Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a rare hereditary multisystem vascular disorder causing visceral arteriovenous malformations and mucocutaneous bleeding. Chronic gastrointestinal bleeding and epistaxis often produce profound anaemia refractory to conventional treatment. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, may be effective in treatment of bleeding in HHT. METHODS: All HHT patients treated with systemic bevacizumab for chronic bleeding were selected for retrospective analysis. Data collected included demographics, baseline HHT characteristics, epistaxis grade, surgical interventions, bevacizumab dosing, adverse events, haemoglobin, red cell transfusions, intravenous iron infusions, and other anaemia and/or bleeding-directed therapies. RESULTS: Thirteen HHT patients were treated with bevacizumab for a median of 13.9 (range 4.9-30.1) months. Compared with pretreatment values, bevacizumab treatment increased the mean haemoglobin by 4.0 g dL-1 (95% CI, 2.6-5.3 g dL-1 ) [mean (95% CI) haemoglobin 8.5 (7.8, 9.9) g dL-1 vs. 12.5 (11.2, 13.7) g dL-1 , P < 0.001)], reduced red cell units transfused by 92% [median of 6 (range 0-59) units vs. 0 (range 0-15) units, P = 0.004] and reduced quantity of iron infused by 73% [mean (95% CI) 462 (257, 668) mg month-1 vs. 126 (75, 178) mg month-1 , P = 0.002]. Epistaxis control was achieved in 85% with bevacizumab versus 0% before treatment (P < 0.001). No patient required nasal or GI procedures during the maintenance period. Two patients (15%) developed grade 3 hypertension requiring medical management. CONCLUSION: Systemic bevacizumab was highly effective to treat chronic bleeding in HHT. Further study is needed to confirm the magnitude of benefit and further define optimal dosing, treatment duration and long-term safety.

Metabolic differences in hepatocytes of obese and lean pigs.

There are important differences in terms of metabolic activity, energy utilization and capacity of protein and fat deposition when Iberian and modern pigs are compared. Primary culture of hepatocytes was used to evaluate hepatic function and sensitivity to hormones between breeds without the interference of circulating blood factors. Hepatocytes were isolated from pure Iberian (n=10) and Landrace (n=8) pigs of similar BW (24.5±12.1 and 32.9±6.1 kg BW, respectively), by collagenase perfusion. Monolayers were established in medium containing fetal bovine serum for 1 day and switched to serum-free medium for the remainder of the culture period. Hepatocytes were maintained in William's E supplemented with ß-mercaptoethanol (0.1 mM), glutamine (2 mM), antibiotics (gentamicin, penicillin, streptomycin and amphotericin B), dimethyl sulfoxide (1 µg/ml), dexamethasone (10-8 M), insulin (0.173 and 17.3 nM) and glucagon (0.287, 2.87 and 28.7 nM) for 24 to 48 h. Gluconeogenesis (GNG), glycogen degradation, triglycerides (TG) content and esterification, ß-hydroxybutyrate (BHB) synthesis, IGF-1 synthesis, albumin and urea synthesis were determined. Iberian pigs had greater capacity of GNG than Landrace (24%, P<0.05), although no difference in glycogen degradation was found (P>0.10). TG content and esterification tended to be lower in hepatocytes from Iberian compared with Landrace pigs (12% and 31%, respectively; 0.100.10). IGF-1 synthesis was diminished in hepatocytes from Iberian compared with Landrace pigs (16%, P<0.05). On the contrary, rate of albumin synthesis was greater in Iberian compared with Landrace pigs (58%, P<0.05). Finally, the capacity of urea synthesis was lower in hepatocytes of Iberian compared with Landrace pigs (37%, P<0.05). When ammonia was added to the media, urea concentration increased (648%, 1108% and 2791% when 0 mM was compared with 2.5, 5 and 10 mM, respectively). Urea synthesis increased on increasing ammonia content (55% and 325% when 0 mM was compared with 5 and 10 mM, respectively; P<0.0001). In conclusion, the genetic background accounts for important differences in protein and energy metabolism pathways found in primary culture of hepatocytes from lean and obese pigs.

Diets rich in starch increase the posthepatic availability of amino acids in dairy cows fed diets at low and normal protein levels.

Five mid-lactation multicatheterized Jersey cows were used in a 4×4 Latin square design to investigate whether the increase in milk N yield associated with diets rich in starch versus fiber could originate from changes in the splanchnic AA metabolism and if these changes depended upon the dietary crude protein (CP) content. Four isoenergetic diets were formulated to provide 2 different carbohydrate compositions [diets rich in starch (350g of starch and 310g of neutral detergent fiber/kg of dry matter) versus rich in fiber (45g of starch and 460g of neutral detergent fiber/kg of dry matter)] crossed by 2 different CP contents (12.0 vs. 16.5% CP). At the end of each treatment period, 6 hourly blood samples were collected from the portal and hepatic veins as well as the mesenteric artery to determine net nutrient fluxes across the portal-drained viscera (PDV), liver, and total splanchnic tissues. Dry matter and calculated energy intake as well as total absorbed energy were similar across treatments. However, the net portal appearance (NPA) of acetate, total volatile fatty acids, and ß-hydroxybutyrate were higher with diets rich in fiber versus starch, whereas that of oxygen, glucose, butyrate, and insulin were lower. Concomitant to these changes, the percentage of N intake recovered as total AA (TAA) in the portal vein was lower for diets rich in fiber versus starch (42.3 vs. 51.4%, respectively), without, however, any difference observed in the NPA of the main AA used as energy fuels by the PDV (Glu, Gln, and Asp). Despite a higher NPA of TAA with starch versus fiber diets, no differences in the net hepatic flux of TAA, essential and nonessential AA were observed, resulting in a higher (+22%) net splanchnic release of AA and, hence, a greater (+7%) milk N yield. The net hepatic flux and hepatic fractional removal of none of the individual AA was affected as the main carbohydrate changed from fiber to starch, except for Gly and Lys, which were higher for the latter. After correcting for differences in NPA of TAA, the net hepatic uptake of TAA tended to be lower with starch versus fiber diets. The higher transfer of N from feed to milk with diets rich in starch is not the consequence of a direct sparing AA effect of glucogenic diets but rather the result of lower energy requirements by the PDV along with a higher microbial N flow to the duodenum. A better AA use by peripheral tissues with starch versus fiber diets was also hypothesized but more studies are warranted to clarify this issue.

Influence of the para-aminohippuric acid analysis method on the net hepatic flux of nutrients in lactating cows.

Para-aminohippuric acid (pAH) is a marker frequently used to measure plasma or blood flow. In sheep studies, it is recognized that its determination must include a deacetylation step to counteract the hepatic acetylation of pAH. Such a procedure is not of common usage in cattle studies although a recent suggestion of hepatic pAH acetylation in dairy cows may have important consequences for hepatic nutrient fluxes. The aims of this study were to evaluate pAH analytical methods according to international procedures of metrology and confirm hepatic acetylation of pAH in dairy cows. The effect of the matrix used to prepare the standard curve was tested, and the influence of the pAH analytical method on blood flows and subsequent net hepatic fluxes of nutrients was determined. For the first objective, accuracy profiles were established and bias, indicators of precision, and limits of quantification were reported for 2 analytical methods (without and with a pAH deacetylation step) using 2 different standard matrices (water and plasma). Second, the net hepatic flux of different nutrients was determined including or not the deacetylation step and preparing the standard curves in plasma using samples collected from 5 multicatheterized lactating Jersey cows. The choice of the matrix had a significant impact on plasma pAH concentrations as illustrated by accuracy profiles. Water matrix decreased (P < 0.01) the slope, y-intercept, and the absorbance at concentration 0 mg pAH/L of the standard curve in both methods (without and with the deacetylation), supporting that standards prepared in water should not be used to analyze plasma samples. Samples collected on cows confirmed hepatic acetylation of pAH across the liver. Deacetylation, performed using plasma as the standard matrix, increased (P < 0.05) plasma pAH concentrations from 18.4, 26, and 23.5 to 21.4, 28.9, and 27.3 mg/L in the artery, portal vein, and hepatic vein, respectively. Deacetylation decreased the hepatic venous and arterial plasma and blood flows (P < 0.05) by 9 and 55%, respectively, modifying the net hepatic flux of acetate, total amino acid, and oxygen by more than 19% (P < 0.05). In conclusion, our results highlight the importance of including a deacetylation step in the pAH analysis method in cattle studies and of using plasma as standard matrix.

Effects of a low-fat diet with antioxidant supplementation on biochemical markers of multiple sclerosis long-term care residents.

INTRODUCTION: Multiple sclerosis (MS) treatment options are primarily limited to immunomodulatory therapies in MS non-progressive forms. Nutrition intervention studies suggest that diet may be considered as a complementary treatment to control disease progression. Therefore, dietary intervention may help to improve wellness and ameliorate symptoms of MS patients. OBJECTIVES: To assess the effect of a low-fat diet with antioxidant supplementation on biochemical markers of institutionalized patients with progressive forms of multiple sclerosis. METHODS: A randomized prospective placebo-controlled study involving 9 participants, 5 of them assigned to the intervention group (low-fat diet and antioxidant supplementation) and the other 4 to the placebo group (low-fat diet). The effect of the dietary intervention, involving diet modification and antioxidant supplementation, was examined for 42 days by measuring anthropometric, biochemical parameters and oxidative stress markers in blood at baseline (day 0), intermediate (day 15) and end (day 42) stages of the treatment. RESULTS: The intervention group obtained C reactive protein levels significantly lower than those observed in the corresponding placebo group at the end of the study. Oxidative stress and inflammatory markers isoprostane 8-iso-PGF2α and interleukine IL-6 values also diminished after dietary intervention in the intervention group. Catalase activity increased significantly in the intervention group prior antioxidant supplementation. No significant differences were observed in other oxidative stress markers. CONCLUSIONS: The results suggest that diet and dietary supplements are involved in cell metabolism modulation and MS-related inflammatory processes. Consequently, low fat diets and antioxidant supplements may be used as complementary therapies for treatment of multiple sclerosis.

Introducción: Las posibilidades de tratamiento de la esclerosis múltiple (EM) se encuentran limitadas principalmente a terapias con inmumoduladores en las formas no progresivas de EM. Los estudios de intervención nutricional sugieren que la dieta puede considerarse como un tratamiento alternativo para controlar la progresión de la enfermedad. Por esta razón, las intervenciones en la dieta pueden ayudar a mejorar el bienestar y mejorar los síntomas de los pacientes con EM. Objetivos: Valorar el efecto de una dieta pobre en grasas con suplementación de antioxidantes en los marcadores bioquímicos de pacientes institucionalizados que presentan formas progresivas de EM. Métodos: Se realizó un estudio prospectivo aleatorizado controlado por placebo con 9 participantes, 5 de los cuales se asignan al grupo de intervención (dieta baja en grasas y suplementación antioxidante) y los 4 restantes al grupo placebo (dieta baja en grasas). Se evaluó el efecto de la intervención dietética que supone modificación de la dieta e introducción de antioxidantes durante 42 días mediante valoraciones de parámetros antropométricos y bioquímicos y marcadores del estrés oxidativo en sangre y orina en las etapas inicial (día 0), intermedia (día 15) y final (día 42) del tratamiento. Resultados: Se obtuvieron niveles de proteína C reactiva significativamente inferiores en el grupo de intervención con respecto al grupo placebo al final del estudio. Los marcadores de estrés oxidativo e inflamación: isoprostanos 8-iso-PGF2e interleucina IL-6 también disminuyeron en el grupo de intervención después de la intervención dietética. La actividad de la enzima catalasa aumentó de forma significativa en el grupo de intervención antes de la suplementación con antioxidantes. No se observaron diferencias significativas en otros marcadores de estrés oxidativo. Conclusiones: Los resultados obtenidos sugieren que la dieta y los suplementos dietéticos están involucrados en la modulación del metabolismo celular y los procesos de inflamación de la EM. En consecuencia, las dietas bajas en grasas y los suplementos antioxidantes podrían ser utilizados como terapias alternativas en el tratamiento de la EM.

Impact of dietary betaine and conjugated linoleic acid on insulin sensitivity, protein and fat metabolism of obese pigs.

To determine possible mechanisms of action that might explain the nutrient partitioning effect of betaine and conjugated linoleic acid (CLA) in Iberian pigs and to address potential adverse effects, twenty gilts were restrictively fed from 20 to 50 kg BW Control, 0.5% betaine, 1% CLA or 0.5% betaine + 1% CLA diets. Serum hormones and metabolites profile were determined at 30 kg BW and an oral glucose test was performed before slaughter. Pigs were slaughtered at 50 kg BW and livers were obtained for chemical and histological analysis. Decreased serum urea in pigs fed betaine and betaine + CLA diets (11%; P = 0.0001) indicated a more efficient N utilization. The increase in serum triacylglycerol (58% and 28%, respectively; P = 0.0098) indicated that CLA and betaine + CLA could have reduced adipose tissue triacylglycerol synthesis from preformed fatty acids. Serum glucose, low-density lipoprotein (LDL) cholesterol and non-esterified fatty acids were unaffected. CLA and betaine + CLA altered serum lipids profile, although liver of pigs fed CLA diet presented no histopathological changes and triglyceride content was not different from Control pigs. Compared with controls, serum growth hormone decreased (20% to 23%; P = 0.0209) for all treatments. Although serum insulin increased in CLA, and especially in betaine + CLA pigs (28% and 83%; P = 0.0001), indices of insulin resistance were unaffected. In conclusion, CLA, and especially betaine + CLA, induced changes in biochemical parameters and hormones that may partially explain a nutrient partitioning effect in young pigs. Nevertheless, they exhibited weak, although detrimental, effects on blood lipids. Moreover, although livers were chemically and histologically normal, pigs fed CLA diet challenged with a glucose load had higher serum glucose than controls.