Transplacental mutagenicity of cisplatin: H-ras codon 12 and 13 mutations in skin tumors of SENCAR mice

Cisplatin is an anticancer agent sometimes used in pregnantwomen. It is also a potent initiator of skin tumors in micewhen administered transplacentally. For characterization ofthe transplacental mutagenicity of cisplatin, tumors initiatedin fetal skin by cisplatin or 7,12-dimethyI-benz[     

Alterations in membrane-bound and cytoplasmic K-ras protein levels in mouse lung induced by treatment with lovastatin,cholestyramine, or niacin: effects are highly mouse strain dependent

Agents that either increase (cholestyramine, CS) or decrease (lovastatin, Lov) de novo peripheral cholesterol synthesis may increase (CS) or decrease (Lov) ras protein membrane localization by altering protein prenylation, and potentially have pro- or anti-carcinogenic effects. Male A/J, Swiss, and C57/BL6 mice were treated with 2 or 4% CS, 1% dietary niacin, or 25mg/kg of Lov three times per week (Lov-3X) or five times per week (Lov-5X). After 3 weeks, serum cholesterol and triglycerides were determined enzymatically. Membrane and cytoplasmic K-ras proteins in lung were determined by immunoprecipitation followed by western blotting with a K-ras specific antibody. Results confirmed the hypothesis only in isolated instances. A/J mice had a significant 30% increase in cytoplasmic K-ras and a 40% decrease in membrane K-ras from Lov treatment, as predicted. C57/BL6 mice had a significant 77% increase in membrane K-ras, as expected from CS feeding. At variance with the hypothesis, Swiss mice had increased levels (3-28%) of membrane K-ras with all treatments (including Lov), and C57/BL6 mice treated with Lov had a 58-78% increase in cytoplasmic K-ras without any reduction in the levels of membrane K-ras. Niacin, predicted to have no effect on ras membrane localization, decreased cytoplasmic K-ras in A/J mice, increased both membrane and cytoplasmic K-ras in Swiss mice, and had no effect in C57/BL6 mice. Results may have differed from those predicted because of strain-dependent differences in response to the cholesterol-lowering agents. A difference in response among the mouse strains suggests that individual genetic differences may alter the effect of hypocholesterolemic agents on K-ras membrane localization, and potentially the risk of ras-dependent cancer.     

Development of a tool for assessment and care planning for dementia-related problem behaviors in home and community-based services programs: the Problem Behavior Inventory

OBJECTIVE: To describe development, validity, and application of the Problem Behavior Inventory (PBI), a tool to assess dementia-related problem behaviors (DRPBs) in community-based populations. DATA SOURCES AND STUDY SETTING: Demographic, contact, and disease-specific data were extracted from client files from a Medicaid-funded home and community-based services program. Primary caregivers completed standard surveys relating to the care recipients' memory, mood, and behaviors. The client (care recipient) completed the Mini-Mental Status Exam (MMSE). STUDY DESIGN: Cognitively impaired clients, enrolled in the Community Care Services Program (CCSP) during a reference month, and their primary caregivers, were identified by CCSP case managers for participation in the study. Primary caregivers completed the Revised Memory and Behavior Problem Checklist (RMBPC). Clients screening positive for the presence of DRPBs based on caregiver responses to the RMBPC were then assessed using the Problem Behavior Inventory (PBI). PRINCIPLE FINDINGS: Within the CCSP sample, the most prevalent behavior was appearing sad or depressed (67%), while the most frequent behavior was seeking attention, occurring at least daily in 58% of the group. The most bothersome behaviors were being sexually inappropriate, wandering, and misbehaving in public. Examination by behavior category (physical, verbal, mood, etc.) revealed a strong relationship between level of bother and behavior frequency. Frequency of verbal behaviors was positively related to MMSE scores, whereas frequency of ADL-related behaviors was inversely related to MMSE scores. Bother scores were not associated with MMSE scores. CONCLUSIONS: This study documents that the PBI is a valid, useful, and feasible tool for assessing DRPBs in community populations. Case managers using the PBI can determine specific problem behavior areas among client populations and for individual clients and institute client-specific interventions to address each issue.     

Nutrient intake of first generation Gujarati Asian Indian immigrants in the U.S

OBJECTIVE: To examine the nutrient intake of Gujarati Asian Indian immigrants in the U.S. and the influence of length of residence in the U.S. and socioeconomic status (SES) on their macronutrient intake. METHODS: Subjects were male (n = 90) and female (n = 99) Gujarati Asian Indian immigrants over the age of 45. Each participant completed a 24-hour dietary recall. Dietary recalls were analyzed using Food Processor nutrient analysis software. Participants were classified into recent immigrants (<10 years length of residence in the U.S.) and long-term immigrants (>10 years length of residence in the U.S.) and into low, medium and high education groups, based on highest level of education achieved, to examine the influence of these variables on their macronutrient intake. RESULTS: The macronutrient contributions to the total energy intake of these Gujarati Asian Indian immigrants were as follows: carbohydrate 57%, protein 12% and total fat 33%. The diets were low in cholesterol (<100 mg/day) and high in dietary fiber (>/=25 g/day). Reported intakes of vitamin D, calcium (women only), potassium (women only), copper and zinc were less than two-thirds of the recommendations. Significant differences (p < 0.05) in macronutrient intake were observed based on length of residence in the U.S. and SES. Regression analysis indicates age, total energy intake, length of residence in the U.S. and SES to have a significant influence on the nutrient intake of these Gujarati Asian Indian immigrants. CONCLUSION: The nutrient intakes of these Gujarati Asian Indian immigrants indicate both inadequacies and excesses of select macro and micronutrients. These nutrient inadequacies and excesses can impact overall health and risk of chronic diseases of these individuals. Further investigation of the influence of the diets of these immigrants on their health is warranted.     

Down-regulation of von Hippel-Lindau protein in N-nitroso compound-induced rat non-clear cell renal tumors

Non-clear cell rat kidney tumors, inducible by N-nitroso compounds but lacking mutations in the von Hippel--Lindau (VHL) coding sequence, were examined for other VHL alterations. Neither mutations nor DNA methylation was detected in a putative promoter region. By immunohistochemistry, however, VHL protein level was evidently reduced in six of the eight eosinophilic renal epithelial tumors and in all the ten nephroblastomas. Immunoblotting of normal kidney detected two VHL proteins of 20 and 22kDa in a 16-day-old fetal rat but only 20kDa protein in an adult rat. This is the first demonstration of VHL alteration at the protein level.     

Antiepileptic drug therapy and its management in sudden unexpected death in epilepsy: a case-control study

PURPOSE: Because frequent seizures constitute a major risk factor for sudden unexpected death in epilepsy (SUDEP), the treatment with antiepileptic drugs (AEDs) may play a role for the occurrence of SUDEP. We used data from routine therapeutic drug monitoring (TDM) to study the association between various aspects of AED treatment and the risk of SUDEP. METHODS: A nested case-control study was based on a cohort consisting of 6,880 patients registered in the Stockholm County In Ward Care Register with a diagnosis of epilepsy. Fifty-seven SUDEP cases, and 171 controls, living epilepsy patients, were selected from the cohort. Clinical data including data on TDM were collected through medical record review. RESULTS: The relative risk (RR) of SUDEP was 3.7 (95% CI, 1.0-13.1) for outpatients who had no TDM compared with those who had one to three TDMs during the 2 years of observation. RR was 9.5 (1.4-66.0) if carbamazepine (CBZ) plasma levels at the last TDM were above and not within the common target range (20-40 microM). High CBZ levels were associated with a higher risk in patients receiving polytherapy and in those with frequent dose changes. Although the subgroup of patients with high CBZ levels was small (six cases of 33 with CBZ therapy), and the result should be interpreted with caution, no similar associations were demonstrated for phenytoin plasma levels and risk of SUDEP. No association was found between SUDEP risk and within-patient variation in AED levels over time. CONCLUSIONS: Polytherapy, frequent dose changes, and high CBZ levels as identified risk factors for SUDEP all point to the risks associated with an unstable severe epilepsy. It is unclear whether high CBZ levels per se represent a risk factor or just reflect other unidentified aspects of a severe epilepsy. Our results, however, prompt further detailed analyses of the possible role of AEDs in SUDEP in larger cohorts and suggest that reasonable monitoring of the drug therapy may be useful to reduce risks.     

Dysgerminoma of the ovary: A retrospective study

A retrospective analysis of 22 patients with ovarian dysgerminoma who were treated between 1980 and 1987 was carried out. The median age at presentation was 24.5 years. A total of 15 patients were in stage I, one patient was in stage II and six patients were in stage III. Bilateral ovarian involvement was present in four patients. Conservative surgery was carried out in nine patients and 11 patients underwent radical surgery. Two patients had biopsy only. Fourteen patients received adjuvant radiotherapy and three patients received salvage radiation for recurrent disease. The 10-year actuarial survival rate was 81.8%. All 15 patients in stage I were alive and disease-free at a median follow-up of 125 months. Four patients (one in stage II and three in stage III) died of progressive or recurrent abdominopelvic disease. Pelvic recurrence occurred after conservative surgery in two patients in stage IA who had a tumour size greater than 10 cm, but they were salvaged with radical surgery, chemotherapy and radiotherapy. There were seven patients aged 20 years or less. All were alive and disease-free at a median follow-up of 127 months.     

Exchange transfusion in neutropenic septicemic neonates: effect on granulocyte functions

Depletion neutropenia caused by overwhelming bacterial infection is associated with fatal outcome and is an objective indicator of the severity of sepsis. Studies on controlled evaluation of exchange transfusion in the management of severe neonatal sepsis have not considered neutropenia as an inclusion critcrion, and randomized, controlled trials on evaluation of ncutrophil functions after exchange transfusion are scarce. This prompted us to carry out the present study. Septicemic neonates were enrolled if they had neutropenia and were randomized to undergo exchange transfusion (study group, n = 20) or not (controls, n= 10). Granulocyte functions were assessed using the nitro blue tetrazolium (NBT) reduction test and the staphylococcicidal index. Blood was drawn for granulocyte function tests once from controls and donors, and before, immediately after and 6 h after exchange transfusion in the study group. Mortality was 35% in the study group and 70% in controls. Gram-negative organisms accounted for 80%, in the study group and 90% in controls. Mean total leukocyte count and neutrophil count increased significantly immediately after exchange transfusion and 6 h later. Absolute band count decreased significantly immediately after exchange transfusion and incrcased 6 h later. NBT reduction in septicemic neonates in the study group, as wclras in controls. was significantly decreascd as compared to donor cells. NBT reduction improved significantly immediately after exchange transfusion and 6 h later. The valucs of the perccntage of viable staphylococci recovered from neutrophils also improved significantly immediately after exchange transfusion and 6 h later. We conclude that exchange transfusion with fresh whole blood in severe neonatal septicemia with neutropenia improves survival, increases the neutrophil count and cnhances neutrophil function.     

A potential mechanism for fumonisin B(1)-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3beta activity

Fumonisin B(1) (FB(1)) is a worldwide corn contaminant and has been epidemiologically linked to the high incidence of human esophageal cancer in South Africa and China. FB(1) is hepatocarcinogenic in rats by an unknown mechanism. Inhibition of ceramide synthase and disruption of membrane phospholipids have been shown to be mechanisms of toxicity. Here we show overexpression of cyclin D1 protein in both preneoplastic and neoplastic liver specimens obtained from a long-term feeding study of FB(1) in rats. In rats fed FB(1) short-term, cyclin D1 protein levels in liver were increased up to five-fold in a dose-responsive manner. Northern blot analysis demonstrated no increase in mRNA levels of cyclin D1. 2D electrophoresis of cyclin D1 protein in FB(1)-treated samples showed a distinct pattern of migration (presence of less negatively charged form of the protein) that differed from controls. Recently, it has been shown that phosphorylation of cyclin D1 by glycogen synthase kinase 3beta (GSK-3beta) on a single threonine residue (Thr-286) positively regulates proteosomal degradation of cyclin D1. In FB(1)-treated samples we detected GSK-3beta phosphorylated on serine 9; activated protein kinase B (Akt) appears to be responsible for this activity-inhibiting phosphorylation. These findings suggest that overexpression of cyclin D1 results from stabilization due to a lack of phosphorylation mediated by GSK-3beta. We also observed an increase in cyclin dependent kinase 4 (Cdk4) complexes with cyclin D1 in FB(1)-treated samples; additionally, elevated Cdk4 activity was shown by increased phosphorylation of the retinoblastoma protein. In summary, the activation of Akt leads to increased survival, inhibition of GSK-3beta activity and post-translational stabilization of cyclin D1, all events responsible for disruption of the cell cycle G(1)/S restriction point in hepatocytes. This is the first report suggesting the mechanism by which FB(1) acts as a carcinogen.