Xerostomia and hypofunction of the salivary glands in cancer therapy.

This review presents data from the literature on oral adverse reactions from the perspectives of subjective feelings of dry mouth (xerostomia) and objective measures of salivary gland hypofunction during and after cancer therapy. Special emphasis is paid to the mechanisms behind xerostomia, impaired saliva secretion and changes in the composition of saliva and to how these relate to radiation therapy involving the salivary glands and to systemic chemotherapy. The oral complications that relate to such iatrogenic changes in salivary gland function are also discussed.     

The analysis of carbohydrate-deficient transferrin, marker of chronic alcoholism, using capillary electrophoresis.

Carbohydrate-deficient transferrin (CDT) is currently considered to be the best available marker for the diagnosis of chronic alcoholism. A large variety of methods have been developed, demonstrating the need for standardisation. Commercially available anion-exchange chromatographic-based assays are easy to use and require no specialised, expensive instruments. However, these methods cannot identify genetic transferrin variants or the carbohydrate-deficient glycoprotein syndrome. In 1989, a capillary isoelectric focusing method was developed for quantitative measurement of CDT. Despite the optimal resolution, this method is not easily applied in a clinical routine environment due to the complexity of analysis. Capillary electrophoresis in a polymer network using coated capillaries allowed full resolution of the sialoforms of human transferrin. The drawbacks due to an expensive and time-consuming sample preparation were eliminated when a method in neat serum was developed. Capillary zone electrophoresis allowed full resolution of the transferrin isoforms with a high analytical performance in a short analysis time thanks to a strong electroosmotic flow. Genetic transferrin variants were easily detected, avoiding false-positive results. Also, using capillary zone electrophoresis, it was shown that CDT is a suitable marker of chronic alcohol abuse detection in transferrin CD (common/cathodal) variants.     

Effects of per- and polyfluorinated compounds on adult rat testicular cells following in vitro exposure

Testicular toxicity is observed following exposure of rats to per- and polyfluorinated compounds (PFCs). Such compounds were also shown to induce oxidative stress and changes in ABC efflux transporters e.g. P-gp, implying two mechanisms which may contribute to testicular toxicity. We studied the toxicity of four PFCs (PFOA, PFNA, 8:2 FTOH and 6:2 FTOH) on primary rat testicular cells. DNA damage was studied by the comet assay including Fpg enzyme treatment to detect oxidative lesions. The levels of the ABC efflux transporters Bcrp1, Oat2 and P-gp were studied by real-time RT-PCR or flow cytometry. A PFNA associated increase in DNA SSBs was attributed to a subpopulation of moderately damaged cells possibly associated with cytotoxicity. No significant increase in oxidative DNA damage was measured for any of the PFCs. Expression levels of ABC efflux transporters suggest that PFCs may increase expression levels of the P-gp protein and the Oat2 gene.     

Calmodulin interacts with PAC1 and VPAC2 receptors and regulates PACAP-induced FOS expression in human neuroblastoma cells

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) mediates its physiological functions through activation of PAC1, VPAC1 and VPAC2 receptors, and the ubiquitous Ca²⁺-sensor calmodulin has been implicated in PACAP-induced signaling. The immediate early response gene FOS is a well-known marker of neuronal activation, so we used a human neuroblastoma cell line NB-1 to explore the role of calmodulin in PACAP-induced FOS gene expression. We observed both short-term and prolonged altered PACAP-mediated activation of the FOS gene in the presence of the calmodulin-antagonist W-7. NB-1 cells were shown to express PAC1 and VPAC2 receptors, and immunoprecipitation of both receptors displayed a co-association with calmodulin in the absence of Ca²⁺. Our findings indicate a novel mechanism of calmodulin in regulating PACAP signaling by possible interaction with the inactive state of PAC1 and VPAC2 receptors.     

Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: inhibitory effects on receptor-mediated uPA activity in vitro and in vivo

Binding of urokinase plasminogen activator (uPA) to its cellular receptor, uPAR, potentiates plasminogen activation and localizes it to the cell surface. Focal plasminogen activation is involved in both normal and pathological tissue remodeling processes including cancer invasion. The interaction between uPA and uPAR therefore represents a potential target for anti-invasive cancer therapy. Inhibitors of the human uPA-uPAR interaction have no effect in the murine system. To enable in-vivo studies in murine cancer models we have now generated murine monoclonal antibodies (mAbs) against murine uPAR (muPAR) by immunizing uPAR-deficient mice with recombinant muPAR and screened for antibodies, which inhibit the muPA-muPAR interaction. Two of the twelve mAbs obtained, mR1 and mR2, interfered with the interaction between muPAR and the amino-terminal fragment of muPA (mATF) when analyzed by surface plasmon resonance. The epitope for mR1 is located on domain I of muPAR, while that of mR2 is on domains (II-III). In cell binding experiments using radiolabelled mATF, the maximal inhibition obtained with mR1 was 85% while that obtained with mR2 was 50%. The IC(50) value for mR1 was 0.67 nM compared to 0.14 nM for mATF. In an assay based on modified anthrax toxins, requiring cell-bound muPA activity for its cytotoxity, an approximately 50% rescue of the cells could be obtained by addition of mR1. Importantly, in-vivo efficacy of mR1 was demonstrated by the ability of mR1 to rescue mice treated with a lethal dose of uPA-activatable anthrax toxins.     

Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study

The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size.     

Small artery structure is an independent predictor of cardiovascular events in essential hypertension

OBJECTIVE: Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon in essential hypertension and can be assessed in vitro as an increase in the media: lumen ratio (M: L) of isolated small arteries. We have investigated whether M: L is a risk predictor in uncomplicated essential hypertensive patients. Recently, high M: L was demonstrated as a prognostic marker in patients at high cardiovascular risk, including normotensive type 2 diabetic patients. Since diabetes is associated with pressure-independent changes in M: L, the relevance of this finding to essential hypertension has been uncertain. METHODS: We conducted a follow-up survey of 159 essential hypertensive patients, who had previously been submitted to a M: L evaluation while participating in a clinical trial. They composed a homogeneous moderate-risk group, with no concomitant diseases, and represented 1661 years of follow-up. RESULTS: Thirty patients suffered a documented predefined cardiovascular event during follow-up. Increased relative risk (RR) was associated with M: L >or= 0.083 (mean level of the hypertensive cohort), RR = 2.34 [95% confidence interval (CI) 1.11-4.95], and with M: L >or= 0.098 (mean level of a normotensive control group + 2SD), RR = 2.49 (95% CI 1.21-5.11). Both results remained significant (RR = 2.19, 95% CI 1.04-4.64, and RR = 2.20, 95% CI 1.06-4.56, respectively) when adjusted for Heart Score level (10-year mortality risk-estimate, integrating age, gender, systolic blood pressure, cholesterol and smoking). CONCLUSION: Abnormal resistance artery structure independently predicts cardiovascular events in essential hypertensive patients at moderate risk.