Synthesis and cholinergic properties of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine.

The histaminergic H2 antagonist, ranitidine, has also been found to significantly inhibit acetylcholinesterase (AChE) in vitro. In an effort to develop novel, nonquaternary AChE inhibitors capable of penetrating into the CNS and alleviating the cholinergic deficit characteristic of Alzheimer's disease, a series of bis[[(dimethylamino)methyl]furanyl] analogues of ranitidine has been synthesized. All compounds were evaluated for human erythrocyte AChE inhibitory activity and compared to ranitidine, physostigmine, and tetrahydro-9-aminoacridine (THA). The most active AChE inhibitors were N,N'-disubstituted derivatives of 2-nitro-1,1-ethenediamine and 4,6-dinitro-1,3-benzenediamine, with compound 8 demonstrating activity greater than physostigmine. Deletion of the diaminonitroethene group in a series of alkyl and aryl bis-thioethers, yielded a number of slightly less active compounds, comparable in potency to THA. The 13 most active AChE inhibitors all demonstrated a more selective inhibition of AChE, as opposed to butyrylcholinesterase inhibition, than did THA. Compounds 3 and 22 were equally active to THA in potentiating rat ileal contractions. Binding studies demonstrated M1 and M2 cholinergic receptor affinities slightly greater than or equal to THA. Differential receptor binding studies showed compound 12 resembled THA in agonist/antagonist activity. Compounds 11-13 significantly elevated mouse brain acetylcholine levels, when administered at 80% of their approximate lethal doses, but were less active than THA or physostigmine.     

Biphasic Shocks Compared with Monophasic Damped Sine Wave Shocks for Direct Ventricular Defibrillation during Open Heart Surgery

Background: Biphasic waveform shocks are more effective than monophasic shocks for transchest ventricular defibrillation, atrial cardioversion, and defibrillation with implantable defibrillators but have not been studied for open chest, intraoperative defibrillation. This prospective, blinded, randomized clinical study compares biphasic and monophasic shock effectiveness and establishes intraoperative energy dose-response curves.

Methods: Patients undergoing cardiothoracic surgery with bypass cardioplegia were randomly assigned to the monophasic or biphasic shock group. Ventricular fibrillation occurring after aortic clamp removal was treated with escalating energies of 2, 5, 7, 10, and 20 J until defibrillation occurred. If ventricular fibrillation persisted, a 20-J crossover shock of the other waveform was used.

Results: Cumulative defibrillation success at 5 J, the primary end point of the study, was higher in the biphasic group than in the monophasic group (25 of 50 vs. 9 of 41 defibrillated;P = 0.011). In addition, the biphasic group required lower threshold energy (6.8 vs. 11.0 J;P = 0.003), less cumulative energy (12.6 vs. 23.4 J;P = 0.002), and fewer shocks (2.5 vs. 3.5;P = 0.002). Crossover-shock effectiveness did not differ between groups. Dose-response curves show biphasic shocks to have higher cumulative success rates at all energies tested.     

Polyamines found in gingival fluid enhance the secretory and oxidative function of human polymorphonuclear leukocytes in vitro

Many bacterial and host cells contain large amounts of polyamines that can be released at infection sites as a result of cell lysis. Consequently, the putrescine and spermidine content of gingival fluid from inflamed periodontal pockets (0.1 to 1 mM) is sharply elevated in comparison to peripheral blood. At these levels, polyamines potentiated fMet-Leu-Phe-induced Ca²⁺ signaling in polymorphonuclear leukocytes (PMNs) in vitro. Consistent with the essential role of Ca²⁺ signaling in PMN activation, secondary granule release and superoxide anion production by fMet-Leu-Phe-stimulated PMNs was enhanced in the presence of polyamines. Thus, polyamines may play a local role in modulating the antimicrobial activity of PMNs in periodontal disease.     

Real-time movie imaging from a single cardiac cycle by NMR

Using a 1-m-bore superconductive magnet at 0.1 T, whole-body transverse images through adult humans have been obtained at repetition times of 57 ms. The techniques used were minor variations of echo-planar imaging (EPI) employing large pulsed gradients to provide complete coverage of the plane in phase space, and low-angle RF excitation sequences allowing rapid repetition of the experiment. In addition active magnetic screening of the gradient coils was implemented to protect the surrounding magnet from the eddy currents induced by the necessarily fast switching of the large gradient fields.     

Differential Distribution of Syntaxin Isoforms 1A and 1B in the Rat Central Nervous System

Syntaxin 1 binds to several proteins of the synaptic terminal and is a central component in the pathway of protein–protein interactions that underlies docking and fusion of synaptic vesicles. Molecular studies revealed the occurrence of two isoforms, syntaxin 1A and syntaxin 1B, which coexpress in neural tissues. However, they display differential expression patterns in endocrine cell types. We generated isoform-specific antibodies that were used in Western blotting and immunocytochemical studies. First, we confirmed the sole presence of syntaxin 1A in endocrine pituitary cells. Second, we found distinctive immunolabelling patterns of each isoform in the rat olfactory system, hippocampus, striatum, thalamus and spinal cord. In addition, the principal white matter commissures displayed distinct immunoreactivity for each isoform. This report shows, for the first time, major differences between the distributions of syntaxin 1A and syntaxin 1B isoforms in the rat central nervous system.     

Techniques in facial identification: Computer-aided facial reconstruction using a laser scanner and video superimposition

A facial image was reconstructed from the skull, part of a complete skeleton found in woodland, of a male person who had hanged himself from a tree. In addition, video superimposition was carried out with antemortem photographs of a person suspected of being the victim, and a good match was obtained. In a further case, a cheaper video-transparency superimposition was carried out, with identity later being confirmed on the basis of dental records. The techniques and the problems encountered are discussed. According to our experience, 3D computer reconstruction and video superimposition have a useful role in the process of identification, particularly in the early stages of an investigation and when other more definitive methods may not be available.     

Testing patients for HIV before surgery: The views of doctors performing surgery

The aim of this study was to investigate the attitudes of doctors performing surgery to the HIV antibody testing of surgical patients. Fifty of eighty (62.5%) doctors performing surgery who are working in two London teaching hospitals returned completed anonymous postal questionnaires. Sixty-six per cent of the sample would like some form of compulsory testing of pre-operative patients, although most of them feel that this is only necessary for patients considered to be in 'high-risk groups'. Eighty-four per cent believe that this would ensure their safety from infection during surgery. Forty-eight per cent agreed with testing patients without their consent. Results suggest that most of the doctors performing surgery in this study agree with compulsory HIV antibody testing of pre-operative patients in the belief that this would protect them from infection during surgery. The problems associated with compulsory testing and relying on such testing in order to protect doctors from infection during surgery are discussed.