Growth modulation of hepatocytes and rat liver epithelial cells (WB-F344) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)

Modulation of DNA synthesis by 2,3,7,8-tetrachlorodi-benzo-p-dioxin(TCDD) was studied in primary cultures of hepatocytes and inrat liver epithelial cells (WB-F344) to develop models for studieson the interactions between the activated Ah receptor and cellulargrowth control. In hepatocytes TCDD either positively or negativelymodulated EGF-stimulated DNA synthesis. In the presence of ethlnylestradiol10^–12 M TCDD moderately increased EGF-stimulated DNA synthyesis(     

Improved Scoring System to Assess Adult Donors For Cadaver Renal Transplantation

We previously proposed a quantitative approach to assess donor organs for cadaver renal transplantation. To improve on our original scoring system, we studied 34 324 patients who received cadaver renal transplants from adult donors between 1994 and 1999 and were reported to the UNOS Scientific Renal Transplant Registry. A scoring system was developed from five donor variables (age, 0-25 points; history of hypertension, 0-4; creatinine clearance before procurement, 0-4; cause of death, 0-3; HLA mismatch, 0-3) that showed a significant correlation with renal function and long-term graft survival. Cadaver kidneys were stratified by cumulative donor score: grade A, 0-9 points; grade B, 10-19; grade C, 20-29; and grade D, 30-39. The influence of donor score on renal function and graft survival was most severe above 20 points, designated 'marginal' kidneys. In summary, a donor scoring system developed from a large population database was useful in predicting outcome after cadaver renal transplantation. The improved system provides a quantitative approach to evaluation of marginal kidneys and may improve allocation of these organs in cadaver renal transplantation.     

A new immune-competent animal model of mucosally derived squamous cell carcinoma.

OBJECTIVES: To develop an immune-competent animal model for mucosally derived squamous cell carcinoma (SCCA). STUDY DESIGN: Fifteen Fischer 344 rats were inoculated with 1, 2, 5, 10, or 20 x 10(6) FAT7 cells in their flanks. The animals were observed for tumor growth and metastasis. RESULTS: All animals developed tumors that grew exponentially. Pulmonary metastases developed in all animals and 13% developed lymph node metastases. CONCLUSION: The FAT7 flank tumor in Fischer 344 rats is a new animal model that closely resembles the behavior of human mucosal head and neck cancer. SIGNIFICANCE: The existence of an immune-competent, mucosally derived, and reliable animal model of SCCA that somewhat resembles human head and neck SCCA gives the opportunity to perform immune-modulating experiments on head and neck cancer in these animals. EBM rating: B-3.     

Longitudinal in vivo effects of growth hormone overexpression on bone in transgenic mice.

In this study we examined the effect of systemic overexpression of GH on bone in transgenic mice longitudinally in vivo over a period of 9 months. We observed substantially increased BMC in GH transgenic mice and a significant reduction in serum osteocalcin. GH effects on bone were strongly dependent on gender and developmental stage. INTRODUCTION: State-of-the-art bone marker and microimaging technology was applied in this longitudinal study to examine bone metabolism, BMC, bone density, and cortical bone structure over the life span of growth hormone (GH) transgenic (tg) mice. MATERIALS AND METHODS: Thirty-eight mice from four genetic groups (male, female, tg, and controls) were examined with DXA, and their femur and tibia were examined with peripheral QCT (pQCT). Osteocalcin (formation) and collagen cross-links (resorption) from serum and urine were also measured at postnatal weeks 3, 6, 9, 12, 18, 26, and 38. RESULTS: GH tg mice displayed a significant increase in body weight (up to 50%) and BMC (up to 90%), but serum osteocalcin was significantly reduced compared with controls. GH tg females (but not males) displayed increased trabecular density over controls up to week 12. In contrast, male (but not female) GH tg mice displayed a higher cortical cross-sectional area than controls. Cortical density was significantly lower in both male and female GH tg mice compared with control mice. CONCLUSIONS: The increase in BMC in GH tg mice is associated with reduced serum osteocalcin levels, indicating that bone turnover may be lower than in the control mice. On a structural level, bone responds to GH excess in a gender-specific manner, with alterations varying substantially between different developmental stages.     

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.     

Verbal memory errors and symptoms in schizophrenia.

OBJECTIVE: To extend and test hypotheses linking positive and negative symptoms to selective aspects of verbal memory in schizophrenia. BACKGROUND: Verbal memory includes the ability to discriminate and prevent the intrusion of irrelevant information into recall and recognition. This ability has been proposed as a cognitive process that differentially mediates positive and negative symptoms. METHOD: Four error discrimination and 1 general recall memory index from the California Verbal Learning Test as well as general ability (IQ) and sex were used as predictors of symptom ratings in 55 schizophrenia patients within a regression framework. RESULTS: Intrusion errors during free recall contributed significantly to the prediction equation for negative symptoms (Brief Psychiatric Rating Scale). In contrast, positive symptoms and general psychopathology were not predicted by any of the discrimination indices. However, general recall memory (California Verbal Learning Test total words trials 1-5) contributed significantly to the prediction of general psychopathology and marginally to the prediction of negative symptoms. CONCLUSIONS: Impaired recall memory predicts levels of nonspecific psychopathology in schizophrenia. Negative symptoms associate with low intrusion error rates, but there is no evidence of an association between elevated errors and positive symptoms.     

The role of alpha- and beta-adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1).(ABSTRACT TRUNCATED AT 250 WORDS)