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INTRODUCTION: Patients with pectus excavatum (PE) often undergo cross-sectional imaging (CSI) to quantify severity for insurance authorization before surgical repair. The modified percent depth (MPD), an external caliper-based metric, was previously validated to be similar to the pectus index and correction index. This study explored family perceptions of CSI and MPD with respect to value and costs. METHODS: This is a cross-sectional survey study including families of patients enrolled in an ongoing prospective multicenter study evaluating the use of MPD as an alternative to CSI for quantifying PE severity. Families of PE patients who underwent both MPD and CSI completed a survey to determine their perceptions of MPD and costs of CSI. Responses were described and associations were evaluated using chi squared, Wilcoxon rank-sum test and logistic regression as appropriate. Statistical significance was set to 0.05. RESULTS: There were 136 surveys completed for a response rate of 88%. Respondents were confident in MPD (86%) and confident in its similarity to CSI (76%). Families of females were less confident in the measurements than males (55% versus 80%, P = 0.02; odds ratio 0.30 (0.11, 0.83). Obtaining CSI required time off work/school in 90% and a copay in 60%. Nearly half (49%) of respondents reported CSI was a time/financial hardship. Increasing copay led to decreased reassurance in CSI (55%: copay > $100 versus 77%: lower copay/75%: no copay; P = 0.04). CONCLUSIONS: From the family perspective, MPD is valuable in assessing the severity of PE. Obtaining CSI was financially burdensome, particularly for those with higher copays. MPD measurements provide high value at low cost in assessing the severity of PE.
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OBJECTIVE: The aim of this study was to quantify and describe baseline patient and parent-proxy health-related quality of life scores in patients with low-flow vascular malformations at a single, tertiary-care vascular anomalies clinic. STUDY DESIGN: This is a retrospective study of data collected on patients with low-flow vascular malformations between the ages of 2 to 25 who were seen at a single, tertiary-care center vascular anomalies clinic. A total of 266 patients are included in this study. RESULTS: Patients with lymphatic malformations report decreased quality of life scores as compared with venous malformations in the emotional, psychological, school, and social domains. Patients with lower extremity malformation report decreased quality of life scores as compared with head/neck, trunk, upper extremity, and multifocal malformations; most notably in the physical domain. CONCLUSIONS: Treatment of low-flow vascular malformations should aim to improve patient quality of life. The use of standardized health-related quality of life measures in this study quantifies baseline quality of life scores among patients with low-flow vascular malformations.
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BACKGROUND: Complications from esophageal button battery impactions remain a real fear for practicing pediatric gastroenterologists and surgeons. This case describes a child who developed an aorto-esophageal fistula 25 days after initial battery ingestion and survived due to prompt placement of an aortic stent via minimally invasive surgery, avoiding an open procedure. CASE PRESENTATION: A 6-year-old female presented acutely with a mid-esophageal button battery impaction witnessed by her parents. Presenting symptoms included chest pain and emesis. Button battery location and size were confirmed on X-ray. She underwent removal with flexible esophagogastroduodenoscopy (EGD) and rigid esophagoscopy. She was admitted to the hospital and received conservative medical management, with serial cross-sectional imaging via chest MRIs to assess the evolution of her injury according to available national guidelines, and was discharged after 12 days of close inpatient monitoring. Despite these measures the patient represented 25 days post-ingestion with hematemesis from a new aorto-esophageal fistula, requiring emergent cardiac catheterization with successful, life-saving aortic stent placement. She remained admitted for an additional 12 days of monitoring as her diet was advanced slowly post-catheterization. Since this second hospitalization she continues to do well, with outpatient follow-up by multiple subspecialists. CONCLUSIONS: This case highlights the continued uncertainty regarding the risk of developing this complication, as well as gaps in the current literature and guidelines for managing these patients following ingestion and esophageal injury. It also details the unique course following development of this complication and its surgical repair.
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INTRODUCTION: Prolonged operative time (OT) is considered a reflection of procedural complexity and may be associated with poor outcomes. Our purpose was to explore the association between prolonged OT and complications in children's surgery. METHODS: 182,857 cases from the 2012-2014 NSQIP-Pediatric were organized into 33 groups. OT for each group was analyzed by quartile, and regression models were used to determine the relationship between prolonged OT and complications. RESULTS: Variations in OT existed for both short and long procedures. Cases in the longest quartile had twice the odds of postoperative complications after adjusting for age, sex and BMI (OR 1.85; 95% CI 1.78-1.91). Procedure-specific prolonged OT was associated with postoperative complications for the majority (85%) of procedural groupings. Prolonged OT was associated with minor complications in gynecologic (OR 4.17; 95% CI 2.19-7.96), urologic (OR 2.88; 95% CI 2.40-3.44), and appendix procedures (OR 2.88; 95% CI 2.49-3.34). There were increased odds of major complications in foregut (OR 6.56; 95% CI 4.99-8.64), gynecologic (OR 3.07; 95% CI 1.84-5.13), and spine procedures (OR 2.99; 95% CI 2.57-3.28). CONCLUSIONS: Prolonged OT is associated with increased odds of postoperative complications across a spectrum of children's surgical procedures. Factors contributing to prolonged OT merit further investigation and may serve as a target for future quality improvement. LEVEL OF EVIDENCE: Level III.
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Duração da Cirurgia , Complicações Pós-Operatórias/etiologia , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Criança , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Melhoria de Qualidade , Fatores de Risco , Infecção da Ferida Cirúrgica/epidemiologia , Fatores de TempoRESUMO
Anorexia nervosa is a medical and psychological disorder classically seen in young women who present with significant weight loss, a distorted body image, and an intense fear of gaining weight despite being underweight. A rare diagnosis that is also associated with weight loss is a trichobezoar, a collection of hair or hair-like fibers in the gastrointestinal tract, primarily in the stomach. In this report, we present the case of a 14.5-year-old girl with weight loss caused by a trichobezoar, initially thought to be due to anorexia nervosa, and we review the details of both disorders.
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Anorexia Nervosa/complicações , Bezoares/complicações , Bezoares/diagnóstico , Adolescente , Bezoares/diagnóstico por imagem , Diagnóstico Tardio , Diagnóstico Diferencial , Feminino , Humanos , Radiografia , Redução de PesoRESUMO
BACKGROUND: Paracetamol (APAP) hepatotoxicity remains the leading cause of drug-induced liver failure. Fish oil, which contains ω-3 fatty acids, has demonstrated therapeutic efficacy in several models of liver disease. Evidence for its use in APAP intoxication, however, is conflicting. The effects of fish oil supplementation on APAP-induced liver failure were investigated. METHODS: Ten C57BL6/J mice were fed a diet based on menhaden fish oil (MEN) or soybean oil (SOY) for 3 weeks followed by APAP intoxication. In a second experiment, the prefeeding period was reduced to 5 days. In a third experiment, 10 mice received the study diets for 3 weeks, after which they received chronic, low-dose APAP administration for another 4 weeks. Finally, 10 mice received oral parenteral nutrition supplemented with either intravenous (IV) soybean-based or fish oil-based lipid emulsion for 19 days, followed by APAP intoxication. RESULTS: The extent of hepatocellular necrosis (3.8 ± 0.2 vs 2.8 ± 0.2; P = .021) and serum alanine aminotransferase values (2807 ± 785 vs 554 ± 141 IU/L; P = .048) were significantly elevated in mice fed a MEN diet compared with SOY-diet fed controls. Long-term, low-dose APAP administration did not lead to liver injury irrespective of study diet. Pretreatment with soybean- or fish oil-based IV lipid emulsions followed by APAP intoxication demonstrated no significant differences in hepatic injury between groups. CONCLUSION: Within therapeutic ranges, APAP is harmless to the liver irrespective of dietary fat composition. IV use of fish oil did not increase APAP-induced hepatotoxicity, but animals fed a fish oil-based diet were more susceptible, rather than resistant, to APAP-induced hepatotoxicity.
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Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas , Gorduras na Dieta/efeitos adversos , Emulsões Gordurosas Intravenosas/efeitos adversos , Óleos de Peixe/efeitos adversos , Falência Hepática/induzido quimicamente , Fígado/efeitos dos fármacos , Alanina Transaminase/sangue , Analgésicos não Narcóticos/administração & dosagem , Analgésicos não Narcóticos/efeitos adversos , Animais , Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Dieta , Suplementos Nutricionais , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Fígado/enzimologia , Fígado/patologia , Falência Hepática/enzimologia , Falência Hepática/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Nutrição Parenteral , Óleo de Soja/farmacologiaRESUMO
OBJECTIVE: Essential fatty acids (EFA) are necessary for growth, development, and biological function, and must be acquired through the diet. While linoleic acid (LA) and alpha-linolenic acid (ALA) have been considered the true EFAs, we previously demonstrated that docosahexaenoic acid (DHA) and arachidonic acid (AA) taken together as the sole source of dietary fatty acids can prevent biochemical essential fatty acid deficiency (EFAD). This study evaluates the effect of varying dietary ratios of DHA:AA in the prevention and reversal of biochemical EFAD in a murine model. METHODS: Using a murine model of EFAD, we provided mice with 2.1% of daily caloric intake in varying DHA:AA ratios (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) for 19 days in association with a liquid high-carbohydrate fat-free diet to evaluate the effect on fatty acid profiles. In a second experiment, we evaluated the provision of varying DHA:AA ratios (20:1, 200:1, 100:0) on the reversal of biochemical EFAD. RESULTS: Mice provided with DHA and AA had no evidence of biochemical EFAD, regardless of the ratio (1:1, 5:1, 10:1, 20:1, 200:1, 100:0) administered. Biochemical EFAD was reversed with DHA:AA ratios of 20:1, 200:1, and 100:0 following 3 and 5 weeks of dietary provision, although the 20:1 ratio was most effective in the reversal and stabilization of the triene:tetraene ratio. CONCLUSION: Provision of DHA and AA, at 2.1% of daily caloric intake in varying ratios can prevent biochemical evidence of EFAD and hepatic steatosis over the short-term, with a ratio of 20:1 DHA:AA most effectively reversing EFAD.
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Ácido Araquidônico/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Essenciais/deficiência , Animais , Dieta , Dieta com Restrição de Gorduras , Carboidratos da Dieta/farmacologia , Gorduras na Dieta/farmacologia , Ácidos Graxos não Esterificados/sangue , Ácidos Graxos não Esterificados/metabolismo , Ácidos Graxos Insaturados/metabolismo , Feminino , Crescimento/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: The aim of this study was to determine the incidence of cholestasis and the correlation between cholestasis and weight-for-age z scores in parenteral nutrition-dependent neonates with gastroschisis. METHODS: A single-center retrospective review of 59 infants born with gastroschisis from January 2000 to June 2007 was conducted. Demographic and clinical data were collected and analyzed. Subjects were divided into cholestatic and noncholestatic groups. Statistical analyses included the Student t test, Wilcoxon rank sum test, Fisher exact test, and a general linear model. RESULTS: Fifty-nine neonates with gastroschisis were identified, and 16 (28%) of 58 patients developed cholestasis. Younger gestational age and cholestasis were found to be independently associated with weight-for-age z score in 30 of 58 patients with available long-term follow-up data. CONCLUSIONS: Parenteral nutrition-dependent neonates with gastroschisis remain at considerable risk for the development of cholestasis. Both gestational age and cholestasis were found to be independent risk factors, predisposing these neonates to poor postnatal growth.
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Colestase/epidemiologia , Gastrosquise/terapia , Transtornos do Crescimento/epidemiologia , Nutrição Parenteral/efeitos adversos , Técnicas de Fechamento de Ferimentos Abdominais , Peso ao Nascer , Peso Corporal , Colestase/etiologia , Feminino , Gastrosquise/cirurgia , Idade Gestacional , Transtornos do Crescimento/etiologia , Humanos , Incidência , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/epidemiologia , Enteropatias/epidemiologia , Tempo de Internação/estatística & dados numéricos , Transplante de Fígado , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Sepse/epidemiologiaRESUMO
OBJECTIVES: Essential fatty acids are important for growth, development, and physiologic function. α-Linolenic acid and linoleic acid are the precursors of docosahexaenoic and arachidonic acid, respectively, and have traditionally been considered the essential fatty acids. However, the authors hypothesized that docosahexaenoic acid and arachidonic acid can function as the essential fatty acids. METHODS: Using a murine model of essential fatty acid deficiency and consequent hepatic steatosis, the authors provided mice with varying amounts of docosahexaenoic and arachidonic acids to determine whether exclusive supplementation of docosahexaenoic and arachidonic acids could prevent essential fatty acid deficiency and inhibit or attenuate hepatic steatosis. RESULTS: Mice supplemented with docosahexaenoic and arachidonic acids at 2.1% or 4.2% of their calories for 19 days had normal liver histology and no biochemical evidence of essential fatty acid deficiency, which persisted when observed after 9 weeks. CONCLUSION: Supplementation of sufficient amounts of docosahexaenoic and arachidonic acids alone without α-linolenic and linoleic acids meets essential fatty acid requirements and prevents hepatic steatosis in a murine model.
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Ácido Araquidônico/administração & dosagem , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Graxos Essenciais/deficiência , Fígado Gorduroso/prevenção & controle , Animais , Óleo de Coco , Modelos Animais de Doenças , Ingestão de Energia , Camundongos , Camundongos Endogâmicos C57BL , Óleos de Plantas/administração & dosagemRESUMO
BACKGROUND: Hepatic steatosis is an established risk factor for complications following major hepatic resection. Pharmacological options to reverse steatosis prior to surgery, however, are lacking. We hypothesized that treatment with the pharmacologic tumor necrosis factor-α converting enzyme (TACE)-inhibitor Marimastat would reverse established steatosis, leading to improved outcome following hepatectomy. METHODOLOGY/PRINCIPAL FINDINGS: C57BL/6 male mice were fed a high fat diet for 9 weeks to establish obesity, hepatic steatosis and insulin resistance, and were administered either Marimastat or vehicle for an additional 2 or 4 weeks. Leptin deficient, hyperinsulinemic ob/ob mice were treated with Marimastat for 4 weeks. Hepatic steatosis was quantified by magnetic resonance spectroscopy and confirmed by histology. After two weeks, Marimastat-treated animals significantly improved surrogate markers for insulin sensitivity and liver histology, and experienced a 66% decrease in steatosis (Pâ=â0.010). These findings were confirmed in ob/ob mice. Transcripts related to fatty acid synthesis were significantly downregulated in Marimastat-treated animals. Following pre-treatment with Marimastat or vehicle for two weeks, high fat fed C57BL/6 mice were subjected to two-thirds hepatectomy. Post-operative liver injury as quantified by serum aspartate aminotransferase levels and alanine aminotransferase levels was significantly decreased by 57% (Pâ=â0.020) and 44% (Pâ=â0.032) respectively, compared to controls. CONCLUSION/SIGNIFICANCE: Treatment with the TACE-inhibitor Marimastat improved surrogate markers for insulin sensitivity and reversed steatosis in mouse models of diet-induced obesity and leptin deficiency, thereby attenuating post-operative injury following hepatectomy. This may suggest a potential therapeutic role in patients with fatty liver disease; especially those who need to undergo hepatic resection.
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Proteínas ADAM/antagonistas & inibidores , Fígado Gorduroso/metabolismo , Fígado Gorduroso/cirurgia , Ácidos Hidroxâmicos/farmacologia , Insulina/metabolismo , Inibidores de Proteases/farmacologia , Proteínas ADAM/metabolismo , Proteína ADAM17 , Adipocinas/sangue , Animais , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia , Retroalimentação Fisiológica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatectomia/efeitos adversos , Ácidos Hidroxâmicos/uso terapêutico , Resistência à Insulina , Leptina/deficiência , Fígado/efeitos dos fármacos , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Inibidores de Proteases/uso terapêutico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: Postoperative abdominal adhesions are a major cause of morbidity and mortality. We previously demonstrated the inhibitory effect of sunitinib, a receptor tyrosine kinase inhibitor, on adhesion formation in a murine model, and now investigate its effects in a rabbit model. METHODS: Forty New Zealand White rabbits underwent a standard adhesion procedure. Preoperatively, animals were randomized to treatment with sunitinib or saline (control). Animals were treated with a total of 11 daily doses, 1 preoperative and 10 postoperative. One group of 20 animals (group 1) was humanely killed on postoperative day 10, and the other (group 2) on postoperative day 30. After killing, adhesions were scored and abdominal wounds were collected for tensile strength and microvessel density measurements. RESULTS: Sunitinib-treated animals in group 1 had a mean tenacity score of 1.67 ± 0.29 compared with 3.60 ± 0.16 in control animals (P < .01). Similarly, the mean tenacity scores for sunitinib-treated and control animals in group 2 were 0.20 ± 0.20 and 2.70 ± 0.37, respectively (P < .01). The mean uterine involvement scores for sunitinib-treated and control animals in group 1 were 1.44 ± 0.29 and 3.70 ± 0.15, respectively (P < .01), and in group 2 were 0.10 ± 0.10 and 2.70 ± 0.45, respectively (P < .01). There were no differences in ultimate or modular wound tensile strength between sunitinib-treated and control animals. CONCLUSION: Sunitinib significantly reduces postoperative adhesions in a rabbit model. This therapy may improve postoperative adhesion-related morbidity and mortality.
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Indóis/farmacologia , Pirróis/farmacologia , Aderências Teciduais/prevenção & controle , Inibidores da Angiogênese/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Microvasos/efeitos dos fármacos , Microvasos/patologia , Inibidores de Proteínas Quinases/farmacologia , Coelhos , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sunitinibe , Resistência à Tração , Aderências Teciduais/patologia , Aderências Teciduais/fisiopatologia , Útero/cirurgia , Ferimentos e Lesões/fisiopatologiaRESUMO
BACKGROUND: Plant-based intravenous lipid emulsions have been shown to contribute to parenteral nutrition-associated liver disease (PNALD). There is mounting evidence that fish oil-based emulsions may prevent this liver injury. This study compares 5 emulsions with different fat compositions and their effect on hepatic steatosis, one of the first hits in PNALD. METHODS: C57BL/6J mice were placed on a fat-free diet and randomized into 5 equal groups. Each group received one of the commercially available intravenous lipid emulsions (Intralipid [Baxter/Fresenius Kabi, Deerfield, Ill], Liposyn II [Hospira Inc, Lake Forest, Ill], ClinOleic [Baxter/Clintec Parenteral SA, Cedex, France], SMOFlipid [Fresenius Kabi, Bad Homburg, Germany], or Omegaven [Fresenius Kabi Deutschland GmbH]) or normal saline. Liver enzymes, degree of steatosis, and fatty acid compositions were analyzed after 19 days. RESULTS: Intralipid, Liposyn II, ClinOleic, and SMOFlipid groups all demonstrated moderate steatosis with hepatic fat contents of 17.4%, 21.9%, 22.5%, and 12.6%, respectively. Omegaven mice, however, had normal livers. Saline control mice developed biochemical evidence of essential fatty acid deficiency (EFAD). Lipid supplementation with Intralipid, Liposyn II, and Omegaven prevented the onset of biochemical EFAD, whereas administration of ClinOleic and SMOFlipid did not. CONCLUSION: The fish oil-based lipid emulsion Omegaven prevented hepatic steatosis and EFAD in this murine model. ω-3 fatty acids may be efficacious in preventing PNALD and should be explored in the development of novel lipid emulsions.
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Colestase/terapia , Emulsões Gordurosas Intravenosas/administração & dosagem , Falência Hepática/prevenção & controle , Nutrição Parenteral/métodos , Fosfolipídeos/administração & dosagem , Óleo de Soja/administração & dosagem , Animais , Colestase/complicações , Modelos Animais de Doenças , Emulsões/administração & dosagem , Falência Hepática/etiologia , Camundongos , Camundongos Endogâmicos C57BL , Resultado do TratamentoRESUMO
BACKGROUND: Parenteral nutrition (PN) is a life-saving therapy but has been associated with dyslipidemia. Because fish oil has been shown to have positive effects on lipid profiles, the authors hypothesize that a parenteral fish oil lipid emulsion will improve lipid profiles in children who are PN dependent. METHODS: The authors examined the lipid profiles of a unique cohort of 10 children who were exclusively administered a fish oil-based lipid emulsion while on PN for a median duration of 14 weeks. Longitudinal data analysis with a generalized estimating equations approach was used to determine the sterol and bilirubin levels based on duration of the fish oil-based lipid emulsion. RESULTS: After 14 weeks of fish oil monotherapy, children had a 24% increase in high-density lipoprotein. Compared to baseline, serum low-density lipoprotein, very low-density lipoprotein, total cholesterol, and triglyceride levels all significantly decreased by 22%, 41%, 17%, and 46%, respectively. Eight children had their bilirubin improved with a decreased direct bilirubin from 6.9 mg/dL (range, 4.4-10.7) at baseline to 2.3 mg/dL (range, 1.3-4.0) after 14 weeks, and a decrease in total bilirubin from 8.7 mg/dL (range, 5.5-13.7) to 3.8 mg/dL (range, 2.2-6.5). CONCLUSION: A fish oil-based lipid emulsion used as monotherapy in children who exclusively depended on PN for survival was associated with significant improvement in all major lipid panels as well as improvement of hyperbilirubinemia. Parenteral fish oil may be the preferred lipid source in children with dyslipidemia.
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Dislipidemias/tratamento farmacológico , Emulsões Gordurosas Intravenosas/uso terapêutico , Óleos de Peixe/uso terapêutico , Reguladores do Metabolismo de Lipídeos/uso terapêutico , Lipídeos/sangue , Hepatopatias/tratamento farmacológico , Nutrição Parenteral/efeitos adversos , Bilirrubina/sangue , Pré-Escolar , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/etiologia , Emulsões Gordurosas Intravenosas/farmacologia , Feminino , Óleos de Peixe/farmacologia , Humanos , Lactente , Recém-Nascido , Reguladores do Metabolismo de Lipídeos/farmacologia , Hepatopatias/sangue , Hepatopatias/etiologia , Estudos Longitudinais , Masculino , Triglicerídeos/sangueRESUMO
BACKGROUND: Liver fibrosis is characterized by excessive synthesis of extracellular matrix proteins, which prevails over their enzymatic degradation, primarily by matrix metalloproteinases (MMPs). The effect of pharmacological MMP inhibition on fibrogenesis, however, is largely unexplored. Inflammation is considered a prerequisite and important co-contributor to fibrosis and is, in part, mediated by tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). We hypothesized that treatment with a broad-spectrum MMP and TACE-inhibitor (Marimastat) would ameliorate injury and inflammation, leading to decreased fibrogenesis during repeated hepatotoxin-induced liver injury. METHODOLOGY/PRINCIPAL FINDINGS: Liver fibrosis was induced in mice by repeated carbon tetrachloride (CCl4) administration, during which the mice received either Marimastat or vehicle twice daily. A single dose of CCl4 was administered to investigate acute liver injury in mice pretreated with Marimastat, mice deficient in Mmp9, or mice deficient in both TNF-alpha receptors. Liver injury was quantified by alanine aminotransferase (ALT) levels and confirmed by histology. Hepatic collagen was determined as hydroxyproline, and expression of fibrogenesis and fibrolysis-related transcripts was determined by quantitative reverse-transcription polymerase chain reaction. Marimastat-treated animals demonstrated significantly attenuated liver injury and inflammation but a 25% increase in collagen deposition. Transcripts related to fibrogenesis were significantly less upregulated compared to vehicle-treated animals, while MMP expression and activity analysis revealed efficient pharmacologic MMP-inhibition and decreased fibrolysis following Marimastat treatment. Marimastat pre-treatment significantly attenuated liver injury following acute CCl4-administration, whereas Mmp9 deficient animals demonstrated no protection. Mice deficient in both TNF-alpha receptors exhibited an 80% reduction of serum ALT, confirming the hepatoprotective effects of Marimastat via the TNF-signaling pathway. CONCLUSIONS/SIGNIFICANCE: Inhibition of MMP and TACE activity with Marimastat during chronic CCl4 administration counterbalanced any beneficial anti-inflammatory effect, resulting in a positive balance of collagen deposition. Since effective inhibition of MMPs accelerates fibrosis progression, MMP inhibitors should be used with caution in patients with chronic liver diseases.
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Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Ácidos Hidroxâmicos/farmacologia , Cirrose Hepática/prevenção & controle , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Alanina Transaminase/sangue , Animais , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/sangue , Regulação para Baixo/efeitos dos fármacos , Cirrose Hepática/sangue , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVES: To update knowledge on the management of parenteral nutrition-associated liver disease (PNALD) and to review the clinical data on the use of parenteral fish oil for reversal of PNALD. DATA SOURCES: A literature review was conducted by searching the MEDLINE database (May 1, 2009) using the keywords parenteral nutrition-associated liver disease, fish oil, omega-3, Omegaven, and lipid emulsion. STUDY SELECTION: All articles reporting clinical cases with the use of parenteral fish oil for management of PNALD. DATA EXTRACTION: Three reviewers independently analyzed the epidemiological, clinical, and treatment data of the articles. DATA SYNTHESIS: Six case reports (10 patients) and 2 cohort studies (12 and 18 patients) were analyzed. CONCLUSIONS: Fish oil-derived emulsions have been demonstrated to reverse preexisting PNALD and to prevent and treat essential fatty acid deficiency. Its ability to prevent PNALD is currently under investigation. Although the mechanism has yet to be fully understood, the advantages of fish oil-based lipid emulsions over soybean oil-based lipid emulsions seen to date suggest that fish oil-based emulsions would be better suited for use in long-term parenteral nutrition.
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Óleos de Peixe/administração & dosagem , Hepatopatias/etiologia , Hepatopatias/terapia , Nutrição Parenteral/efeitos adversos , Animais , Modelos Animais de Doenças , Emulsões Gordurosas Intravenosas/efeitos adversos , Emulsões Gordurosas Intravenosas/uso terapêutico , Ácidos Graxos Ômega-3/efeitos adversos , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Seguimentos , Humanos , Testes de Função Hepática , Masculino , Camundongos , Nutrição Parenteral/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
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.
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Gorduras na Dieta/administração & dosagem , Nutrição Enteral , Leptina/deficiência , Obesidade/etiologia , Obesidade/genética , Fenótipo , Adiposidade , Alanina Transaminase/sangue , Animais , Glicemia/análise , Peso Corporal , Colesterol/sangue , Ingestão de Alimentos , Ingestão de Energia , Jejum/sangue , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Resistência à Insulina , Fígado/patologia , Espectroscopia de Ressonância Magnética , Masculino , Síndrome Metabólica/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Tamanho do Órgão , Índice de Gravidade de Doença , Estresse Fisiológico , Fatores de Tempo , Triglicerídeos/sangue , Aumento de PesoRESUMO
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.
Assuntos
Gorduras na Dieta/administração & dosagem , Ingestão de Energia , Fígado Gorduroso/etiologia , Alanina Transaminase/sangue , Animais , Modelos Animais de Doenças , Hiperfagia/etiologia , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão , Estearoil-CoA Dessaturase/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Aumento de PesoRESUMO
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 the present study was to examine fatty acid profiles of patients receiving no enteral energy, while completely dependent on PN and an intravenous fish oil-based lipid emulsion, for onset of EFAD and maintenance of growth. PATIENTS AND METHODS: Prospectively collected data from 10 patients were reviewed for evidence of EFAD, defined as a triene:tetraene ratio >0.2. Gestational age-adjusted z scores for length, growth, and head circumference at baseline were compared with the corresponding z scores at time of censoring. All of the patients received PN with a fish oil-based lipid emulsion at 1 g . kg . day as the sole source of fat energy for at least 1 month. The fish oil monotherapy was used under a compassionate use protocol. RESULTS: Median gestational age at the time of birth was 35 weeks, and median age at the start of treatment was 3.5 months. After a median time of 3.8 months on exclusive PN and fish oil-based lipid emulsion, none of the patients developed biochemical or clinical evidence of EFAD. z scores were not statistically different, indicating no growth impairment. Median direct bilirubin levels improved in 9 patients from 6.8 to 0.9 mg/dL (P = 0.009). CONCLUSIONS: : When dosed appropriately, fish oil-based lipid emulsions contain sufficient amounts of essential fatty acids to prevent EFAD and sustain growth in patients who are completely dependent on PN.
Assuntos
Bilirrubina/sangue , Gorduras na Dieta/sangue , Emulsões Gordurosas Intravenosas/efeitos adversos , Ácidos Graxos Essenciais/deficiência , Óleos de Peixe/administração & dosagem , Nutrição Parenteral/efeitos adversos , Pré-Escolar , Gorduras na Dieta/administração & dosagem , Emulsões Gordurosas Intravenosas/administração & dosagem , Ácidos Graxos Essenciais/sangue , Humanos , Lactente , Recém-Nascido , Nutrição Parenteral/métodos , Estudos ProspectivosRESUMO
OBJECTIVE: The objective was to determine the safety and efficacy of a fish oil-based intravenous lipid emulsion (ILE) in the treatment of parenteral nutrition-associated liver disease (PNALD). SUMMARY AND BACKGROUND DATA: PNALD can be a lethal complication in children with short bowel syndrome (SBS). ILE based on soybean oil administered with parenteral nutrition (PN) may contribute to its etiology. METHODS: We performed an open-labeled trial of a fish oil-based ILE in 42 infants with SBS who developed cholestasis (serum direct bilirubin >2 mg/dL) while receiving soybean oil-based ILE. Safety and efficacy outcomes were compared with those from a contemporary cohort of 49 infants with SBS and cholestasis whose PN course included soybean ILE only. The primary efficacy end-point was time to reversal of cholestasis (direct bilirubin <=2 mg/dL). RESULTS: Three deaths and 1 liver transplantation occurred in the fish oil cohort, compared with 12 deaths and 6 transplants in the soybean oil cohort (P = 0.005). Among survivors not transplanted during PN, cholestasis reversed while receiving PN in 19 of 38 patients in the fish oil cohort versus 2 of 36 patients in the soybean oil cohort. Based on Cox models, subjects receiving fish oil-based ILE experienced reversal of cholestasis 6 times faster (95% CI: 2.0-37.3) than those receiving soybean oil-based ILE. The provision of fish oil-based ILE was not associated with hypertriglyceridemia, coagulopathy, or essential fatty acid deficiency. Moreover, hypertriglyceridemic events and abnormal international normalized ratio levels were more common among controls. CONCLUSIONS: Fish oil-based ILE is safe, may be effective in treating PNALD, and may reduce mortality and organ transplantation rates in children with SBS.
Assuntos
Colestase/terapia , Emulsões Gordurosas Intravenosas/uso terapêutico , Óleos de Peixe/uso terapêutico , Nutrição Parenteral/métodos , Síndrome do Intestino Curto/complicações , Síndrome do Intestino Curto/terapia , Óleo de Soja/efeitos adversos , Colestase/etiologia , Interpretação Estatística de Dados , Emulsões Gordurosas Intravenosas/efeitos adversos , Feminino , Óleos de Peixe/efeitos adversos , Humanos , Lactente , Testes de Função Hepática , Transplante de Fígado/estatística & dados numéricos , Masculino , Nutrição Parenteral/efeitos adversos , Estudos Prospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Parenteral nutrition-associated liver disease (PNALD) is the most prevalent and most severe complication of long-term parenteral nutrition. Its underlying pathophysiology, however, largely remains to be elucidated. The currently approved parenteral lipid emulsions in the United States contain safflower or soybean oils, both rich in omega-6 polyunsaturated fatty acids (PUFAs). Mounting evidence indicates that the omega-6 PUFAs originating from plant oils in these lipid emulsions may play a role in the onset of liver injury. Fish oil-based lipid emulsions, in contrast, are primarily composed of omega-3 PUFAs, thus providing a promising alternative. The authors review the literature on the role of lipid emulsions in the onset of PNALD and discuss prevention and treatment strategies using a fish oil-based lipid emulsion. They conclude that a fish oil-based emulsion is hepatoprotective in a murine model of PNALD, and it appears to be safe and efficacious for the treatment of this type of liver disease in children. A prospective randomized trial that is currently under way at the authors' institution will objectively determine the place of fish oil monotherapy in the prevention of PNALD.