Sendia Kim

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.

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.

Risk of Vascular Anomalies With Down Syndrome

OBJECTIVE. Patients with Down syndrome have a reduced risk of developing solid tumors. This protective effect has been attributed to increased gene dosage from an additional copy of chromosome 21, and elevated expression of endostatin has been implicated. We hypothesized that vascular anomalies, including infantile hemangioma, an angiogenesis-dependent vascular tumor, and vascular malformations might be similarly inhibited in patients with Down syndrome. PATIENTS AND METHODS. The Childrens Hospital Boston Vascular Anomalies Center database was searched for patients with Down syndrome between 1999 and 2007. In addition, the records of patients with Down syndrome treated at Childrens Hospital Boston and the National Birth Defects Center between 1985 and 2007 were reviewed to find concurrent vascular anomalies. Two-sided exact binomial tests were used to evaluate whether patients with vascular anomalies are at reduced risk for Down syndrome or if patients with Down syndrome are at less risk for vascular anomalies compared with the general population. Ninety-five–percent confidence intervals were calculated on the basis of the risk of Down syndrome (1 in 800) and vascular anomalies (1 in 22) in the general population. RESULTS. Two of the 7354 patients evaluated in our vascular anomalies unit had Down syndrome. Both patients had a lymphatic malformation: one in the orbit and the other in the lower extremity. Six of the 633 patients with Down syndrome had a vascular anomaly (infantile hemangioma [n = 4] or lymphatic malformation [n = 2]). The risk of concurrent Down syndrome and vascular anomalies was different from the corresponding risk in the general population. CONCLUSIONS. Patients with Down syndrome have a reduced risk of vascular anomalies compared with the general population. Elevated expression of antiangiogenic proteins may protect these patients from developing vascular anomalies, as well as solid tumors.

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.

Reduction of hepatocellular injury after common bile duct ligation using omega-3 fatty acids

PURPOSE Bile duct obstruction and subsequent cholestasis produces hepatocellular injury and an inflammatory response. Fatty acid constitution of cell membranes plays a major role in the inflammatory cascade. Omega-3 fatty acids are antiinflammatory. We proposed that omega-3 fatty acid supplementation would reduce hepatocellular damage and cell death in a model of murine common bile duct ligation. METHODS Mice underwent bile duct ligation and were administered either control soy diet (omega-6) or Menhaden diet (omega-3), and parameters of liver injury were measured at postoperative days 1, 4, and 8. Serum was analyzed for liver function tests. Liver tissue was scored for histologic necrosis and inflammation, and apoptosis was qualitatively measured. RESULTS At day 8, comparing control and Menhaden, liver function tests were not significantly different. The H&E slides were analyzed and scored. At day 4, the mean necrosis scores for the Menhaden-fed group was 0.01 +/- 0.028 and 0.46 +/- 0.108 for the soy-fed group (P = .001) and at day 8, 0.420 +/- 0.107 and 1.22 +/- 0.132 (P < .001). The mean portal inflammation score for day 4 Menhaden-fed and soy-fed mice was 1.40 +/- 0.245 for both groups (P = 1.00) and for day 8, 1.80 +/- 0.200 and 2.80 +/- 0.200 (P = .008). At day 1, the median terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling scores of the Menhaden vs soy group were 6.0 and 0.0 (P < .001); day 4, 24.0 and 3.0 (P < .001); and day 8, 0.0 and 3.0 (P < .001), respectively. CONCLUSION Although there appears to be a trend toward biochemical protection and a marked reduction of necrosis and inflammation, there was no significant liver function test difference between control and Menhaden groups. Considering our data of blunted histologic hepatotoxicity with omega-3 fatty acid supplementation, we hypothesize that this may be a method of reducing long-term complications of liver injury secondary to diseases of cholestasis such as biliary atresia, namely fibrosis and cirrhosis.

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.

Pediatric rib lesions: a 13-year experience.

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,

Acute necrotizing cholecystitis: a rare complication of ceftriaxone-associated pseudolithiasis

BACKGROUND Rib lesions in the pediatric population are rare but significant processes and are often neoplastic. METHODS All patients with primary rib lesions evaluated by the Department of Surgery at Childrens Hospital Boston from 1992 to 2005 were studied. The patients diagnosis, sex, symptoms and their duration, radiologic evaluation, biopsy status, surgical procedure, and follow-up were assessed. RESULTS Thirty-three patients, ages 3 to 23 years (median, 12.7 years), were evaluated. Sixteen patients (48%) had benign and 17 (52%) had malignant lesions. Within the benign cohort of 16 patients, there were 6 osteochondromas, 4 aneurysmal bone cysts, and 2 fibrous dysplasias as well as 1 of each of the following: enchondroma, periosteal chondroma, eosinophilic granuloma, and chondrophyte. Within the malignant cohort of 17 patients, 13 were diagnosed with Ewings sarcoma, 3 with osteogenic sarcoma, and 1 with chondrosarcoma. The sex distribution for the malignant group was 11 (65%) females and 6 (35%) males. CONCLUSIONS Rib tumors are rare entities in the pediatric population. However, a significant number of rib lesions are malignant. Therefore, proper diagnosis and expeditious treatment are critical.

Perioperative corticosteroid reduces hospital stay after fronto-orbital advancement.

A 16-year-old male patient (59 kg) who presented to his primary care physician with a 3 week history of lethargy and myalgias. His physical examination was notable for a 5-cm bullseye lesion on his right foot, which was thought to be a spider bite. This resolved without treatment after 1 week. He developed a similar lesion on his left forearm, which also resolved on its own after 1 week. Four weeks after his symptoms began, he presented to our institution with a headache, jaw stiffness, and left-sided facial weakness (Bell’s Palsy). He had a white blood cell count of 32,000 (normal 4,000–10,000). Lyme titers were positive. A lumbar puncture was performed and he was diagnosed with Lyme meningitis. He was treated with ceftriaxone 2 g intravenously twice a day for 4 weeks. The patient developed right upper quadrant pain 1 week after completing his treatment. The pain was intermittent and gradually became more severe over the next 2 weeks. He was seen again at our institution and an abdominal ultrasound was performed. It showed multiple gallstones with one gallstone in the gallbladder neck and mild gallbladder wall thickening (4 mm). There was no pericholecystic fluid and the common bile duct appeared normal. Due to his persistent and worsening symptoms, he underwent a laparoscopic cholecystectomy. He had a significant amount of inflammation around the gallbladder with indiscernible anatomy, and thus we converted to an open procedure. The pathological analysis showed acute necrotizing cholecystitis with surface erosions. The stone analysis by polarization microscopy and infrared spectroscopy revealed that the stone compositionwas 100%ceftriaxone (Laboratory for Stone Research, Newton, MA, USA).