Biomedical subjects
Publications and source records attributed to P David.
This report describes an unusual cephalocele originating in the temporobasal region and protruding through the sphenopetral area into the oral cavity. A rapid and nonaggressive endoscopic procedure was performed. The relationship between this type of cephalocele, spontaneous anteroinferior temporal encephaloceles, and nasopharyngeal brain heterotopia is discussed.
This report deals with a series of 20 patients admitted for a spinal hemangioblastoma between 1970 and 1993, 18 of whom between 1978 and 1993. There are 8 men and 12 women and the onset of spinal symptoms is before the age of 50 years for 76% of the patients. Nineteen patients have an intra-dural tumor (extramedullary 15.5%, intramedullary 75% with 62.5% close to the dorsal surface, 37.5% partly out, none totally enclosed with spinal cord) and only one patient has an extra-dural tumor. Cysts are present in 70% of our cases. Two cases have been revealed by an hemorrhagic syndrome. Ten cases belong to a von Hippel-Lindau (vHL) disease. Nineteen patients were operated on, one patient died. Total resection of the tumor was performed in 17. Symptoms improved postoperatively in 8 patients, were inchanged in 6, and worsened temporary in 4. MRI with gadolinium is the best procedure for both the diagnosis and the follow-up. After surgery, the prognosis is very good for sporadic cases with a single spinal lesion whereas it is very poor in case of vHl disease. For these patients (50% of our cases), half of them died because of the evolution of multifocal lesions even if they were operated on several times. Thus, each patient should have a precise check-up (SNC and visceral lesions). The gene causing vHL disease located on the short arm of the chromosome 3 has just been characterized. This will help to elaborate a presymptomatic diagnosis and a better screening of the patients with the hope of a specific treatment.
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Information on cation occlusion sites of renal NA,K-ATPase has been obtained by comparing the ability of competitive Na-like antagonists (David, P., Mayan, H., Cohen, H., Tal, D. M., and Karlish, S. J. D. (1992) J. Biol. Chem. 267, 1141-1149) with that of transported alkali metal cations to protect against covalent modification and structural perturbations of the protein. Sodium antagonists include p- or m-xylylenebisguanidium, guanidinium ions, and ethylenediamine. Experiments with proteoliposomes reconstituted with Na,K-ATPase demonstrate that p-xylylenebisguanidium has pronounced selectivity for the cytoplasmic surface. Tryptic digestion of Na,K-ATPase leading to "19-kDa membranes," a specifically truncated enzyme with intact cation occlusion sites, requires the presence of alkali metal cations. Sodium antagonists do not protect 19-kDa membranes against further digestion, and occlusion is destroyed. Incubation of 19-kDa membranes at 37 degrees C, in the absence of occluded ions, leads rapidly to loss of ability to occlude rubidium ions. Rubidium, sodium, or other alkali metal cations protect fully, whereas sodium antagonists do not protect against this thermal inactivation. Like the alkali metal cations, sodium antagonists protect Na,K-ATPase and, somewhat less effectively, 19-kDa membranes against inactivation by the carboxyl reagent N,N'-dicyclohexylcarbodiimide. Cation occlusion from the cytoplasmic surface is suggested to occur in two steps. In an initial recognition, either transported cations or sodium antagonists interact with carboxyl groups. The second step is selective for transported cations and involves occlusion of cations (either potassium or sodium ions) and a conformational change to a compact structure, which is resistant to proteolysis and thermal inactivation. Sodium antagonists are sterically hindered from becoming occluded and block Na,K-ATPase activity. Implications for the structural basis of cation specificity of the Na/K pump are discussed.
The presence of synaptic proteins involved in excitation/secretion coupling was examined in ten small cell lung cancer lines. N-Type calcium channels (omega-conotoxin receptors), synaptotagmin (p65) and syntaxin (HPC-1) were detected in eight. Co-immunoprecipitation experiments indicated that syntaxin can form a complex with synaptotagmin and calcium channels. The expression of synaptotagmin in small cell lung cancer may elicit an autoimmune response that reduces transmitter release at the nerve terminal.
In a search for an organic analogue of K+ or Na+ ions that binds to the cation binding sites of Na+/K(+)-ATPase with high affinity, the potency of the diuretic amiloride and its derivatives in blocking Rb+ occlusion has been tested. Although amiloride itself has a low affinity (> 200 microM), insertion of short alkyl chains in position 5 of the pyrazine ring of the molecule dramatically increased the affinity of the compound. For example, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) competes with a Ki approximately 10 microM. In derivatives lacking a halogen in position 6 of the ring, a 6-fold decrease in affinity was found. Substitutions in the guanidinium moiety did not produce high affinity inhibitors of Rb+ occlusion. Several derivatives at positions 5 and 6 of the pyrazine ring were found to be strictly competitive inhibitors with respect to Rb+ ions. The highest affinity was observed around pH 8.0-8.2, and low temperature. EIPA and 5-(N-methyl-N-isobutyl)amiloride (MIBA) stabilized the E1 form of FITC1-labelled Na+/K(+)-ATPase, behaving as Na+ analogues. The present findings are similar to our previous results, showing that alkyl- and arylguanidinium derivatives are competitive Na(+)-like antagonists in cation sites. Conclusions concerning the structural features of amiloride derivatives which are necessary to produce the highest binding affinity, are being exploited in synthesis of competitive cation analogues. Derivatives with sufficiently high affinity (0.1-1 microM) will be converted to affinity and photoaffinity reagents.
The modern neurodiagnostic techniques of MR imaging, CT scanning and angiography provide valuable morphological information that, although highly sensitive to tumour localisation, still lacks comparable specificity as to the exact histological nature of those lesions demonstrated. Biopsy remains necessary. To patients with potentially inoperable lesions or lesions best treated by chemotherapy or irradiation, modern techniques of neurosurgery now offer the option of precise stereotactic biopsy through small twist-drill burr holes as opposed to open biopsy. The interrelationships between MR, CT, angiography and stereotactic biopsy and their respective roles in the establishment of a definitive diagnosis are discussed.
Plasma from patients with Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease of neuromuscular transmission, contains antibodies that immunoprecipitate 125I-omega-conotoxin GVIA labeled-calcium channels solubilized from rat brain. These antibodies label a 58-kDa protein in Western blots of partially purified 125I-omega-conotoxin receptor preparations. Monoclonal antibody 1D12, produced by immunizing mice with synaptic membranes, has similar properties as these LEMS IgG. 1D12 antigen was purified by immunoaffinity chromatography and shown to bind LEMS IgG. The antigen was identified by immunoscreening a rat brain cDNA library with mAb 1D12 and found to have strong homology to the synaptic vesicle protein synaptotagmin. These antibodies immunoprecipitate calcium channels by binding to synpatotagmin, an associated protein. We suggest that the interaction between synaptotagmin and omega-conotoxin sensitive calcium channels plays a role in docking synaptic vesicles at the plasma membrane prior to rapid neurotransmitter release. Autoantibody binding to a synaptotagmin-calcium channel complex may be involved in the etiology of LEMS.
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The prevalence and features of malnutrition in COPD patients have been studied extensively in stable conditions but are poorly defined in the presence of acute respiratory failure (ARF). Nutritional status was prospectively assessed, on hospital admission, in 50 consecutive COPD patients presenting with ARF, 27 of them requiring mechanical ventilation (MV). Malnutrition, defined on a multiparameter nutritional index, was observed in 60 percent (30/50) of all patients, and in 39 percent (13/33) of those whose body weight was equal to or above 90 percent ideal body weight (IBW). Malnutrition was more frequent in those patients who required MV than in those who did not (74 percent vs 43 percent, p < 0.05). Subcutaneous fat stores were decreased (triceps skinfold thickness [TSF] < 80 percent pred) in 68 percent of patients, and markedly depleted (TSF < 60 percent pred) in 52 percent of them. The indices of lean body mass, ie, mid-arm muscle circumference (MAMC) and creatinine height index (CHI) were decreased in, respectively, 42 percent and 71 percent of patients, but MAMC was severely depressed (< 60 percent pred) in only 6 percent of them. A severe decrease of prealbumin (< 100 mg/L), retinol-binding-protein (< 20 mg/L), and albumin (< 20 g/L) serum concentrations was observed in, respectively, 22 percent, 28 percent, and 4 percent of patients. These results suggest that an assessment of nutritional status using a multiparameter approach should be systematically performed in COPD patients with ARF, especially in those requiring MV, as malnutrition may have deleterious effects on weaning off MV.
Lumbar subdural abscesses have rarely been reported in the literature, and the complications of epidural infiltrations predominantly include arachnoiditis, meningitis and epidural abscesses. We report a case of lumbar subdural abscess confirmed by surgery, which appeared following epidural infiltration for lumbar sciatica and was examined with computed tomography and MRI. Only the latter technique alone showed the abscess, after gadolinium injection, and established its intradural site.
We have established a study site in a malaria endemic region around Kataragama in the south of Sri Lanka. A population of about 3,000 individuals in a group of villages around Kataragama have been provided with access to a small field clinic enabling us to monitor aspects of malarial infection under conditions of natural transmission. At the present time, both Plasmodium falciparum and Plasmodium vivax are prevalent to a similar degree although prior to about five years ago P. falciparum had been virtually absent for most of the previous ten years.
The development of atherosclerotic vascular disease is influenced by multiple factors present since early age. Abnormal lipid metabolism, a major cause of atherosclerosis, results from genetic predisposition and is influenced by a variety of exogenous conditions. This article reviews the published studies of serum cholesterol tracking. The Sherbrooke cohort study on serum cholesterol tracking from early infancy to adolescence is described. The role of dietary habits, nutrient intake and other lifestyle-associated factors are scrutinized. Finally, a family-oriented detection of coronary risk factors in adolescence is discussed with emphasis on the future implementation of new genetic techniques.
MRI has transformed the diagnosis of cavernous hemangioma, a hamartoma that is most often located in the central nervous system. The appearance of this lesion is fairly characteristic with MRI. This technique has allowed distinguishing multiple forms. Encephalic sites are most frequent, with rare medullary sites, and double brain and cord locations are exceptional. Many cases of single or multiple brain involvement have now been reported. Series of medullary involvement are much less frequent and include few cases. Double sites in the brain and cord are exceptional. The authors present a case of cavernous hemangiomas of the central nervous system with multiple encephalic sites associated with a single medullary site confirmed by surgery.
Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating condition of the central nervous system, usually developing after a viral infection or vaccination. We report a case of ADEM predominantly affecting the spinal cord in an 8-year old boy evaluated by MRI. The radiographic picture consisted of multiple focal lesions of the spinal cord, a left posterior thalamic lesion and a subcortical right posterior parietal lesion. These lesions regressed several weeks after corticosteroid treatment. The clinical presentation, the laboratory results and the radiological findings suggest the diagnosis of ADEM secondary to viral infection by Coxsackie B.
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Immunoglobulin G fractions from patients with Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disease of neuromuscular transmission, immunoprecipitate 125I-labeled omega-conotoxin GVIA-labeled calcium channels solubilized from rat brain. A 58-kDa antigen was detected by probing Western blots of partially purified calcium channels with LEMS plasma and IgG and was shown to be the relevant antigen in omega-conotoxin receptor immunoprecipitation. Monoclonal antibody 1D12, produced by immunizing mice with synaptic membranes, has properties similar to these autoimmune IgGs in both immunoprecipitation and Western blotting assays. 1D12 antigen was purified by immunoaffinity chromatography and shown to bind LEMS IgG. The antigen was identified by screening a rat brain cDNA library with 1D12 and was found to have strong homology to the synaptic vesicle membrane protein synaptotagmin. Our results indicate therefore that these antibodies immunoprecipitate omega-conotoxin receptors by binding to synaptotagmin that is associated with calcium channels. We suggest that the interaction between synaptotagmin and the voltage-gated calcium channel plays a role in docking synaptic vesicles at the plasma membrane prior to rapid neurotransmitter release and that autoantibody binding to a synaptotagmin-calcium-channel complex may be involved in the etiology of LEMS.
We have screened various alkyl- and arylguanidinium derivatives as possible competitors of Na+ or Rb+ for the cation sites on renal Na+,K(+)-ATPase. Alkyl-monoguanidinium or alkylbisguanidinium (BisG) compounds (chain lengths of C3 to C10) competitively inhibit the occlusion of Rb+ and Na+ with an order of affinities C10 greater than C8 greater than C6 greater than C4 greater than C3. BisG compounds are approximately twice as effective as the equivalent alkylmonoguanidinium compounds. In media of high ionic strength, affinities of tens of micromolar are observed, e.g. 26 microM for BisG 8. m-(mXBG)- and p-xylylenebisguanidinium were synthesized and were found to compete with Rb+ or Na+ with intrinsic affinities of 7.7 and 8.2 microM, respectively. The hydrophobicity rather than the degree of proximity of the guanidinium groups in all BisG compounds appears to determine the binding affinity. A systematic search has been made of conditions in occlusion assays for which the inhibitor affinities are highest. When the pH is raised from 7.0 to 8.5, a 5-fold increase in affinity is observed, suggesting that the guanidinium derivatives compete with protons at sites of pKa approximately 7.5. Replacing Tris-HCl with choline chloride-containing media raised apparent affinities approximately 2-fold. All guanidinium derivatives stabilize the E1 conformation of fluorescein-labeled Na+,K(+)-ATPase, acting as competitive Na+ analogues. In media containing only 1 mM Tris-HCl, pH 8.55, very high affinities were observed for binding to the fluorescein-labeled enzyme (e.g. 0.08 microM for mXBG). In very low ionic strength medium, the inhibition was still competitive with Rb+ ions. However, there was also evidence for nonspecific adsorption to the membranes. The following findings show that mXBG, a typical guanidinium derivative, behaves as a Na(+)-like antagonist. (a) It inhibits Na+,K(+)-ATPase activity, competing strongly with Na+ but only weakly with K+ ions. (b) It inhibits phosphorylation from ATP, competing with Na+ ions. (c) Like Na+ ions, it blocks phosphorylation from inorganic phosphate. Based on these results, we propose that the guanidinium group binds to a relatively wide vestibule at the cytoplasmic surface; but, unlike Na+ or K+ ions, it cannot pass into a narrower region of the cation transport path within the membrane. Therefore, it blocks the occlusion and active transport of cations. In the future, high affinity guanidinium derivatives may serve the purpose of locating cation-binding domains of the pump protein after being converted to reactive affinity or photoaffinity covalent labels.