Dietary supplementation with omega-3 in cystic fibrosis patients

Accumulation of neutr ophils releasing proteolytic enzymes and free radicals induceprogressive lung tissue destruction in CF. Among several hfflammatory mediatorsimplicated in this process, leukotriene B 4 (LTB4) product of arachidonic (AA;20:4n 6) omega 6 polytmsaturated fatty acid (PUFA) plays an important role.Various anti inflammatory strategies including dietary supplementation of omega 3PUFA, known to favor the synthesis of less active leukotriene B 5 (LTBs), have beeninvestigated. To further explore this nutritional approach, biological effects of anomega 3 PUFA oral supplementation (n 3 OS) were measured in 17 CF patients haa prospective, randomized, double blind, crossover study. CF patients (mean age:18 + 9 years, FEVI: 66 + 29 %) received a dietary supplementation enriched, or not,ha omega 3 PUFA during a 2 x 6 months period. A modification in neutrophilmembrane PUFA composition was observed under n 3 OS with an increase in EPA(20:5n 3) PUFA (from 0.66 ± 0.56 to 1.60 ± 0.61 ~tmol %, P< 0.01). The LTB jLTB 5ratio was decreased (from 72 + 27 to 24 + 7, P< 0.C~31), in CF patients taking n 3OS. However, n 3 OS supplementation did neither affect the internalization of bothIL 8 receptors following IL 8 exposure, nor IL 8 induced neutrophil chemotaxis.Our results show that n 3 PUFA are absorbed and incorporated in neutrophilmembrmae. The consecutive decrease ha LTBjLTB 5 ratio suggests that, ha theseconditions, neutr ophils may produce less toxic mediators from the AA pathway. Thepotential clinical benefit for CF patients still needs to be assessed with furtherstudies of longer duration and including more patients.

Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia.

The aberrant accumulation of lipids in the liver ("fatty liver") is tightly associated with several components of the metabolic syndrome, including type 2 diabetes, coronary heart disease, and atherosclerosis. Here we show that the impaired hepatic expression of transcriptional cofactor transducin beta-like (TBL) 1 represents a common feature of mono- and multigenic fatty liver mouse models. Indeed, the liver-specific ablation of TBL1 gene expression in healthy mice promoted hypertriglyceridemia and hepatic steatosis under both normal and high-fat dietary conditions. TBL1 deficiency resulted in inhibition of fatty acid oxidation due to impaired functional cooperation with its heterodimerization partner TBL-related (TBLR) 1 and the nuclear receptor peroxisome proliferator-activated receptor (PPAR) α. As TBL1 expression levels were found to also inversely correlate with liver fat content in human patients, the lack of hepatic TBL1/TBLR1 cofactor activity may represent a molecular rationale for hepatic steatosis in subjects with obesity and the metabolic syndrome.

Combined islet-lung transplantation in a cystic fibrosis patient.

The prevalence of insulin-dependent diabetes mellitus (IDDM) in cystic fibrosis patients ranges from 2 to 8% and glucose intolerance up to 15%. In recent years, lung transplantation has helped to prolong life expectancy of cystic fibrosis patients and represents 10 to 30% of all indications for lung transplantation. The postoperative need for immunosuppressive therapy using diabetogenic agents has decompensatory effects on glucose regulation and will probably increase the number of insulin-dependent cystic fibrosis patients. We report the case of an insulin-dependent cystic fibrosis patient transplanted with a combined islet-lung allograft. The pre-transplantation C-peptide level was below 0.04 nmol/l and preoperative insulin requirement was some 100 U per day. A sequential bipulmonary lung transplantation was performed and, using the pancreas of the same donor, we isolated and purified the islets of Langerhans by a modified automated method. We obtained 232,200 islets equivalent, which were injected into the liver by portal embolization. The postoperative course was uncomplicated, the insulin requirement decreased to 50% of the preoperative need and the C-peptide value increased to normal values and remained with the normal range during a follow-up period of 15 months. In conclusion, we believe that, besides type I diabetic patients, insulin-dependent cystic fibrosis patients with a negative C-peptide value could also be good candidates for combined islet-lung allotransplantation.

Disposition of venlafaxine enantiomers in rats with hepatic encephalopathy after chronic drug treatment.

Portacaval shunted (PCS) rats, a model of hepatic encephalopathy, and control animals were administered racemic venlafaxine for 14 days (10 mg/kg). The levels of the S- and R-enantiomers and the S/R-enantiomer ratios of venlafaxine and its metabolites were assessed by an enantiomer-selective chromatographic assay in serum, brain parenchyma, and brain dialysate of both groups. Higher levels of the S- and R-enantiomers of venlafaxine were found in serum and brain of PCS vs. normal rats (median values of S- and R-venlafaxine in serum: 290 and 201 nM in PCS; 97 and 66 nM in normal rats; median values of S- and R-venlafaxine in cortex: 956 and 939 nM in PCS; 357 and 318 nM in normal rats). Interestingly, similar S/R-venlafaxine ratios were observed in PCS and normal rats both in serum (S/R = 1.4) and brain compartments (S/R = l.0-1.1). These findings may have clinical relevance for the safety of venlafaxine in chronic hepatic encephalopathy.

Thérapies inhalées dans la mucoviscidose [Inhaled therapies for cystic fibrosis].

Inhaled therapies play a significant role in the management of cystic fibrosis patients. Mucolytic and airway-rehydrating agents improve mucociliary clearance and respiratory functional status. Nebulized antibiotherapy achieve high local concentration, while reducing systemic toxicity. Tolerance to inhaled treatments is good excepting frequent bronchoconstriction which can usually be prevented by prior administration of beta2-mimetics. The majority of treatments are only available in liquid formulations. Thus, nebulization is the most frequently used inhalation mode. Vibrating-mesh nebulizers have significantly reduced inhalation time.

Exacerbations aiguës au cours de la fibrose pulmonaire idiopathique [Acute exacerbations of idiopathic pulmonary fibrosis].

Although generally considered as a slowly evolving disease, idiopathic pulmonary fibrosis (IPF) is also characterized by episods of rapid deterioration with worsening of dyspnea and hypoxemia, and new ground glass opacities at imaging. These events called "acute exacerbations" (AE) are responsible for half of all deaths in IPF. Pathophysiologic mechanisms of AE are poorly understood. The effectiveness of corticosteroids and immunosuppressive agents appears limited. The mortality of AE is 60-70%. Preventing or controlling AE could improve the overall prognosis of IPF. AE also exist in other interstitial lung diseases.

Treatment of mediastinal fibrosis with mycophenolate mofetil.

We present the case of a 67-year-old male patient with mediastinal and retroperitoneal fibrosis. In Europe, this is a rare disease. Treatment was established to prevent complications due to strictures or compressions. Because of his diabetes, a therapy of low-dose prednisone combined with mycophenolate mofetil, known as steroid sparing agent, was applied. As a result, the radiological follow-up showed a marked decrease in the mediastinal and retroperitoneal masses.

Ostéo-arthropathie hypertrophiante révélatrice d'un hémangio-endothéliome épithélioïde multifocal hépatique et pulmonaire [Hypertrophic osteoarthropathy disclosing hepatic and pulmonary multifocal epithelioid hemangioendothelioma]

Epithelioid hemangioendothelioma is a rare, low-grade vascular malignancy reported for the first time in 1982 by Weiss and Enzinger. It involves one or, more rarely, several organs. We report a case involving the lungs and liver, in which the first manifestation was symptomatic hypertrophic osteoarthropathy. Findings four years after the diagnosis included very slow tumor spread, resolution of symptoms, and stabilization of radiological changes.

Effects of lactate infusion on hepatic gluconeogenesis and glycogenolysis.

Endogenous glucose production rate (EGPR) remains constant when lactate is infused in healthy humans. A decrease of glycogenolysis or of gluconeogenesis from endogenous precursors or a stimulation of glycogen synthesis, may all be involved; This autoregulation does not depend on changes in glucoregulatory hormones. It may be speculated that alterations in basal sympathetic tone may be involved. To gain insights into the mechanisms responsible for autoregulation of EGPR, glycogenolysis and gluconeogenesis were measured, with a novel method (based on the prelabelling of endogenous glycogen with 13C glucose, and determination of hepatic 13C glycogen enrichment from breath 13CO2 and respiratory gas exchanges) in healthy humans infused with lactate or saline. These measurements were performed with or without beta-adrenergic receptor blockade (propranolol). Infusion of lactate increased energy expenditure, but did not increase EGPR; the relative contributions of gluconeogenesis and glycogenolysis to EGPR were also unaltered. This indicates that autoregulation is attained, at least in part, by inhibition of gluconeogenesis from endogenous precursors. beta-adrenergic receptor blockade alone (with propranolol) did not alter EGPR, glycogenolysis or gluconeogenesis. During infusion of lactate, propranolol decreased the thermic effect of lactate but EGPR remained constant. This indicates that alterations of beta-adrenergic activity is not required for autoregulation of EGPR.

Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, and inflammatory and cell death signaling pathways in diabetic cardiomyopathy.

Objectives In this study, we have investigated the effects of cannabidiol (CBD) on myocardial dysfunction, inflammation, oxidative/nitrative stress, cell death, and interrelated signaling pathways, using a mouse model of type I diabetic cardiomyopathy and primary human cardiomyocytes exposed to high glucose. Background Cannabidiol, the most abundant nonpsychoactive constituent of Cannabis sativa (marijuana) plant, exerts anti-inflammatory effects in various disease models and alleviates pain and spasticity associated with multiple sclerosis in humans. Methods Left ventricular function was measured by the pressure-volume system. Oxidative stress, cell death, and fibrosis markers were evaluated by molecular biology/biochemical techniques, electron spin resonance spectroscopy, and flow cytometry. Results Diabetic cardiomyopathy was characterized by declined diastolic and systolic myocardial performance associated with increased oxidative-nitrative stress, nuclear factor-kappa B and mitogen-activated protein kinase (c-Jun N-terminal kinase, p-38, p38 alpha) activation, enhanced expression of adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1), tumor necrosis factor-alpha, markers of fibrosis (transforming growth factor-beta, connective tissue growth factor, fibronectin, collagen-1, matrix metalloproteinase-2 and -9), enhanced cell death (caspase 3/7 and poly[adenosine diphosphate-ribose] polymerase activity, chromatin fragmentation, and terminal deoxynucleotidyl transferase dUTP nick end labeling), and diminished Akt phosphorylation. Remarkably, CBD attenuated myocardial dysfunction, cardiac fibrosis, oxidative/nitrative stress, inflammation, cell death, and interrelated signaling pathways. Furthermore, CBD also attenuated the high glucose-induced increased reactive oxygen species generation, nuclear factor-kappa B activation, and cell death in primary human cardiomyocytes. Conclusions Collectively, these results coupled with the excellent safety and tolerability profile of CBD in humans, strongly suggest that it may have great therapeutic potential in the treatment of diabetic complications, and perhaps other cardiovascular disorders, by attenuating oxidative/nitrative stress, inflammation, cell death and fibrosis. (J Am Coll Cardiol 2010;56:2115-25) (C) 2010 by the American College of Cardiology Foundation.

Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men.

High-fructose diet stimulates hepatic de novo lipogenesis (DNL) and causes hypertriglyceridemia and insulin resistance in rodents. Fructose-induced insulin resistance may be secondary to alterations of lipid metabolism. In contrast, fish oil supplementation decreases triglycerides and may improve insulin resistance. Therefore, we studied the effect of high-fructose diet and fish oil on DNL and VLDL triglycerides and their impact on insulin resistance. Seven normal men were studied on four occasions: after fish oil (7.2 g/day) for 28 days; a 6-day high-fructose diet (corresponding to an extra 25% of total calories); fish oil plus high-fructose diet; and control conditions. Following each condition, fasting fractional DNL and endogenous glucose production (EGP) were evaluated using [1-13C]sodium acetate and 6,6-2H2 glucose and a two-step hyperinsulinemic-euglycemic clamp was performed to assess insulin sensitivity. High-fructose diet significantly increased fasting glycemia (7 +/- 2%), triglycerides (79 +/- 22%), fractional DNL (sixfold), and EGP (14 +/- 3%, all P < 0.05). It also impaired insulin-induced suppression of adipose tissue lipolysis and EGP (P < 0.05) but had no effect on whole- body insulin-mediated glucose disposal. Fish oil significantly decreased triglycerides (37%, P < 0.05) after high-fructose diet compared with high-fructose diet without fish oil and tended to reduce DNL but had no other significant effect. In conclusion, high-fructose diet induced dyslipidemia and hepatic and adipose tissue insulin resistance. Fish oil reversed dyslipidemia but not insulin resistance.

Oxidative phosphorylation flexibility in the liver of mice resistant to high-fat diet-induced hepatic steatosis.

OBJECTIVE To identify metabolic pathways that may underlie susceptibility or resistance to high-fat diet-induced hepatic steatosis. RESEARCH DESIGN AND METHODS We performed comparative transcriptomic analysis of the livers of A/J and C57Bl/6 mice, which are, respectively, resistant and susceptible to high-fat diet-induced hepatosteatosis and obesity. Mice from both strains were fed a normal chow or a high-fat diet for 2, 10, and 30 days, and transcriptomic data were analyzed by time-dependent gene set enrichment analysis. Biochemical analysis of mitochondrial respiration was performed to confirm the transcriptomic analysis. RESULTS Time-dependent gene set enrichment analysis revealed a rapid, transient, and coordinate upregulation of 13 oxidative phosphorylation genes after initiation of high-fat diet feeding in the A/J, but not in the C57Bl/6, mouse livers. Biochemical analysis using liver mitochondria from both strains of mice confirmed a rapid increase by high-fat diet feeding of the respiration rate in A/J but not C57Bl/6 mice. Importantly, ATP production was the same in both types of mitochondria, indicating increased uncoupling of the A/J mitochondria. CONCLUSIONS Together with previous data showing increased expression of mitochondrial β-oxidation genes in C57Bl/6 but not A/J mouse livers, our present study suggests that an important aspect of the adaptation of livers to high-fat diet feeding is to increase the activity of the oxidative phosphorylation chain and its uncoupling to dissipate the excess of incoming metabolic energy and to reduce the production of reactive oxygen species. The flexibility in oxidative phosphorylation activity may thus participate in the protection of A/J mouse livers against the initial damages induced by high-fat diet feeding that may lead to hepatosteatosis.

Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease.

Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6(-/-) mice received allogeneic non-T cell-depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6(-/-) recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6(-/-) recipients' liver. When mice received 0.5 x 10(6) allogeneic T cells with T cell-depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6(-/-) than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6(-/-) T-cell proliferation. We therefore assessed the response of WT or Gas6(-/-) ECs to tumor necrosis factor-alpha. Lymphocyte transmigration was less extensive through Gas6(-/-) than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

IL28B polymorphisms leading to poor response to treatment are associated with low necroinflammatory activity and slow fibrosis progression in HCV genotype non-1-infected patients

Background and Aims: Genetic polymorphisms near IL28Bhave been associated with spontaneous and treatment-inducedclearance of hepatitis C virus (HCV). This is believed to proceed viathe appropriate activation of innate and adaptive immune responsestargeting infected hepatocytes. Intrahepatic inflammation is thereflection of the host cell immune response, but its relationshipwith IL28B polymorphisms has yet to be fully appreciated.Methods: We analyzed the association of IL28B polymorphismswith Metavir activity (≥1) and fibrosis scores (≥2) in 1114 HCVinfectedCaucasian patients enrolled in the Swiss Hepatitis C CohortStudy (629, 127, 268 and 110 infected with HCV genotype 1, 2, 3and 4, respectively). In a subgroup of 915 patients with an estimateddate of infection, the association between IL28B polymorphismsand fibrosis progression rate (FPR > median) was assessed. Singlenucleotide polymorphisms (SNPs) of interest were extracted froma dataset generated in a genome-wide association study and/orgenotyped by TaqMan assay. Associations of alleles with differentdegrees of activity and fibrosis were evaluated using an additivemodel of inheritance by multivariate logistic regression, accountingfor all relevant covariates.Results: The rare G allele at marker rs8099917 was associated withlower activity (P = 0.008) and fibrosis (P = 0.01), as well as slower FPR(P = 0.02). Most striking associations were observed among patientsinfected with non-1 genotypes (P = 0.002 for activity, P = 0.002 forfibrosis and P = 0.005 for FPR). In genotype 1-infected patients, theassociation with activity was observed only in the recessive model(P = 0.04), whereas other associations were not significant (P = 0.7for fibrosis and P = 0.4 for FPR).Conclusions: In chronic hepatitis C, IL28B polymorphisms linkedwith a poor virological response to therapy are also associated withreduced intrahepatic necroinflammation and slower liver diseaseprogression. These observations underscore the role played by thehost immune response in clearing HCV, especially in patients withHCV genotypes non-1.