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)     

Human spumaretrovirus antibody reactivity in multiple sclerosis

The role of human spumaretrovirus (HSRV) infections in the pathogenesis of multiple sclerosis (MS) was investigated with recombinant HSRV env-specific enzyme-linked immunosorbent assay. The presence of HSRV antibodies was determined in pairs of serum and cerebrospinal fluid (CSF) samples from 60 MS patients. In 7 of these patients serial serum and CSF samples were obtained in relation to the clinical activity of the disease during a period of 2 years. No increased antibody reactivity was demonstrable in the MS population compared with 14 aseptic meningitis patients, 50 blood donors and 16 healthy controls. Slightly elevated levels of antibodies were demonstrable in serum and/or CSF in 4 MS patients but also in 1 patient with aseptic meningitis, 1 blood donor and 1 child. No marked serum or CSF HSRV antibody fluctuation was observed in the MS patients followed longitudinally. Thus, this study does not support the involvement of HSRV in the pathogenesis of MS.     

The relationship of cancer incidence to terrestrial radiation and population density in Connecticut, 1935-1974

The relationship of cancer incidence to terrestrial radiation and population density was investigated. Cancer incidence was obtained using 40 years of age-standardized data from the Connecticut Tumor Registry, and environmental radiation was estimated using data from an airborne gamma radiation survey of the entire state. These variables were examined ecologically, using the 169 towns of the state as the analytic units in a weighted regression analysis. The study design involves a large population base in a state having relatively high terrestrial radiation exposure levels overall and reasonable variation in exposure between towns. For all cancer combined, only one of the eight sex-specific analyses by decade yielded a significant radiation regression coefficient, and this was negative. In the sex- and site-specific analyses, almost all the coefficients for radiation were not significantly different from zero. In contrast, significant positive relationships of cancer incidence with population density were found for all cancer, for cancer of the lung for both sexes, for stomach, colonic, and prostatic cancer for males, and for lymphomas, thyroid, breast, and ovarian cancer for females. Both the radiation and population density relationships were adjusted for socioeconomic status. Socioeconomic status was significantly negatively associated with stomach and lung cancer in males and with cervical cancer in females; it was also positively associated with lymphomas and breast cancer in females. A power calculation revealed that, despite the relatively large size of this study, there was only a small probability of detecting a radiation effect of the strength anticipated from previous estimates.