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Biomedical subjects

Vickie E Baracos

Publications and source records attributed to Vickie E Baracos.

At least 19 recordsLinked to original sources
PubMed2006

Glutamine supplementation influences immune development in the newly weaned piglet.

A study was conducted to determine changes that occur in immune function during the early post-weaning period and the effect of supplementing glutamine (gln, 4% w/w) to the weaning diet of piglets. Dutch-Landrace piglets (n=10/group) were killed prior to weaning (21 d) or randomized to one of two nutritionally complete weaning diets with or without gln. With age there was an increased ability of peripheral blood mononuclear cells (PBMC) and mesenteric lymph nodes (MLN) cells to proliferate (rate of (3)H-thymidine uptake) to T cell mitogens (P<0.05). PBMC from older piglets produced less of a Th-1 type response after stimulation (P<0.05). Adding gln to the weaning diet significantly (P<0.05) modified immune cells in the MLN, in a potentially beneficial manner (with respect to mucosal infections) by preventing an increase in antigen naïve CD4+ cells, increasing the proliferative response to pokeweed mitogen and supporting a Th-1 type cytokine response after T cell (phytohemagglutinin) stimulation.

Animals↗
PubMed2006

Drug utilization review on a tertiary palliative care unit.

Drugs are indispensable for the management of symptoms in palliative care patients, and account for a significant proportion of expenditures on a Tertiary Palliative Care Unit (TPCU). Drug expenditures for Edmonton's TPCU increased by 40% in 2002 compared to 2001. Fifty-five percent of the increase was attributable to injectable fentanyl, oral and injectable ondansetron, and total parenteral nutrition (TPN). As there was no increase in the unit cost of these drugs between 2001 and 2002, the increased expenditures reflected increased utilization. The hypothesis of this study was that the increased utilization of these drugs reflected appropriate prescribing. The objective was to compare the indications for prescribing these drugs in 2002 against evidence- and consensus-based criteria. Patients who received these drugs while admitted to the TPCU from January 1 to December 31, 2002 were identified through the pharmacy database. Evidence- and consensus-based criteria for drug utilization were developed. Prescribing indications were retrospectively compared against the criteria. Drug prescriptions were categorized as follows: (1) meeting criteria, (2) not meeting criteria, or (3) uncertain. The drugs under study were prescribed during 48 out of 234 admissions to the TPCU in 2002. Prescriptions for fentanyl met criteria in 26 of 29 cases. Indications were unsuccessful therapy with morphine, hydromorphone, and oxycodone (20), requirement for rapid titration from fentanyl patch (5), renal failure (2), and sublingual administration for breakthrough pain (1). Prescriptions for ondansetron met criteria in 19 of 21 cases. Indications were nausea refractory to metoclopramide and dexamethasone (13), and nausea related to radiotherapy or chemotherapy (6). Prescriptions for TPN met criteria for initiation in only one of five cases. However, in all cases, TPN had been started prior to admission. In cases where death was considered imminent, TPN was continued pending consultation with the patient and family regarding discontinuation. These data indicate that the increased prescribing of fentanyl and ondansetron on the TPCU satisfied evidence- and consensus-based criteria in most cases, apparently justifying the associated increase in drug expenditures. This type of analysis may be useful whenever increased drug utilization requires review. A cost effectiveness analysis would be the next step in evaluating the costs vs. the benefits. The issue of discontinuing TPN in palliative care patients requires further investigation.

Adult↗
PubMed2006

Dietary patterns in patients with advanced cancer: implications for anorexia-cachexia therapy.

BACKGROUND: Severe malnutrition and wasting are considered hallmarks of advanced malignant disease, and clinical research into anorexia-cachexia therapy and nutritional support for cancer patients is ongoing. However, information on typical dietary intakes and food choices for this population is notably lacking; proposed therapies for anorexia and wasting are not framed within the context of current intake. OBJECTIVE: The objective of the study was to characterize the food intake patterns of patients with advanced cancer. DESIGN: Patients with advanced cancer (n = 151) recruited from a regional cancer center and palliative-care program completed a 3-d dietary record a mean (+/-SD) 8 +/- 7 mo before death. Food items were categorized according to macronutrient content and dietary use and subsequently entered into cluster analysis. RESULTS: Wide variations in intakes of energy (range: 4-53 kcal . kg body wt(-1) . d(-1); x +/- SD: 25.1 +/- 10.0 kcal . kg body wt(-1) . d(-1)) and protein (range: 0.2-2.7 g . kg body wt(-1) . d(-1); x +/- SD: 1.0 +/- 0.4 g . kg body wt(-1) . d(-1)) were observed. Even the subjects with the highest intakes had a recent history of weight loss, which suggests that the diets of those persons were consistently inadequate for weight maintenance. Cluster analysis found 3 dietary patterns that differed in food choice and caloric intake. Low intakes and a high risk of weight loss were associated with decreased frequency of eating and dietary profiles with little variety and unusually high proportions of liquids. CONCLUSION: These data provide a glimpse into dietary habits toward the end of life. Unique dietary patterns were found in this nutritionally vulnerable patient population.

Aged↗
PubMed2006

Investigations of branched-chain amino acids and their metabolites in animal models of cancer.

Many of the features of BCAA metabolism in the tumor-bearing state are similar to the other disease states that feature involuntary weight loss and skeletal muscle atrophy. These states are generally characterized by altered BCAA availability (low BCAA intakes, elevated rates of BCAA oxidation, and gluconeogenesis), which are concurrent with activation of proteolysis and suppression of protein synthesis in skeletal muscle and ultimately lead to erosion of lean tissue mass. These features in turn imply BCAA deficiency compared with whole-body requirements and are the basis of suggestions for dietary supplementation with BCAA or their metabolites. Recent studies on BCAA supplementation in cancer focus on leucine and its derivative, beta-methyl beta-hydroxybutyrate, as regulators of skeletal muscle metabolism, although their relative efficacy is unknown. However, what would otherwise be a relatively straightforward consideration of amino acid supply and demand is confounded by the presence of the tumor and its potential utilization of BCAA for its proliferative and invasive activities. Positron emission tomography with (11)C-leucine, used for in vivo tumor imaging, points to the high avidity of tumor amino acid uptake. These features have incited research in opposing directions, probing BCAA deprivation, with a view to limiting tumor growth, as well as BCAA supplementation, with a view to supporting maintenance of host lean tissue. No clear conclusion is presently available from the sum of these efforts. Animal models with relevant clinical features are essential to determine if amino acid therapy can alter the balance between the host and the tumor in a manner that favors the host overall.

Amino Acids, Branched-Chain↗
PubMed2006

Integration of amino acid metabolism during intense lactation.

PURPOSE OF REVIEW: This review focuses on research from the author's laboratory and that of N.L. Trottier concerning protein and amino acid metabolism during intense lactation, a physiological state characterized by high rates of the net transfer of amino acids from physiological reserves in skeletal muscle to the mammary gland. These studies have broader interest for our understanding of the supply and distribution of amino acids towards key processes. RECENT FINDINGS: The synthesis of milk protein occurs at a distinct anatomical location, such that arterio-venous differences may be employed to identify all amino acid inputs into the mammary gland. These approaches can be used to determine the relative contributions to the mammary amino acid supply of systemic amino acid availability, transport system regulation and blood flow. Milk protein synthesis is partly reliant on the mobilization of endogenously stored protein in skeletal muscle, and our ability to modulate the size of physiological protein reserves and their rate of mobilization in an experimental context can be used to clarify the regulatory events that underlie the access to and eventual depletion of skeletal muscle protein. SUMMARY: Massive rates of milk production are achieved by increased mammary blood flow and amino acid extraction. Muscle protein mobilization is a key resource in the overall amino acid supply, and the absolute size of the protein reserve at parturition is a key factor in supporting lactation. The progressive depletion of muscle may ultimately provide insufficient substrate to support this process.

Amino Acids↗
PubMed2006

Cancer-associated cachexia and underlying biological mechanisms.

Cancer metastases (spread to distant organs from the primary tumor site) signify systemic, progressive, and essentially incurable malignant disease. Anorexia and wasting develop continuously throughout the course of incurable cancer. Overall, in Westernized countries nearly exactly half of current cancer diagnoses end in cure and the other half end in death; thus, cancer-associated cachexia has a high prevalence. The pathophysiology of cancer-associated cachexia has two principal components: a failure of food intake and a systemic hypermetabolism/hypercatabolism syndrome. The superimposed metabolic changes result in a rate of depletion of physiological reserves of energy and protein that is greater than would be expected based on the prevailing level of food intake. These features indicate a need for nutritional support, metabolic management, and a clear appreciation of the context of life-limiting illness.

Appetite↗
PubMed2006

The management of anorexia by patients with advanced cancer: a critical review of the literature.

This report presents the results of a critical review of the literature on the experience of anorexia (loss of appetite) by patients with advanced cancer. Although several studies have investigated this experience, the adaptive strategies used by patients to compensate for appetite loss remain poorly elucidated. Based on the small body of extant research, it was concluded that, in many instances, a gap exists between the ability of patients and caregivers to come to terms and deal realistically with the emotional and social consequences of patient anorexia. Patients generally appear to suffer greater discord as a result of this disparity, than from the direct psychological impact of anorexia. A greater understanding of the management of anorexia by patients is essential for the development of dietary and psychosocial interventions that would aid both patients and caregivers to cope with this common symptom.

Adaptation, Psychological↗
PubMed2005

Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts.

PURPOSE: Exercise is becoming readily accepted as a beneficial adjunct therapy to maintain or enhance quality of life in breast cancer patients undergoing adjuvant chemotherapy. An essential precursor to these studies is to investigate whether exercise modulates the antitumor efficacy of chemotherapeutic agents. EXPERIMENTAL DESIGN: Athymic female mice were transplanted with MDA-MB-231 breast xenografts and randomly assigned to one of four groups (n = 21 per group): (a) control, (b) exercise-only, (c) doxorubicin-only, or (d) exercise + doxorubicin. Exercise groups performed progressive treadmill running up to 18 m/min at 0% grade for 45 minutes, 5 d/wk for 8 weeks. RESULTS: Tumor growth delay was significantly longer in the doxorubicin-only and exercise + doxorubicin groups compared with the control (median 42 versus 25 days, P = 0.0082; 36 versus 25 days, P = 0.029, respectively) and exercise-only groups (median 42 versus 25 days, P = 0.029; 36 versus 25 days, P = 0.080, respectively). There was no significant difference between the doxorubicin-only and exercise + doxorubicin groups (median 42 versus 36 days, P = 0.33), suggesting that moderate intensity exercise does not significantly influence doxorubicin-induced tumor growth delay. CONCLUSION: These studies are essential to fully understand the safety and application of exercise as a supportive intervention in cancer control.

Animals↗
PubMed2005

A proinflammatory tumor that activates protein degradation sensitizes rats to catabolic effects of endotoxin.

Chronic or acute inflammation may participate in the etiology of cancer cachexia. To investigate the interaction between tumor and a secondary inflammatory stimulus on muscle wasting, rats with and without tumors (Yoshida ascites hepatoma) received low doses of endotoxin (LPS, 400 microg/kg sc) or saline. Nitrogen balance was measured 24 h before and after LPS/saline. Epitrochlearis muscle was used to measure in vitro protein metabolism, and gastrocnemius muscle was used for quantification of the mRNA for components of the ubiquitin proteolytic pathway. The YAH reduced muscle mass (P = 0.002), increased muscle protein degradation (P = 0.042), and elevated mRNA expression of components of the ubiquitin proteolytic pathway (P < 0.01) including ubiquitin, ubiquitin-conjugating enzyme E2(14k), and ubiquitin ligases muscle RING Finger 1 and atrogin-1. Although the selected low dose of LPS had no impact on protein metabolism in control rats, LPS in rats bearing YAH caused weight loss (P = 0.0007), lowered nitrogen balance (P = <0.0001), and increased muscle protein degradation (P = 0.0336). In conclusion, the presence of a tumor can potentiate whole body and muscle-specific catabolic losses of protein in response to a stimulus that is not catabolic in healthy animals. This effect might be dependent on the inflammatory nature of the tumor.

Animals↗
PubMed2004

Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia.

The progressive depletion of skeletal muscle is a hallmark of many types of advanced cancer and frequently is associated with debility, morbidity, and mortality. Muscle wasting is primarily mediated by the activation of the ubiquitin-proteasome system, which is responsible for degrading the bulk of intracellular proteins. E3 ubiquitin ligases control polyubiquitination, a rate-limiting step in the ubiquitin-proteasome system, but their direct involvement in muscle protein catabolism in cancer remains obscure. Here, we report the full-length cloning of E3alpha-II, a novel "N-end rule" ubiquitin ligase, and its functional involvement in cancer cachexia. E3alpha-II is highly enriched in skeletal muscle, and its expression is regulated by proinflammatory cytokines. In two different animal models of cancer cachexia, E3alpha-II was significantly induced at the onset and during the progression of muscle wasting. The E3alpha-II activation in skeletal muscle was accompanied by a sharp increase in protein ubiquitination, which could be blocked by arginine methylester, an E3alpha-selective inhibitor. Treatment of myotubes with tumor necrosis factor alpha or interleukin 6 elicited marked increases in E3alpha-II but not E3alpha-I expression and ubiquitin conjugation activity in parallel. E3alpha-II transfection markedly accelerated ubiquitin conjugation to endogenous cellular proteins in muscle cultures. These findings show that E3alpha-II plays an important role in muscle protein catabolism during cancer cachexia and suggest that E3alpha-II is a potential therapeutic target for muscle wasting.

Amino Acid Sequence↗
PubMed2004

Skeletal muscle protein mobilization during the progression of lactation.

To investigate changes in muscle metabolism during lactation, serial biopsy of the triceps brachii was conducted in first-parity sows subjected to three degrees of selective protein mobilization through restriction of dietary protein intake (see Clowes EJ, Aherne FX, Foxcroft GR, and Baracos VE. J Anim Sci 81: 753-764, 2003). Muscle biopsies were taken 7 days before parturition and at 12 and 23 days of lactation. The following changes occurred after parturition, were progressive, and were significantly magnified in animals under the greatest degree of dietary protein restriction and hence of protein mobilization. Decreased RNA-to-DNA ratio (capacity for protein synthesis) was observed. The presence of increased expression of several elements of the ubiquitin proteasome proteolytic pathway suggested a robust catabolic response. However, as lactation progressed, and especially under conditions of increased dietary protein restriction, protein mobilization increased, muscle RNA-to-DNA ratio fell further, protease gene expression continued to rise, tissue free glutamine levels rose dramatically, and essential amino acid levels, especially branched-chain amino acids and threonine, fell to below prepartum levels.

Amino Acids↗
PubMed2004

Animal models of amino acid metabolism: a focus on the intestine.

One important advantage of animal models is that they permit invasive approaches and can be especially valuable when evaluating tissue and specific features of metabolism in situ. The focus of this presentation is current models, which are providing insights into the pivotal importance of the gastrointestinal tract in amino acid metabolism. Intestinal amino acid metabolism is conceptually and technically difficult to approach and multiple processes must be accounted for: protein synthesis and degradation; transit of amino acids in both directions across the basolateral surface of enterocytes, in addition to uptake on the apical side; arterio-portal differences as well as net portal appearance during uptake of defined amino acid mixtures appearing on the luminal side; first pass amino acid metabolism. These key features are largely impossible to study without access to invasive approaches in vivo and cannot be reproduced in vitro. Douglas Burrin, Ron Ball, and Vickie Baracos and their co-workers have used the domestic piglet to study intestinal protein metabolism in situ in three distinctly different and complementary approaches. Collectively, their approaches allow a means to describe the key elements of intestinal amino acid capture (and release) and the means to probe their physiological and pathological variation. It seems evident that the portal-drained viscera represent sites of quantitatively important amino acid catabolism, and that this capacity combined with hepatic metabolism would largely limit the possibility of toxic sequelae of amino acids taken orally.

Amino Acids↗
PubMed2003

Modulation of intestinal protein synthesis and protease mRNA by luminal and systemic nutrients.

Route of nutrient supply is important in regulation of intestinal protein metabolism, because total parenteral nutrition, compared with enteral feeding, leads to profound atrophy. Participation of the fractional rate of protein synthesis (Ks), their degradation in regulation of gut protein balance, and their possible modulation by specific nutrients are the focus of our work. We developed an in situ experimental system that allows controlled exposure of intestinal mucosa to nutrients systemically, luminally, or both. We examined the effects of systemic glucose and amino acid (AA) infusion in overnight-fasted piglets. Jejunal segments within each piglet were simultaneously, luminally perfused with solutions containing various AAs or glucose. Intravenous infusion of glucose increased mucosal Ks by 16% (P < 0.05), whereas intravenous infusion of AA had no effect on Ks. Systemic glucose infusion had no effect on mRNA levels for components of the ubiquitin-proteasome proteolytic pathway. However, levels of these mRNA were reduced by intravenous or luminal AA supply. This effect was greatest (-50%) when highest tissue concentrations of AAs were achieved by the simultaneous infusion of AA by both routes (P < 0.05). Our findings suggest that not only is the modulation of protein balance in the intestine in response to nutrients in part attributable to anabolic stimulation of protein synthesis initiated by the systemic appearance of glucose, but a fall in protein degradation is also a likely contributor. AAs appear to be a key factor required to reduce expression of genes connected with proteolysis.

Amino Acids↗
PubMed2003

Expression and activity of matrix metallo proteinases 2 and 9 and their inhibitors in rat lungs during the perinatal period and in diaphragmatic hernia.

During lung development, the extracellular matrix undergoes dynamic remodeling. Matrix metalloproteinases (MMPs), and tissue inhibitors of matrix metalloproteinases (TIMPs), are important enzymes that participate in regulating tissue remodeling. There is an abnormal balance of the synthesis and degradation of collagen and elastin in perinatal lung associated with congenital diaphragmatic hernia (CDH). This study was designed to (1) determine the expression and gelatinolytic activity patterns of MMPs 2 and 9 and TIMPs 1 and 2 in rat lungs during the perinatal period, and (2) to test the hypothesis that they are abnormal in nitrofen-induced CDH. Measurements were made using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and zymography. The mRNA expression and activity of MMP 2 did not change significantly from embryonic day 16 to postnatal day 14. The most striking feature found was the rapid increase in the expression of MMP 9 soon after birth. Measurements were repeated on lung tissue isolated from embryonic rats with nitrofen-induced CDH. The expression and activity of MMPs and TIMPs were similar to control values and thus we conclude that these proteins appear not to be responsible for the altered extracellular matrix and morphological abnormalities noted in CDH lungs at birth.

Animals↗
PubMed2002

Hypercatabolism and hypermetabolism in wasting states.

The year 2001/2002 has been marked by a number of exciting new results for our understanding of anabolic and catabolic mediators and their participation in wasting states, as reflected by the contents of this section. It becomes ever more apparent that a clear understanding of how to shut off hypercatabolic and hypermetabolic processes is needed to underpin effective strategies for wasting syndromes. A particularly interesting development in the control of degradative processes in skeletal muscle is the discovery of several muscle-specific ubiquitin ligases. These enzymes, which confer specificity to the degradation of myofibrillar proteins and are situated in a pathway of proteolysis common to a variety of wasting states, may prove to be a valuable point of intervention in muscle atrophy. In the clinical arena, studies on non-small cell lung cancer patients as well as broader patient populations with solid tumours provide more evidence for a high incidence of hypermetabolism as well as low energy intake. The best therapies currently available for the cancer cachexia/anorexia syndrome have numerous limitations and tend mainly to attenuate losses rather than to promote a net gain of weight or lean body mass. Sustained hypermetabolism over the long course of disease progression constitutes an important contributor to negative energy balance, and its presence is likely to be a limiting factor to the success of current treatment approaches.

Anorexia↗
PubMed2002

Increased muscle proteolysis after local trauma mainly reflects macrophage-associated lysosomal proteolysis.

Rat gastrocnemius showed increased protein degradation (+75-115%) at 48 h after traumatic injury. Injured muscle showed increased cathepsin B activity (+327%) and mRNA encoding cathepsin B (+670%), cathepsin L (+298%), cathepsin H (+159%), and cathepsin C (+268%). In in situ hybridization, cathepsin B mRNA localized to the mononuclear cell infiltrate in injured muscle, and only background levels of hybridization were observed either over muscle cells in injured tissue or in uninjured muscle. Immunogold/electron microscopy showed specific staining for cathepsin B only in lysosome-like structures in cells of the mononuclear cell infiltrate in injured muscle. Muscle cells were uniformly negative in the immunocytochemistry. Matrix metalloproteinase-9 (granulocyte-macrophage gelatinase) mRNA and activity were not present in uninjured muscle but were expressed after trauma. There was no activation of the ATP-ubiquitin-proteasome-dependent proteolytic pathway in injured muscle, by contrast to diverse forms of muscle wasting where the activity of this system and the expression of genes encoding ubiquitin and proteasome elements rise. These results suggest that proteolytic systems of the muscle cells remain unstimulated after local injury and that lysosomal enzymes of the inflammatory infiltrated cells are likely to be the major participant in protein catabolism associated with local trauma.

Animals↗