Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females

Emedastine is registered in its country of origin (Japan) as an antihistamine for the indication of seasonal allergic rhinitis. Further research on the drug's sedating properties was needed to secure its registration elsewhere. The present study was designed to compare the effects of emedastine 2 mg and 4 mg twice daily after single and repeated doses, on actual driving performance versus those of cetirizine 10 mg once daily and placebo; and to determine how repeated doses of each drug interact with alcohol to affect driving. Each treatment was administered for 5 days to 19 healthy volunteers (nine men and ten women, aged 21-45 years) according to a four-period double-blind cross-over design. Driving performance was measured in a standardized test between 3 and 4 h after administration of the morning dose on days 1, 4 and 5. Alcohol, sufficient for achieving a blood alcohol concentration of 0.05 g/dl was given before driving on day 5 of each period. Both emedastine doses similarly and significantly impaired driving in every test. The effects of cetirizine were less. They were significant over days 1, 4 and 5 combined, although not separately. Women were more impaired by both drugs. Alcohol increased driving impairment similarly in every condition. Subjects were only able to discriminate the sedating and impairing effects of the first dose of emedastine 4 mg from placebo. Emedastine, in oral doses of 2 mg and 4 mg twice daily, is sedating and impairs driving. The drug could therefore constitute a traffic hazard and its users should be warned accordingly.     

Mac-1 (CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to melanoma

Antibody-reliant destruction of tumor cells by immune effector cells is mediated by antibody-dependent cellular cytotoxicity, in which Fc receptor (FcR) engagement is crucial. This study documents an important role for the beta(2) integrin Mac-1 (CD11b/CD18) in FcR-mediated protection against melanoma. CD11b-deficient mice, those that lack Mac-1, were less protected by melanoma-specific monoclonal antibody TA99 than wild-type (WT) mice. Significantly more lung metastases and higher tumor loads were observed in Mac-1(-/-) mice. Histologic analyses revealed no differences in neutrophil infiltration of lung tumors between Mac-1(-/-) and WT mice. Importantly, Mac-1(-/-) phagocytes retained the capacity to bind tumor cells, implying that Mac-1 is essential during actual FcR-mediated cytotoxicity. In summary, this study documents Mac-1 to be required for FcR-mediated antimelanoma immunity in vivo and, furthermore, supports a role for neutrophils in melanoma rejection.     

Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease

Experimental evidence from animal models has provided a framework for our current understanding of autoimmune disease pathogenesis and supports the importance of genetic predisposition, molecular mimicry, and immune dysregulation. However, only recently has evidence emerged to support the role of immune dysregulation in human organ-specific autoimmune disease. In the current study of the "late" manifestation of autoimmune thyroid disease (AITD) in a cohort of human immunodeficiency virus (HIV)-positive patients following highly active antiretroviral therapy (HAART), we discuss how immune dysregulation and factors associated with the immunopathology of HIV infection fit the current understanding of autoimmunity and provide a plausible basis for our clinical observations. De novo diagnoses of thyroid disease were identified between 1996 and 2002 in 7 HIV treatment centers (5/7 centers completed the study). Patients were diagnosed as clinical case entities and not discovered through thyroid function test screening. Paired plasma specimens were used to demonstrate sequential rise in thyroid antibodies.Seventeen patients were diagnosed with AITD (median age, 38 yr; 65% were of black African or black Caribbean ethnicity; and 82% were female). The median duration of immune reconstitution was 17 months. Graves disease (GD) was diagnosed in 15 of 17 patients. One patient developed hashithyrotoxicosis with atypically raised C-reactive protein, and another developed hypothyroidism. One GD patient had associated secondary hypoadrenalism. The estimated combined prevalence of GD for 4 treatment centers for female patients was 7/234 and for males was 2/1289. The denominator numbers were matched controls, from 4 centers able to provide data, who commenced HAART during the same time (January 1996 to July 2002) and who did not develop clinical AITD. The mean baseline pre-HAART CD4 count was 67 cells/mL, and the mean increase from nadir to AITD presentation was 355 cells/mL. AITD patients were more likely than controls (95% confidence interval, chi-square test) to be severely compromised at baseline (as defined by a CD4 count < 200 cells/mL or the presence of an acquired immunodeficiency syndrome [AIDS]-defining diagnosis), and to experience greater CD4 increments following HAART. AITD may be a late manifestation of immune reconstitution in HIV-positive patients taking HAART, and immune dysregulation may be an important factor.     

Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model

BACKGROUND: Matrix metalloproteinases (MMPs) are essential for extracellular matrix remodelling and may contribute to the development of endometriosis. Transplantation of endometrium onto the chicken chorioallantoic membrane (CAM) results in endometriosis-like lesion formation, a process that requires extensive tissue remodelling. We investigated the expression of a wide range of MMPs in menstrual endometrium, endometriosis-like lesions in CAMs, in peritoneal endometriosis and in endometriosis in the rectovaginal space, as well as the function of MMPs in early lesion formation in the CAM model. METHODS: Expression of MMPs was evaluated by immunohistochemistry and MMP function was studied in the CAM by inhibiting MMP activity during lesion formation. RESULTS: Nearly all MMPs were present in all tissues studied. No significant differences in the expression of a majority of MMPs were found in endometriosis-like lesions in CAMs when compared with human endometriosis. Inhibition of MMP-1, -2, -3, -7 and -13 activities significantly impaired endometriosis-like lesion formation in CAMs. CONCLUSIONS: The MMP expression profiles of experimentally induced endometriosis in CAMs and human endometriosis are similar. The prevention of endometriosis-like lesion formation in the CAM by inhibiting MMP activity strongly suggests that MMPs have a function in the early development of endometriotic lesions.     

Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer

In vitro studies suggest that a deficient mismatch repair (MMR) system reduces 5-Fluorouracil cytotoxicity. Colon cancer (CC) in hereditary nonpolyposis colorectal cancer (HNPCC) is due to a dysfunctioning MMR gene that leads to microsatellite instability (MSI). Clinical studies on the efficacy of 5-Fluorouracil (5-FU) in MSI high tumours are contradictory. In a retrospective study, we compared the survival of subjects with stage III CC from HNPCC families that were treated with and without adjuvant 5-FU. The Dutch HNPCC family registry was used. Information on adjuvant chemotherapy for stage III CC was obtained from subjects of families with a mutation and/or who fulfilled the AMS criteria or who were strongly suspicious for HNPCC. CC specific survival was calculated. Observation time was measured either until the date of death, date of a second primary CC or until the closing date of the study, i.e., June 1, 2001. Statistical analysis was done by Kaplan-Meier survival analysis. A total of 92 subjects with stage III CC were included. Twenty-eight of them (17 males) had adjuvant treatment with 5-FU. The median follow-up was 4 (range: 1-17) years; 8 subjects died of CC. The 5-year survival was 70% (95% Cl: 49-90). Sixty-four subjects (36 males) did not have adjuvant therapy. Their median follow-up was 6 (range: 0-23) years. Twenty of them died of CC. The 5-year survival in this group was also 70% (95% Cl: 59-83). To date, the selection of patients with CC for 5-FU treatment is based on the stage rather than the biology of the tumour. In our study, the 5-year survival of subjects treated with and without adjuvant 5-FU did not differ. Further studies are necessary to elucidate the role of MSI in 5-FU treatment of MSI-H tumours in HNPCC.     

Left-right differences in Eustachian tube function in children with ventilation tubes

OBJECTIVE: To study the intraindividual variation in Eustachian tube (ET) function in children with ventilation tubes. METHODS: The forced response test, the pressure equilibration test and the sniff test were performed on both ears of 148 children. The results of both ears were compared. RESULTS: No systematic differences were found between the left and the right ears. However, the intraindividual variation was very pronounced. The variation in passive ET function within children was of similar magnitude as the variation in passive ET function between children. Twenty-eight percent of the children had different active ET function in both ears and 15% had an opposite result in each ear with respect to the sniff test. CONCLUSIONS: This study shows that ET function is much more a characteristic of the individual ear than of the individual child. These findings also question the validity of trials on ET function or middle ear disease that use the opposite ear as a control (split level design).     

Drug resistance genotypes predict response to amprenavir-containing regimens in highly drug-experienced HIV-1-infected patients

We have undertaken a study of virological responses to amprenavir-containing antiretroviral regimens, during the expanded access programme within the UK. Ninety-five HIV-1-infected patients were included for which virological and immunological follow-up was available for 75, and baseline drug resistance data available for 51. These were highly drug-experienced patients, having previously received a median of nine antiviral drugs, within all available classes. Eighty-eight percent of patients had a virological response to the new regimen, with a median maximal decline of 1.45 log10 copies/ml, and 34% of patients reached <400 copies/ml on treatment. Although 68% of patients with resistance data had protease inhibitor resistance mutations, only 10% patients had key amprenavir resistance mutations, and virological response was predicted by the number of active drugs utilized in the amprenavir-containing regimen, as determined by the baseline genotypic resistance test. Other independent predictors of viral load decline were a higher baseline viral load and fewer previous antiviral drugs. We conclude that amprenavir can contribute to antiviral efficacy in salvage regimens, and that resistance testing may help to optimize its use in this scenario. New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus.     

Intestinal bile salt absorption in Atp8b1 deficient mice

BACKGROUND/AIMS: Mutations in the ATP8B1 gene can cause Progressive Familial Intrahepatic Cholestasis type 1. We have previously reported that Atp8b1(G308V/G308V) mice, a model for PFIC1, have slightly, but significantly, higher baseline serum bile salt (BS) concentrations compared to wt mice. Upon BS feeding, serum BS concentrations strongly increased in Atp8b1-deficient mice. Despite these findings, we observed only mildly impaired canalicular BS transport. In the present report we tested the hypothesis that Atp8b1(G308V/G308V) mice hyperabsorb BS in the intestine during BS feeding. METHODS: Intestinal BS absorption was measured in intestinal perfusion and in intestinal explants. In addition, we measured BS concentrations in portal blood. Ileal expression of the Fxr-targets Asbt, Ilbp and Shp was assessed. RESULTS: In wt and Atp8b1(G308V/G308V) mice, intestinal taurocholate absorption is primarily mediated by the ileal bile salt transporter Asbt. Neither of the experimental systems revealed enhanced absorption of BS in Atp8b1(G308V/G308V) mice compared to wt mice. In line with these observations, we found no difference in the ileal protein expression of Asbt. Induction of Shp expression during BS feeding also demonstrated that Fxr signalling is intact in Atp8b1(G308V/G308V) mice. CONCLUSIONS: The accumulation of BS in plasma of Atp8b1(G308V/G308V) mice during BS feeding is not caused by increased intestinal BS absorption.     

The irrelevant speech effect and the level of interference in aging

In general, no disproportionate detrimental effects of irrelevant background speech on cognition are found in aging individuals, although this is predicted by the inhibitory view of aging. This may be due to the nature of the primary task (most studies involve a verbal learning task) or the cognitive level at which irrelevant speech interferes with this task. In this study, the irrelevant speech effect on a numeric working memory task was investigated among 20 young (M = 21.8 years) and 20 older (M = 68.1 years) native Dutch individuals. Level of interference (LOI) was manipulated by presenting white noise (no interference), Russian words (low interference), Dutch words (phonological interference), and Dutch numbers (semantic interference) in the background. Results showed that reaction time increases as a function of LOI relative to silence, whereas accuracy remains unaffected. However, no interaction between LOI and age group was found, which suggests that the elderly were not disproportionately affected by an increased level of interference. These results are discussed in the light of the inhibitory view of aging.