Biomedical subjects
Publications and source records attributed to H Morris.
We have assessed whether apolipoprotein E (ApoE) genotype influences the age of onset of dementia in a series of families with frontal temporal dementia with defined mutations in the tau gene. In contrast to the situation in Alzheimer's disease (AD), we could find no evidence that the age of onset of disease was influenced by the ApoE genotype.
Glutamatergic hypofunction occurs in Alzheimer's disease (AD). MK801, a noncompetitive blocker of glutamate N-methyl-D-aspartate receptors, was used to disrupt the cognitive performance of rats trained on a delayed nonmatching to sample radial maze task. Drugs which act by blocking serotonin (5-HT) receptors were evaluated for their ability to reduce the cognitive impairment produced by MK801. Specifically, WAY-100635, a selective 5-HT1A receptor antagonist, buspirone, a 5-HT1A partial agonist, ritanserin, a 5-HT2 antagonist, and ondansetron, a 5-HT3 antagonist, were assessed. In addition, the muscarinic agonist arecoline was evaluated for its potential cognitive benefit in this model. It was found that WAY-100635 significantly reduced the cognitive impairment induced by MK801. Treatment with single doses of ritanserin, ondansetron, or arecoline in combination with MK801 did not result in a cognitive impairment, indicating that these drugs attenuated the MK801 impairment. The combination of buspirone and MK801 resulted in an inability of the animals to complete the task. These results suggest that interactions between 5-HT and glutamate may mediate the beneficial effects of reducing cognitive impairment and that 5-HT antagonists, especially selective 5-HT1A antagonists, may be useful in treating AD. Further, it is indicated that the MK801 model of cognitive impairment may add to the armamentarium of tools available to predict treatment efficacy in AD.
Historically, seizure semiology was the main feature in the differential diagnosis of epileptic syndromes. With the development of clinical EEG, the definition of electroclinical complexes became an essential tool to define epileptic syndromes, particularly focal epileptic syndromes. Modern advances in diagnostic technology, particularly in neuroimaging and molecular biology, now permit better definitions of epileptic syndromes. At the same time detailed studies showed that there does not necessarily exist a one-to-one relationship between epileptic seizures or electroclinical complexes and epileptic syndromes. These developments call for the reintroduction of an epileptic seizure classification based exclusively on clinical semiology, similar to the seizure classifications which were used by neurologists before the introduction of the modern diagnostic methods. This classification of epileptic seizures should always be complemented by an epileptic syndrome classification based on all the available clinical information (clinical history, neurological exam, ictal semiology, EEG, anatomical and functional neuroimaging, etc.). Such an approach is more consistent with mainstream clinical neurology and would avoid the current confusion between the classification of epileptic seizures (which in the International Seizure Classification is actually a classification of electroclinical complexes) and the classification of epileptic syndromes.
We propose an epileptic seizure classification based exclusively on ictal semiology. In this semiological seizure classification (SSC), seizures are classified as follows: a. Auras are ictal manifestations having sensory, psychosensory, and experiential symptoms. b. Autonomic seizures are seizures in which the main ictal manifestations are objectively documented autonomic alterations. c. "Dialeptic" seizures have as their main ictal manifestations an alteration of consciousness that is independent of ictal EEG manifestations. The new term "dialeptic" seizure has been coined to differentiate this concept from absence seizures (dialeptic seizures with a generalized ictal EEG) and complex partial seizures (dialeptic seizures with a focal ictal EEG). d. Motor seizures are characterized mainly by motor symptoms and are subclassified as simple or complex. Simple motor seizures are characterized by simple, unnatural movements that can be elicited by electrical stimulation of the primary and supplementary motor area (myoclonic, tonic, clonic and tonic-clonic, versive). Complex motor seizures are characterized by complex motor movements that resemble natural movements but that occur in an inappropriate setting ("automatisms"). e. Special seizures include seizures characterized by "negative" features (atonic, astatic, hypomotor, akinetic, and aphasic seizures). The SSC identifies in detail the somatotopic distribution of the ictal semiology as well as the seizure evolution. The advantages of a pure SSC, as opposed to the current classification of the International League Against Epilepsy (ILAE), which is actually a classification of electroclinical syndromes, are discussed.
A patient is reported on with isolated upbeating nystagmus with a linear slow phase in whom a solitary lesion, probably inflammatory, was detected radiologically in the dorsal paramedian caudal medulla, encompassing the most caudal of the perihypoglossal nuclei, the nucleus intercalatus of Staderini. The conjunction of a vestibular pattern of nystagmus with this focal lesion runs contrary to a previous suggestion that the nucleus intercalatus may act as a neural integrator for vertical conjugate eye movements.
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Recombinant human procollagenase-3 and a C-terminal truncated form (Delta249-451 procollagenase-3) have been stably expressed in myeloma cells and purified. The truncated proenzyme could be processed by aminophenylmercuric acetate via a short-lived intermediate form (N-terminal Leu58) to the final active form (N-terminal Tyr85). The kinetics of activation were not affected by removal of the hemopexin-like C-terminal domain. The specific activities of both collagenase-3 and Delta249-451 collagenase-3 were found to be similar using two quenched fluorescent substrates, but Delta249-451 collagenase-3 failed to cleave native triple helical collagens (types I and II) into characteristic one- and three-quarter fragments. It was noted, however, that the beta1,2(I) chains of type I collagen were susceptible to Delta249-451 collagenase-3, which indicates that the catalytic domain displays telopeptidase activity, thereby generating alpha1,2(I) chains that are slightly shorter than those in native type I collagen. It can be concluded that the C-terminal domain is only essential for the triple helicase activity of collagenase-3. Binding of procollagenase-3 and active collagenase-3 to type I collagen is mediated by the C-terminal domain. Both collagenase-3 and Delta249-451 collagenase-3 hydrolyzed the large tenascin C isoform, fibronectin, recombinant fibronectin fragments, and type IV, IX, X, and XIV collagens; thus, these events were independent from C-terminal domain interactions. In contrast, the minor cartilage type XI collagen was resistant to cleavage. Kinetic analysis of the mechanism of inhibition of wild-type and Delta249-451 collagenase-3 by wild-type and mutant tissue inhibitors of metalloproteinase (TIMPs) revealed that the association rates for complex formation were influenced by both N- and C-terminal domain interactions. The C-terminal domain of wild-type collagenase-3 promoted increased association rates with the full-length inhibitors TIMP-1 and TIMP-3 and the hybrid N.TIMP-2/C.TIMP-1 by a factor of up to 33. In contrast, the association rates for complex formation with TIMP-2 and N.TIMP-1/C.TIMP-2 were only marginally affected by C-terminal domain interactions.
Movement of line-like samples with lengths from 5 to 50 mm along the x-axis of the double TE104 rectangular cavity has been analyzed. The observed dependencies of the EPR signal intensity versus sample position showed: (i) a sharp maximum for sample lengths from 5 to 20 mm; (ii) a plateau, over which the EPR signal intensity remained constant within experimental errors of 0.26-1.07%, for lengths from 30 to 40 mm; and (iii) a "sloping plateau," which could be approximated by the linear function (correlation, r = 0.98) for sample length 50 mm. Theoretical values of the experimentally observed dependencies of the intensity versus sample position were calculated using the modified sine-squared function and the correlation between observed and theoretically predicted dependencies is very good. The experimental dependence of the EPR signal intensity versus the sample length for samples situated at the same point in the cavity was nonlinear with a maximum for the 40-mm sample. The dependence of the EPR signal intensity upon the movement of a large cylindrical sample (o.d. 4 mm and length 100 mm) along the x-axis of the cavity was similar to that found for the 50-mm sample. However, an additional oscillating signal superimposed on the sloping plateau was observed. The presence of a large sample fixed in the complementary cavity of the double TE104 cavity caused an additional deformation of the signal intensity for a 30-mm sample which was moving in the first cavity. The primary effect was that the plateau was replaced by a region in which the intensity increased linearly with sample position, r = 0.99. Each of the above phenomena may be a source of significant errors in quantitative EPR spectroscopy. Cylindrical samples to be compared should be of identical length and internal diameter. Accurate and precise positioning of each sample in the microwave cavity is essential. Copyright 1997 Academic Press. Copyright 1997Academic Press
Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to-position radial maze task, received bilateral stereotaxic injections of a selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3 microliters/lateral ventricle). Animals treated with AF64A made significantly more total postdelay errors than vehicle controls. Sustained delivery, via miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14 days) attenuated the AF64A-induced cognitive impairment in a dose-dependent manner, producing an inverted U-shaped dose-response function which was optimal at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was significantly reduced in hippocampi extracted from the AF64A-treated rats, indicating successful cholinotoxicity. This paradigm may be useful as a possible screen for potential Alzheimer's disease therapeutic agents. This conclusion is supported by published reports of beneficial arecoline effects observed following 2-week intravenous infusions in patients with Alzheimer's disease (Soncrant, Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
1. The high-resolution 1H NMR (MRS) spectra of human brain tumor homogenates revealed a broad resonance at 5.3-5.4 ppm in glioblastoma multiforme (N = 16) and brain metastases (N = 3). The broad resonance was identified as ceramide, a sphingosine-fatty acid combination portion of ganglioside, indicating an elevated abundance of monounsaturated fatty acids. GLC analysis of gangliosides in the highly malignant glioblastoma multiforme revealed that the elevated monounsaturated fatty acid is oleic acid (C18:1). The resonance at 5.3-5.4 ppm region was not detectable in normal human brain (N = 2), in meningiomas (N = 2), or in low-grade astrocytomas (N = 12). In normal human brain the abundance of monounsaturated fatty acid is minimal. 2. This investigation was made possible because the method of producing homogenate resulted in (i) no loss of lipids during the process and (ii) a well-homogenised sample, with (iii) no loss in chemical integrity. 3. The properties of tumor gangliosides include antigenic specificity and immunosuppressive activity and the ceramide, a sphingosine-fatty acid combination, noticeably influences the ganglioside immunosuppressive activity. 4. The observation of 1H NMR ceramide resonance in high-malignant brain tumors emphasizes the dramatic role of aberant gangliosides and ceramide precursors on the grade of malignancy and invasiveness. 5. Further insight into the specific nature of the ceramide portion of gangliosides in grading the malignancy of brain tumors should be investigated further.
The advantages of the prosthetic replacement after resection of bone tumours include: 1) relatively simple technique, 2) modularity, 3) immediate function, 4) no disease transmission, 5) arthroplasty is possible. The disadvantages include: 1) late complications-asceptic loosening, bearing failure, fracture, 2) muscle re-attachment, 3) bone stock loss.
Protection of the gametes from potential immune responses is a primary function in human reproduction. The primary cell type responsible for the innate immune response in the uterus is the natural killer (NK) cell. NK cells normally recognize Class I major histocompatibility (MHC) molecules on potential target cells. Since both human spermatozoa and human oocytes do not express Class I MHC molecules on their surfaces, the appropriate cell surface signal that abrogates potential NK cell-mediated responses directed against these gametes is unknown. Recent evidence indicates that surface expression of bisecting-type N-linked glycans protects cells sensitive to NK cell-mediated lysis. We report that the zona pellucida of the human egg and plasma membranes of human spermatozoa potentially bind a lectin probe specific for bisecting type glycans in a carbohydrate-dependent manner. Since the innate immune response in the uterus is primarily mediated by NK cells, our results indicate that human gametes may be protected from this response by expressing bisecting type N-linked glycans on their surfaces.
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Thiyl radicals (RS.) are formed when positive muons (mu+) are implanted into solutions of thiocarbonyl compounds (C = S) in ethanol, tetrahydrofuran or formamide solvents. A solvent dependence is found, which reflects changing electronic interactions and overall conformations, suggesting that the properties of RS. radicals may be dependent on the polarity (philicity) of the environment in which they are formed.
This trial evaluated whether the intravenous injection of an ultrasound contrast agent (Infoson) facilitates the assessment of systolic function in 40 low-echogenic patients undergoing low-dose (4 mcg/kg/min) dopamine echocardiography. Interobserver difference in calculated ejection fraction at entry was > 10%. Echocardiographic monitoring was performed in the apical 4-chamber view at four intervals: baseline, no contrast; first Infoson injection; dopamine infusion, no contrast; dopamine infusion+second Infoson injection. The left ventricle was divided into 5 segments and analysis was performed by two blinded observers. Wall motion abnormalities, ejection fraction and the confidence in detecting the endocardial border, were assessed. Infoson provided adequate left ventricular opacification in 90% of the injections, with a significant improvement in endocardial border detection. The interobserver variability of ejection fraction measurements was significantly reduced. The probability of attaining concordance between the investigators on wall motion assessment improved significantly. These results suggest potential applications in stress echocardiography.
In patients with previous myocardial infarction and left ventricular asynergy, dipyridamole infusion may have the capacity to unmask myocardial viability through transient recovery of contractile function in asynergic segments. The purpose of this study was to assess simultaneous changes in myocardial perfusion and LV function--elicited by dipyridamole infusion--in infarcted, asynergic segments. The echo contrast agent Albunex was injected into the left coronary artery of 19 patients (17 males, age 49-70 years) with previous myocardial infarction and baseline left ventricular asynergy, both before and after dipyridamole infusion (up to 0.56 mg.kg-1, i.v.). Analysis was not possible in three patients due to inadequate image quality and in two due to weak contrast. There were no major adverse events, or changes in vital signs or demonstrated on the electrocardiogram. After dipyridamole, 7/14 patients, showed an improvement in regional function of asynergic segments ('responders'), whereas seven patients did not ('non-responders'). Among non-responders, five had a myocardial perfusion deficit corresponding to 41% of the total left ventricular area before dipyridamole and to 38% after dipyridamole. No baseline perfusion deficits were observed in the remaining two non-responders; one of these, however, developed transient asynergy and perfusion deficit after dipyridamole. Among responders, five showed a normal perfusion pattern, both before and after dipyridamole, while the remaining two showed a perfusion deficit which markedly decreased after dipyridamole (from 32% to 13% of total left ventricular area). Thus, residual contractile reserve of asynergic, infarcted ventricular segments appears to be associated with myocardial perfusion either preserved at baseline or recruitable by a coronary dilator stimulus.
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