Longitudinal examination of American National Adult Reading Test (AMNART) performance in dementia of the Alzheimer type (DAT): validation and correction based on degree of cognitive decline

The American National Adult Reading Test (AMNART) was constructed to provide a valid and stable estimate of premorbid verbal IQ (VIQ) in dementing individuals. However, recent studies have brought into question its validity in patients with dementia of the Alzheimer type (DAT). The present study was designed to longitudinally assess the validity of the AMNART in 40 DAT patients and 40 demographically matched normal control (NC) subjects. The results showed that VIQ estimates for patients with DAT were significantly lower than those of NC subjects and declined significantly over time with increasing dementia severity as measured by the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale (DRS). An MMSE-based correction factor was derived for the DAT group which allows for the effective estimation of premorbid VIQ in these patients.     

Developmental and environmental factors that enhance binding of Bordetella pertussis to human epithelial cells in relation to sudden infant death syndrome (SIDS)

The pharmacokinetic properties of glucagon-like peptide-1(7-36)amide (GLP-1(7-37) were compared. Four beagle dogs received on 4 separate occasions s.c. bolus doses of 50 micrograms/kg, and 2 min i.v. infusions of 50 micrograms/kg of each peptide. The plasma immunoreactivity of GLP-1 (P-GLP-1-IR) was measured by a sandwich enzyme-linked immunosorbent assay (ELISA). After i.v. infusion, the plasma half-life in the first-phase was 2.1 +/- 0.1 and 2.4 +/- 0.3 min, in the final-phase 68 +/- 6 and 81 +/- 3 min, the total plasma clearance 25 +/- 3 and 22 +/- 4 ml/kg.min, the volume of distribution at steady state 0.16 +/- 0.02 and 0.84 +/- 0.24 l/kg, and the mean residence time 6.2 +/- 0.3 and 36 +/- 5 min for GLP-1(7-36)amide and GLP-1(7-37), respectively. After s.c. administration, the maximum plasma concentration was reached after 15 +/- 5 and 19 +/- 4 min and the absolute bioavailability was 48 +/- 7 and 49 +/- 13% for GLP-1(7-36)amide and GLP-1(7-37), respectively. P-GLP-1-IR, measured by a radioimmunoassay (RIA), was considerably higher than when measured by ELISA. This discrepancy was due to cross-reactivity with metabolites of the parent peptide. The plasma degradation was studied in vitro in dog plasma at 37 degrees C, and the half-lives were found to be 61 +/- 9 and 132 +/- 16 min for GLP-1(7-36)amide and GLP-1(7-37), respectively (n = 6). Bacitracin inhibited the degradation of both peptides.     

Genetic control of anti-idiotypic vaccination against coronavirus infection

The idiotypic network can be experimentally altered to induce protective immune responses against microbial pathogens. Both internal image and noninternal image anti-idiotypic (anti-Id) antibodies have been shown to trigger antigen (Ag)-specific immune responses. Therefore, mechanisms of anti-Id vaccination appear to go beyond structural mimicry of Ag, but remain undefined. Using the neurotropic murine coronavirus animal model, we have previously shown that a polyclonal noninternal image anti-Id (Ab2) could vaccinate BALB/c mice. To characterize its mode of action, we have examined the immune modulating capability of this Ab2 in vivo in strains of mice with different H-2 haplotypes. Even though only internal image anti-Id are expected to induce non-genetically restricted immunity, this noninternal image Ab2 induced protective immunity in four of eight genetically different strains of mice susceptible to coronavirus infection. These were BALB/c (H-2d), DBA/2 (H-2d), DBA/1 (H-2q), and SWR (H-2q) mice. Protection was generally correlated with the induction of specific antiviral Ab (Ab3) that showed biological properties, such as virus neutralization in vitro, similar to the initial Ab1. To evaluate the genetic implication of the H-2 haplotypes in protection, congenic mice were also tested. Vaccination profiles suggest that cooperation between background gene(s) of the BALB/c mouse with H-2d and H-2q loci is necessary for an optimal protective immune response, although the main genetic element(s) regulating the antiviral response to Ab2 inoculation appeared to be located outside the major histocompatibility complex. These results are consistent with the ability of Ab2 to induce protective antiviral antibodies in genetically different animals by biological mimicry.     

8-Alkylamino-substituted analogs of N6-cyclopentyladenosine are partial agonists for the cardiovascular adenosine A1 receptors in vivo

Partial adenosine A1 receptor agonists with reduced intrinsic activity at the cardiovascular system would be promising for therapeutic application (e.g., as antilipolytic agents). In the present study a series of 8-alkylamino [methyl (M)-, ethyl (E)-, propyl (P)-, butyl (B)- and cyclopentyl (CP)-] derivatives of N6-cyclopentyladenosine (CPA) were investigated in conscious normotensive rats. After intravenous administration of the compounds to rats, heart rate (HR) and mean arterial pressure were monitored continuously, and serial arterial blood samples were drawn for determination of the pharmacokinetics. The concentration-heart rate relationships of the compounds were described on the basis of an integrated pharmacokinetic-pharmacodynamic model. The blood concentration-time profiles of the compounds could be described best by a biexponential function. The derivatives of CPA had uniform pharmacokinetic properties. The larger volume of distribution at steady state of the 8-substituted analogs resulted in terminal half-lives (ranging from 17 to 24 min) which were significantly longer than for CPA (7 min). All derivatives of CPA produced less pronounced reductions in HR and MAP than CPA. The relationship between concentration and the reduction in HR was adequately described by the sigmoidal Emax model in individual rats given 8MCPA, 8ECPA and 8PCPA. 8BCPA and 8CPCPA were nearly inactive on heart rate. The in vivo EC50,u values for the reduction in HR (366 nM, 210 nM, 170 nM and 175 nM for 8MCPA, 8ECPA, 8PCPA and 8BCPA, respectively) were in the same order of magnitude as the affinities in receptor binding studies. The order of magnitude of the intrinsic activities (Emax) was CPA > 8MCPA > 8ECPA = 8PCPA > 8BCPA > 8CPCPA, which indicated partial agonism of the compounds in vivo. The in vivo parameter Emax correlated highly (r = 0.97) to the GTP shift observed in radioligand binding experiments.     

Regulation of phosducin phosphorylation in retinal rods by Ca2+/calmodulin-dependent adenylyl cyclase

The phosphoprotein phosducin (Pd) regulates many guanine nucleotide binding protein (G protein)-linked signaling pathways. In visual signal transduction, unphosphorylated Pd blocks the interaction of light-activated rhodopsin with its G protein (Gt) by binding to the beta gamma subunits of Gt and preventing their association with the Gt alpha subunit. When Pd is phosphorylated by cAMP-dependent protein kinase, it no longer inhibits Gt subunit interactions. Thus, factors that determine the phosphorylation state of Pd in rod outer segments are important in controlling the number of Gts available for activation by rhodopsin. The cyclic nucleotide dependencies of the rate of Pd phosphorylation by endogenous cAMP-dependent protein kinase suggest that cAMP, and not cGMP, controls Pd phosphorylation. The synthesis of cAMP by adenylyl cyclase in rod outer segment preparations was found to be dependent on Ca2+ and calmodulin. The Ca2+ dependence was within the physiological range of Ca2+ concentrations in rods (K1/2 = 230 +/- 9 nM) and was highly cooperative (n app = 3.6 +/- 0.5). Through its effect on adenylyl cyclase and cAMP-dependent protein kinase, physiologically high Ca2+ (1100 nM) was found to increase the rate of Pd phosphorylation 3-fold compared to the rate of phosphorylation at physiologically low Ca2+ (8 nM). No evidence for Pd phosphorylation by other (Ca2+)-dependent kinases was found. These results suggest that Ca2+ can regulate the light response at the level of Gt activation through its effect on the phosphorylation state of Pd.     

Lipoprotein(a) in endurance athletes, power athletes, and sedentary controls

Elevated concentrations of lipoprotein(a) [Lp(a)] have been shown to be an independent risk factor for atherosclerotic disease. Physical activity and physical fitness have been shown to improve lipoprotein metabolism and reduce the risk of coronary artery disease. Studies on the influence of physical activity and physical fitness on Lp(a) levels including a large number of endurance as well as power athletes have not been performed before. Therefore, we determined parameters of physical fitness (maximal oxygen consumption), physical activity, and lipoproteins in 105 endurance athletes, 57 power athletes, and 87 sedentary young men. As expected, we found that endurance athletes with a good physical fitness had significantly higher concentrations of high-density lipoprotein cholesterol than power athletes and sedentary controls. Regarding mean Lp(a) levels (rocket immunoelectrophoresis), however, there were no significant differences between endurance athletes, power athletes, and sedentary controls. Even when including only those with Lp(a) values > 10 mg.dl-1, no differences were observed between the groups. These findings indicate that intensive training over years and good aerobic fitness improve the ratio of low-density lipoprotein to high-density lipoprotein cholesterol but have no or only minor effects on Lp(a) concentrations.     

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride]: II. A novel cholinergic channel modulator with effects on cognitive performance in rats and monkeys

ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine dihydrochloride], a novel ligand at neuronal nicotinic acetylcholine receptors with reduced adverse effects and improved oral bioavailability relative to (-)-nicotine, was tested in a variety of cognitive tests in rats and monkeys. Administered acutely, ABT-089 only marginally improved the spatial discrimination water maze performance of septal-lesioned rats. However, more robust improvement (45% error reduction on the last training day) was observed when ABT-089 was administered continuously via subcutaneous osmotic pumps (minimum effective dose: 1.3 micromol/kg/day). Continuous infusion of (-)-nicotine produced comparable improvement in the spatial discrimination water maze performance of septal-lesioned rats, but a 40-fold higher dose of (-)-nicotine was required (62 micromol/kg/day). Continuous infusion of ABT-089 to aged rats enhanced spatial learning in a standard Morris water maze, as indexed by spatial bias exhibited during a probe trial conducted after 4 days of training, but not when they were subsequently trained in a two-platform spatial discrimination water maze. The compound induced a small impairment in young rats on the standard water maze, but not on the two-platform task. A probe trial conducted after additional training in the standard water maze revealed no age or drug effects. ABT-089 did not affect performance of either the aged or young rats during inhibitory (passive) avoidance training. Also, continuous infusion of ABT-089 did not affect responses to acoustic startle or prepulse inhibition of acoustic startle in young, aged or septal-lesioned rats and did not affect locomotor activity in either sham-lesioned or septal-lesioned rats. In monkeys, acute administration of ABT-089 modestly improved the delayed matching-to-sample performance of mature, adult monkeys and more robustly improved performance in aged monkeys. Improved performance in the aged monkeys was restricted to the longest delay intervals and was not accompanied by changes in response latencies.     

Simultaneous high-performance capillary electrophoresis analysis of the reduced and oxidised forms of ascorbate and glutathione

We describe here a procedure for the simultaneous analysis of the oxidised and reduced forms of the major cellular hydrophillic antioxidants, ascorbic acid (vitamin C) and glutathione (gamma-L-glutamyl-L-cysteinylglycine), by high-performance capillary electrophoresis. Separations are performed in uncoated fused-silica capillaries using 200 mmol/l borate pH 9.0, containing 20% (v/v) acetonitrile as the background electrolyte with fixed-wavelength UV absorbance detection at 185 nm. The influence of pH, organic solvent and other additives on the resolution of these compounds is described and we show that the optimised protocol is capable of simultaneously resolving other thiol components including, N-acetylcysteine and methyl-S-glutathione. The method is suitable for the analysis of these antioxidants in Arabidopsis and Nicotiana leaf tissue and is compatible with the use of the high ionic strength, acidic extraction solvents which are necessary to quench the redox equilibria of these labile components.     

Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor (ER) cDNA

The accuracy of multichannel magnetocardiography (MCG) for the non-invasive localization of cardiac arrhythmias was investigated. A non-magnetic catheter was used in phantom studies and for cardiac pacing of 6 patients. In a clinical setting, 32 patients with WPW-syndrome, 37 patients with premature ventricular complexes and 12 patients with ventricular tachycardia were studied and the MCG results compared to reference methods, including invasive electrophysiological mapping. Phantom and pacing studies demonstrated the spatial localization accuracy to be better than 15 mm for a dipole-to-dewar distance below 15 cm. In all patients with structural cardiac disease, the ectopic focus was localized at the margin of the damaged area, serving as a proof of MCG localization. Invasive mapping confirmed the MCG result whenever performed (42 patients). In 11 patients (9 WPW, 2 VT) the MCG localization result was verified by successful HF catheter ablation as a gold standard. MCG permits the non-invasive localization of cardiac arrhythmias with high spatial accuracy. MCG guided HF catheter ablation constitutes a new concept of non-invasive localization and minimally invasive causal therapy.