Hau Le - Academia.edu (original) (raw)

Papers by Hau Le

Research paper thumbnail of Parenteral fish oil as monotherapy for patients with parenteral nutrition-associated liver disease

Pediatric Surgery International, 2009

Dear Editor,We read the paper by Diamond et al. [1] which provided a brief overview of the use of... more Dear Editor,We read the paper by Diamond et al. [1] which provided a brief overview of the use of fish oil in patients with short bowel syndrome and parenteral nutrition-associated liver disease (PNALD). In their article, the authors discourage the use of the fish oil-based Omegaven® (Fresenius Kabi, Bad Homburg, Germany) as the sole lipid source in patients on parenteral nutrition, which in our opinion is unwarranted.At our institution, we use Omegaven® at a dose of 1 g kg−1 day−1 as the sole source of lipid for the treatment of infants with PNALD under a compassionate use protocol [2, 3]. The author’s group from Canada mix Omegaven® with the standard soy bean oil-based lipid emulsion Intralipid® (Fresenius Kabi, Bad Homburg, Germany), as they believe that such a balanced mix makes more sense physiologically than an emulsion composed primarily of either omega-6 fatty acids (e.g., Intralipid®) or omega-3 fatty acids (e.g., Omegaven®). Unlike Intralipid®, however, the lipid component in ...

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid–deficient diet alters the response to endotoxin in rats

Metabolism-clinical and Experimental, 2000

This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional ... more This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid–deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase–1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Repetitive orogastric gavage affects the phenotype of diet-induced obese mice

Physiology & Behavior, 2010

Interest in pharmacological intervention to combat metabolic syndrome and its complications is in... more Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Tumor Necrosis Factor alpha-Converting Enzyme Inhibition Reverses Hepatic Steatosis and Improves Insulin Sensitivity Markers and Surgical Outcome in Mice

Research paper thumbnail of Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid–deficient diet alters the response to endotoxin in rats

Metabolism-clinical and Experimental, 2000

This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional ... more This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid–deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase–1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model

Metabolism-clinical and Experimental, 2010

Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing... more Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established, and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J male mice were fed either a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance, and obesity when switched to a 10%-fat diet for an additional 9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat–fed animals. Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity, and insulin resistance in the C57BL/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation of a potential treatment of patients with nonalcoholic fatty liver disease.

Research paper thumbnail of Repetitive orogastric gavage affects the phenotype of diet-induced obese mice

Physiology & Behavior, 2010

Interest in pharmacological intervention to combat metabolic syndrome and its complications is in... more Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of Using Parenteral Fish Oil In Nash

Nutrition, Diet Therapy, and the Liver, 2009

Research paper thumbnail of Parenteral fish oil as monotherapy for patients with parenteral nutrition-associated liver disease

Pediatric Surgery International, 2009

Dear Editor,We read the paper by Diamond et al. [1] which provided a brief overview of the use of... more Dear Editor,We read the paper by Diamond et al. [1] which provided a brief overview of the use of fish oil in patients with short bowel syndrome and parenteral nutrition-associated liver disease (PNALD). In their article, the authors discourage the use of the fish oil-based Omegaven® (Fresenius Kabi, Bad Homburg, Germany) as the sole lipid source in patients on parenteral nutrition, which in our opinion is unwarranted.At our institution, we use Omegaven® at a dose of 1 g kg−1 day−1 as the sole source of lipid for the treatment of infants with PNALD under a compassionate use protocol [2, 3]. The author’s group from Canada mix Omegaven® with the standard soy bean oil-based lipid emulsion Intralipid® (Fresenius Kabi, Bad Homburg, Germany), as they believe that such a balanced mix makes more sense physiologically than an emulsion composed primarily of either omega-6 fatty acids (e.g., Intralipid®) or omega-3 fatty acids (e.g., Omegaven®). Unlike Intralipid®, however, the lipid component in ...

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid–deficient diet alters the response to endotoxin in rats

Metabolism-clinical and Experimental, 2000

This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional ... more This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid–deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase–1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Repetitive orogastric gavage affects the phenotype of diet-induced obese mice

Physiology & Behavior, 2010

Interest in pharmacological intervention to combat metabolic syndrome and its complications is in... more Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of The essentiality of arachidonic acid and docosahexaenoic acid

Prostaglandins Leukotrienes and Essential Fatty Acids, 2009

The purpose of this review is to correlate the clinical finding that patients receiving parentera... more The purpose of this review is to correlate the clinical finding that patients receiving parenteral nutrition with a fish oil-based lipid emulsion do not develop essential fatty acid deficiency (EFAD) with an experimental murine model, thus showing that arachidonic acid (AA) and docosahexaenoic acid (DHA) are likely to be the essential fatty acids.Conventional belief is that linoleic acid (LA, omega-6) and alpha-linolenic acid (ALA, omega-3) are the essential fatty acids (EFAs). We have shown that a fish oil-based lipid emulsion containing AA (omega-6) and docosahexaenoic acid (omega-3) and insignificant quantities of LA and ALA is efficacious in the treatment of parenteral nutrition-associated liver disease (PNALD), a major cause of liver-related morbidity and mortality. The prospect of using a fish oil-based lipid emulsion as monotherapy has raised concerns of EFAD development, hindering its adoption into clinical practice.Data from patients in our institution who received PN with a fish oil-based lipid emulsion was reviewed for clinical and biochemical evidence of EFAD, defined as an elevated triene–tetraene ratio (Mead acid/AA>0.2). We also investigated the minimum amount of fish oil required to prevent EFAD in a murine model and determined whether DHA and AA alone can prevent EFAD.No patients receiving PN with a fish oil-based lipid emulsion in our institution have developed biochemical or clinical evidence of EFAD such as an elevated triene–tetraene ratio, growth retardation or dermatitis. This observation parallels our previously published animal studies, which demonstrated prevention of EFAD when 13% of total calories were from fish oil. Moreover, current work in our laboratory shows that AA and DHA provision alone is sufficient to prevent biochemical and physiologic evidence of EFAD in a murine model.When dosed appropriately, fish oil-based lipid emulsions contain sufficient EFAs to prevent EFAD. Furthermore, AA and DHA alone may be the true EFAs.

Research paper thumbnail of Tumor Necrosis Factor alpha-Converting Enzyme Inhibition Reverses Hepatic Steatosis and Improves Insulin Sensitivity Markers and Surgical Outcome in Mice

Research paper thumbnail of Arachidonic acid and docosahexaenoic acid supplemented to an essential fatty acid–deficient diet alters the response to endotoxin in rats

Metabolism-clinical and Experimental, 2000

This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional ... more This study examined fatty acid profiles, triene-tetraene ratios (20:3n9/20:4n6), and nutritional and inflammatory markers in rats fed an essential fatty acid–deficient (EFAD) diet provided as 2% hydrogenated coconut oil (HCO) alone for 2 weeks or with 1.3 mg of arachidonic acid (AA) and 3.3 mg of docosahexaenoic acid (DHA) (AA + DHA) added to achieve 2% fat. Healthy controls were fed an AIN 93M diet (AIN) with 2% soybean oil. The HCO and AA + DHA diets led to significant reductions of linoleic acid, α-linolenic acid, and AA (20:4n6) and increases in Mead acid (20:3n9) in plasma and liver compared with the AIN diet; but the triene-tetraene levels remained well within normal. However, levels of 20:3n9 and 20:4n6 were lower in liver phospholipids in the AA + DHA than in HCO group, suggesting reduced elongation and desaturation in ω-9 and -6 pathways. The AA + DHA group also had significantly lower levels of 18:1n9 and 16:1n7 as well as 18:1n9/18:0 and 16:1n7/16:0 than the HCO group, suggesting inhibition of stearyl-Co A desaturase–1 activity. In response to lipopolysaccharide, the levels of tumor necrosis factor and interleukin-6 were significantly lower with HCO, reflecting reduced inflammation. The AA + DHA group had higher levels of IL-6 and C-reactive protein than the HCO group but significantly lower than the AIN group. However, in response to endotoxin, interleukin-6 was higher with AA + DHA than with AIN. Feeding an EFAD diet reduces baseline inflammation and inflammatory response to endotoxin long before the development of EFAD, and added AA + DHA modifies this response.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Inhibition of Intra-Abdominal Adhesion Formation With the Angiogenesis Inhibitor Sunitinib

Journal of Surgical Research, 2008

To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) ... more To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions.In the United States, complications from adhesions cost $1 billion and account for 846,000 inpatient days annually. Endothelial mitogens, such as VEGF, are up-regulated during adhesion formation. Sunitinib, a tyrosine kinase inhibitor with antiangiogenic and antitumor properties, may prevent or reduce postoperative abdominal adhesions by VEGFR-2 inhibition.The cecum of 37 mice were abraded to promote adhesion formation and a silicone patch was sutured to the abdominal wall. The mice were randomized into two groups: Group 1 was treated with sunitinib in methylcellulose by oral gavage daily and Group 2 (control) received methylcellulose alone. After 10 d the mice were sacrificed and intra-abdominal adhesions were scored. The experiment was then repeated and mice were sacrificed on postoperative day 30 to assess the long-term effects of sunitinib.All 19 control mice developed intra-abdominal adhesions. Six of the 18 (33.3%) mice in the treatment group were adhesion-free. Collectively, the sunitinib-treated mice had a lower adhesion score [2.0 (IQR 0.0–5.0; range 0–8.0)] than the control group [5.0 (IQR 3.0–8.0; range 2.0–10.0) (P = 0.002)]. Long-term results were consistent with this finding [sunitinib 0.0 (IQR 0.0–3.0; range 0–7) and control 6.0 (IQR 3.0–7.0; range 0–12) (P = 0.049)].Adhesion formation is angiogenesis-dependent and is in part mediated through VEGFR-2. Sunitinib, a VEGFR-2 antagonist, significantly reduces adhesion formation in a murine model. Antiangiogenic therapy may be an efficacious strategy to prevent or treat adhesions after intra-abdominal procedures.

Research paper thumbnail of Dietary fat intake promotes the development of hepatic steatosis independently from excess caloric consumption in a murine model

Metabolism-clinical and Experimental, 2010

Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing... more Nonalcoholic fatty liver disease results from overconsumption and is a significant and increasing cause of liver failure. The type of diet that is conducive to the development of this disease has not been established, and evidence-based treatment options are currently lacking. We hypothesized that the onset of hepatic steatosis is linked to the consumption of a diet with a high fat content, rather than related to excess caloric intake. In addition, we also hypothesized that fully manifested hepatic steatosis could be reversed by reducing the fat percentage in the diet of obese mice. C57BL/6J male mice were fed either a purified rodent diet containing 10% fat or a diet with 60% of calories derived from fat. A pair-feeding design was used to distinguish the effects of dietary fat content and caloric intake on dietary-induced hepatic lipid accumulation and associated injury. Livers were analyzed by quantitative reverse transcriptase polymerase chain reaction for lipid metabolism-related gene expression. After 9 weeks, mice on the 60%-fat diet exhibited more weight gain, insulin resistance, and hepatic steatosis compared with mice on a 10%-fat diet with equal caloric intake. Furthermore, mice with established metabolic syndrome at 9 weeks showed reversal of hepatic steatosis, insulin resistance, and obesity when switched to a 10%-fat diet for an additional 9 weeks, independent of caloric intake. Quantitative reverse transcriptase polymerase chain reaction revealed that transcripts related to both de novo lipogenesis and increased uptake of free fatty acids were significantly up-regulated in mice pair-fed a 60%-fat diet compared with 10%-fat–fed animals. Dietary fat content, independent from caloric intake, is a crucial factor in the development of hepatic steatosis, obesity, and insulin resistance in the C57BL/6J diet-induced obesity model caused by increased uptake of free fatty acids and de novo lipogenesis. In addition, once established, all these features of the metabolic syndrome can be successfully reversed after switching obese mice to a diet low in fat. Low-fat diets deserve attention in the investigation of a potential treatment of patients with nonalcoholic fatty liver disease.

Research paper thumbnail of Repetitive orogastric gavage affects the phenotype of diet-induced obese mice

Physiology & Behavior, 2010

Interest in pharmacological intervention to combat metabolic syndrome and its complications is in... more Interest in pharmacological intervention to combat metabolic syndrome and its complications is increasing as the prevalence of obesity is reaching epidemic proportions. The potential efficacy of drugs is often tested in animal models; however, the method of drug delivery is frequently overlooked and may act as a confounder due to stress. We hypothesized that long-term orogastric gavage would negatively influence the development of hepatic steatosis and the metabolic syndrome in a murine model of diet-induced obesity. C57BL/6J male mice were fed a high fat diet and were gavaged with a vehicle once or twice daily for 9 weeks. A group without orogastric gavaging served as control. A similar experiment was performed using leptin deficient ob/ob mice that were fed a standard diet for 4 weeks. Food intake was monitored, insulin resistance determined, and steatosis was assessed by histology and quantified via magnetic resonance spectroscopy. After 9 weeks, control C57BL/6J mice exhibited significantly more weight gain, insulin resistance and hepatic steatosis, compared to mice that were gavaged daily, or twice daily. This effect was likely due to decreased food consumption associated with gavage-induced stress. In contrast, the phenotype of leptin deficient ob/ob mice was not affected by orogastric gavage. Therefore, we concluded that orogastric gavage may lead to increased stress, thereby affecting food intake and the development of diet-induced obesity in a murine model. The effects of what may seem to be trivial laboratory routines, such as orogastric gavage, should be taken into account when designing animal studies for drug development.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of Parenteral Fish Oil as Monotherapy Prevents Essential Fatty Acid Deficiency in Parenteral Nutrition–dependent Patients

Journal of Pediatric Gastroenterology and Nutrition, 2010

Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving pa... more Objective-The use of fish oil-based emulsions as the sole source of fat for patients receiving parenteral nutrition (PN) has raised concerns for the development of essential fatty acid deficiency (EFAD), hindering its adoption into clinical practice. The purpose of this study was to examine fatty acid profiles of patients receiving no enteral calories, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth.

Research paper thumbnail of Using Parenteral Fish Oil In Nash

Nutrition, Diet Therapy, and the Liver, 2009