Paul Pencharz - Academia.edu (original) (raw)

Papers by Paul Pencharz

Pediatric Research, 2013

Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requ... more Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production.

The Journal of nutrition, Jan 9, 2016

The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ⋅ kg(-1) ⋅ ... more The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ⋅ kg(-1) ⋅ d(-1), respectively, for adults, including older men, are based on nitrogen balance data analyzed by monolinear regression. Recent studies in young men and older women that used the indicator amino acid oxidation (IAAO) technique suggest that those values may be too low. This observation is supported by 2-phase linear crossover analysis of the nitrogen balance data. The main objective of this study was to determine the protein requirement for older men by using the IAAO technique. Six men aged >65 y were studied; each individual was tested 7 times with protein intakes ranging from 0.2 to 2.0 g ⋅ kg(-1) ⋅ d(-1) in random order for a total of 42 studies. The diets provided energy at 1.5 times the resting energy expenditure and were isocaloric. Protein was consumed hourly for 8 h as an amino acid mixture with the composition of egg protein with l-[1-(13)C]phenylalanine as the indicator a...

The American Journal of Clinical Nutrition, Feb 1, 2005

Background: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus... more Background: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus loss of lean body mass. Cystic fibrosis-related diabetes (CFRD) is associated with undernutrition and increased mortality. Objective: We hypothesized that CFRD is associated with increased whole-body protein breakdown, which results in negative protein balance, and that correction of the glucose intolerance with insulin therapy would normalize whole-body protein metabolism. Design: Rates of whole-body protein turnover and protein balance were measured in 28 adults with cystic fibrosis (17 M, 11 F). Subjects were assessed with a modified oral-glucose-tolerance test and categorized as having normal glucose tolerance, impaired glucose tolerance, or CFRD with and without fasting hyperglycemia; then they were compared with previously diagnosed CFRD adults already receiving insulin therapy. Indexes of protein turnover were calculated from [ 15 N]glycine and 15 N in urinary urea. Results: Analysis of variance for the 28 subjects showed that wholebody protein breakdown was highest (P 0.05) in patients with CFRD. Whole-body protein synthesis was not significantly affected by impaired glucose tolerance. Significant (P 0.05) improvement in net protein synthesis occurred in the CFRD group 3 mo after insulin therapy was administered. Follow-up studies of 3 subjects with CFRD showed significant improvement in net protein synthesis after insulin therapy. Monitoring of the protein homeostasis of the impaired glucose tolerance group gave clues to the progression of their metabolic homeostasis. Conclusion: CFRD has an adverse effect on protein homeostasis by increasing net protein synthesis.

Bmj British Medical Journal, Sep 24, 1999

change in alcohol use over time lead to underestimation of an elevated relative risk. 4 However, ... more change in alcohol use over time lead to underestimation of an elevated relative risk. 4 However, we found a clear association between level of alcohol use at conscription and risk of subsequent hospitalisation or death with a diagnosis of alcoholism, alcohol psychosis, or alcohol intoxication, with a significant relative risk of 5.71 for consumers of >15 g ethanol/day, indicating a stability over time. The results also indicate a cardioprotective effect of alcohol use in relatively young men, in whom myocardial infarction is rare. Possible biological mechanisms include an increase in high density lipoprotein cholesterol, a decrease in platelet coagulability, and a decrease in plasma fibrinogen associated with alcohol intake. 1 Calculation of the attributable proportions clearly indicated that alcohol consumption had a negative net effect on the subjects' health up to the age of 45. The results support a restrictive alcohol policy and recommendations for little or no alcohol consumption by young men. 5

The Journal of Nutrition, Aug 1, 2002

To investigate whether splanchnic uptake of the indicator amino acid ([1-13 C] phenylalanine) dur... more To investigate whether splanchnic uptake of the indicator amino acid ([1-13 C] phenylalanine) during the fed state alters the estimate of lysine requirement, five healthy men were studied at graded levels of lysine intake, with either an oral or intravenous (IV) tracer protocol, in a randomized, crossover design. Splanchnic extraction of the oral tracer was expressed as the difference between the ratio of the enrichments in urinary phenylalanine between tracer protocols. The rate of release of 13 CO 2 from 13 C-phenylalanine oxidation (F 13 CO 2 ) was measured and a two-phase linear regression crossover model was applied to determine the lysine requirement. Mean splanchnic extraction of the oral tracer was ϳ19%. Although actual F 13 CO 2 was higher during oral tracer infusion (P Ͻ 0.001), the breakpoint was not different from that determined with IV infusion (P ϭ 0.98), with both yielding a mean lysine requirement of 36.6 mg/(kg ⅐ d). The upper 95% confidence intervals were 52.5 and 53.3 mg/(kg ⅐ d) for the oral and IV isotope infusions, respectively. These results demonstrate that routes of isotope administration using the indicator amino acid oxidation technique do not affect the estimated amino acid requirement. Therefore, the indicator amino acid oxidation method using the oral route, which is less invasive and allows for studies in vulnerable groups such as infants and children, should be the preferred method for studying amino acid requirements.

Eur J Gastroenterol Hepatol, 1996

The Journal of Nutrition, Oct 1, 2002

The requirements for branched-chain amino acids (BCAA), isoleucine, leucine and valine, in neonat... more The requirements for branched-chain amino acids (BCAA), isoleucine, leucine and valine, in neonates have not been determined previously. Furthermore, the BCAA are considered to be catabolized primarily in the muscle and their metabolism in the small intestine has received little attention. In this study, the parenteral and enteral BCAA requirements were determined by the indicator amino acid oxidation (IAAO) technique. Male Yorkshire piglets (n ϭ 32) received amino acid-based diets containing adequate nutrients for 5 d. On d 6 and 8, the piglets were randomly assigned to one of the test diets containing a fixed ratio of BCAA (1:1.8:1.2; isoleucine/ leucine/valine). Diets were infused continuously via intravenous catheters for parenterally fed piglets or via gastric catheters for enterally fed piglets. Phenylalanine kinetics and oxidation were determined from a 4-h primed, constant infusion of L-[1-14 C]phenylalanine. Phenylalanine oxidation (% of dose) decreased linearly (P Ͻ 0.05) as the BCAA intake increased from 0.2 to 1.53 g/(kg ⅐ d) and from 0.2 to 2.64 g/(kg ⅐ d) for parenterally and enterally fed piglets, respectively, after which the phenylalanine oxidation was low and the slope was not different from zero. Using breakpoint analysis, the mean total BCAA requirements were determined to be 1.53 and 2.64 g/(kg ⅐ d) for parenterally and enterally fed piglets, respectively. Thus, the parenteral requirement for total BCAA is 56% of the enteral requirement, suggesting that 44% of total BCAA is extracted by first-pass splanchnic metabolism. J. Nutr. 132: 3123-3129, 2002.

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity ha... more Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity have increased sleep-disordered breathing (SDB). The objectives of this study were to compare the prevalence of SDB in adolescents with craniopharyngioma-related obesity compared with body mass index (BMI)-matched controls and to explore possible relationships between SDB, insulin resistance, and adipocytokines. This was a cross-sectional study of obese craniopharyngioma and obese control adolescents. Subjects were evaluated in the clinical investigation unit at the Hospital for Sick Children, Toronto. Fifteen patients with craniopharyngioma-related obesity and 15 BMI-matched controls were recruited and tested. Each subject underwent fasting blood work, frequent sampled iv glucose tolerance test, polysomnography, and abdominal magnetic resonance imaging with calculation of visceral and sc adipose tissue. Main measures included insulin sensitivity, sleep efficiency, and fragmentation. Insulin sensitivity was lower in craniopharyngioma subjects compared with control subjects (0.96 +/- 0.34 vs. 1.67 +/- 0.7, P = 0.01). Sleep-onset latency (19.3 +/- 27.8 vs. 31.9 +/- 23.4, P = 0.03) and oxygen saturations (rapid eye movement sleep: 89.0 +/- 5.1 vs. 94.2 +/- 2.3, P < 0.001; non-rapid eye movement sleep: 88.4 +/- 5.6 vs. 94.3 +/- 1.5, P < 0.001) were lower in craniopharyngioma. Obstructive apnea-hypopnea index (OAHI) (7.5 +/- 9.0 vs. 1.5 +/- 1.5, P = 0.03) was higher in craniopharyngioma. Respiratory distress index and OAHI correlated negatively with adiponectin concentrations (r = -0.61, P = 0.03, r = -0.71, P = 0.006, respectively) in craniopharyngioma. On multiple regression, TNF-alpha and craniopharyngioma were independent positive predictors of sleep-onset latency and adiponectin and craniopharyngioma were significant predictors (negative and positive, respectively) of OAHI. SDB is increased in adolescents with craniopharyngioma-related obesity compared with BMI-matched controls. Routine polysomnography should be considered in obese patients with craniopharyngioma and appropriate treatment initiated.

The Journal of Nutrition, Jul 1, 2006

Although neonatal piglets can synthesize some arginine from proline, there is a limit to this syn... more Although neonatal piglets can synthesize some arginine from proline, there is a limit to this synthesis, and piglets fed an arginine-deficient diet have diminished whole-body arginine status. To help elucidate where the limitation in arginine synthesis may occur, our objective was to determine the most effective arginine precursor in 1-wk-old enterally fed piglets. Piglets were administered either an arginine-deficient (basal) diet [1.15 mmol arginine/(kgÁd)] or the basal diet supplemented with equimolar [9.18 mmol/(kgÁd)] amounts of proline (1Pro), ornithine (1Orn), citrulline (1Cit) or arginine (1Arg) for 5 d (n ¼ 5/diet). Daily blood samples were taken and indicators of whole-body arginine status including plasma amino acid, ammonia, and urea concentrations were measured. A primed, constant intragastric (i.g.) infusion of L-[U-14 C]proline was given to measure the proline to arginine conversion, and intravenous (i.v.) and i.g. infusions of L-[guanido-14 C]arginine were given to determine arginine flux and to quantify the splanchnic extraction of dietary arginine. Piglets fed the 1Cit and 1Arg diets had lower plasma ammonia and urea concentrations (P , 0.05) and higher plasma arginine concentrations (P , 0.0001) and arginine fluxes (P , 0.05) than piglets fed the other 3 diets. Piglets fed 1Cit and 1Arg had a lower proline to arginine conversion (P , 0.05). During first-pass splanchnic metabolism, 52% of the dietary arginine was extracted, and this extraction was not affected by whole-body arginine status (P . 0.05). These data indicate that citrulline, but not ornithine or proline, is an effective arginine precursor, and that either citrulline formation or availability appears to limit arginine synthesis in neonatal piglets. J. Nutr. 136: 1806Nutr. 136: -1813Nutr. 136: , 2006.

The Journal of Nutrition, Nov 1, 2003

The current WHO/FAO/UNU recommendations for BCAA requirements in school-aged children are based o... more The current WHO/FAO/UNU recommendations for BCAA requirements in school-aged children are based on nitrogen balance studies that have tended to produce lower estimates of amino acid requirements that those determined using stable isotope methodologies. The new dietary reference intake (DRI) recommendations for total BCAA requirements in children were determined using a factorial approach that included adult BCAA requirements plus the additional needs for growth. The purpose of this study was to determine directly total BCAA requirements in school children aged 6 -10 y using indicator amino acid oxidation (IAAO). Five children (8.5 Ϯ 1.2 y) were assigned randomly to receive 7 graded intakes of total BCAA. Individual BCAA in the test diet were provided in the same proportions as those present in egg protein to minimize the potential interactive effects of individual BCAA on assessment of requirement. Total BCAA requirement was determined by measuring the oxidation of L-[1-13 C] phenylalanine to 13 CO 2 [F 13 CO 2 in mol/(kg ⅐ h)], after a primed, continuous infusion of the labeled tracer and using a two-phase linear crossover regression analysis. The mean requirement and the population-safe intake level (upper limit of the 95% CI) of the total BCAA in healthy school aged children were 147 and 192 mg/(kg ⅐ d), respectively. The estimated mean requirements of the total BCAA as determined by IAAO is ϳ48% higher than the current DRI recommendations, suggesting that these recommendations may be too low to meet the needs of school-aged children. J. Nutr. 133: 3540 -3545, 2003.

The Faseb Journal, Apr 1, 2009

ABSTRACT Controversy exists as to whether the parenterally (PN) fed human neonate is capable of s... more ABSTRACT Controversy exists as to whether the parenterally (PN) fed human neonate is capable of synthesizing adequate cysteine from methionine if the total dietary requirement for sulfur amino acid (SAA) is provided as methionine only. The goal of this study was to gather data on whether glutathione (GSH) synthesis is maximized at a methionine intake previously shown to be adequate for protein synthesis in the PN-fed human neonate. We measured GSH concentration, fractional, and absolute synthesis rate in five PN-fed human neonates. Each neonate underwent two isotope infusion studies of 7 h duration after a 2-d adaptation to the total SAA requirement (methionine only) and again after a further 2-d adaptation to the same methionine intake supplemented with cysteine at 10 mg x kg(-1) x d(-1). Cysteine supplementation did not significantly affect GSH synthesis. These data suggest that term infants are capable of synthesizing cysteine from methionine, not only for protein but also for GSH synthesis.

The American Journal of Clinical Nutrition, 1999

Background: Plasma threonine concentrations are elevated in infants fed formula containing a whey... more Background: Plasma threonine concentrations are elevated in infants fed formula containing a whey-to-casein protein ratio of 60:40 compared with concentrations in infants fed formula containing a ratio of 20:80 or human milk (60:40). Objective: We studied whether degradation of excess threonine was lower in formula-fed infants than in infants fed their mothers' milk. Design: Threonine kinetics were examined in 17 preterm infants (gestational age: 31 ± 2 wk; birth weight: 1720 ± 330 g) by using an 18-h oral infusion of [1-13 C]threonine at a postnatal age of 21 ± 11 d and weight of 1971 ± 270 g. Five infants received breast milk. Formula-fed infants (n = 12) were randomly assigned to receive 1 of 3 formulas (5.3 g protein/MJ) that differed only in the whey-to-casein ratio (20:80, 40:60, and 60:40). Results: Threonine intake increased significantly in formula-fed infants with increasing whey content of the formula (48.5, 56.4, and 63.2 mol · kg Ϫ1 · h Ϫ1 , respectively; pooled SD: 2.2; P = 0.0001), as did plasma threonine concentrations (228, 344, and 419 mol/L, respectively; pooled SD: 75; P = 0.03). Despite a generous threonine intake by infants fed breast milk (58.0 ± 16.0 mol · kg Ϫ1 · h Ϫ1 ), plasma threonine concentrations remained low (208 ± 41 mol/L). Fecal threonine excretion and net threonine tissue gain, estimated by nitrogen balance, did not differ significantly among groups. Threonine oxidation did not differ significantly among formula-fed infants but was significantly lower in formula-fed infants fed than in infants fed breast milk (17.1% compared with 24.3% of threonine intake, respectively). Conclusion: Formula-fed infants have a lower capacity to oxidize threonine than do infants fed breast milk.

The Journal of Pediatrics, Jan 12, 1991

To determine whether the increase in resting energy expenditure in cystic fibrosis is associated ... more To determine whether the increase in resting energy expenditure in cystic fibrosis is associated with the primary genetic defect (AFs08) or with declining pulmonary function, or both, we tested resting every energy expenditure prospectively in 32 male subjects (aged 7 to 39 years) who were normally nourished and had good pulmonary function. They were categorized into three genotype groups on the basis of the presence or absence of AF508 and pancreatic function. Mean resting energy expenditure was 104% of the predicted value and was not associated with genotype. When 29 subjects with normal nutritional status but variable lung function were added to the group, there was a strong correlation between declining pulmonary function and increased resting energy expenditure. We conclude that increased resting energy expenditure in normally nourished boys and men with cystic fibrosis appears to be more closely associated with declining pulmonary function than with genotype. (J PEDIATR 1991;119:913-6)

The Journal of Nutrition, Nov 1, 2003

Recently, we defined an estimate for total branched-chain amino acids (BCAA) using the indicator ... more Recently, we defined an estimate for total branched-chain amino acids (BCAA) using the indicator amino acid oxidation technique in men fed the three BCAA (leucine, isoleucine and valine) in the proportion present in egg protein. Although egg protein is regarded as a high quality dietary protein source, it is not known whether the proportions of the three BCAA are optimal. Five men with known total BCAA requirements were restudied. Each men was studied with isoleucine, leucine or valine held constant at that individual's requirement level while the intake of the other two BCAA was reduced; one BCAA was held constant and the intake of the other two was reduced by 10 and 20% in random order. The label appearance from the oxidation of L-[ 13 C]-phenylalanine to 13 CO 2 (F 13 CO 2 ) in breath was monitored in response to the change in amino acid intake. When either isoleucine or leucine was held constant, and the other two BCAA reduced by 20% (valine and leucine, or valine and isoleucine, respectively) F 13 CO 2 increased (P ϭ 0.007, P ϭ 0.038, respectively). We conclude that valine may be the first limiting BCAA in egg protein. J. Nutr. 133: 3533-3539, 2003.

The Journal of Nutrition, Jun 1, 2007

Dietary aromatic amino acids are needed to meet the requirements for phenylalanine and tyrosine f... more Dietary aromatic amino acids are needed to meet the requirements for phenylalanine and tyrosine for protein synthesis.

The Journal of Pediatrics, Feb 1, 2003

To evaluate the relations among glucose intolerance, genotype, and exocrine pancreatic status in ... more To evaluate the relations among glucose intolerance, genotype, and exocrine pancreatic status in patients with cystic fibrosis (CF). Data on 335 patients <18 years of age were from the Toronto CF database. A modified oral glucose tolerance test was given to 94 patients 10 to 18 years of age without recognized CF-related diabetes. CF transmembrane conductance regulator mutations and exocrine pancreatic status were determined for all patients. CF-related diabetes was clinically recognized in 9 of 335 (2.7%) patients <18 years of age, all of whom were pancreatic insufficient, and 8 of 9 had severe (classes I through III) mutations on both alleles. The ninth patient had unidentified mutations. Although all patients given the oral glucose tolerance test were asymptomatic and had normal fasting blood glucose, 16 of 94 (17%) had impaired glucose tolerance and 4 of 94 (4.3%) had CF-related diabetes without fasting hyperglycemia. Abnormal glucose tolerance was associated exclusively with severe mutations and exocrine pancreatic insufficiency. Glycosylated hemoglobin (HbA(1)C) levels did not correlate with glucose tolerance results. Screening of pancreatic-insufficient, adolescent patients with CF identified more with abnormal oral glucose tolerance than was suspected clinically and is recommended as a routine practice. HbA(1)C was not useful in screening for CF-related glucose intolerance.

The Journal of Nutrition, 1994

The Faseb Journal, Apr 1, 2013

The Journal of Nutrition, Feb 1, 1999

Study of the amino acid metabolism of vulnerable groups, such as pregnant women, children and pat... more Study of the amino acid metabolism of vulnerable groups, such as pregnant women, children and patients, is needed. Our existing protocol is preceded by 2 d of adaptation to a low 13 C formula diet at a protein intake of 1 g ⅐ kg Ϫ1 ⅐ d Ϫ1 to minimize variations in breath 13 CO 2 enrichment and protein metabolism. To expand on our potential study populations, a less invasive protocol needs to be developed. We have already established that a stable background 13 CO 2 enrichment can be achieved on the study day without prior adaptation to the low 13 C formula. Therefore, this study investigates phenylalanine kinetics in response to variations in prior protein intake. Healthy adult subjects were each fed nutritionally adequate mixed diets containing 0.8, 1.4 and 2.0 g protein ⅐ kg Ϫ1 ⅐ d Ϫ1 for 2 d. On d 3, subjects consumed an amino acid-based formula diet containing the equivalent of 1 g protein ⅐ kg Ϫ1 ⅐ d Ϫ1 hourly for 10 h and primed hourly oral doses of L-[1-13 C]phenylalanine for the final 6 h. Phenylalanine kinetics were calculated from plasma-free phenylalanine enrichment and breath 13 CO 2 excretion. A significant quadratic response of prior protein intake on phenylalanine flux (P ϭ 0.012) and oxidation (P ϭ 0.009) was identified, such that both variables were lower following adaptation to a protein intake of 1.4 g ⅐ kg Ϫ1 ⅐ d Ϫ1 . We conclude that variations in protein intake, between 0.8 and 2.0 g ⅐ kg Ϫ1 ⅐ d Ϫ1 , prior to the study day may affect amino acid kinetics and; therefore, it is prudent to continue to control protein intake prior to an amino acid kinetics study.

The Journal of Nutrition, Apr 1, 2006

Malnutrition is prevalent in children with chronic cholestatic liver disease. Using the noninvasi... more Malnutrition is prevalent in children with chronic cholestatic liver disease. Using the noninvasive indicator amino acid oxidation (IAAO) technique, we recently determined that mild-to-moderate chronic cholestatic (MCC) liver disease increases the need for branched-chain amino acids (BCAA) in children. To examine the underlying mechanisms responsible for this increased need for BCAA in liver disease, we measured L-[1-13 C]-leucine oxidation in the postabsorptive and fed states in 10 children with MCC liver disease (8.8 6 3.5 y) and in 11 healthy children (9.4 6 2.2 y). The oxidation of L-[1-13 C]-leucine to 13 CO 2 [F 13 CO 2 in mmol/(kgÁh)] was determined after a primed, continuous oral administration of the tracer. Total BCAA in diet was provided at 300 mg/(kgÁd) to ensure that leucine oxidation was measured when leucine intake was in excess of requirements. In the postabsorptive state, the rate of release of 13 CO 2 from 13 C-leucine oxidation (F 13 CO 2 ) and whole-body leucine oxidation were significantly higher in children with MCC liver disease (P , 0.05). However, F 13 CO 2 and whole-body leucine oxidation did not differ in the fed state. We conclude that the increased need for dietary BCAA in MCC liver disease is mediated in part by increased leucine oxidation in the postabsorptive state. J. Nutr. 136: 965-970, 2006.

Pediatric Research, 2013

Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requ... more Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production.

The Journal of nutrition, Jan 9, 2016

The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ⋅ kg(-1) ⋅ ... more The current estimated average requirement (EAR) and RDA for protein of 0.66 and 0.8 g ⋅ kg(-1) ⋅ d(-1), respectively, for adults, including older men, are based on nitrogen balance data analyzed by monolinear regression. Recent studies in young men and older women that used the indicator amino acid oxidation (IAAO) technique suggest that those values may be too low. This observation is supported by 2-phase linear crossover analysis of the nitrogen balance data. The main objective of this study was to determine the protein requirement for older men by using the IAAO technique. Six men aged >65 y were studied; each individual was tested 7 times with protein intakes ranging from 0.2 to 2.0 g ⋅ kg(-1) ⋅ d(-1) in random order for a total of 42 studies. The diets provided energy at 1.5 times the resting energy expenditure and were isocaloric. Protein was consumed hourly for 8 h as an amino acid mixture with the composition of egg protein with l-[1-(13)C]phenylalanine as the indicator a...

The American Journal of Clinical Nutrition, Feb 1, 2005

Background: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus... more Background: Diabetes mellitus has been reported to increase whole-body protein breakdown and thus loss of lean body mass. Cystic fibrosis-related diabetes (CFRD) is associated with undernutrition and increased mortality. Objective: We hypothesized that CFRD is associated with increased whole-body protein breakdown, which results in negative protein balance, and that correction of the glucose intolerance with insulin therapy would normalize whole-body protein metabolism. Design: Rates of whole-body protein turnover and protein balance were measured in 28 adults with cystic fibrosis (17 M, 11 F). Subjects were assessed with a modified oral-glucose-tolerance test and categorized as having normal glucose tolerance, impaired glucose tolerance, or CFRD with and without fasting hyperglycemia; then they were compared with previously diagnosed CFRD adults already receiving insulin therapy. Indexes of protein turnover were calculated from [ 15 N]glycine and 15 N in urinary urea. Results: Analysis of variance for the 28 subjects showed that wholebody protein breakdown was highest (P 0.05) in patients with CFRD. Whole-body protein synthesis was not significantly affected by impaired glucose tolerance. Significant (P 0.05) improvement in net protein synthesis occurred in the CFRD group 3 mo after insulin therapy was administered. Follow-up studies of 3 subjects with CFRD showed significant improvement in net protein synthesis after insulin therapy. Monitoring of the protein homeostasis of the impaired glucose tolerance group gave clues to the progression of their metabolic homeostasis. Conclusion: CFRD has an adverse effect on protein homeostasis by increasing net protein synthesis.

Bmj British Medical Journal, Sep 24, 1999

change in alcohol use over time lead to underestimation of an elevated relative risk. 4 However, ... more change in alcohol use over time lead to underestimation of an elevated relative risk. 4 However, we found a clear association between level of alcohol use at conscription and risk of subsequent hospitalisation or death with a diagnosis of alcoholism, alcohol psychosis, or alcohol intoxication, with a significant relative risk of 5.71 for consumers of >15 g ethanol/day, indicating a stability over time. The results also indicate a cardioprotective effect of alcohol use in relatively young men, in whom myocardial infarction is rare. Possible biological mechanisms include an increase in high density lipoprotein cholesterol, a decrease in platelet coagulability, and a decrease in plasma fibrinogen associated with alcohol intake. 1 Calculation of the attributable proportions clearly indicated that alcohol consumption had a negative net effect on the subjects' health up to the age of 45. The results support a restrictive alcohol policy and recommendations for little or no alcohol consumption by young men. 5

The Journal of Nutrition, Aug 1, 2002

To investigate whether splanchnic uptake of the indicator amino acid ([1-13 C] phenylalanine) dur... more To investigate whether splanchnic uptake of the indicator amino acid ([1-13 C] phenylalanine) during the fed state alters the estimate of lysine requirement, five healthy men were studied at graded levels of lysine intake, with either an oral or intravenous (IV) tracer protocol, in a randomized, crossover design. Splanchnic extraction of the oral tracer was expressed as the difference between the ratio of the enrichments in urinary phenylalanine between tracer protocols. The rate of release of 13 CO 2 from 13 C-phenylalanine oxidation (F 13 CO 2 ) was measured and a two-phase linear regression crossover model was applied to determine the lysine requirement. Mean splanchnic extraction of the oral tracer was ϳ19%. Although actual F 13 CO 2 was higher during oral tracer infusion (P Ͻ 0.001), the breakpoint was not different from that determined with IV infusion (P ϭ 0.98), with both yielding a mean lysine requirement of 36.6 mg/(kg ⅐ d). The upper 95% confidence intervals were 52.5 and 53.3 mg/(kg ⅐ d) for the oral and IV isotope infusions, respectively. These results demonstrate that routes of isotope administration using the indicator amino acid oxidation technique do not affect the estimated amino acid requirement. Therefore, the indicator amino acid oxidation method using the oral route, which is less invasive and allows for studies in vulnerable groups such as infants and children, should be the preferred method for studying amino acid requirements.

Eur J Gastroenterol Hepatol, 1996

The Journal of Nutrition, Oct 1, 2002

The requirements for branched-chain amino acids (BCAA), isoleucine, leucine and valine, in neonat... more The requirements for branched-chain amino acids (BCAA), isoleucine, leucine and valine, in neonates have not been determined previously. Furthermore, the BCAA are considered to be catabolized primarily in the muscle and their metabolism in the small intestine has received little attention. In this study, the parenteral and enteral BCAA requirements were determined by the indicator amino acid oxidation (IAAO) technique. Male Yorkshire piglets (n ϭ 32) received amino acid-based diets containing adequate nutrients for 5 d. On d 6 and 8, the piglets were randomly assigned to one of the test diets containing a fixed ratio of BCAA (1:1.8:1.2; isoleucine/ leucine/valine). Diets were infused continuously via intravenous catheters for parenterally fed piglets or via gastric catheters for enterally fed piglets. Phenylalanine kinetics and oxidation were determined from a 4-h primed, constant infusion of L-[1-14 C]phenylalanine. Phenylalanine oxidation (% of dose) decreased linearly (P Ͻ 0.05) as the BCAA intake increased from 0.2 to 1.53 g/(kg ⅐ d) and from 0.2 to 2.64 g/(kg ⅐ d) for parenterally and enterally fed piglets, respectively, after which the phenylalanine oxidation was low and the slope was not different from zero. Using breakpoint analysis, the mean total BCAA requirements were determined to be 1.53 and 2.64 g/(kg ⅐ d) for parenterally and enterally fed piglets, respectively. Thus, the parenteral requirement for total BCAA is 56% of the enteral requirement, suggesting that 44% of total BCAA is extracted by first-pass splanchnic metabolism. J. Nutr. 132: 3123-3129, 2002.

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity ha... more Retrospective studies suggest that adolescents with craniopharyngioma and hypothalamic obesity have increased sleep-disordered breathing (SDB). The objectives of this study were to compare the prevalence of SDB in adolescents with craniopharyngioma-related obesity compared with body mass index (BMI)-matched controls and to explore possible relationships between SDB, insulin resistance, and adipocytokines. This was a cross-sectional study of obese craniopharyngioma and obese control adolescents. Subjects were evaluated in the clinical investigation unit at the Hospital for Sick Children, Toronto. Fifteen patients with craniopharyngioma-related obesity and 15 BMI-matched controls were recruited and tested. Each subject underwent fasting blood work, frequent sampled iv glucose tolerance test, polysomnography, and abdominal magnetic resonance imaging with calculation of visceral and sc adipose tissue. Main measures included insulin sensitivity, sleep efficiency, and fragmentation. Insulin sensitivity was lower in craniopharyngioma subjects compared with control subjects (0.96 +/- 0.34 vs. 1.67 +/- 0.7, P = 0.01). Sleep-onset latency (19.3 +/- 27.8 vs. 31.9 +/- 23.4, P = 0.03) and oxygen saturations (rapid eye movement sleep: 89.0 +/- 5.1 vs. 94.2 +/- 2.3, P < 0.001; non-rapid eye movement sleep: 88.4 +/- 5.6 vs. 94.3 +/- 1.5, P < 0.001) were lower in craniopharyngioma. Obstructive apnea-hypopnea index (OAHI) (7.5 +/- 9.0 vs. 1.5 +/- 1.5, P = 0.03) was higher in craniopharyngioma. Respiratory distress index and OAHI correlated negatively with adiponectin concentrations (r = -0.61, P = 0.03, r = -0.71, P = 0.006, respectively) in craniopharyngioma. On multiple regression, TNF-alpha and craniopharyngioma were independent positive predictors of sleep-onset latency and adiponectin and craniopharyngioma were significant predictors (negative and positive, respectively) of OAHI. SDB is increased in adolescents with craniopharyngioma-related obesity compared with BMI-matched controls. Routine polysomnography should be considered in obese patients with craniopharyngioma and appropriate treatment initiated.

The Journal of Nutrition, Jul 1, 2006

Although neonatal piglets can synthesize some arginine from proline, there is a limit to this syn... more Although neonatal piglets can synthesize some arginine from proline, there is a limit to this synthesis, and piglets fed an arginine-deficient diet have diminished whole-body arginine status. To help elucidate where the limitation in arginine synthesis may occur, our objective was to determine the most effective arginine precursor in 1-wk-old enterally fed piglets. Piglets were administered either an arginine-deficient (basal) diet [1.15 mmol arginine/(kgÁd)] or the basal diet supplemented with equimolar [9.18 mmol/(kgÁd)] amounts of proline (1Pro), ornithine (1Orn), citrulline (1Cit) or arginine (1Arg) for 5 d (n ¼ 5/diet). Daily blood samples were taken and indicators of whole-body arginine status including plasma amino acid, ammonia, and urea concentrations were measured. A primed, constant intragastric (i.g.) infusion of L-[U-14 C]proline was given to measure the proline to arginine conversion, and intravenous (i.v.) and i.g. infusions of L-[guanido-14 C]arginine were given to determine arginine flux and to quantify the splanchnic extraction of dietary arginine. Piglets fed the 1Cit and 1Arg diets had lower plasma ammonia and urea concentrations (P , 0.05) and higher plasma arginine concentrations (P , 0.0001) and arginine fluxes (P , 0.05) than piglets fed the other 3 diets. Piglets fed 1Cit and 1Arg had a lower proline to arginine conversion (P , 0.05). During first-pass splanchnic metabolism, 52% of the dietary arginine was extracted, and this extraction was not affected by whole-body arginine status (P . 0.05). These data indicate that citrulline, but not ornithine or proline, is an effective arginine precursor, and that either citrulline formation or availability appears to limit arginine synthesis in neonatal piglets. J. Nutr. 136: 1806Nutr. 136: -1813Nutr. 136: , 2006.

The Journal of Nutrition, Nov 1, 2003

The current WHO/FAO/UNU recommendations for BCAA requirements in school-aged children are based o... more The current WHO/FAO/UNU recommendations for BCAA requirements in school-aged children are based on nitrogen balance studies that have tended to produce lower estimates of amino acid requirements that those determined using stable isotope methodologies. The new dietary reference intake (DRI) recommendations for total BCAA requirements in children were determined using a factorial approach that included adult BCAA requirements plus the additional needs for growth. The purpose of this study was to determine directly total BCAA requirements in school children aged 6 -10 y using indicator amino acid oxidation (IAAO). Five children (8.5 Ϯ 1.2 y) were assigned randomly to receive 7 graded intakes of total BCAA. Individual BCAA in the test diet were provided in the same proportions as those present in egg protein to minimize the potential interactive effects of individual BCAA on assessment of requirement. Total BCAA requirement was determined by measuring the oxidation of L-[1-13 C] phenylalanine to 13 CO 2 [F 13 CO 2 in mol/(kg ⅐ h)], after a primed, continuous infusion of the labeled tracer and using a two-phase linear crossover regression analysis. The mean requirement and the population-safe intake level (upper limit of the 95% CI) of the total BCAA in healthy school aged children were 147 and 192 mg/(kg ⅐ d), respectively. The estimated mean requirements of the total BCAA as determined by IAAO is ϳ48% higher than the current DRI recommendations, suggesting that these recommendations may be too low to meet the needs of school-aged children. J. Nutr. 133: 3540 -3545, 2003.

The Faseb Journal, Apr 1, 2009

ABSTRACT Controversy exists as to whether the parenterally (PN) fed human neonate is capable of s... more ABSTRACT Controversy exists as to whether the parenterally (PN) fed human neonate is capable of synthesizing adequate cysteine from methionine if the total dietary requirement for sulfur amino acid (SAA) is provided as methionine only. The goal of this study was to gather data on whether glutathione (GSH) synthesis is maximized at a methionine intake previously shown to be adequate for protein synthesis in the PN-fed human neonate. We measured GSH concentration, fractional, and absolute synthesis rate in five PN-fed human neonates. Each neonate underwent two isotope infusion studies of 7 h duration after a 2-d adaptation to the total SAA requirement (methionine only) and again after a further 2-d adaptation to the same methionine intake supplemented with cysteine at 10 mg x kg(-1) x d(-1). Cysteine supplementation did not significantly affect GSH synthesis. These data suggest that term infants are capable of synthesizing cysteine from methionine, not only for protein but also for GSH synthesis.

The American Journal of Clinical Nutrition, 1999

Background: Plasma threonine concentrations are elevated in infants fed formula containing a whey... more Background: Plasma threonine concentrations are elevated in infants fed formula containing a whey-to-casein protein ratio of 60:40 compared with concentrations in infants fed formula containing a ratio of 20:80 or human milk (60:40). Objective: We studied whether degradation of excess threonine was lower in formula-fed infants than in infants fed their mothers' milk. Design: Threonine kinetics were examined in 17 preterm infants (gestational age: 31 ± 2 wk; birth weight: 1720 ± 330 g) by using an 18-h oral infusion of [1-13 C]threonine at a postnatal age of 21 ± 11 d and weight of 1971 ± 270 g. Five infants received breast milk. Formula-fed infants (n = 12) were randomly assigned to receive 1 of 3 formulas (5.3 g protein/MJ) that differed only in the whey-to-casein ratio (20:80, 40:60, and 60:40). Results: Threonine intake increased significantly in formula-fed infants with increasing whey content of the formula (48.5, 56.4, and 63.2 mol · kg Ϫ1 · h Ϫ1 , respectively; pooled SD: 2.2; P = 0.0001), as did plasma threonine concentrations (228, 344, and 419 mol/L, respectively; pooled SD: 75; P = 0.03). Despite a generous threonine intake by infants fed breast milk (58.0 ± 16.0 mol · kg Ϫ1 · h Ϫ1 ), plasma threonine concentrations remained low (208 ± 41 mol/L). Fecal threonine excretion and net threonine tissue gain, estimated by nitrogen balance, did not differ significantly among groups. Threonine oxidation did not differ significantly among formula-fed infants but was significantly lower in formula-fed infants fed than in infants fed breast milk (17.1% compared with 24.3% of threonine intake, respectively). Conclusion: Formula-fed infants have a lower capacity to oxidize threonine than do infants fed breast milk.

The Journal of Pediatrics, Jan 12, 1991

To determine whether the increase in resting energy expenditure in cystic fibrosis is associated ... more To determine whether the increase in resting energy expenditure in cystic fibrosis is associated with the primary genetic defect (AFs08) or with declining pulmonary function, or both, we tested resting every energy expenditure prospectively in 32 male subjects (aged 7 to 39 years) who were normally nourished and had good pulmonary function. They were categorized into three genotype groups on the basis of the presence or absence of AF508 and pancreatic function. Mean resting energy expenditure was 104% of the predicted value and was not associated with genotype. When 29 subjects with normal nutritional status but variable lung function were added to the group, there was a strong correlation between declining pulmonary function and increased resting energy expenditure. We conclude that increased resting energy expenditure in normally nourished boys and men with cystic fibrosis appears to be more closely associated with declining pulmonary function than with genotype. (J PEDIATR 1991;119:913-6)

The Journal of Nutrition, Nov 1, 2003

Recently, we defined an estimate for total branched-chain amino acids (BCAA) using the indicator ... more Recently, we defined an estimate for total branched-chain amino acids (BCAA) using the indicator amino acid oxidation technique in men fed the three BCAA (leucine, isoleucine and valine) in the proportion present in egg protein. Although egg protein is regarded as a high quality dietary protein source, it is not known whether the proportions of the three BCAA are optimal. Five men with known total BCAA requirements were restudied. Each men was studied with isoleucine, leucine or valine held constant at that individual's requirement level while the intake of the other two BCAA was reduced; one BCAA was held constant and the intake of the other two was reduced by 10 and 20% in random order. The label appearance from the oxidation of L-[ 13 C]-phenylalanine to 13 CO 2 (F 13 CO 2 ) in breath was monitored in response to the change in amino acid intake. When either isoleucine or leucine was held constant, and the other two BCAA reduced by 20% (valine and leucine, or valine and isoleucine, respectively) F 13 CO 2 increased (P ϭ 0.007, P ϭ 0.038, respectively). We conclude that valine may be the first limiting BCAA in egg protein. J. Nutr. 133: 3533-3539, 2003.

The Journal of Nutrition, Jun 1, 2007

Dietary aromatic amino acids are needed to meet the requirements for phenylalanine and tyrosine f... more Dietary aromatic amino acids are needed to meet the requirements for phenylalanine and tyrosine for protein synthesis.

The Journal of Pediatrics, Feb 1, 2003

To evaluate the relations among glucose intolerance, genotype, and exocrine pancreatic status in ... more To evaluate the relations among glucose intolerance, genotype, and exocrine pancreatic status in patients with cystic fibrosis (CF). Data on 335 patients <18 years of age were from the Toronto CF database. A modified oral glucose tolerance test was given to 94 patients 10 to 18 years of age without recognized CF-related diabetes. CF transmembrane conductance regulator mutations and exocrine pancreatic status were determined for all patients. CF-related diabetes was clinically recognized in 9 of 335 (2.7%) patients <18 years of age, all of whom were pancreatic insufficient, and 8 of 9 had severe (classes I through III) mutations on both alleles. The ninth patient had unidentified mutations. Although all patients given the oral glucose tolerance test were asymptomatic and had normal fasting blood glucose, 16 of 94 (17%) had impaired glucose tolerance and 4 of 94 (4.3%) had CF-related diabetes without fasting hyperglycemia. Abnormal glucose tolerance was associated exclusively with severe mutations and exocrine pancreatic insufficiency. Glycosylated hemoglobin (HbA(1)C) levels did not correlate with glucose tolerance results. Screening of pancreatic-insufficient, adolescent patients with CF identified more with abnormal oral glucose tolerance than was suspected clinically and is recommended as a routine practice. HbA(1)C was not useful in screening for CF-related glucose intolerance.

The Journal of Nutrition, 1994

The Faseb Journal, Apr 1, 2013

The Journal of Nutrition, Feb 1, 1999

Study of the amino acid metabolism of vulnerable groups, such as pregnant women, children and pat... more Study of the amino acid metabolism of vulnerable groups, such as pregnant women, children and patients, is needed. Our existing protocol is preceded by 2 d of adaptation to a low 13 C formula diet at a protein intake of 1 g ⅐ kg Ϫ1 ⅐ d Ϫ1 to minimize variations in breath 13 CO 2 enrichment and protein metabolism. To expand on our potential study populations, a less invasive protocol needs to be developed. We have already established that a stable background 13 CO 2 enrichment can be achieved on the study day without prior adaptation to the low 13 C formula. Therefore, this study investigates phenylalanine kinetics in response to variations in prior protein intake. Healthy adult subjects were each fed nutritionally adequate mixed diets containing 0.8, 1.4 and 2.0 g protein ⅐ kg Ϫ1 ⅐ d Ϫ1 for 2 d. On d 3, subjects consumed an amino acid-based formula diet containing the equivalent of 1 g protein ⅐ kg Ϫ1 ⅐ d Ϫ1 hourly for 10 h and primed hourly oral doses of L-[1-13 C]phenylalanine for the final 6 h. Phenylalanine kinetics were calculated from plasma-free phenylalanine enrichment and breath 13 CO 2 excretion. A significant quadratic response of prior protein intake on phenylalanine flux (P ϭ 0.012) and oxidation (P ϭ 0.009) was identified, such that both variables were lower following adaptation to a protein intake of 1.4 g ⅐ kg Ϫ1 ⅐ d Ϫ1 . We conclude that variations in protein intake, between 0.8 and 2.0 g ⅐ kg Ϫ1 ⅐ d Ϫ1 , prior to the study day may affect amino acid kinetics and; therefore, it is prudent to continue to control protein intake prior to an amino acid kinetics study.

The Journal of Nutrition, Apr 1, 2006

Malnutrition is prevalent in children with chronic cholestatic liver disease. Using the noninvasi... more Malnutrition is prevalent in children with chronic cholestatic liver disease. Using the noninvasive indicator amino acid oxidation (IAAO) technique, we recently determined that mild-to-moderate chronic cholestatic (MCC) liver disease increases the need for branched-chain amino acids (BCAA) in children. To examine the underlying mechanisms responsible for this increased need for BCAA in liver disease, we measured L-[1-13 C]-leucine oxidation in the postabsorptive and fed states in 10 children with MCC liver disease (8.8 6 3.5 y) and in 11 healthy children (9.4 6 2.2 y). The oxidation of L-[1-13 C]-leucine to 13 CO 2 [F 13 CO 2 in mmol/(kgÁh)] was determined after a primed, continuous oral administration of the tracer. Total BCAA in diet was provided at 300 mg/(kgÁd) to ensure that leucine oxidation was measured when leucine intake was in excess of requirements. In the postabsorptive state, the rate of release of 13 CO 2 from 13 C-leucine oxidation (F 13 CO 2 ) and whole-body leucine oxidation were significantly higher in children with MCC liver disease (P , 0.05). However, F 13 CO 2 and whole-body leucine oxidation did not differ in the fed state. We conclude that the increased need for dietary BCAA in MCC liver disease is mediated in part by increased leucine oxidation in the postabsorptive state. J. Nutr. 136: 965-970, 2006.