Effects of a 20-HETE antagonist and agonists on cerebral vascular tone

This study examined the effects of a 20-hydroxyeicosatetraenoic acid (20-HETE) antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (WIT002) and two agonists, 4-amino-N-(20-hydroxy-eicosa-5(Z),14(Z)-dienoyl) benzenesulfonamide (ABSA) and 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (WIT003), on the diameter of rat middle cerebral arteries in vitro and on cerebral blood flow in vivo. WIT003, ABSA and 20-HETE all had a similar effect to reduce the diameter of the middle cerebral artery by 26%. WIT003 and 20-HETE both increased intracellular Ca2+ concentration ([Ca2+]i) in vascular smooth muscle cells isolated from the middle cerebral artery. In contrast, WIT002 had no effect on the basal diameter of the middle cerebral artery but it attenuated the vasoconstrictor responses and the rise in [Ca2+]i in vascular smooth muscle cells following administration of 20-HETE and 5-hydroxytryptamine (5-HT). WIT003 partially restored the vasoconstrictor response to 5-HT in the middle cerebral artery after administration of an inhibitor of the endogenous synthesis of 20-HETE. Infusion of the 20-HETE agonists, WIT003 and ABSA, into cisterna magna of rats reduced baseline cerebral blood flow by 20%, whereas administration of the 20-HETE antagonist, WIT002, had no effect. Intracisternal injection of WIT002 attenuated the fall in cerebral blood flow following injection of blood into the cisterna magna, whereas administration of the 20-HETE agonist, ABSA, potentiated this response. These findings indicate that the 20-HETE agonists, WIT003 and ABSA, increase cerebral vascular tone both in vivo and in vitro and suggest blocking the vasoconstrictor actions of 20-HETE may be useful to prevent the acute fall in cerebral blood flow following subarachnoid hemorrhage.     

Autoimmunization induced by interferon alpha therapy in chronic hepatitis C

We report the case of a 56 year-old woman with post-transfusion chronic hepatitis C who presented with a severe ALT flare up associated with a rapid progression of liver fibrosis during interferon alpha 2b therapy. Several hypotheses were considered to explain the etiology of this ALT flare: there was no viral super infection by other hepatotropic viruses, no toxic hepatitis, no metabolic disease, and no other specific liver diseases could be identified. HLA typing showed a specific profile A1 B8 DR3 (risk factor of auto-immunization during interferon alpha therapy) with antinuclear antibodies and anti smooth muscle antibodies. This case suggests that auto-immunization induced by interferon alpha should be investigated in case of ALT flare that is not followed by an HCV breakthrough.     

Screening for eating disorders and high-risk behavior: caution

OBJECTIVE: The current study reviews the state of eating disorder screens. METHODS: Screens were classified by their purported screening function: identification of cases with (a) anorexia nervosa only; (b) bulimia nervosa only; (c) eating disorders in general; (d) partial syndrome, eating disorder not otherwise specified (EDNOS), or subclinical; (e) not a-d but at high risk. Information is presented on development, psychometric properties, and external validation (e.g., sensitivity, specificity, positive predictive values, and negative predictive values). RESULTS: Screens differ widely with regard to objective, psychometric properties and the validation methodology used. Most screens that identify cases are not appropriate for the identification of at-risk behaviors. Little data on the external validity of screens are available. DISCUSSION: Screens should be used with caution. A sequential procedure, in which subjects identified as being at risk during the first stage is followed by more specific diagnostic tests during the second stage, might overcome some of the limitations of the one-stage screening approach.     

Preeclampsia in the parous woman: who is at risk?

OBJECTIVE: The purpose of this study was to identify risk factors for preeclampsia in second pregnancies and to determine whether gestational age at delivery in the first pregnancy increases the risk of recurrent preeclampsia. STUDY DESIGN: We conducted a population-based, case-control study using birth certificate data from the Missouri maternally linked cohort. Data from women delivered of their first 2 singleton pregnancies between 1989 and 1997 (2332 cases with preeclampsia in the second pregnancy and 2370 control cases) were analyzed with logistic regression. RESULTS: Significant risk factors for preeclampsia in a second pregnancy include longer birth interval, previous preterm delivery, previous small-for-gestational-age newborn, renal disease, chronic hypertension, diabetes mellitus, obesity, black race, and inadequate prenatal care. Smoking and same paternity are protective. A history of preeclampsia confers the highest risk for preeclampsia in the second pregnancy; the risk is inversely proportional to gestational age at delivery of the first pregnancy: adjusted odds ratio, 15.0; 95% CI, 6.3-35.4 for 20 to 33 weeks; adjusted odds ratio, 10.2; 95% CI, 6.2-17.0 for 33 to 36 weeks; and adjusted odds ratio, 7.9; 95% CI, 6.3-10.0 for 37 to 45 weeks. CONCLUSION: The relative risk of recurrent preeclampsia increases with earlier gestational age at delivery of the first pregnancy that was complicated by preeclampsia.     

No association between the lipoprotein lipase S447X polymorphism and Alzheimer's disease

Results from various genetic association studies of the lipoprotein lipase (LPL) S447X polymorphism and Alzheimer's disease (AD), range from a statistically significant negative association of clinically examined patients to a non-significant but consistent trend for under-representation of the X447 allele in neuropathologically confirmed subjects. In this report we have compared the distribution of the above polymorphism in an independent group of clinically diagnosed AD patients, including a subgroup where the disease was pathologically confirmed, and a spousal control group. No statistically significant differences emerged from this comparison. We conclude that LPL cannot be a major factor in pathogenesis of AD.     

Treatment of colon and breast carcinoma cells with 5-fluorouracil enhances expression of carcinoembryonic antigen and susceptibility to HLA-A(*)02.01 restricted,CEA-peptide-specific cytotoxic T cells in vitro

Cancer vaccines directed against tumor associate antigen (TAA) have produced encouraging results in preclinical models but not in cancer patients. A major limitation of this strategy is the relative degree of tolerance to these antigens and the low and heterogeneous tumor cell expression of TAA and major histocompatibility complex (MHC). Previous studies have shown that 5-fluorouracil (5-FU) can upregulate the expression of membrane-associated carcino-embryonic antigen (CEA), and MHC molecules in colon and breast carcinoma cell lines. We have investigated whether this drug can also enhance their sensitivity to the lytic effects of CEA-peptide specific Cytotoxic T cell lymphocytes (CTL). The CEA peptide-specific CTLs generated in our laboratory from normal HLA-A(*)02.01(+) donor PBMCs, were able to kill HLA-A(*)02.01(+)/CEA(+) breast (MCF-7-T103) and colon (HLA-A(*)02.01 gene-transfected HT-29 and C22.20) carcinoma cells in HLA-A(*)02.01 restricted manner. The treatment of target cells with 5-FU, enhanced their CEA expression and susceptibility to CTL-mediated lysis. Cold competition assays confirmed these results, thus supporting the hypothesis that immune target cell lysis and 5-FU mediated enhancement were dependent on CEA peptide presentation by cancer cells. 5-FU treatment of functionally "mature" CTL after in vitro expansion, did not reduce their cytolytic activity against MT-2 target cells but, when the anti-metabolite was added during the immune-sensitization phase, CTL generation was significantly inhibited. These results provide a rationale for investigating a possible new role of 5-FU as an immuno targeting amplifier agent in breast and colorectal cancer patients immunized with CEA-directed cancer vaccines.     

Cannabinoid mechanism in reinstatement of heroin-seeking after a long period of abstinence in rats

Because opioid and cannabinoid systems have been reported to interact in the modulation of addictive behaviour, this study was aimed at investigating the ability of cannabinoid agents to reinstate or prevent heroin-seeking behaviour after a prolonged period of extinction. In rats previously trained to self-administer heroin intravenously, non-contingent non-reinforced priming administrations of heroin and cannabinoids were presented after long-term extinction, and lever pressing following injections was observed. Results showed that: (i) intravenous priming infusions of heroin (0.1 and 0.2 mg/kg) lead to reinstatement of drug-seeking behaviour; (ii) intraperitoneal priming injections of the central cannabinoid receptor agonists R-(+)-(2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol[1,2,3-de]-1,4-benzoxazinyl) (1-naphthalenyl)methanonemesylate (WIN 55,212-2, 0.15 and 0.3 mg/kg) and (-)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55,940, 0.05 and 0.1 mg/kg), but not delta9-tetrahydrocannabinol (delta9-THC, 0.1-1.0 mg/kg), effectively restored heroin-seeking behaviour; (iii) intraperitoneal priming injection of the central cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)4-methyl-1H-pyrazole-3-carboxamide (SR 141716A, 0.3 mg/kg) did not reinstate responding, but (iv) completely prevented heroin-induced reinstatement of drug-seeking behaviour. Moreover, heroin-seeking behaviour was still present for a few days following cannabinoid primings, indicating a long-lasting effect of cannabinoids on responding for heroin. These findings indicate that relapse to heroin after an extended drug-free period is triggered by cannabinoid agonists and that SR 141716A prevents drug-seeking behaviour, suggesting that the use of the cannabinoid antagonist could have some therapeutic benefits in heroin-induced relapse.     

Akzeptanz und Nutzung öffentlicher Automaten durch Ältere: Ergebnisse einer europäischen Untersuchung

This article examines the use and acceptance of ticket machines, automatic teller machines (ATMs) and telephone cards by the elderly in four European regions. The analyses are based on data from an international project entitled "Keeping the Elderly Mobile", collected in Mannheim (former West Germany; N = 404 home-dwelling respondents), Chemnitz (former East Germany; N = 400), Ancona (Italy; N = 600), and Jyv?skyl? (Finland; N = 618). The random sample was stratified by age and gender in each country. Two generations of men and women (aged 55-74 and 75+ years, respectively) participated in the study. Results show that respondents generally made little use of the three technologies under investigation: in fact, the majority of respondents does not use them at all. The most frequently used devices were ATMs in Chemnitz and ticket machines and telephone cards in Mannheim. On the basis of logistic regression analysis, age was the most important explanatory factor for the three technologies and for all four regions, i.e., the users were mostly the "young-old." Education was a more important variable than gender. In all four regions, the majority of the respondents who used the technologies assessed felt that each of them made life easier; nevertheless, ticket machines make life more difficult to almost every third user in Mannheim. Interesting differences and similarities among the towns were also found. The present study exhibits preliminary results regarding elderly and technology which future research should investigate in greater depth.     

Gingival hyperplasia: a side effect of nifedipine and diltiazem

Currently, calcium channel blockers are being used increasingly for the treatment of hypertension in the elderly. Several case reports in the dental literature suggest that patients treated with the calcium channel blockers manifest gingival hyperplasia similar to that seen in patients taking phenytoin (Dilantin, Parke-Davis). A small study of 89 patients undertaken at the Westside Veterans Administration Medical Center, Chicago seems to indicate that nifedipine and diltiazem do indeed cause gingival hyperplasia. A total of 83% of the patients studied receiving nifedipine showed evidence of hyperplastic tissue and 74% of those on diltiazem were found to have hyperplastic tissue     

Evidence of pituitary adenylate cyclase activating polypeptide (PACAP) in pancreatic islet cells by confocal microscopy.

Several studies have shown that pituitary adenylate cyclase activating polypeptide (PACAP) stimulates at very low concentration insulin release from pancreatic beta cells. In addition, PACAP has been evidenced in pancreatic nervous fibers surrounding the islets, the core of the islet, and the capillaries. The aim of the present study was to demonstrate internalization of PACAP in pancreatic islet cells. Pancreatic islets were obtained from Wistar rat pancreata by modified Lacy's isolation method. The isolated islets were incubated in the presence of Fluo-PACAP 27, a fluorescent ligand specific for PACAP receptors. At the end of incubation the islets were fixed in paraformaldehyde and then observed by confocal microscope. Fluo-PACAP 27 was internalized into pancreatic islet cells, and this process was time- and temperature-dependent (37 degrees C). The fluorescent molecules converged toward the nucleus where an intense fluorescence was evidenced after 60 minutes. Incubation with phenyl arsine oxide as well as with PACAP 6-38, a receptor antagonist, prevented the internalization process. Further studies are required to explain the internalization process of PACAP 27 into the nucleus of pancreatic islet cells.