Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients

Oxidative stress is implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In the present study, hepatic and plasma oxidative stress-related parameters were measured and correlated with clinical and histological findings in 31 NAFLD patients showing increased body mass index. Liver protein carbonyl content was enhanced by 403% in patients with steatosis (n=15) compared with control values (n=12), whereas glutathione content, superoxide dismutase (SOD) activity and the ferric reducing ability of plasma (FRAP) were decreased by 57%, 48% and 21% (P<0.05) respectively. No changes in microsomal p-nitrophenol hydroxylation and the total content of cytochrome P450 (CYP) or CYP2E1 were observed. Patients with steatohepatitis (n=16) exhibited protein carbonyl content comparable with that of controls, whereas glutathione content, SOD and catalase activities were decreased by 27%, 64% and 48% (P<0.05). In addition, FRAP values in patients with steatohepatitis were reduced by 33% and 15% (P<0.05) when compared with controls and patients with steatosis respectively, whereas p-nitrophenol hydroxylation (52%) and CYP2E1 content (142%) were significantly increased (P<0.05) compared with controls. It is concluded that oxidative stress is developed in the liver of NAFLD patients with steatosis and is exacerbated further in patients with steatohepatitis, which is associated with CYP2E1 induction. Substantial protein oxidation is followed by proteolysis of the modified proteins, which may explain the co-existence of a diminished antioxidant capacity and protein oxidation in the liver of patients with steatohepatitis.     

Dietary Assessment of Individuals with Chronic Kidney Disease

Examining the quality and quantity of food intake by appropriate methods is critical in the management of patients with chronic kidney disease (CKD). The four commonly used dietary assessment methods in CKD patients include short‐term dietary recalls, several days of food records with or without dietary interviews, urea kinetic based estimates such as protein nitrogen appearance calculation, and food histories including food screeners and food frequency questionnaires (FFQ). There are a number of strengths and limitations of these dietary assessment methods. Accordingly, none of the four methods is suitable in and of itself to give sufficiently accurate dietary information for all purposes. Food frequency questionnaires, which is the preferred method for epidemiological studies, should be used for dietary comparisons of patients within a given population rather than individual assessment. Food histories including FFQ and dietary recalls may underestimate important nutrients, especially in CKD patients. Given the large and increasing number of dialysis patients and work responsibilities of renal dietitians, routine analysis of dietary records and recalls is becoming less feasible. Ongoing and future studies will ascertain additional strengths and limitations of dietary assessment methods in CKD populations including the assessment of food intake during an actual hemodialysis treatment.     

Factors Determining Prenatal HIV Testing for Prevention of Mother to Child Transmission of HIV in Mpumalanga,South Africa

This study assessed factors associated with participation in HIV counseling and testing and reported reasons for not taking part in Voluntary HIV Counseling and Testing among 930 pregnant women attending clinics for antenatal care in South Africa. Results indicate that from 930 clients interviewed 87% had agreed to participate in individual pre-test HIV counseling and 81.2% had received their test results in post-test counseling. Fear for taking the test, lack of confidentiality and knowing one’s HIV status were the main reasons why women refused to test. In multivariable analysis trust of HCT provider was associated with participation in HIV pre-test counseling and no risky drinking was associated with participation in HIV post-test counseling. These findings suggest mistrust towards HCT providers should be reduced and screening and brief intervention for alcohol problems provided.     

Occupational exposure to indium: what does biomonitoring tell us?

Background

The industrial uses of indium, a rare metal with no known physiological role in humans, have increased dramatically over the past 15 years.The results of animal toxicity studies showing pulmonary and systemic effects as well as some reports in workers have created a growing concern about the possible occurrence of toxic effects in exposed workers. Validated biomarkers to assess exposure to indium are not available.

Objectives

This work aimed at investigating the kinetics of indium in urine (In-U) and plasma (In-Pl) in workers manufacturing In ingots and mainly exposed to hardly water-soluble In compounds. All nine workers from the In department of a large metallurgical concern participated in the study as well as 5 retired workers and 20 controls.

Methods

Personal breathing zone air was collected throughout the work shift on Monday and Friday. Blood and urine samples were collected, before and after the shift, on the same day as the air sampling and on preshift the next Monday after a non-working week-end. Moreover, rats were given either InCl₃ by intraperitoneal injection or In₂O₃ by pharyngeal aspiration, In was followed in plasma during 120 days and measured in tissues 120 days after exposure.

Results

Higher In-Pl and In-U concentrations were found in both current (range 0.32–12.61 μg/L plasma; 0.22–3.50 μg/g creat) and former (0.03–4.38 μg/L plasma; 0.02–0.69 μg/g creat) workers compared with controls (<0.03 μg/L plasma; <0.02 μg/g creat). Both biological parameters were highly correlated but no correlation was found between In-air (10–1030 μg/m³) and In-Pl or In-U. Normalizing In-U by the urinary creatinine concentration reduced the inter- (from 90% to 70%) and intra-individual variability (from 54% to 35%). In-Pl remained remarkably stable along the working week (inter- and intra-individual variability: 89% and 10%, respectively). Neither In-U nor In-Pl significantly increased during the day or the week. A week-end without occupational exposure was not sufficient to reach the background In-Pl and In-U levels measured in controls. The results of the experimental investigations confirmed the hypothesis that inhalation of hardly soluble In compounds may cause accumulation of In in the body leading to a prolonged “endogenous exposure” from both a lung depot of “insoluble” particles that are progressively absorbed and from a retention depot in other internal organs.

Conclusion

This study shows that in workers exposed to hardly soluble In compounds, In-U and In-Pl are very sensitive to detect exposure and mainly reflect long-term exposure. In-Pl levels are particularly stable for a given individual. In-U might be more influenced than In-Pl by recent exposure. Both parameters remained high years after withdrawal from exposure, indicating a possible endogenous exposure and a prolonged risk of pulmonary and systemic diseases even after work exposure has ceased.     

Phosphodiesterase 5A inhibition induces Na+/H+ exchanger blockade and protection against myocardial infarction

Acute phosphodiesterase 5A inhibition by sildenafil or EMD360527/5 promoted profound inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1), detected by the almost null intracellular pH recovery from an acute acid load (ammonium prepulse) in isolated papillary muscles from Wistar rats. Inhibition of phosphoglycerate kinase-1 (KT5823) restored normal NHE-1 activity, suggesting a causal link between phosphoglycerate kinase-1 increase and NHE-1 inhibition. We then tested whether the beneficial effects of NHE-1 inhibitors against the deleterious postmyocardial infarction (MI) remodeling can be detected after sildenafil-mediated NHE-1 inhibition. MI was induced by left anterior descending coronary artery ligation in Wistar rats, which were randomized to placebo or sildenafil (100 mg kg(-1) day(-1)) for 6 weeks. Sildenafil significantly increased left ventricular phosphoglycerate kinase-1 activity in the post-MI group without affecting its expression. MI increased heart weight/body weight ratio, left ventricular myocyte cross-sectional area, interstitial fibrosis, and brain natriuretic peptide and NHE-1 expression. Sildenafil blunted these effects. Neither a significant change in infarct size nor a change in arterial or left ventricular systolic pressure was detected after sildenafil. MI decreased fractional shortening and the ratio of the maximum rate of rise of LVP divided by the pressure at the moment such maximum occurs, effects that were prevented by sildenafil. Intracellular pH recovery after an acid load was faster in papillary muscles from post-MI hearts (versus sham), whereas sildenafil significantly inhibited NHE-1 activity in both post-MI and sildenafil-treated sham groups. We conclude that increased phosphoglycerate kinase-1 activity after acute phosphodiesterase 5A inhibition blunts NHE-1 activity and protects the heart against post-MI remodeling and dysfunction.     

Abdominal obesity and body mass index as risk factors for Barrett's esophagus

BACKGROUND: Barrett's esophagus is a strong risk factor for esophageal adenocarcinoma, but little is known about its associations with body mass index (BMI) or abdominal obesity. METHODS: We conducted a case-control study within the Kaiser Permanente Northern California population. Persons with a new diagnosis of Barrett's esophagus (cases) were matched to subjects with gastroesophageal reflux disease (GERD) without Barrett's esophagus and to population controls. Subjects completed questionnaires and an anthropometric examination. RESULTS: We interviewed 320 cases, 316 patients with GERD, and 317 controls. There was a general association between Barrett's esophagus and a larger abdominal circumference (independent of BMI) compared with population controls (odds ratio, 2.24; 95% confidence interval, 1.21-4.15; circumference, >80 cm vs <80 cm). There was a possible risk plateau, with increased risk evident only at circumferences >80 cm and no significant trend for further increases in circumference. There was a trend for association compared with patients with GERD (test for trend, P = .03). There was no association between Barrett's esophagus and BMI. Abdominal circumference was associated with GERD symptom severity (odds ratio, 1.86; 95% confidence interval, 1.03-3.38; risk of severe weekly GERD, per 10-cm circumference); adjustment for GERD partially attenuated the association between Barrett's esophagus and circumference. CONCLUSIONS: Waist circumference, but not BMI, had some modest independent associations with the risk of Barrett's esophagus. The findings provide partial support for the hypothesis that abdominal obesity contributes to GERD, which may in turn increase the risk of Barrett's esophagus.     

Assessment of sarcopenia: longitudinal versus cross sectional body composition data

BACKGROUND AND AIMS: An accurate diagnosis of sarcopenia is required. The aim of this study is to correlate the results of two methods to define sarcopenia using cross sectional body composition data, with actual loss of fat free mass. METHODS: Healthy older subjects (926 females and 381 males aged 70 years or more) and healthy young adults (425 females and 151 males aged 20 to 40 years) were studied. Body composition was assessed by double beam X ray absorptiometry (DEXA). Among older subjects, a contemporary subsample of 148 females and 45 males had two or more measurements, separated by 4.8+/-1.5 years and loss of fat free mass per year was calculated. In the whole sample, total and appendicular lean body mass index were calculated as total or appendicular lean body mass/height. Using data from young people, sex specific t scores were obtained. In older subjects residuals were derived from a regression equation, using total or appendicular fat free mass as the dependent variable and height, fat free mass and age as independent variables. RESULTS: The concordance between residuals and t scores to define sarcopenia was 68 and 72%, respectively. Among subjects with two or more measurements, men and women lost a mean of 521+/-454 and 221+/-399 g/year of fat free mass, respectively. The odds ratio of losing more than 822 g lean body mass /year among men or 514 g lean body mass /year among women was 2.63 and 2.64 for subjects classified in the two lowest quintiles of sarcopenia, using t scores or residuals, respectively. CONCLUSIONS: Cross sectional body composition data can predict loss of fat free mass among older people.     

Accumulation of neurotoxic thioether metabolites of 3,4-(+/-)-methylenedioxymethamphetamine in rat brain

The serotonergic neurotoxicity of 3,4-(+/-)-methylenedioxymethamphetamine (MDMA) appears dependent upon systemic metabolism because direct injection of MDMA into the brain fails to reproduce the neurotoxicity. MDMA is demethylenated to the catechol metabolite N-methyl-alpha-methyldopamine (N-Me-alpha-MeDA). Thioether (glutathione and N-acetylcysteine) metabolites of N-Me-alpha-MeDA are neurotoxic and are present in rat brain following s.c. injection of MDMA. Because multidose administration of MDMA is typical of drug intake during rave parties, the present study was designed to determine the effects of multiple doses of MDMA on the concentration of neurotoxic thioether metabolites in rat brain. Administration of MDMA (20 mg/kg s.c.) at 12-h intervals for a total of four injections led to a significant accumulation of the N-Me-alpha-MeDA thioether metabolites in striatal dialysate. The area under the curve (AUC)(0-300 min) for 5-(glutathion-S-yl)-N-Me-alpha-MeDA increased 33% between the first and fourth injections and essentially doubled for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA. Likewise, accumulation of the mercapturic acid metabolites was reflected by increases in the AUC(0-300 min) for both 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (35%) and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA (85%), probably because processes for their elimination become saturated. Indeed, the elimination half-life of 5-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA increased by 53 and 28%, respectively, between the first and third doses. Finally, although the C(max) values for the monothioether conjugates were essentially unchanged after each injection, the values increased by 38 and approximately 50% for 2,5-bis-(glutathion-S-yl)-N-Me-alpha-MeDA and 2,5-bis-(N-acetylcystein-S-yl)-N-Me-alpha-MeDA, respectively, between the first and fourth injections. The data indicate that neurotoxic metabolites of MDMA may accumulate in brain after multiple dosing.     

The acceptance and feasibility of breast cancer screening in the East

Breast cancer, traditionally a disease prevalent among women in the West, has become an increasing disease burden in the East. In Hong Kong, breast cancer is the number one incident cancer in women. In Asian countries, due to the lower incidence rate, population screening is still controversial. Most screening programs are not population-based, and are either self-financed privately or partially subsidized by the government. Since the first government-subsidized screening program was set up in 1991 in Hong Kong, numerous private and government health centres for women have been set up. A dedicated private Breast Care Centre was set up at the Hong Kong Sanatorium and Hospital (HKSH) in 1999. Over an 8-year period from October 1999 to September 2006, 14,596 women were screened, of whom 11,408 were asymptomatic. This study aims to produce the first report on breast screening experience in the largest cohort of asymptomatic Chinese women in the private sector. An overall malignancy detection rate of 2.3 per 1000 screens and a recall rate of 9.2% were found. Despite culture differences and differences in breast characteristics (denser and smaller breasts), breast screening is feasible and acceptable in the East.