Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells.

Non-neuronal expression of components of the glutamatergic system has been increasingly observed, and our laboratory previously had demonstrated the etiological role of ectopically expressed metabotropic glutamate receptor 1 (Grm1/mGluR1) in mouse models of melanoma. We hypothesize that inappropriate glutamatergic signaling in other cell types can dysregulate growth leading to transformation and tumorigenesis. As most cancers are carcinomas, we selected an immortalized primary baby mouse kidney (iBMK) cell model to assess whether Grm1 can transform epithelial cells. These iBMK cells, engineered to be immortal yet nontumorigenic and retaining normal epithelial characteristics, were used as recipients for exogenous Grm1 cDNA. Several stable Grm1-expressing clones were isolated and the Grm1-receptors were shown to be functional, as evidenced by the accumulation of second messengers in response to Grm1 agonist. Additionally activated by agonist were mitogen-activated protein kinase (MAPK) and AKT/protein kinase B signaling cascades, the major intracellular pathways shown by many investigators to be critical in melanomagenesis and other neoplasms. These Grm1-iBMK cells exhibited enhanced cell proliferation in in vitro methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and significant tumorigenicity in in vivo allografts. Persistent Grm1 expression was required for the maintenance of the in vivo tumorigenic phenotype as demonstrated by an inducible Grm1-silencing RNA. These are the first results that indicate that Grm1 can be an oncogene in epithelial cells. In addition, relevance to human disease in the corresponding tumor type of renal cell carcinoma (RCC) may be suggested by observed expression of GRM1/mGluR1 in a number of RCC tumor biopsy samples and cell lines, and the effects of GRM1 modulation on tumorigenicity therein. Moreover, RCC cell lines exhibited elevated levels of extracellular glutamate, and some lines responded to drugs, which modulate the glutamatergic system. These findings imply a possible role for glutamate signaling apparatus in RCC cell growth, and that the glutamatergic system may be a therapeutic target in RCC.

Influence of starting strategy on cycling time trial performance in the heat.

The purpose of this study was to determine the influence of starting strategy on time trial performance in the heat. Eleven endurance trained male cyclists (30+/-5 years, 79.5+/-4.6 kg, VO(2max) 58.5+/-5.0 ml x kg x (-1) min(-1)) performed four 20-km time trials in the heat (32.7+/-0.7 degrees C and 55% relative humidity). The first time trial was completed at a self-selected pace (SPTT). During the following time trials, subjects performed the initial 2.5-km at power outputs 10% above (10% ATT), 10% below (10% BTT) or equal (ETT) to that of the average power during the initial 2.5-km of the self-selected trial; the remaining 17.5-km was self-paced. Throughout each time trial, power output, rectal temperature, skin temperature, heat storage, pain intensity and thermal sensation were taken. Despite significantly (P<0.05) greater power outputs for 10% BTT (273+/-45W) compared with the ETT (267+/-48W) and 10% ATT (265+/-41W) during the final 17.5-km, overall 20-km performance time was not significantly different amongst trials. There were no differences in any of the other measured variables between trials. These data show that varying starting power by +/-10% did not affect 20 km time trial performance in the heat.

Parent responses to pediatric headache.

Evaluated child and parent report versions of a 16-item parent response to children's recurrent pain episodes scale (PR-PAIN) on a sample of 153 pediatric headache patients. Factor analyses yielded three factors--Solicitous, Affiliative/Distracting, and Negative responses--for each report form. Correlations among factor scores provided evidence for convergent and discriminant validity. Factor scores from the parent and child report scales were differentially related to levels of episode-specific disability and overall behavior problems, supporting the criterion-related validity of both the child and parent measures. The PR-PAIN scale may assist in performing a thorough functional analysis of pediatric headache and other pain-related problems.

Lack of a renal-protective effect of misoprostol in rheumatoid arthritis patients receiving cyclosporin A. Results of a randomized, placebo-controlled trial.

OBJECTIVE: To assess whether the synthetic prostaglandin misoprostol is renal protective in rheumatoid arthritis (RA) patients who are beginning cyclosporin A (CSA) therapy. METHODS: In this randomized, placebo-controlled, multicenter trial, 50 patients with active RA were randomized to receive either misoprostol (800 micrograms/day) or placebo for 16 weeks. After 2 weeks of pretreatment with misoprostol or placebo, all patients concomitantly received CSA at an initial and maximum dosage of 5 mg/kg/day for 12 weeks. RESULTS: A significant increase in the serum creatinine level was observed in both treatment groups, with no difference noted between groups. There was a high withdrawal rate in both groups, primarily due to adverse events. CONCLUSION: A renal-protective effect was not demonstrated for misoprostol compared with placebo in RA patients who are beginning CSA therapy.

A vasculopathy with deposition of lambda light chain crystals.

An 82-year-old man and a 34-year-old woman developed subacute, obstructive, fatal vasculopathies characterized by extensive crystalline tissue deposits and monoclonal lambda light chain serum components. Cryocrystalglobulinemia was also present in one patient, and the purified crystals contained only lambda light chain dimers. Although the presentation of these patients resembled that of systemic necrotizing vasculitis, histologic evidence of inflammation was lacking and their subsequent rapid clinical deterioration was not altered by corticosteroid therapy, and in one case cyclophosphamide and plasmapheresis. Both patients died within 3 weeks of presentation.

Nifedipine-induced gingival hyperplasia. A histochemical and ultrastructural study.

Gingival hyperplasia induced by nifedipine (Procardia), a calcium channel-blocking agent used as an anti-anginal drug, was studied. In recent months, the role of nifedipine in the etiology of gingival hyperplasia has attracted interest. The purpose of this study was to determine the causal relationship and compare nifedipine to other drug-induced (phenytoin) and nondrug-induced gingival hyperplasias. Histochemical studies revealed increased numbers of fibroblasts containing strongly sulfated mucopolysaccharides in the nifedipine- and phenytoin- (Dilantin) induced gingival hyperplasias as compared to the nondrug-induced cases. Numerous secretory granules were also noted in the fibroblast cytoplasm in the nifedipine-treated case studied by electron microscopy. These results imply that there is an increase in acid mucopolysaccharide production in the nifedipine- and phenytoin-induced gingival hyperplasias. The potential significance and comparisons of the drugs' effects at the cellular level are discussed.

Increased incidence of recurrent hematuria in ankylosing spondylitis: a possible association with IgA nephropathy.

A retrospective analysis of our patients with ankylosing spondylitis revealed a 17.8% incidence of recurrent hematuria. Two of the five patients with recurrent hematuria had previously undergone renal biopsies showing a focal proliferative glomerulonephritis. The only specimen examined by immunofluorescent staining showed the typical changes of IgA nephropathy. A control group of patients with rheumatoid arthritis did not show recurrent hematuria. Recurrent hematuria may be a frequent occurrence in ankylosing spondylitis and may signify the presence of one of the glomerulonephritides such as IgA nephropathy.