Parametric x-ray radiation observed in diamond at low electron energies.
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Journal Article↗
Biomedical subjects
A Richter
Publications and source records attributed to A Richter.
Dose-dependent anticonvulsant and proconvulsant effects of nitric oxide synthase inhibitors on seizure threshold in a cortical stimulation model in rats.
In the central nervous system, nitric oxide (NO) is increasingly being considered as a trans-synaptic retrograde messenger, being involved for instance in cellular responses to stimulation of glutamate receptors of the NMDA subtype. Thus, compounds that modify NO production, such as NO synthase inhibitors, may provide a means of altering NMDA receptor function. The functional consequences of NO synthase inhibition are, however, complicated by the fact that NO not only serves as a messenger to activate guanylyl cyclase and so to raise cGMP in target cells in response to NMDA receptor stimulation but also to induce feedback inhibition of the NMDA receptor via a redox modulatory site on the receptor complex. This may explain the contrasting results obtained previously with NO synthase inhibitors in animal models of ischaemia and seizures. In the present study, we tried to resolve the reported discrepancies about the effects of NO synthase inhibitors in seizure models by studying such drugs at various doses in a novel model of cortical seizure threshold. In this model, the threshold for seizures in rats is determined at short time intervals by applying ramp-shaped electrical pulse-trains directly to the cerebral cortex, allowing one to determine the time course of anti- or proconvulsant drug effects in individual rats. Two NO synthase inhibitors, NG-nitro-L-arginine and NG-nitro-L-arginine methyl ester, were compared with a clinically effective antiepileptic drug, i.e. valproate.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Oxidoreductases↗
Growth inhibitory effects of FK506 and cyclosporin A independent of inhibition of calcineurin.
The ability of the immunosuppressive agent FK506 to affect growth of the epidermal growth factor-receptor (EGF-R) overexpressing cell line, A431, was compared with that of the structurally unrelated immunosuppressive compound, cyclosporin A (CyA). Both were shown to inhibit growth, although neither of them caused down-regulation of the EGF-R or affected epidermal growth factor (EGF)-induced tyrosine phosphorylation of the EGF-R. Inhibition of growth was not specific to EGF-R pathways, as both FK506 and CyA also inhibited EGF- and platelet-derived growth factor (PDGF)-induced DNA synthesis in fibroblasts. In all assays FK506 was less potent than CyA even though it is 10-100 times more potent as an immunosuppressive agent. The role of calcineurin in CyA- or FK506-induced growth inhibition was investigated using the synthetic pyrethroid insecticides: cypermethrin, deltamethrin and fenvalerate, which are known calcineurin inhibitors. Failure of these agents to block cell growth or influence growth factor-induced mitogenesis indicated that the biochemical pathway(s) by which CyA or FK506 inhibited cell growth did not depend solely on inhibition of calcineurin.
Calcineurin↗
Contribution of the transforming growth factor alpha B-loop beta-sheet to binding and activation of the epidermal growth factor receptor.
We have exploited the differences in binding affinities of the chicken epidermal growth factor (EGF) receptor for EGF and transforming growth factor alpha (TGF alpha) to study the role of the B-loop beta-sheet of these ligands in receptor recognition and activation. Although EGF and TGF alpha share similar secondary and tertiary structures imposed by three highly conserved intramolecular disulfide bonds, they have only 30-40% overall sequence identity. The B-loop beta-sheet is the major structural element in EGF and TGF alpha, but sequence similarity in this region is low. To investigate its role in receptor binding, we constructed two chimeric growth factors (mEGF/hTGF alpha 21-30 and mEGF/hTGF alpha 21-32) composed of the murine EGF (mEGF) amino acid sequence with residues 21-30 of the B-loop beta-sheet replaced by the equivalent residues of human TGF alpha (hTGF alpha); in chimera mEGF/hTGF alpha 21-32, asparagine 32, which lies at the boundary of the amino and carboxyl domains of mEGF, was also replaced by its hTGF alpha counterpart (valine). In initial studies using unpurified medium, it was found that the recombinant growth factors exhibited differing mitogenic potencies (mEGF/hTGF alpha 21-32 > mEGF/hTGF alpha 21-30 > mEGF) when assayed on chicken fibroblasts, even though they were equivalent in mitogenesis assays using cells expressing the human EGF receptor. After purification, mEGF/hTGF alpha 21-32 was found to be 50 times more potent than mEGF in the chick fibroblast mitogenesis assay and exhibited a 10-fold increase in relative affinity for the chicken EGF receptor; both growth factors still exhibited equivalent mitogenic and receptor binding activity when tested on cells expressing human EGF receptors. We conclude that the B-loop beta-sheet of hTGF alpha is an important determinant of EGF receptor binding affinity and biological activity.
Amino Acid Sequence↗
Gaussian orthogonal ensemble statistics in a microwave stadium billiard with chaotic dynamics: Porter-Thomas distribution and algebraic decay of time correlations.
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Journal Article↗
Gonadal sex hormones and dystonia: experimental studies in genetically dystonic hamsters.
In some kinds of idiopathic dystonia, including paroxysmal dystonia, a role of sex hormones has been suggested because of female predominance and onset, recurrence, or exacerbation of dystonic symptoms with pregnancy. Similar effects of pregnancy have recently been reported in a model of paroxysmal dystonia, the genetically dystonic hamster. Dystonia in mutant hamsters of both genders is transient, i.e., exhibits spontaneous remission at around puberty, strongly suggesting involvement of gonadal sex hormones. For exploration of the role of sex hormones in dystonia, we undertook a series of ontogenetic experiments in male and female dystonic hamsters. Mutant animals of both genders exhibited the same postnatal development of dystonia with maximum severity of dystonic attacks between weaning and approximately 40 days of age and spontaneous remission thereafter. As shown by plasma sex hormone determinations and, in females, vaginal cytology, spontaneous improvement of the movement disorder coincided with puberty in both genders. Male and female hamsters had about the same plasma levels of progesterone. Compared with nondystonic hamsters, onset of puberty was significantly retarded in both male and female dystonic hamsters. Furthermore, body weight gain was lower in dystonic animals, indicating retarded postnatal development. Gonadectomy at time of weaning did not alter the age-dependent development and remission of dystonia, suggesting that gonadal sex hormones are not critically involved in the disease in hamsters. We propose that transient paroxysmal dystonia in mutant hamsters is caused by postnatal retardation of brain development resulting in a temporary impairment of brain functions with spontaneous remission independent of gonadal sex hormones. In view of the fact that the brain can synthesize steroids such as progesterone independent of peripheral glands in both genders, such neurosteroids might be involved in the postnatal brain maturation that leads to remission of dystonia at around puberty in mutant hamsters.
Age Factors↗
The "campus syndrome" in pigs: neurological, neurophysiological, and neuropharmacological characterization of a new genetic animal model of high-frequency tremor.
Inherited neurological diseases in animals are of interest to a wide range of scientific disciplines, particularly because such animals may be suited as genetic animal models for respective human disorders. Because the pig has a number of anatomic and physiologic features similar to those of human beings, this species is becoming increasingly popular in biomedical research. The usefulness of pigs as genetic models of neurological diseases is illustrated by the porcine model of malignant hyperthermia (MH), i.e., a frequently fatal myopathic disease in both pigs and humans. In the present study, we describe a new hereditary movement disorder in Pietrain pigs, which may represent a useful genetic animal model of high-frequency tremor. Because the disorder was first detected in the offspring of a boar named "Campus," we use the term "Campus syndrome" in this respect. Segregation analysis of breeding studies indicates that the syndrome is inherited as a monogenic dominant trait. DNA-based testing of the mutation involved in MH myopathy showed that expression of the Campus syndrome in pigs is not dependent on homozygosity for the MH mutation. In affected pigs, the Campus syndrome develops at an average age of 27 days. The syndrome is characterized by muscular weakness and a very intense tremor of the legs when standing and walking but not when at rest in a lying position. The intensity of tremor and muscular weakness progressively increases with age, resulting in pronounced postural instability. Despite these neurological abnormalities, body weight gain in affected pigs does not differ from that in unaffected siblings.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Heart rate fluctuations of lower frequencies than the respiratoryrhythm but caused by it.
In conscious adult rabbits, "classical" respiratory sinus arrhythmia does not occur because the respiratory frequency (RF) always exceeds half the heart rate (HR). However, slow HR fluctuations, not synchronous with the respiratory rhythm but affected by it, occur systematically. We have shown that these can be calculated by using aliasing rules. During general anaesthesia, when the RF decreases so that respiratory frequency is less than half the heart rate, classical respiratory sinus arrhythmia occurs and can be greatly reduced by vagal blockade. The slow HR fluctuations which are not synchronous with the respiratory rhythms, but are affected by it are mainly vagally mediated, because vagal blockade virtually eliminates them.
Animals↗
Behavioural response to pharmacologic manipulation of serotonin receptors in the genetically dystonic hamster.
The genetically dystonic (dtsz) hamster is an autosomal recessive mutant that shares several features with paroxysmal dystonia, i.e., a subcategory of inherited idiopathic dystonia in humans. Because the serotonin (5-HT) system has been suggested to be involved in dystonia, we examined the functional responsiveness of the 5-HT system in dystonic hamsters by administering various 5-HT agonists and antagonists selective for different receptor subtypes and observing the effects on dystonic attacks as well as the behavioural responses associated with drug administration. Paradoxically, marked prodystonic effects (i.e., increased severity and/or decreased latency of dystonic attacks) were seen with both the selective 5-HT1A receptor agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and the selective and "silent" 5-HT1A receptor antagonist, N-tert-butyl-3[4-(2-methoxyphenyl)piperazin-1-yl]-2- phenylpropionamide [(+)-WAY-100135], whereas other 5-HT1A receptor antagonists, i.e., methyl 4[4-(4-[1,1,3-trioxo-2H-1,2-benzoiosothiazol-2-yl]butyl)-1- piperazinyl]1-H-indole-2-carboxylate (SDZ 216-525) and N1-bromoacetyl-N8-3'-(4-indolyloxy)-2'-hydroxypropyl-(Z)-1,8- diamino-p-methane (pindobind-5-HT1A) did not alter dystonia to any comparable extent. Because among these 5-HT1A receptor antagonists, (+)-WAY-100135 is the only drug known to be not only silent at postsynaptic but also presynaptic (somatodendritic) 5-HT1A receptors, the marked prodystonic effect of this drug could relate to increased 5-HT release as a result of the blockade of somatodendritic 5-HT1A receptors. The only 5-HT1A receptor antagonist that exerted antidystonic effects in hamsters was pindolol, which, however, could be related to its beta-adrenoceptor blocking action. The 5-HT1A receptor partial agonist ipsapirone exerted moderate prodystonic activity. Prodystonic activity was also determined for the mixed 5-HT1A/5-HT2 receptor agonist 5-methoxy-N,N-dimethyltryptamine, although this drug was less potent in this regard than 8-OH-DPAT. The 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerted prodystonic effects in mutant hamsters, which, however, were also seen after the administration of the 5-HT2 receptor antagonist ritanserin. Collectively, the results of this study demonstrate that dystonia in genetically dystonic hamsters can be affected by pharmacologic manipulation of 5-HT receptors. The data may also indicate that dystonia is not a potential clinical application for selective 5-HT1A or 5-HT2 receptor antagonists.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Alterations in the brain GABAA/benzodiazepine receptor-chloride ionophore complex in a genetic model of paroxysmal dystonia: a quantitative autoradiographic analysis.
Dystonia is a relatively common syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The most frequent type of dystonia is idiopathic generalized dystonia, whose pathophysiology is largely unknown. In this respect, mutant animal strains with inborn dystonia may be helpful to elucidate the pathophysiological defects involved in idiopathic dystonia. The genetically dystonic (dtsz) hamster is an animal model of paroxysmal dystonia that displays attacks of generalized dystonia either spontaneously or in response to mild environmental stimuli. In the present study, a quantitative autoradiographic analysis of ligand binding to different sites of the GABAA/benzodiazepine receptor-chloride ionophore complex was carried out in 123 brain areas from genetically dystonic mutant hamsters and age-matched control hamsters. Animals were killed 2 weeks after their last dystonic attack. Analysis of the GABA-binding site of the receptor complex, using the ligand [3H]muscimol, and the benzodiazepine site labelled with [3H]flunitrazepam revealed no significant alterations in the binding of either ligand in any of the brain regions examined. In contrast, widespread changes were observed in binding densities of [35S]t-butylbicyclophosphorothionate ([35S]t-butylbicyclophosphorothionate), which labels the picrotoxinin site of the GABAA receptor-chloride ionophore complex. Significantly increased [35S]t-butylbicyclophosphorothionate binding was found in several parts of the thalamus, cortex, and hippocampus as well as in the red nucleus, the subthalamic nucleus, and the granular layer of the cerebellum. Since high-affinity [35S]TBPS binding is thought to represent the closed conformation of the GABA-gated chloride ionophore, increased TBPS binding would indicate an impaired GABAergic function. The study is consistent with the concept that dystonia is caused by impaired connections between the basal ganglia, the thalamus, and frontal association areas. The data on increased [35S]TBPS binding are the first evidence implicating alterations in the GABA-gated chloride ion channel function in a movement disorder, i.e. idiopathic generalized dystonia.
Animals↗
Regionally selective and age-dependent alterations in benzodiazepine receptor binding in the genetically dystonic hamster.
Previous pharmacological studies have indicated that impairment of GABAergic transmission may be involved in the pathophysiology of dystonia in the mutant dtsz hamster, i.e., a genetic animal model for idiopathic dystonia. In the present experiments, the kinetic constants of [3H]flumazenil binding to the benzodiazepine site of the GABAA receptor were calculated from equilibrium binding measurements in various brain regions of genetically dystonic hamsters and age-matched controls. Because dystonia in mutant dtsz hamsters is transient and disappears after approximately 60-70 days of age, [3H]flumazenil binding was studied at the age of maximum severity of dystonia (30-40 days) and after disappearance of the disease, to examine which neurochemical changes were related to dystonia. In mutant hamsters with the maximum severity of dystonia, receptor affinity of [3H]flumazenil was increased in olfactory bulb, striatum, tectum, and cerebellum, as exemplified by significantly decreased dissociation constants (KD) in these regions. An increased number of binding sites (Bmax) were seen in striatum and frontal cortex but not in the other eight regions studied in this regard. All these changes in [3H]flumazenil binding disappeared in parallel with dystonia, implicating a causal relationship between altered benzodiazepine receptor binding and dystonia in mutant dtsz hamsters.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
Alterations of inositol polyphosphates in skeletal muscle during porcine malignant hyperthermia.
Malignant hyperthermia (MH) may result from increased intracellular calcium concentrations. Increased 1,4,5-IP3 concentrations could mediate this increase in Ca2+. In this study we measured inositol polyphosphates in selectively bred MH susceptible (MHS) and MH non-susceptible (MHN) swine. MH crisis was induced by halothane challenge, and dantrolene was administered in order to measure inositol polyphosphates after MH reversal. Muscle biopsies of skeletal muscles of the hind limbs were obtained in random order and inositol polyphosphates determined by high pressure liquid chromatography using a metal dye detection method. Inositol polyphosphates were determined in three groups: (1) MHS vs MHN basal, (2) during MH crisis induced by halothane and (3) following treatment with dantrolene after halothane challenge. Clinical variables (P(_)VO2, P(-)VCO2, PE'CO2 and pH) indicated that MH was readily induced in MHS swine. Basal concentrations of all inositol polyphosphates were higher in MHS swine compared with MHN swine. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 concentrations increased in MHS animals compared with the respective baseline values, whereas no changes in MHN animals could be detected. Dantrolene administration decreased inositol polyphosphate concentrations in MHS swine. MHN swine showed no changes in inositol polyphosphates after dantrolene. These findings indicate that inositol polyphosphates may be involved in metabolic changes after triggering and treatment of MH.
Anesthetics, Inhalation↗
Inhibition of Western-diet induced hyperproliferation and hyperplasia in mouse colon by two sources of calcium.
A Western-style diet containing high-fat and phosphate, and low calcium and vitamin D was fed to mice for 20 weeks. Starting at week 8, subgroups of animals received the Western-style diet supplemented by two different calcium sources: tricalcium phosphate and calcium citrate malate. Hyperproliferation (increased [3H]thymidine-labelled cells/colonic crypt) and hyperplasia (increased total epithelial cells/crypt) developed in the sigmoid colon after 8 weeks of feeding the Western-style diet confirming previous results, and these were reversed at later periods by the addition of the two calcium sources to the Western-style diet. Findings indicate that the modified colonic epithelial cell hyperproliferation and hyperplasia which have been associated with subsequent development of colonic neoplasia, are induced in mice fed a Western-style diet, and the addition of calcium to the diet inhibited their development in the colonic mucosa.
Animals↗
Missing anti-proliferative effect of fish oil on rectal epithelium in healthy volunteers consuming a high-fat diet: potential role of the n-3:n-6 fatty acid ratio.
Several studies have indicated dietary fish oil (FO) as a protective agent in colon carcinogenesis. Rectal cell proliferation as an intermediate biomarker of cancer risk was shown to be reduced by dietary FO in patients with adenomatous polyps and healthy subjects consuming a low-fat diet. Because the synthesis of prostaglandins (PG) which seem to be involved in this process is dependent on the ratio of n-3:n-6 fatty acids in the diet, the present study was designed to investigate whether this FO effect is also detectable in volunteers eating a high-fat diet (50% of energy) with a low n-3:n-6 ratio of 0.25. Twelve healthy volunteers received in addition to a controlled basal diet either FO (4.4 g n-3 fatty acids/day) or corn oil supplements (double-blind, crossover) for two 4-week periods. No significant differences between the two study periods were found for rectal cell proliferation as assessed by bromodeoxyuridine immunohistochemistry and ornithine decarboxylase activity, as well as for mucosal PGE2 release and mucosal membrane fatty acid composition. The results emphasize the importance of dietary n-3:n-6 ratio in determining the effects of FO on rectal cell proliferation.
Administration, Oral↗
Constitutive expression of human cytomegalovirus glycoprotein B (gpUL55) with mutagenized carboxy-terminal hydrophobic domains.
Stable transfectants were selected from human astrocytoma cells (U373) after transfection with recombinant expression vectors carrying the human cytomegalovirus (HCMV) glycoprotein B (gB; gpUL55) gene with alternative deletions of hydrophobic domain segment 1 (hd1) or segment 2 (hd2) of the carboxy-terminal potential bipartite membrane anchor domain. Comparative analysis of HCMV gB forms from cell lines gB(Mhd1) and gB(Mhd2), expressing mutagenized gB, and those from cells expressing authentic gB showed that deletion of hd1, but not that of hd2, interfered with efficient proteolytic cleavage of the gB precursor. Both mutagenized gB forms exhibited correct transport to the cell surface. Deletion of hd2, but not that of hd1, caused loss of membrane anchoring of the gB molecule, resulting in secretion of the respective gB form into the culture medium. The carboxy-terminal cleavage product of the soluble gB molecule, which migrated more slowly than its authentic counterpart, was modified by complex carbohydrate side chains and formed disulphide-linked complexes. Our observations indicate that hd2 is essential as well as sufficient for membrane anchoring of the HCMV gB molecule. For hd1, a potential fusogenic role is suggested by the conserved positional pattern of glycine residues, which is comparable to that of known fusion peptides of other viruses.
Amino Acid Sequence↗
Magnetic octupole strength in rare-earth nuclei: A sum-rule approach.
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Journal Article↗
New injectable aqueous carbamazepine solution through complexing with 2-hydroxypropyl-beta-cyclodextrin: tolerability and pharmacokinetics after intravenous injection in comparison to a glycofurol-based formulation.
The poor water solubility of the antiepileptic drug (AED) carbamazepine (CBZ) is generally considered an absolute contraindication to parenteral administration in epileptic patients. However, the water solubility of CBZ can be largely enhanced through formation of an inclusion complex with an amorphous cyclodextrin derivative, 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). We studied tolerability and pharmacokinetics of an aqueous CBZ:HP beta CD solution after intravenous (i.v.) administration in dogs. For comparison, a conventional glycofurol-based solution of CBZ was used. We also administered a commercial liquid formulation of CBZ orally (p.o.). Infusion of CBZ:HP beta CD solutions or HP beta CD "placebo" formulations i.v. was well tolerated by the animals. In contrast, infusion of CBZ:glycofurol solutions and glycofurol placebo solutions induced marked behavioral and cardiovascular adverse effects. Pharmacokinetic studies indicated that glycofurol inhibited CBZ metabolism by decreasing formation of the major CBZ metabolite CBZ-10,11-epoxide (CBZ-E). With infusion of CBZ:HP beta CD 10 ml/min for 12-15 min, resulting in a CBZ dose of CBZ 5 mg/kg body weight, peak CBZ plasma levels of approximately 3.6 micrograms/ml were obtained. This relatively low peak concentration is primarily due to the rapid elimination of CBZ in dogs [half-life (t1/2) < 1 h]. Comparison of peak plasma levels determined after p.o. administration of CBZ to dogs with peak CBZ levels previously determined after p.o. administration in humans indicated that about four times higher doses are needed in dogs to attain the same peak plasma levels as in humans.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Hydroxypropyl-beta-cyclodextrin↗
[Peripheral vascular injuries in polytrauma].
Between 1972 und 1993 a total of 68 patients were treated at the Department of Surgery of the University Clinic of Mannheim for peripheral vascular injury resulting from multiple trauma. The average age of these patients was 31.3 years, and most of them were male (88.2%; n = 60). The injured vessels were localized evenly in all the extremities: 31 patients (45.5%) presented with arterial damage of the upper extremity, and 37 (54.5%) showed lesions along the femoro-popliteal arteries. The most frequent location of injured vessels in the multiply traumatized patient was the popliteal artery (n = 18, 26.5%), the distal part of the superficial femoral artery (n = 12, 17.6%), the brachial artery (n = 14, 20.6%) and the axillary artery (n = 10, 14.6%). The dominant cause, of trauma was road traffic accidents (72%), and 20 patients (29%) acquired their vascular injuries as motorcyclists. There were also 13 occupational accidents (19%) involving vascular injuries. In addition to a vascular trauma 34 patients (50%) had complicated fractures, and a further 34 patients (50%) had multiple fractures: 12 (17.6%) had head and brain damage, 5 (7.3%) had blunt abdominal trauma and 6 (8.8%) had blunt thoracic injury. The general amputation rate was 2.9% (n = 2). One patient died on the table of a torn off subclavian artery combined with multiple other injuries. Paresis of the plexus is a particular problem after vascular lesions of the upper extremity: in 22 patients (71%) paresis of the plexus persisted after successful vascular reconstruction (follow-up period between 3 months and 16 years, median time 3.45 years).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗