Danielle A. Arsenault

Safety and Efficacy of a Fish-Oil–Based Fat Emulsion in the Treatment of Parenteral Nutrition–Associated Liver Disease

BACKGROUND. Parenteral nutrition–associated liver disease can be a progressive and fatal entity in children with short-bowel syndrome. Soybean-fat emulsions provided as part of standard parenteral nutrition may contribute to its pathophysiology. METHODS. We compared safety and efficacy outcomes of a fish-oil–based fat emulsion in 18 infants with short-bowel syndrome who developed cholestasis (serum direct bilirubin level of >2 mg/dL) while receiving soybean emulsions with those from a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving soybean emulsions. The primary end point was time to reversal of cholestasis (3 consecutive measurements of serum direct bilirubin level of ≤2 mg/dL). RESULTS. Among survivors, the median time to reversal of cholestasis was 9.4 and 44.1 weeks in the fish-oil and historical cohorts, respectively. Subjects who received fish-oil–based emulsion experienced reversal of cholestasis 4.8 times faster than those who received soybean emulsions and 6.8 times faster in analysis adjusted for baseline bilirubin concentration, gestational age, and the diagnosis of necrotizing enterocolitis. A total of 2 deaths and 0 liver transplantations were recorded in the fish-oil cohort and 7 deaths and 2 transplantations in the historical cohort. The provision of fish-oil–based fat emulsion was not associated with essential fatty acid deficiency, hypertriglyceridemia, coagulopathy, infections, or growth delay. CONCLUSIONS. Parenteral fish-oil–based fat emulsions are safe and may be effective in the treatment of parenteral nutrition–associated liver disease.

Microdeformational wound therapy: effects on angiogenesis and matrix metalloproteinases in chronic wounds of 3 debilitated patients.

The vacuum-assisted closure (VAC) device causes microdeformations of the wound surface in contact with the foam. Because angiogenesis and matrix metalloproteinase (MMP) activity are altered in chronic wounds, we hypothesized that microdeformations stimulate capillary formation and affect MMP activity. A VAC device was used to deliver microdeformational wound therapy (MDWT) to the chronic wounds of 3 debilitated patients. Debrided tissue was obtained from wound areas with and without foam contact. Microvessel density and MMP activity were determined by immunohistochemistry and zymography, respectively. Microvessel density of MDWT-treated wounds was 4.5% (±0.8) compared with areas not covered by foam [1.6% (±0.1)] (P = 0.05) during the first week of treatment and 2.7% (±0.3) compared with untreated tissue [1.3% (±0.1)] (P = 0.03) during the second treatment week. Wounds subjected to MDWT had greater microvessel density compared with the same wound prior to treatment [1.5% (±0.3)] (P = 0.02). MMP-9/NGAL (neutrophil gelatinase-associated lipocalin), MMP-9, latent MMP-2, and active MMP-2 were reduced by 15%–76% in MDWT-treated wounds. MDWT provides a favorable wound-healing environment by increasing angiogenesis and decreasing MMP activity in chronic wounds.

Current Clinical Applications of Ω-6 and Ω-3 Fatty Acids

BACKGROUND Recent years have brought a resurgence of research interest in fatty acids, with studied fields running the gamut of human disease. This movement has run in parallel with an increased interest in using nutrition modalities as therapeutic measures, as opposed to their conventional role as energy sources. The aim of this manuscript is to provide a basic review of current clinical applications of ω-6 and ω-3 fatty acids, with a particular focus on the latter. METHODS A selective review of the voluminous literature, including randomized controlled trials, meta-analyses, population studies, and case reports, was used to compile data and identify trends in pertinent clinical applications of fatty acid therapy. CONCLUSIONS There are a myriad of disorders and maladies that seem to benefit from fatty acid supplementation, specifically ω-3 fatty acids. It has clearly been shown that ω-3 fatty acid supplementation provides a protective benefit in heart disease, and in particular sudden cardiac death. Rheumatoid arthritis (RA) is another disease entity that has been proven to benefit from this nutrition intervention, with improvement in symptoms and diminished nonsteroidal antiinflammatory drug (NSAID) usage. In addition, many psychiatric disorders, particularly schizophrenia and major depressive disorder (MDD), have shown positive results when supplementation has been used as an adjunct to standard pharmacotherapy. The remainder of clinical applications for ω-3 fatty acids requires further investigation. Specifically, according to preliminary clinical evidence, parenteral administration of fatty acids warrants further study.

Impact of Fish Oil-Based Lipid Emulsion on Serum Triglyceride, Bilirubin, and Albumin Levels in Children With Parenteral Nutrition-Associated Liver Disease

Parenteral nutrition is known to cause liver injury in babies. The aim of this study is to investigate the effects of different lipid emulsions on parenteral nutrition-associated cholestasis in infants. In addition, there may be a relationship between the lipid emulsion and triglyceride levels. Furthermore, triglyceride levels may correlate with direct bilirubin and albumin, as markers of liver impairment and nutritional status. Patients with parenteral nutrition-associated cholestasis who were treated with a fish oil-based lipid emulsion (n = 18) were prospectively followed for triglyceride, direct bilirubin, and albumin levels and compared with patients who were maintained on a soy-based lipid emulsion (n = 59). Triglyceride levels decreased in the fish oil cohort from a mean of 140 mg/dL at wk 0 to 40 mg/dL at wk 20 but remained unchanged at ∼140 mg/dL in the soybean cohort. Triglyceride levels of patients treated with fish oil declined over time, while those receiving soybean oil did not. Also, changes in triglyceride levels over time were directly correlated with direct bilirubin and inversely related to albumin levels. These findings may indicate an added benefit of reduced triglyceride levels for patients treated with fish oil and this effect coincides with markers for improved liver function and nutritional status.

FISH OIL PREVENTS ESSENTIAL FATTY ACID DEFICIENCY AND ENHANCES GROWTH: CLINICAL AND BIOCHEMICAL IMPLICATIONS

Fish oil, a rich source of omega-3 fatty acids, has never been used as the sole source of lipid in clinical practice for fear of development of essential fatty acid deficiency, as it lacks the believed requisite levels of linoleic acid, an omega-6 fatty acid. The objectives of this study were to establish biochemical standards for fish oil as the sole fat and to test the hypothesis that fish oil contains adequate amounts of omega-6 fatty acids to prevent essential fatty acid deficiency. Forty mice were divided into 2 groups that were either pair fed or allowed to eat ad libitum. In each group, 4 subgroups of 5 mice were fed 1%, 5%, and 10% fish oil diets by weight or a control soybean diet for 9 weeks. Blood was collected at 4 time points, and fatty acid analysis was performed. Food intake and weight status were monitored. All groups but the pair-fed 1% fish oil group gained weight, and the 5% fish oil group showed the highest caloric efficiency in both pair-fed and ad libitum groups. Fatty acid profiles for the 1% fish oil group displayed clear essential fatty acid deficiency, 5% fish oil appeared marginal, and 10% and soybean oil diets were found to prevent essential fatty acid deficiency. Fish oil enhances growth through higher caloric efficiency. We established a total omega-6 fatty acid requirement of between 0.30% and 0.56% of dietary energy, approximately half of the conventionally believed 1% as linoleic acid. This can presumably be attributed to the fact that fish oil contains not only a small amount of linoleic acid, but also arachidonic acid, which has greater efficiency to meet omega-6 fatty acid requirements.

A critical role for matrix metalloproteinases in liver regeneration.

BACKGROUND Matrix metalloproteinases (MMPs), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) are mediators of liver regeneration. To determine whether MMPs are required for normal hepatic regeneration, we performed 67% hepatectomies on mice treated with a broad-spectrum MMP-inhibitor, and assessed the effect on liver regeneration and urinary MMP activity. METHODS Mice were subjected to sham operations, 67% hepatectomy, or 67% hepatectomy plus treatment with the broad-spectrum MMP inhibitor Marimastat. Urine collected preoperatively and for 8 d postoperatively was tested for MMP-2 and MMP-9 activity using zymography. Serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, TNF-alpha, IL-6, and hepatocyte growth factor levels were measured. Liver sections were analyzed by CD31 immunohistochemistry and microvessel density. Mitotic index and proliferating cell nuclear antigen labeling index were determined. RESULTS The mean regenerating liver weight on postoperative day 8 was 0.72 +/- 0.01 grams for the hepatectomy Marimastat group, and 0.83 +/- 0.02 grams for the hepatectomy control group (P < 0.001). Urinary MMP-9 activity was elevated during hepatic regeneration, and decreased on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from hepatectomy Marimastat mice, in which liver regeneration was successfully inhibited, showed consistently low levels of MMP-2 and MMP-9 activity. The hepatectomy Marimastat group also exhibited elevated serum IL-6 levels on post-operative day 8, while serum TNF-alpha soluble receptor II levels were unchanged. Hepatocyte growth factor levels were not significantly different between the control hepatectomy and hepatectomy Marimastat groups at days 2, 4, and 8. Liver microvessel density was reduced in the hepatectomy Marimastat group at day 4. Mitotic index and proliferating cell nuclear antigen index were significantly decreased in the Marimastat hepatectomy group at post-operative day 2. CONCLUSIONS The broad-spectrum MMP-inhibitor Marimastat inhibits liver regeneration. Microvessel density is reduced at day 4. Furthermore, urinary MMP-9 is elevated during liver regeneration, and this effect is not observed when regeneration is inhibited by the broad-spectrum MMP-inhibitor Marimastat.

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

OBJECTIVE To determine the effects of sunitinib, a vascular endothelial growth factor receptor 2 (VEGFR-2) antagonist, on intra-abdominal adhesions. BACKGROUND In the United States, complications from adhesions cost

A.S.P.E.N. Clinical Guidelines Hyperglycemia and Hypoglycemia in the Neonate Receiving Parenteral Nutrition

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. METHODS 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. RESULTS 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)]. CONCLUSION 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.

Acid sphingomyelinase involvement in tumor necrosis factor α-regulated vascular and steroid disruption during luteolysis in vivo

This Clinical Guideline has been developed to guide clinical practice based on the authors’ assessment of current published evidence on glycemic control in the neonate (within the first month of life) receiving parenteral nutrition (PN). The neonate receiving PN is worthy of special consideration with respect to glucose control, as this population carries an elevated risk of hyperand hypoglycemia and may be more susceptible to deleterious effects associated with these conditions. Untreated hyperor hypoglycemia may lead to undesirable clinical outcomes. Prolonged or symptomatic hypoglycemia may result in neurodevelopmental impairment. Severe hyperglycemia can lead to osmotic diuresis resulting in dehydration and electrolyte imbalance. Furthermore there is some evidence to suggest that hyperglycemia in premature infants (particularly those that are very low birth weight (VLBW <1500 g) or extremely low birth weight (ELBW <1000 g)) has been positively correlated with morbidity and mortality, spurring questions about more proactive measures of managing elevated blood glucose levels in this group of patients. Thus, hyperglycemia and hypoglycemia are clinically-relevant complications that should be considered in caring for the neonate receiving PN and it is important to examine the parameters for defining,

Pediatric rib lesions: a 13-year experience.

TNF is well known for its role in inflammation, including direct effects on the vasculature. TNF also is implicated in the regulation of reproduction by its actions to affect ovarian steroidogenic cells and to induce apoptosis of corpus luteum (CL)-derived endothelial cells in vitro. We hypothesized that the disruption of TNF signaling would postpone the regression of the highly vascularized CL in vivo, and this effect could be replicated in mutant mouse models lacking TNF receptor (TNFRI−/−) and/or a critical enzyme of TNF signaling, acid sphingomyelinase (ASMase−/−). In the current study, the treatment of pseudopregnant mice with the luteolytic mediator prostaglandin F2-α (PGF) significantly increased TNF in the ovaries when compared with saline-treated controls. Treatment with PGF also reduced serum progesterone (P4) concentrations and caused involution of the CL. However, pretreatment of pseudopregnant mice with Etanercept (ETA), a TNF-neutralizing antibody, inhibited the PGF-induced decrease in P4 and delayed luteal regression. A similar outcome was evident in pseudopregnant TNFRI−/− animals. Treatment of luteal microvascular endothelial cells (MVECs) with TNF provoked a significant increase in ASMase activity when compared with the corresponding controls. Furthermore, TNF-induced MVEC death was inhibited in the ASMase−/− mice. The ASMase−/− mice displayed no obvious evidence of luteal regression 24 h after treatment with PGF and were resistant to the PGF-induced decrease in P4. Together these data provide evidence that TNF plays an active role in luteolysis. Further studies are required to determine the deleterious effects of anti-inflammatory agents on basic ovarian processes.