Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain

The receptor mGluR5 is a metabotropic glutamate receptor with messenger RNA abundantly present throughout cortex, hippocampus, and caudate/putamen that is also coupled to phosphatidyl inositide hydrolysis and calcium mobilization. In this study, the distribution of mGluR5 was examined in rat brain by immunocytochemistry. The antibody utilized is highly specific and does not cross react with the most closely related other metabotropic glutamate receptor, as determined by Western blot analysis of nonneuronal cells transfected with metabotropic receptor coding sequences. The receptor mGluR5 is widely expressed with the highest density in olfactory bulb, caudate/putamen, lateral septum, cortex, and hippocampus, as confirmed with both immunocytochemistry and Western blot analysis. Electron microscopic studies in hippocampus and cortex indicate that the labeling is mostly on membranes of dendritic spines and shafts. Light and electron microscopic evidence indicates that some mGluR5 immunoreactivity is located in presynaptic axon terminals, suggesting that mGluR5 may function as a presynaptic receptor.     

A comparison of the effects of scopolamine and diazepam on acquisition and retention of inhibitory avoidance in mice

Administration of either the muscarinic antagonist scopolamine or the benzodiazepine diazepam prior to training produced a dose-dependent impairment in the retention of one-trial inhibitory avoidance training in mice. To investigate the nature of this drug effect, the effects of scopolamine and diazepam were subsequently assessed on both acquisition and retention of inhibitory avoidance using a multiple-trial, training-to-criterion procedure. The training was conducted using either continuous trials in which the mouse was free to shuttle back and forth between shock and safe compartments or discrete trials in which the mouse was moved from the shock compartment of the safe compartment at the start of each trial. In either case, training continued until the mouse refrained from crossing into the shock compartment for a specified length of time on a single trial. Scopolamine (1.0 mg/kg) administered before training significantly increased the number of trials required to attain criterion, but did not affect retention when these mice were tested 2, 16, or 28 days later. In contrast, diazepam (1.0 mg/kg) did not significantly alter the number of trials necessary to reach criterion, but impaired retention of the inhibitory response in mice trained using discrete trials. The differences in the amnestic effects of scopolamine and diazepam revealed by this detailed analysis suggest that diazepam does not impair inhibitory avoidance performance through an effect on cholinergic function.     

Indirect radionuclide cystography: a sensitive technique for the detection of vesico-ureteral reflux

The detection or exclusion of vesico-ureteral reflux (VUR) has classically been by micturating cystourethrography (MCUG). Radionuclide cystography will detect VUR but fails to provide the same detailed anatomical informations as MCUG. This study allowed a comparison of indirect radionuclide cystography (IRC) and MCUG in 65 children. Renal reflux was detected by IRC in 32% of renal units, while VUR was seen in 36% by MCUG. When a comparison was made with MCUG, IRC had a sensitivity of 74.1% and a specificity of 90.5%. The markedly reduced radiation dose, avoidance of a bladder catheter plus the ability to monitor the urinary tract constantly during the entire procedure should ensure that IRC is the examination of choice in follow-up studies for VUR in all toilet-trained children.     

Neural classifier construction using regularization, pruning and test error estimation

In this paper we propose a method for construction of feed-forward neural classifiers based on regularization and adaptive architectures. Using a penalized maximum likelihood scheme, we derive a modified form of the entropic error measure and an algebraic estimate of the test error. In conjunction with optimal brain damage pruning, a test error estimate is used to select the network architecture. The scheme is evaluated on four classification problems.     

Effects of D1 and D2 dopamine receptor antagonists and catecholamine depleting agents on the locomotor stimulation induced by dizocilpine in mice

Low doses of the uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) induce locomotor stimulation in mice, whereas higher doses are associated with ataxia, stereotyped behaviors and catalepsy. We investigated the role of dopamine receptors and presynaptic dopamine neurons in the locomotor effects of dizocilpine. For comparison, we studied several other drugs that induce locomotor stimulation in mice. Pretreatment of male mice with haloperidol (0.1 mg/kg, i.p.) completely prevented the stimulation of normally coordinated locomotion induced by a non-intoxicating dose of dizocilpine (0.1 mg/kg, i.p.); haloperidol also attenuated the locomotor stimulation produced by phencyclidine (PCP, 1 and 2 mg/kg, i.p.), d-amphetamine (2 and 5 mg/kg, i.p.) and diazepam (0.5 mg/kg, i.p.). Haloperidol (doses up to 2.5 mg/kg) did not attenuate the ataxia and decreased locomotion induced by higher doses of dizocilpine (1 and 2 mg/kg). The active cis isomer of flupenthixol (0.5 mg/kg, i.p.), an antagonist of both D1 and D2 dopamine receptors, also diminished the stimulant actions of all of the test drugs, whereas its inactive trans form did not. The selective D1 antagonist R(±)-SCH 23390 (0.1 mg/kg) and the selective D2 antagonist raclopride (1 mg/kg) had little effect on the stimulatory effect of dizocilpine, although they did reduce the stimulation produced by PCP, d-amphetamine and diazepam. However, pretreatment with a combination of R(±)-SCH 23390 and raclopride completely prevented dizocilpine-induced locomotor stimulation. Pretreatment with α-methyl-p-tyrosine (AMPT, 50 and 250 mg/kg), an inhibitor of tyrosine hydroxylase, or with 6-hydroxydopamine (6-OH-DA, 50 μg, i.c.v.), a neurotoxin that destroys brain dopaminergic and noradrenergic neurons, did not attenuate the locomotor stimulation induced by dizocilpine, although these treatments did reduce the stimulant effects of d-amphetamine. In AMPT or 6-OH-DA pretreated mice, haloperidol (0.125 mg/kg) prevented the stimulatory effect of dizocilpine. These results support a role for dopamine receptors in the stimulation of normally coordinated locomotion by dizocilpine. However, the locomotor stimulant effect of dizocilpine, unlike that of d-amphetamine, can be expressed in the presence of D1 or D2 dopamine receptor blockade and does not appear to be dependent on intact presynaptic mechanisms.     

Evaluation of Hemoperitoneum Using a Single- vs Multiple-view Ultrasonographic Examination

Objective: To compare the sensitivities, specificities, and accuracies between a single-view ultrasonography (US) technique and a multiple-view technique for identifying hemoperitoneum in multiple-trauma patients.
Methods: Data from a prior prospective study of US for trauma diagnosis at a level I trauma center were retrospectively analyzed. A convenience sample of adult patients (≥ 18 years of age) who had presented with major blunt or penetrating torso trauma and had undergone rapid trauma US examinations to detect hemoperitoneum were reviewed. The US interpretations by emergency physicians had been recorded prior to obtaining other diagnostic tests. Five views were evaluated, including the right intercostal oblique view examining Morison's pouch. Evidence of free intraperitoneal fluid by exploratory laparotomy, CT, or diagnostic peritoneal lavage (DPL) was used as the criterion standard.
Results: Of the 245 patients entered into the study, 37 had free intraperitoneal fluid, confirmed by CT, DPL, or exploratory laparotomy. With the multiple-view technique, US was 87% (95% CI = 71%, 96%) sensitive, 100% (95% CI = 97%, 100%) specific, and 98% (95% CI = 95%, 100%) accurate. The single-view technique, evaluating only Morison's pouch, was 51% (95% CI = 34%, 68%) sensitive, 100% (95% CI = 98%, 100%) specific, and 93% (95%. CI = 89%, 96%) accurate.
Conclusions: An initial trauma US examination using a multiple-view technique is more sensitive than that using a single-view technique for detecting hemoperitoneum in trauma patients.     

High-dose vecuronium neuromuscular block: a comparison of arrhythmias and onset of block during sufentanil anaesthesia

This study compared the heamodynamic effects of sufentanil with those observed following concomitant sufentanil and highdose vecuronium administration to determine whether vecuronium induces bradyarrhythmias. Sixty coronary artery bypass patients were stratified into beta blocker (n = 30) or non-beta blocker (n = 30) groups and following induction with sufentanil (9 ± 3 μg · kg^?1) and midazolam (0.07 ± 0.04 mg · kg^?1), received either succinylcholine 1 mg · kg^?1 (SxCh), vecuronium 0.3 mg · kg^?1 (Vec 0.3), or vecuronium 0.5 mg · kg^?1 (Vec 0.5). Using a Holter ECG monitor, bradyarrhythmias were classified as mild (HR 46–50), moderate (HR 40–45) or severe (HR < 40). In the pre-induction period, there were no differences in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups, in either the beta blocker or non-beta blocker groups. Following induction, there were similar reductions in mean heart rate and mean arterial pressure in all three muscle relaxant groups in both the beta and the non-beta blocker groups; however, there was no difference in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups. The Vec 0.5 beta blocker group had a higher incidence of mild bradyarrhythmias (32 ± 36%) than the Vec 0.5 non-beta blocker group (2 ± 3% P = 0.017). Using EMG recording, the onset time of maximal neuromuscular block for the Vec 0.3 group (108 ± 17 sec) was longer (P < 0.05) than the SxCh (76 ±21 sec) and Vec 0.5 (82 ± 13 sec) groups, which were similar. We conclude: (i) vecuronium does not affect HR or the incidence of bradyarrhythmias following sufentanil administration and that the observed reduction in HR and mean arterial pressure were due to sufentanil administration, (ii) vecuronium (0.5 mg · kg^?1) provides an onset time of neuromuscular block similar to SxCh, and (iii) patients taking beta blockers preoperatively are more prone to develop bradyarrhythmias during sufentanil administration.     

New approaches to QSAR: Neural networks and machine learning

Summary Neural networks and machine learning are two methods that are increasingly being used to model QSARs. They make few statistical assumptions and are nonlinear and nonparametric. We describe back-propagation from the field of neural networks, and GOLEM from machine learning, and illustrate their learning mechanisms using a simple expository problem. Back-propagation and GOLEM are then compared with multiple linear regression (using the parameters and their squares) on two real drug design problems: the inhibition ofEscherichia coli dihydrofolate reductase (DHFR) by pyrimidines and the inhibition of rat/mouse tumour DHFR by triazines.     

Drug analysis with polarographic methods. 33. Electroanalytic studies of a new benzodiazepine: [6(o-chlorophenyl)-2,4-dihydro-2-[(4-methyl-1-piperazinyl) methylene]-8-nitro-1H-imidazol[1,2-a][1,4]benzodiazepine-1-one (WHO) (loprazolam,1)] and content determination its drug forms

Loprazolam (1) is a tricyclic benzodiazepine containing a new butazadiene moiety, which has not been investigated by polarography up to now. 1 is reduced in three waves at a DME over the whole pH-region. In BRP (pH 2-9) 10 electrons are consumed in this process. The first step is suitable for the determination of 1 in Loprazolam tablets containing 1 or 2 mg. These tablets are on the pharmaceutical market in several European countries. The mechanism of the electrode process will be reported in the communication XXXIV.