Protective effects of whey on rat liver damage induced by chronic alcohol intake.

In 2012, alcohol liver disease resulted in 3.3 million-5.9% of global deaths. This study introduced whey protection capacity against chronic alcohol-induced liver injury. Rats were orally administered to 12% ethanol solution in water (ad libitum, average 8.14 g of ethanol/kg body weight (b.w.)/day) alone or combined with whey ( per os, 2 g/kg b.w./day). After 6-week treatment, chronic ethanol consumption induced significant histopathological liver changes: congestion, central vein dilation, hepatic portal vein branch dilation, Kupffer cells hyperplasia, fatty liver changes, and hepatocytes focal necrosis. Ethanol significantly increased liver catalase activity and glutathione reductase protein expression without significant effects on antioxidative enzymes: glutathione peroxidase (GPx), copper-zinc-containing superoxide dismutase (CuZnSOD) and manganese-containing superoxide dismutase (MnSOD). Co-treatment with whey significantly attenuated pathohistological changes induced by ethanol ingestion and increased GSH-Px and nuclear factor kappa B (NF-κB) protein expression. Our results showed positive effects of whey on liver chronically exposed to ethanol, which seem to be associated with NF-κB-GPx signaling.

Maturity-onset diabetes of the young type 5 in a family with diabetes and mild kidney disease diagnosed by whole exome sequencing.

Exome sequencing is being increasingly used to identify disease-associated gene mutations. We used whole exome sequencing to determine the genetic basis of a syndrome of diabetes and renal disease affecting a mother and her son. We identified a mutation in the hepatocyte nuclear factor 1-b (HNF1B) gene that encoded a methionine to valine amino acid change (M160V) in the HNF1B protein. This leads us to the previously unappreciated diagnosis of maturity-onset diabetes of the young type 5 and provided a basis for genetic counselling of other family members.

Intellectual ability in the duchenne muscular dystrophy and dystrophin gene mutation location.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

Incidence of brain metastases in early stage HER2 3+ breast cancer patients; is there a role for brain CT in asymptomatic patients?

PURPOSE: Human epidermal growth factor receptor 2 overexpression (HER2 3+) is reported in retrospective studies as a factor that contributes to higher incidence of brain metastases (BM) in patients with metastatic breast carcinoma. Although there are some reports suggesting higher incidence of BM in adjuvant trastuzumab trials, the true incidence, as well as the time of occurrence of BM in early-stage high risk breast carcinoma patients, has not been widely prospectively explored. The main objective of this study was to prospectively explore the incidence of BM during and after adjuvant trastuzumab administration in HER2 3+ early-breast carcinoma patients. METHODS: Two hundred and fifty-eight patients with early, HER2 3+ breast carcinoma have been included in this analysis. Brain computed tomography (CT) scan was scheduled once during adjuvant trastuzumab therapy and thereafter only if central nervous system (CNS) symptoms occurred. RESULTS: Eighty-five patients (33%) underwent brain CT in the absence of CNS symptoms. The median number of trastuzumab cycles at the time of brain CT was 9 (range 4-18). There were no BM detected by brain CT in these 85 asymptomatic patients. However, during a median follow up of 18 months 5/258 patients (1.93%) developed BM, but only 2 (0.77%) while still receiving adjuvant trastuzumab. The median time from breast cancer diagnosis to BM was 24 months (range 14-43). CONCLUSION: BM are a rare event during adjuvant trastuzumab treatment and brain CT screening is not justified in asymptomatic patients with early HER2 3+ breast carcinoma.

Prognostic value of CA125 kinetics and half-life in advanced ovarian cancer.

This retrospective study was undertaken in order to assess the prognostic value of prechemotherapy serum CA125 level, CA125 kinetics, and CA125 half-life compared to the ten common clinicopathological variables in patients with advanced ovarian cancer (AOC). CA125 serum levels were determined before and during induction cisplatin polychemotherapy in 222 patients. A prechemotherapy CA125 level higher than 35 U/mL was found in 134 patients. Blood samples were further obtained before each course of chemotherapy (CT). CA125 half-life values were calculated in 112 patients with CA125 levels above 60 U/mL using van der Burg's exponential regression model. The prechemotherapy CA125 level had no prognostic value for survival. However, the median survival time of patients with CA125 levels below the upper normal limit of normality after two courses of CT was 101 months compared to a median survival of 21 months in patients without CA125 normalization (p=0.0000). Half-life calculation showed a significant correlation with survival. The median survival times of patients with T1/2 <20 days and T1/2 >20 days were 101+ and 18 months, respectively (p=0.0003). In a survival analysis using the Cox proportional hazard model, independent prognostic variables for survival included therapeutic response (p<0.0001), Karnofsky index (p<0.0001), residual disease (p<0.0001), tumor grade (p=0.0002), CA125 half-life (p=0.007), and CA125 kinetics (p=0.04). As a consequence, the possibility to predict treatment response by the CA125 half-life during chemotherapy and the time needed for normalization of CA125 levels can divide patients into good and poor prognostic groups early during chemotherapy.

Mitoxantrone, 5-fluorouracil and low-dose leucovorin in doxorubicin-resistant advanced breast cancer patients: a phase II study.

AIM: Twenty-two anthracycline-resistant advanced breast cancer patients were entered from June 1995 till November 1997 in a phase II study to assess the activity and tolerability of second-line chemotherapy consisting of mitoxantrone, 5-fluorouracil and low-dose leucovorin. STUDY DESIGN: Patients were eligible if they failed to respond to doxorubicin-containing chemotherapy, given as first-line chemotherapy for metastatic disease. Treatment consisted of mitoxantrone, 12 mg/m2 iv infusion on day 1, and leucovorin, 50 mg iv 1 hr before 5-fluorouracil, 350 mg/m2 iv infusion on days 1-3, every three weeks. RESULTS: Nineteen patients were eligible for response, 2 refused further therapy after 2 cycles, and 1 was excluded because grade 3 myelotoxicity developed during the first cycle. Partial remission of 15 months duration occurred in 1 patient, in 7/19 women disease remained stable with a median duration of 11 months (range, 5-24), and 11/19 patients experienced progressive disease. Median time to disease progression was 2 months (range, 0-17), and median survival was 8 months (range, 0-24). Toxicity was generally mild and acceptable. One patient was excluded because of grade 3 granulocytopenia and thrombocytopenia, and one due to cardiotoxicity assessed by the drop of left ventricular ejection fraction to more than 20% below the initial value. CONCLUSIONS: In spite of the very low objective response rate, almost one-fourth of our anthracycline-resistant patients achieved a disease stabilization of 27 weeks duration during mitoxantrone-based second-line chemotherapy. Hence, mitoxantrone in combination with 5-fluorouracil, especially continuous infusion, should be further investigated in this setting, particularly if new and expensive drugs, considered the most active, are not readily available.

Effects of oral propafenone administration before electrical cardioversion of chronic atrial fibrillation: a placebo-controlled study.

OBJECTIVES: Our aim was to evaluate the benefits and risks of administering propafenone before electrical defibrillation for chronic atrial fibrillation. BACKGROUND: In this context, an antiarrhythmic drug-although potentially useful in preventing early recurrence of arrhythmia-could adversely affect the defibrillation threshold and reduce the cardioversion success rate. METHODS: We randomly assigned 100 patients with chronic atrial fibrillation to oral treatment with either placebo (51 patients) or 750 mg/day of propafenone (49 patients) for 48 h before administration of direct current shock. After successful cardioversion, all patients received propafenone therapy and were followed up for 48 h. RESULTS: Before defibrillation, three patients in the propafenone group (6.1%) had reversion to sinus rhythm and one had sustained ventricular tachycardia. Shock efficacy (82.4% vs. 84.4%) and the cumulative effective energy (395 +/- 258 vs. 421 +/- 236 J) were not different between the placebo and propafenone groups. In the propafenone group, 11 patients had their arrhythmia transformed into atrial flutter and required a lower energy level for arrhythmia conversion than did the other patients with continued atrial fibrillation (245 +/- 197 vs. 493 +/- 215 J, p < 0.01); the latter patients showed a trend (p < 0.10) toward higher energy requirements than that of patients who received placebo. The incidence of asymptomatic bradyarrhythmias was higher in the propafenone group (28.9% vs. 7.1%, p < 0.02), but more patients who received placebo had early recurrence of atrial fibrillation (16.7% vs. 0%, p < 0.02). Two days after cardioversion, more patients given propafenone (73.5% vs. 52.9%, p < 0.05) were discharged from the hospital with sinus rhythm. During the in-hospital stay, propafenone was withdrawn from six patients (6.6%) because of side effects. CONCLUSIONS: Propafenone, given before electrical cardioversion for chronic atrial fibrillation does not affect the mean defibrillation threshold or the rate of successful arrhythmia conversion. It decreases the recurrence of atrial fibrillation early after shock, thus allowing more patients to be discharged from the hospital with sinus rhythm.

Effect of neuroleptics on ethanol-treated rats.

The subject of the present study is the effect of neuroleptic anaesthetics on sleeping time and some biochemical parameters of ethanol-treated and untreated rats. In one set of experiments involving four groups of animals, we studied how ethanol (12%, v/v) consumption for 10, 20 and 30 days influenced the sleeping time of animals after administration of a single dose of the investigated anaesthetics. In the other set of experiments, we studied the combined effect of 30 day ethanol consumption and each of the anaesthetics administered to the animals in multiple doses for 3 h, by determining the contents of cytochrome P450 and glutathione and the activities of glutathione peroxidase and lipid peroxidation. The results show that statistically significant changes of measured parameters are due to the action of ethanol and not of the neuroleptic anaesthetics.

Effect of fentanyl, ketamine and thalamonal on some biochemical parameters in ethanol-treated and untreated dogs.

The effects of fentanyl, ketamine and thalamonal on some biochemical parameters of ethanol-treated and untreated dogs, were studied. The study was carried out on mongrel dogs. The animals were divided into two main groups: one which had free access to food and to 12% (v/v) ethanol, instead of water, and a control group which had food and water ad libitum. The animals in both groups were exposed to the action of anaesthetics for 3 h. The results show that, under the given experimental conditions, the anaesthetics did not significantly change the investigated parameters of blood and liver, either in ethanol-treated or untreated dogs. However, the action of ethanol caused remarkable changes in almost all the investigated parameters. An increased content of cytochrome P450 caused by the action of ethanol suggests possible changes in the metabolism of anaesthetics, which should be of concern to anaesthetists when dealing with patients potentially intoxicated with ethanol.

Biochemical evaluation of colchicine and related analogs.

Transformation of ten colchicinoids by isolated rat liver microsomes resulted in the mixture of C-2, C-3, and C-10 O-demethylated metabolites. Colchicinoids administered i.p. to rats (2.5 mumol/kg) increased serum and liver activities of alkaline phosphatase and decreased liver microsomal demethylase activity as well as cytochrome P-450 content. The changes of acid phosphatase level were less pronounced. The aspartate and alanine aminotransferase activities were significantly increased only in colchicine treated rats. No relations between enzyme activity changes and colchicinoid hydrophobicities quantified by partition coefficients (log P) were found. However, the enzyme activity changes were related to the type of substitution at C-3, C-7, and C-10 of colchicinoids. Particularly, O-demethylation at C-3 resulted into the fall of alkaline phosphatase response. On the other hand, the microsomal demethylation and cytochrome P-450 content were related to the modification of the nitrogen substituent at C-7.

The in vitro and in vivo biotransformation of N-deacetyl-N-formylcolchicine.

The major pathway of metabolic transformation of N-deacetyl-N-formylcolchicine is the oxidative cytochrome P450 dependent O-demethylation of substituents in the aromatic ring A and tropolone ring C. It was found that O-demethylation (both, in vitro and in vivo) takes place predominantly in the aromatic ring, especially at position 2.