M. Camilo

Dietary Counseling Improves Patient Outcomes: A Prospective, Randomized, Controlled Trial in Colorectal Cancer Patients Undergoing Radiotherapy

PURPOSE To investigate the impact of dietary counseling or nutritional supplements on outcomes in cancer patients: nutritional, morbidity, and quality of life (QoL) during and 3 months after radiotherapy. PATIENTS AND METHODS A total of 111 colorectal cancer outpatients referred for radiotherapy, stratified by staging, were randomly assigned: group 1 (G1; n = 37), dietary counseling (regular foods); group 2 (G2; n = 37), protein supplements; and group 3 (G3; n = 37), ad libitum intake. Nutritional intake (diet history), status (Otterys Subjective Global Assessment), and QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0) were evaluated at baseline, at the end, and 3 months after radiotherapy. RESULTS At radiotherapy completion, energy intake increased in G1/G2 (P < or = .04), G1 more than G2 (P = .001), and decreased in G3 (P < .01). Protein intake increased in G1/G2 (P < or = .007), G1 less than G2 (not significant), and decreased in G3 (P < .01). At 3 months, G1 maintained nutritional intake and G2/G3 returned to baseline. After radiotherapy and at 3 months, rates of anorexia, nausea, vomiting, and diarrhea were higher in G3 (P < .05). At radiotherapy completion, in G1 all QoL function scores improved proportionally to adequate intake or nutritional status (P < .05); whereas in G2 only three of six function scores improved proportionally to protein intake (P = .04), and in G3 all scores worsened (P < .05). At 3 months, G1 patients maintained/improved function, symptoms, and single-item scores (P < .02); in G2, only few function and symptom scales improved (P < .05); in G3, QoL remained as poor as after radiotherapy. In G1/G2, respectively, improvement/deterioration of QoL correlated with better or poorer intake or nutritional status (P < .003). CONCLUSION During radiotherapy, both interventions positively influenced outcomes; dietary counseling was of similar or higher benefit, whereas even 3 months after RT, it was the only method to sustain a significant impact on patient outcomes.

Impact of nutrition on outcome : A prospective randomized controlled trial in patients with head and neck cancer undergoing radiotherapy

We aimed to determine the effect of dietary counseling or oral supplements on outcome for patients with cancer, specifically, nutritional outcome, morbidity, and quality of life (QOL), during and 3 months after radiotherapy.

Increased, homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease

BACKGROUND The pathogenic mechanism of homocysteines effect on cardiovascular risk is poorly understood. Recent studies show that DNA hypomethylation induced by increases in S-adenosylhomocysteine (AdoHcy), an intermediate of Hcy metabolism and a potent inhibitor of methyltransferases, may be involved in homocysteine-related pathology. METHODS We measured fasting plasma total Hcy (tHcy), AdoHcy, and S-adenosylmethionine (AdoMet) and methylation in leukocytes in 17 patients with vascular disease and in 15 healthy, age- and sex-matched controls. RESULTS Patient with vascular disease had significantly higher plasma tHcy and AdoHcy concentrations and significantly lower plasma AdoMet/AdoHcy ratios and genomic DNA methylation. AdoMet concentrations were not significantly different between the two groups. More than 50% of the patients fell into the highest quartiles of plasma tHcy, AdoHcy, and [(3)H]dCTP incorporation/ micro g of DNA (meaning the lowest quartile of DNA methylation status) and into the lowest quartile of the AdoMet/AdoHcy ratios of the control group. Plasma tHcy was significantly correlated with plasma AdoHcy and AdoMet/AdoHcy ratios (n = 32; P < 0.001). DNA methylation status was significantly correlated with plasma tHcy and AdoHcy (n = 32; P < 0.01) but not with plasma AdoMet/AdoHcy ratios. CONCLUSION Global DNA methylation may be altered in vascular disease, with a concomitant increase in plasma tHcy and AdoHcy.

Hepatocyte apoptosis, expression of death receptors, and activation of NF-κB in the liver of nonalcoholic and alcoholic steatohepatitis patients

OBJECTIVES:The increasing incidence of nonalcoholic (NASH) and alcoholic steatohepatitis (ASH), associated with lack of effective treatment, has prompted intensive studies on disease pathogenesis. Apoptosis is recognized as common in liver injury and may also contribute to tissue inflammation, fibrogenesis, and development of cirrhosis. In this study, we identified mechanisms of apoptosis induction in human steatohepatitis, and evaluated potential associations between apoptosis, liver pathology, and clinical presentation in NASH and ASH.METHODS:Hepatocyte apoptosis was evaluated by the TUNEL assay in 20 patients with NASH (all ambulatory), 40 with ASH (20 ambulatory, 20 hospitalized), and 20 controls. Liver biopsies were also graded for inflammation and fibrosis. Immunohistochemistry was performed for death receptors (Fas and TNF-R1), activated caspase-3, NF-κB p65, antiapoptotic Bcl-2 protein, and uncoupling protein 2 (UCP-2).RESULTS:TUNEL-positive hepatocytes were markedly increased in NASH (p < 0.05) and ASH (p < 0.01). Similar results were obtained for activated caspase-3, confirming the occurrence of apoptosis. The Fas receptor was upregulated in ASH, especially in hospitalized patients (p < 0.01), whereas TNF-R1 was expressed both in NASH and ASH (p < 0.01). In addition, patients with ASH showed a remarkable expression of active NF-κB, as compared to NASH and controls (p < 0.01). Degrees of inflammation and fibrosis correlated with NF-κB p65 expression, which in turn coincided with apoptosis albeit Bcl-2 and UCP-2 expression.CONCLUSIONS:Liver injury in NASH and ASH is associated with increased hepatocyte apoptosis mediated by death receptors. Further, apoptosis correlates with active NF-κB expression, and disease severity. This potential mechanistic link might provide multiple interesting targets for therapeutic intervention.

Non-alcoholic fatty liver: another feature of the metabolicsyndrome?

Abstract Background and aims: Hepatic steatosis and nonalcoholic steatohepatitis (NASH) have been associated with obesity, non insulin-dependent diabetes mellitus and hyperlipidemia. The present study was designed in order to evaluate whether patients with steatosis/NASH presented common features with the metabolic syndrome. Methods: In 30 patients with nonalcoholic fatty liver the prevalence of hypertension and diabetes; the glucose/insulin profile, lipid profile, and serum leptin were evaluated and correlated with body composition and energy expenditure, assessed by bioimpedance spectroscopy and indirect calorimetry, respectively. Results were compared with a group of eight controls. Results: Obesity was present in 80% of patients, hypertension in 50% and non insulin dependent diabetes in 33%. Glucose metabolism was altered in 69%, with elevated insulin in 14 patients. Serum leptin, higher in women, was increased in patients: 33.9 ± 38.9 vs 9.6 ± 6.9 ng/ml, P Conclusions: There is a strong association between nonalcoholic fatty liver and features of the metabolicsyndrome, suggesting a simultaneous insulin resistance and decreased sensitivity to leptin.

5,10-methylenetetrahydrofolate reductase (MTHFR) 677C→T and 1298A→C mutations are associated with DNA hypomethylation

A growing body of evidence has highlighted the role of abnormal DNA methylation patterns on inappropriate gene expression and promotion of disease.1–3 DNA methylation patterns are maintained by DNA methyltransferases,4–7 using S-adenosylmethionine (AdoMet) as the methyl group donor; AdoMet is then converted to S-adenosylhomocysteine (AdoHcy). Intracellular homocysteine (Hcy) is derived from AdoHcy hydrolysis through the action of AdoHcy hydrolase, a reversible reaction with a dynamic equilibrium that strongly favours AdoHcy synthesis rather than hydrolysis.8 Thus, an efficient metabolic removal of Hcy is required to prevent AdoHcy accumulation. The toxicity of intracellular AdoHcy accumulation lies in its high affinity binding to the catalytic region of most AdoMet dependent methyltransferases (including DNA methyltransferases), acting as its inhibitor.9 Thereby, any disturbance in Hcy metabolism is likely to disturb cellular methylation processes, including DNA methylation patterns. 5,10-methylenetetrahydrofolate reductase (MTHFR) is one of the main regulatory enzymes of Hcy metabolism that catalyses the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the methyl donor for the remethylation of Hcy to methionine. A common 677C→T transition in the MTHFR gene is a well established genetic determinant of hyperhomocysteinaemia, and results in a thermolabile protein, with a decreased enzymatic activity. The molecular basis of this thermolability is a missense mutation in the exon 4 of the MTHFR gene, a cytosine to thymine substitution at nucleotide 677, which converts an alanine to a valine codon in the N-terminal catalytic domain of the protein. The association between this MTHFR genotype and the total Hcy (tHcy) circulating levels is well known to be contingent on folate status.10,11 Recently, a second polymorphism associated with decreased enzymatic activity but not with thermolability was discovered in the MTHFR gene.12 This genetic variant corresponds to an adenosine to cytosine transversion at nucleotide 1298, in exon 7, leading to …

Bile acid levels are increased in the liver of patients with steatohepatitis

Background/aims The pathogenesis of steatohepatitis remains largely unknown; however, bile acids may play a role as potential mediators of liver damage. The aim of this study was to characterize bile acid profiles in liver tissue of patients with steatohepatitis. Methods Bile acid composition was determined by gas–liquid chromatography in liver tissue from patients with nonalcoholic steatohepatitis (NASH; n=15), patients with alcoholic steatohepatitis (ASH; n=14), and controls (n=8). Liver biopsies were graded for steatosis, inflammation, and fibrosis. Results Bile acids were moderately increased in liver tissue of steatohepatitis patients compared with controls (P<0.05). Deoxycholic, chenodeoxycholic, and cholic acids were elevated by 92, 64, and 43%, respectively, in patients with steatohepatitis (P<0.05). Cholic acid was the prevailing bile acid in NASH patients and in controls. More hydrophobic bile acid species were elevated in ASH patients compared with controls (P<0.05). Significant correlations were found in NASH patients between hepatic chenodeoxycholic acid and fibrosis, and between cholic acid and trihydroxy/dihydroxy bile acids and inflammation (P<0.05). In patients with ASH, cholic acid and trihydroxy/dihydroxy bile acids were correlated with steatosis (P<0.01). Conclusion This study shows a distinct pattern of bile acids in the liver of patients with steatohepatitis. Further, the association between bile acids and histological liver injury suggests an association of specific bile acids and disease progression, possibly through bile acid-induced liver injury.

Trends of food intake in Portugal, 1987-1999: results from the National Health Surveys.

Objective:To assess trends of food intake in Portugal.Design:Analysis of three cross-sectional studies: 1987, 1995–1996 and 1998–1999.Setting:Representative samples of free-living individuals.Subjects:64 734 men and 71 282 women.Interventions:Food intake was assessed by questionnaires inquiring the number of meals and which foodstuffs (fish, meat, milk, rice/pasta/potatoes, soup, vegetables and fruit) had been consumed the day before.Results:Age-adjusted average number of meals decreased from 3.3±0.1 in 1987 to 2.9±0.1 in 1998–1999 in both genders (P<0.001). In men, the percentage of subjects consuming meat, milk and potatoes/rice/pasta increased from 73, 66 and 91% in 1987 to 83, 74 and 95% in 1998–1999, respectively. The percentage of subjects consuming soup and fish decreased from 70 and 56% in 1987 to 62 and 53% in 1998–1999, respectively. In women, the percentage of subjects consuming meat, milk, potatoes/rice/pasta and vegetable increased from 70, 66, 89 and 71% in 1987 to 78, 77, 93 and 83% in 1998–1999, respectively. The percentage of subjects consuming soup and fish decreased from 70 and 55% in 1987 to 64 and 53% in 1998–1999, respectively. These trends were more pronounced in the younger age, which also displayed a higher frequency of snacking. Multivariate analysis adjusting for age group, region and educational level showed that the consumption of meat, milk and vegetables increased and the consumption of soup, fish and fruit decreased in 1998–1999 relative to 1995–1996.Conclusions:Within a decade, the Portuguese dietary pattern has changed considerably, shifting from a traditional, south European to a more Westernized, protein-rich diet.Sponsorship:The Unidade de Nutrição e Metabolismo of the Instituto de Medicina Molecular is partially funded by a grant from the FCT (Fundação para a Ciência e a Tecnologia) ref. RUN 437.

Tamoxifen-associated steatohepatitis - report of three cases

The authors describe three cases of tamoxifen-associated steatohepatitis, which resulted from a daily dosage of 20 mg used as the adjuvant treatment of breast carcinoma. Liver tests became normal after discontinuation of tamoxifen.

Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis.

Objectives Apoptosis may play a role in the pathogenesis of alcoholic (ASH) and non-alcoholic steatohepatitis (NASH). In this study, we investigated the modulation of apoptosis-related liver proteins in steatohepatitis. Methods Hepatocyte apoptosis was evaluated by the TUNEL assay in liver tissue of 12 patients with NASH, 12 with ASH and in histologically normal controls. In addition, caspase-3 processing was evaluated by immunoblot analysis. Expression of death receptors, Bcl-2 family members, and NF-κB inhibitor (IκB) were determined by western blot. Liver biopsies were also graded for inflammation and fibrosis. Results Apoptotic hepatocytes were markedly increased in NASH (P<0.05) and ASH (P<0.001) as compared to controls. Active caspase-3 was also elevated in steatohepatitis (P<0.01), coinciding with upregulation of pro-apoptotic Bax (P<0.001). Further, production of tumour necrosis factor-receptor 1 was increased up to 4-fold (P<0.05). Degradation of IκB increased >70% in steatohepatitis (P<0.001). Notably, Bcl-2 was also strongly expressed (>100-fold; P<0.001). These data were significantly correlated with relative degrees of portal and lobular inflammation. Conclusion The results show that liver injury in NASH and ASH is associated with apoptosis and NF-κB activation. Anti-apoptotic Bcl-2 is strongly expressed, probably reflecting an adaptive response to obesity or alcohol-related stress.