous porcine somatotropin (pST) treatment consistently improves growth performance and reduces fat deposition in pigs, and it is hypothesized that one component of the mechanism is through altering the sensitivity and/or responsiveness to insulin. Therefore, a study was conducted to investigate the effect of pST treatment on whole-body glucose metabolism in response to varying doses of insulin. Eight barrows were surgically prepared with indwelling catheters and randomly assigned to one of two treatment groups (0 or 120 µg pST/kg BW · d) for 13 d. Whole-body glucose kinetics were measured during infusion of [6-(3)H]-glucose under basal conditions and during hyperinsulinemic-euglycemic clamps at various insulin infusion rates (7, 28, and 140, and 14, 70, and 280 ng insulin/kg BW · min) and alterations in the dose-response parameters were calculated with nonlinear regression. Treatment with pST increased basal plasma concentrations of glucose (36%; P = 0.005), insulin (276%; P = 0.001), and NEFAs (177%; P = 0.01) and decreased the rate of glucose disappearance (-59%; P = 0.001). The responsiveness (maximum response) for steady state glucose infusion rate to maintain glycemia was not altered by pST (112 vs 106 µmol/min · kg; P = 0.78), whereas the sensitivity (effective dose at 50% of maximum response) was increased almost 7-fold (1.3 vs 8.7 ng/mL; P = 0.027). Similar responses were observed for rate of glucose disappearance and insulin-dependent glucose utilization. Therefore, pST-induced insulin resistance with regard to whole-body glucose uptake is due to a reduced sensitivity to insulin, rather than a change in responsiveness.

Pancreatic enzyme replacement therapy in chronic pancreatitis.

Exocrine pancreatic insufficiency (EPI) is a serious condition which occurs in several diseases including chronic pancreatitis (CP), cystic fibrosis, pancreatic cancer, and as a result of pancreatic surgery. The lack or absence of pancreatic enzymes leads to an inadequate absorption of fat, proteins, and carbohydrates, causing steatorrhoea and creathorrhea which results in abdominal discomfort, weight loss, and nutritional deficiencies. To avoid malnutrition related morbidity and mortality, it is pivotal to commence pancreatic enzyme replacement therapy (PERT) as soon as EPI is diagnosed. Factors as early acidic inactivation of ingested enzymes, under dosage, and patient incompliance may prevent normalisation of nutrient absorption, in particular of fat digestion. This review focuses on the current status of how to diagnose and treat EPI.

Removable fully covered self-expandable metal stents in the treatment of common bile duct strictures due to chronic pancreatitis: a case series.

The aim of this study was to test the removability of fully covered self-expandable metal stents (FCSEMS) in patients with a benign common bile duct (CBD) stricture. A FCSEMS was inserted in six patients with a CBD stricture due to chronic pancreatitis who were considered to be unfit for surgery, and stent removal was attempted after predefined intervals of 4 and 6 months. FCSEMS were successfully placed in all patients (100 % placement success) and stent extraction was accomplished in four patients (66 % removal rate), all of whom achieved stricture resolution (66 % resolution rate). In one patient a recurrent stenosis developed after 6 months (recurrence rate 25 %). Proximal stent migration occurred in two patients. In conclusion, FCSEMS removal was possible in the majority of patients and results regarding stricture dilation were promising. Nevertheless, before FCSEMS can become an acceptable treatment option for benign CBD strictures, innovative stent design modifications are necessary and removability must be ascertained.

[Surgical drainage of the pancreatic duct in patients with chronic pancreatitis is more effective than endoscopic drainage: randomized trial]. / Chirurgische drainage van de ductus pancreaticus bij patiënten met chronische pancreatitis effectiever dan endoscopische drainage: gerandomiseerde trial.

OBJECTIVE: To compare endoscopic and surgical drainage of the pancreatic duct for ductal decompression in patients with severe pain due to chronic pancreatitis and a dilated pancreatic duct. DESIGN: Randomized clinical trial. METHOD: All symptomatic patients with chronic pancreatitis and a distal obstruction of the pancreatic duct, but without an inflammatory mass, were eligible for this study. Patients were randomized to endoscopic transampullary pancreatic duct drainage or to operative pancreaticojejunostomy. The primary end point was the average Izbicki pain score, measured during 2 years of follow-up. The secondary endpoints were pain relief at the end of follow-up, physical and mental health, morbidity, mortality, hospital stay and number of procedures performed. RESULTS: Of 118 patients who were evaluated between January 2000-October 2004 39 patients were randomized; 19 were treated endoscopically (16 of whom underwent lithotripsy) and 20 by operative pancreaticojejunostomy. During 24 months of follow-up, compared with endoscopic drainage, surgery was associated with lower Izbicki pain scores (51 versus 25; p < 0.001) and better SF-36 physical health summary scores (p = 0.003). Furthermore, at the end of follow-up, pain relief was achieved in 32% of patients randomized to endoscopic drainage and 75% of patients randomized to surgical drainage (p = 0.007). Complication rates and hospital stay were similar, but endoscopic treatment required more procedures (median 8 versus 3; p < 0.001).

Endoscopic drainage of pancreatic pseudocysts: long-term outcome and procedural factors associated with safe and successful treatment.

BACKGROUND AND STUDY AIMS: Endoscopic drainage is a widely used treatment modality for pancreatic pseudocysts and has challenged more traditional drainage techniques. This retrospective study evaluates the short-term and long-term results with this technique and aims to identify procedural modifications that may improve its safety and efficacy. PATIENTS AND METHODS: All consecutive patients who underwent endoscopic drainage of pancreatic pseudocysts in our hospital between 1983 and 2000 were included in the study. The patients' charts were reviewed, and long-term follow-up data were obtained by written questionnaires sent to the patients at the end of the follow-up period in November 2002. RESULTS: A total of 92 patients were included (66 men, 26 women; median age 49 years). The technical success rate of the drainage procedure was 97 % and the mortality rate was 1 %. Complications occurred in 31 patients (34 %), eight of which (9 %) were major and required surgery: hemorrhage in four cases (three of which were caused by erosion of a straight endoprosthesis through the cyst wall), secondary infection in three, and perforation in one. During a median follow-up period of 43 months, 10 patients (11 %) underwent additional (nonendoscopic) treatment for a persistent cyst and five (5 %) for a recurrent cyst. Overall, endoscopic drainage was successful in 65 patients (71 %). CONCLUSIONS: Endoscopic drainage is an effective treatment for pancreatic pseudocysts and offers a definitive solution in almost three-quarters of the cases. The majority of major complications might have been prevented by using pigtail stents instead of straight stents and by taking a more aggressive approach to the prevention and treatment of secondary cyst infection.

The role of insulin, glucagon, dexamethasone, and leptin in the regulation of ketogenesis and glycogen storage in primary cultures of porcine hepatocytes prepared from 60 kg pigs.

A study was conducted to elucidate hormonal control of ketogenesis and glycogen deposition in primary cultures of porcine hepatocytes. Hepatocytes were isolated from pigs (54-68 kg) by collagenase perfusion and seeded into collagen-coated T-25 flasks. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to a serum-free medium for the remainder of the culture period. Hepatocytes were maintained in DMEM/M199 containing 1% DMSO, dexamethasone (10(-6) or 10(-7) M), linoleic acid (3.4 x 10(-5) M), and carnitine (10(-3) M) for 3 days. On the first day of serum-free culture, insulin was added at 1 or 100 ng/ml and glucagon was added at 0, 1, or 100 ng/ml. Recombinant human leptin (200 ng/ml) was added during the final 24 h; medium and all cells were harvested on the third day. Concentrations of acetoacetate and beta-hydroxybutyrate (ketone bodies) in media and glycogen deposition in the cellular compartment were determined. Ketogenesis was highly stimulated by glucagon (1 and 100 ng/ml) and inhibited by insulin. In contrast, glycogen deposition was stimulated by insulin and attenuated by glucagon; high insulin was also associated with a reduction in the ketone body ratio (acetoacetate:beta-hydroxybutyrate). High levels of dexamethasone stimulated ketogenesis, but inhibited glycogen deposition at low insulin. Culture of cells with leptin for 24 h, over the range of insulin, glucagon, and dexamethasone concentrations had no effect on either glycogen deposition or ketogenesis. These data suggest that while adult porcine hepatocytes are indeed sensitive to hormonal manipulation, leptin has no direct influence on hepatic energy metabolism in swine.

Self-expanding metal stents in benign biliary strictures due to chronic pancreatitis.

BACKGROUND AND STUDY AIMS: In selected patients with chronic pancreatitis in whom conventional plastic stenting fails and in whom surgery is contraindicated or declined, insertion of a biliary self-expanding metal stent (SEMS) may be a valuable treatment option. PATIENTS AND METHODS: Between 1994 and 1999, 13 patients with chronic pancreatitis received SEMS for benign biliary strictures (four women and nine men; mean age 56). The indications for SEMS placement were: contraindication to surgery (n = 10), presumed inoperable pancreatic carcinoma (n = 1), concomitant unresectable lung cancer (n = 1), and declined surgery (n = 1). The success of treatment was defined as adequate biliary drainage due to SEMS therapy. RESULTS: The mean follow-up period was 50 months (range 6 days - 86 months). Nine patients (69 %) were successfully treated with SEMS therapy: a patent first SEMS (n = 5); a patent second SEMS inserted through the first SEMS (n = 3); and one patent SEMS after balloon cleaning. SEMS treatment was not successful in four patients (due to stent migration in one case and occlusion in three ). The mean patency period of the SEMS was 60 months (95 % CI, 43 months - 77 months). At 33 months, the probability of adequate biliary drainage with SEMS therapy was 75 %. CONCLUSIONS: SEMS therapy was safe and provided successful and prolonged biliary drainage in a selected group of patients with benign biliary strictures due to chronic pancreatitis in whom surgical intervention was not possible or desirable.

An integrative model of amino acid metabolism in the liver of the lactating dairy cow.

The objective of this work was to construct a dynamic model of hepatic amino acid metabolism in the lactating dairy cow that could be parameterized using net flow data from in vivo experiments. The model considers 22 amino acids, ammonia, urea, and 13 energetic metabolites, and was parameterized using a steady-state balance model and two in vivo, net flow experiments conducted with mid-lactation dairy cows. Extracellular flows were derived directly from the observed data. An optimization routine was used to derive nine intracellular flows. The resulting dynamic model was found to be stable across a range of inputs suggesting that it can be perturbed and applied to other physiological states. Although nitrogen was generally in balance, leucine was in slight deficit compared to predicted needs for export protein synthesis, suggesting that an alternative source of leucine (e.g. peptides) was utilized. Simulations of varying glucagon concentrations indicated that an additional 5 mol/d of glucose could be synthesized at the reference substrate concentrations and blood flows. The increased glucose production was supported by increased removal from blood of lactate, glutamate, aspartate, alanine, asparagine, and glutamine. As glucose output increased, ketone body and acetate release increased while CO(2) release declined. The pattern of amino acids appearing in hepatic vein blood was affected by changes in amino acid concentration in portal vein blood, portal blood flow rate and glucagon concentration, with methionine and phenylalanine being the most affected of essential amino acids. Experimental evidence is insufficient to determine whether essential amino acids are affected by varying gluconeogenic demands.

Effect of dietary betaine on nutrient utilization and partitioning in the young growing feed-restricted pig.

The purpose of this study was to examine the effects of dietary betaine over a range of concentrations (between 0 and 0.5%) on growth and body composition in young feed-restricted pigs. Betaine is associated with decreased lipid deposition and altered protein utilization in finishing pigs, and it has been suggested that the positive effects of betaine on growth and carcass composition may be greater in energy-restricted pigs. Thirty-two barrows (36 kg, n = 8 pigs per group) were restrictively fed one of four corn-soybean meal-skim milk based diets (18.6% crude protein, 3.23 Mcal ME/kg) and supplemented with 0, 0.125, 0.25, or 0.5% betaine. Feed allotment was adjusted weekly according to BW, such that average feed intake was approximately 1.7 kg for all groups. At 64 kg, pigs were slaughtered and visceral tissue was removed and weighed. Carcasses were chilled for 24 h to obtain carcass measurements. Subsequently, one-half of each carcass and whole visceral tissue were ground for chemical analysis. Linear regression analysis indicated that, as betaine content of the diet was elevated from 0 to 0.5%, carcass fat concentration (P = 0.06), P3 fat depth (P = 0.14) and viscera weight (P = 0.129) were decreased, whereas total carcass protein (P = 0.124), protein deposition rate (P = 0.98), and lean gain efficiency (P = 0.115) were increased. The greatest differences over control pigs were observed in pigs consuming 0.5% betaine, where carcass fat concentration and P3 fat depth were decreased by 10 and 26%, respectively. Other fat depth measurements were not different (P > 0.15) from those of control pigs. In addition, pigs consuming the highest betaine level had a 19% increase in the carcass protein:fat ratio, 23% higher carcass protein deposition rate, and a 24% increase in lean gain efficiency compared with controls. Dietary betaine had no effects (P > 0.15) on growth performance, visceral tissue chemical composition, carcass fat deposition rate, visceral fat and protein deposition rates, or serum urea and ammonia concentrations. These data suggest that betaine alters nutrient partitioning such that carcass protein deposition is enhanced at the expense of carcass fat and in part, visceral tissue.