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G Schmid

Publications and source records attributed to G Schmid.

At least 91 records · Page 5Linked to original sources
PubMed1997

A clinical comparison of the rate of maxillary canine retraction into healed and recent extraction sites--a pilot study.

The rate of movement of the maxillary canines into the healed or recent extraction alveolus of the first premolar was measured in 22 patients aged 10-27 years. On one side of the dental arch, the first premolar was extracted. After a median time of 86 days, the contralateral first premolar was extracted and the distalization of both canines started using Gjessing canine retraction springs. The experiment was ended when one of the two canines had been sufficiently distalized. Recordings of the positions of the canines at the beginning of the study, at the start of the distalization and at the end were made from dental casts and standardized intraoral radiographs. The canine on the recent extraction side moved faster than that on the healed side, but also tipped somewhat more. The reasons for the increased tipping and the faster movement are discussed.

Adolescent↗
PubMed1997

Increased presynaptic protein kinase C activity and glutamate release in rats with a prenatally induced hippocampal lesion.

We have previously shown that protein kinase C (PKC) activity is up-regulated in nerve terminals of animals that have been subjected to targeted cellular ablation of cortical and hippocampal neurons by treatment with methylazoxymethanol (MAM), which results in impaired long-term potentiation (LTP) and cognitive deficit. In this study we investigated the consequences of increased membrane-bound PKC in the regulation of release of glutamate, the major excitatory transmitter involved in LTP. We show that nerve terminals of MAM-treated rats show higher PKC activity, as monitored by the in situ phosphorylation of B-50/GAP-43, in both basal and phorbol ester-stimulated conditions. In these animals, hippocampal nerve endings release a greater amount of glutamate than those of controls, both in basal conditions and when synaptosomes are stimulated with KCl or 3,4-diaminopyridine. The potentiation observed in MAM-treated rats was counteracted by the PKC blocker H-7 and the clostridial tetanus toxin. On the contrary, GABA release was not significantly up-regulated, either in basal or in depolarization-evoked conditions. Therefore our data show that the increase in synaptosomal PKC activity is paralleled by increased glutamate but not GABA release in this animal model. Whether this reflects specific up-regulation of membrane PKC activity in glutamatergic terminals or an alteration in the regulation of glutamate release remains to be determined.

Animals↗
PubMed1996

ADP-ribosylation of wild-type p53 in vitro: binding of p53 protein to specific p53 consensus sequence prevents its modification.

We have recently reported that mutant but not wild-type (wt) p53 protein was ADP-ribosylated in primary rat cells overexpressing the temperature-sensitive murine p53val135 gene. To examine whether the lack of susceptibility to modification is a specific feature of p53val135 adopting wt conformation or rather a general property of this tumor suppressor protein, we have studied ADP-ribosylation of wt p53 of different origin in vitro using semi-purified poly(ADP-ribose) transferase (pADPRT). In vitro pADPRT modified human and mouse wt p53 and p53val135. Under limiting substrate concentration, the molar mass of ADP-ribosylated p53 was only slightly altered. Chase experiments with high NAD concentration resulted in the formation of poly(ADP-ribosyl)ated p53 protein shifted to 64 kD. However, preincubation of wt p53 proteins with a p53 consensus sequence resulting in complex formation abolished the modification of wt p53. This indicates that in the cellular environment the specific DNA binding of wt p53 prevents its covalent modification by poly(ADP-ribose).

Adenosine Diphosphate Ribose↗
PubMed1996

Purification and in vitro-phospholabeling of secretory envelope proteins E1 and E2 of hepatitis C virus expressed in insect cells.

The putative envelope glycoproteins of hepatitis C virus (HCV), E1 and E2, were expressed as recombinant, secretory proteins in Sf9 insect cells through infection with recombinant baculoviruses. The influenza virus hemagglutinin signal sequence (HASS) was inserted upstream of the HCV-cDNAs in order to effect secretion. Furthermore, a hexa-histidine tag for purification on a Ni(2+)-nitrilotriacetic acid (Ni(2+)-NTA) column and a protein kinase A (PKA) recognition sequence for in vitro-phospholabeling were fused upstream of the HCV-cDNA. E1- and E2 proteins lacking their carboxy-terminal, hydrophobic sequence were produced by baculovirus-infected insect cells in bioreactors of 23 1. The medium was concentrated and proteins were purified under native conditions on Ni(2+)-NTA columns. Purified proteins could be phospholabeled in vitro using the catalytic subunit of protein kinase. A isolated from bovine heart and gamma-[32P]ATP. Labeled E1 and E2 proteins expressed in insect cells could be immunoprecipitated with sera from HCV-infected patients. Co-expression of these E1 and E2 proteins led to the formation of E1-E2 complexes within the insect cell and to secretion of these complexes into the medium.

Adenosine Triphosphate↗
PubMed1996

Functional evidence for two native GABAA receptor subtypes in adult rat hippocampus and cerebellum.

Studies of molecular cloning predict great heterogeneity for the GABAA receptor; however, evidence for functionally and pharmacologically distinct native GABAA receptors is relatively scarce. In this work we have compared some of the functional and pharmacological properties of two GABAA receptors previously shown to be present in the adult rat central nervous system. In superfused hippocampal synaptosomes activation of GABAA receptors increased the basal release of [3H]noradrenaline (EC50 for GABA = 3.2 microM). In contrast, the overflow evoked by depolarization with high-K+ (12 or 35 mM) was not affected. Conversely, GABAA receptor activation led to potentiation of the K(+)-evoked overflow of [3H]D-aspartate from cerebellar synaptosomes (EC50 for GABA = 1.3 microM) whereas the basal release remained unchanged. GABA and muscimol also potentiated the K(+)-evoked overflow of endogenous glutamate in cerebellum. Diazepam enhanced the GABA (3 microM)-evoked [3H]noradrenaline release (EC50 = 65 nM). The diazepam potentiation of the GABA- or muscimol-evoked release of [3H]noradrenaline was inversely related to the agonist concentration. The effect of diazepam was reversed by the benzodiazepine antagonist flumazenil. Zolpidem mimicked diazepam (EC50 = 14 nM). The increase of the K(+)-evoked overflow of [3H]D-aspartate (or of endogenous glutamate) elicited by GABA or muscimol in cerebellar synaptosomes was not affected by benzodiazepines (diazepam or clonazepam) or by zolpidem. On the other hand, Ro 15-4513, an inverse agonist at the benzodiazepine site, strongly inhibited (EC50 = 7 nM) the enhancement by GABA (3 microM) of the K(+)-evoked [3H]D-aspartate overflow in cerebellar synaptosomes; the effect of Ro 15-4513 was reversed by flumazenil. These results suggest the existence in the central nervous system of the adult rat of two native pharmacological-subtypes of the GABAA receptor having different function, regional distribution and neuronal location; the receptors require different membrane potential to be activated and display different sensitivity to benzodiazepines and to drugs acting at benzodiazepine sites.

Animals↗
PubMed1996

Human brain somatostatin release from isolated cortical nerve endings and its modulation through GABAB receptors.

UNLABELLED: 1. The release of somatostatin-like immunoreactivity (SRIF-LI) in the human brain was studied in synaptosomal preparations from fresh neocortical specimens obtained from patients undergoing neurosurgery to remove deeply sited tumours. 2. The basal outflow of SRIF-LI from superfused synaptosomes was increased about 3 fold during exposure to a depolarizing medium containing 15 mM KCl. The K(+)-evoked overflow of SRIF-LI was almost totally dependent on the presence of Ca2+ in the superfusion medium. 3. The GABAB receptor agonist, (-)-baclofen (0.3 - 100 microM), inhibited the overflow of SRIF-LI in a concentration-dependent manner (EC50 = 1.84 +/- 0.20 microM; maximal effect: about 50%). The novel GABAB receptor ligand, 3-aminopropyl(difluoromethyl)phosphinic acid (CGP 47656) mimicked (-)-baclofen in inhibiting the SRIF-LI overflow (EC50 = 3.06 +/- 0.52 microM; maximal effect: about 50%), whereas the GABAA receptor agonist, muscimol, was ineffective up to 100 microM. 4. The inhibition by 10 microM (-)-baclofen of the K(+)-evoked SRIF-LI overflow was concentration-dependently prevented by two selective GABAB receptor antagonists, 3-amino-propyl (diethoxymethyl)-phosphinic acid (CGP 35348) (IC50 = 24.40 +/- 2.52 microM) and [3-[[(3,4-dichlorophenyl) methyl]amino]propyl] (diethoxymethyl) phosphinic acid (CGP 52432) (IC50 = 0.06 +/- 0.005 microM). 5. The inhibition of SRIF-LI overflow caused by 10 microM CGP 47656 was abolished by 1 microM CGP 52432. 6. When human synaptosomes were labelled with [3H]-GABA and depolarized in superfusion with 15 mM KCl, the inhibition by 10 microM (-)-baclofen of the depolarization-evoked [3H]-GABA overflow was largely prevented by 10 microM CGP 47656 which therefore behaved as an autoreceptor antagonist. 7. IN CONCLUSION: (a) the characteristics of SRIF-LI release from synaptosomal preparations of human neocortex are compatible with a neuronal origin; (b) the nerve terminals releasing the neuropeptide possess inhibitory receptors of the GABAB type; (c) these receptors differ pharmacologically from the GABAB autoreceptors present on human neocortex nerve terminals since the latter have been shown to be CGP 35348-insensitive but can be blocked by CGP 47656.

Adult↗
PubMed1996

Neurotransmitter and monoaminergic amino acid precursor levels in rat brain: effects of chronic renal failure and of malnutrition.

Effects of chronic renal failure on brain neurotransmitters (dopamine, norepinephrine, serotonin and histamine) and on monoaminergic amino acid precursors (tyrosine, phenylalanine and histidine) were investigated. To eliminate the consequences of uremia-induced restriction of food intake, rats with malnutrition (pair-fed animals) were also studied and both were compared with control rats fed ad libitum. Malnutrition of a moderate degree (food intake 84% of controls) had no effect on amino acid concentrations in plasma and brain or on neurotransmitter levels in brain. Concerning plasma amino acids in chronic renal failure a lowered tyrosine level was found resulting in a diminished tyr/phe ratio. In brain tissue, the tyr/phe ratio was found to be normal, because brain tyrosine levels in chronic renal failure were similar to controls. Histidine, which was normal in plasma at this degree of chronic renal failure, was found to be significantly enhanced in brain in uremia. Also the neurotransmitters studied were found to be elevated in brain of chronic uremia, depending on the stage of renal insufficiency.

Amino Acids↗
PubMed1996

[Idiopathic pulmonary hemosiderosis. Clinical and radiological assessment of re-exacerbation].

Predominant characteristics of idiopathic pulmonary hemosiderosis (IPH), a rare pathology of unknown etiology, are recurrent alveolar hemorrhage, hemoptysis and iron deficiency anemia. No evidence of vascular disorders, infections, cancer, pulmonary embolus, veno-occlusive diseases must also be considered for the diagnosis. A case of chronic IPH with long asymptomatic periods and stages of riacutization with severe dyspnoea, high fever, cough with rusty coloured spitting, asthenia and serious respiratory insufficiency is described. The patient adds to our understanding in one of such riacutization in that she agreed to high-resolution computed tomography (HRCT) testing, in addition to common routine testing. It became possible to underline the importance of HRCT both in the diagnosis of IPH without hemoptysis, awaiting invasive investigations like fiberoptic bronchoscopy and lung biopsy, and in the clinical evaluation of the riacutization. Such analysis leads to forwarding the installment of the most appropriate therapy and to the limitation of fibrotic evolution, when possible.

Acute Disease↗
PubMed1996

Human brain cholecystokinin: release of cholecystokinin-like immunoreactivity (CCK-LI) from isolated cortical nerve endings and its modulation through GABA(B) receptors.

The release of cholecystokinin-like immunoreactivity (CCK-LI) in human brain was investigated using synaptosomes prepared from neocortical specimens removed during neurosurgery. CCK-LI basal release from superfused synaptosomes was increased 3 to 4-fold during depolarization with 15 mM KCI. The K(+)-evoked overflow of CCK-LI was strictly Ca(++)-dependent. The gamma-aminobutyric acidB (GABA(B)) receptor agonist (-)baclofen (0.3-100 microM) inhibited CCK-LI overflow in a concentration-dependent manner (EC50 = 2.20 microM; maximal effect: 45%). The novel GABA(B) receptor ligand CGP 47656 mimicked (-)baclofen (EC50 = 2.45 microM; maximal effect: 50%), whereas the GABA(A) agonist muscimol was ineffective up to 100 microM. The inhibitory effect of 10 microM (-)baclofen on the CCK-LI overflow was concentration-dependently prevented by two selective GABA(B) receptor antagonists, CGP 35348 (IC50 = 13.91 microM) and CGP 52432 (IC50 = 0.08 microM). The effect of 10 microM CGP 47656 was abolished by 1 microM CGP 52432. In experiments on [3H]GABA release, CGP 47656 behaved as an antagonist at the GABA(B) autoreceptors: added at 10 microM, it prevented the inhibitory effect of 10 microM (-)baclofen on the K+ (15 mM)-evoked release of [3H]GABA from human synaptosomes. We conclude that 1) the release of CCK-LI evoked from human brain tissue appears of neuronal origin; 2) the CCK-releasing terminal possess inhibitory presynaptic GABA(B) receptors; 3) these receptors differ pharmacologically from human neocortex GABA(B) autoreceptors, which are CGP 35348-insensitive (Fassio et al., 1994) but can be blocked by CGP 47656; 4) because cholecystokinin has been implicated in anxiety, the GABA(B) receptors here characterized may represent targets for novel anxiolytic agents.

Benzylamines↗
PubMed1995

Interferon gamma receptor extracellular domain expressed as IgG fusion protein in Chinese hamster ovary cells. Purification, biochemical characterization, and stoichiometry of binding.

Agents that antagonize the functions of interferon gamma (IFN gamma) are potential pharmaceuticals against several immunological and inflammatory disorders. IFN gamma receptor-immunoglobulin G fusion proteins (IFN gamma R-IgG) function as antagonists of endogenous IFN gamma and have longer half-lives in vivo in comparison with soluble IFN gamma receptors (sIFN gamma R), consisting of the extracellular region of the native sequence. A fusion protein comprising the extracellular domain of the human IFN gamma receptor and the hinge, CH2 and CH3 domains of the human IgG3 constant region, was expressed in Chinese hamster ovary cells. The IFN gamma R-IgG3 fusion protein was secreted into the culture medium as a 175-kDa glycoprotein and was purified over Protein G-Sepharose, DEAE-Sepharose, and size exclusion chromatography. IFN gamma R-IgG3 bound IFN gamma in solid phase assays and ligand blots, competed for the binding of radiolabeled IFN gamma to the cell surface receptor of Raji cells, and inhibited the IFN gamma-mediated antiviral activity with an efficiency at least one order of magnitude higher than that of the soluble receptor produced in the same expression system. Two IFN gamma R-IgG3 fusion proteins bound two IFN gamma dimers forming a complex of approximately 380 kDa. In immunodiffusion assays, the IFN gamma R-IgG3 fusion protein did not precipitate IFN gamma. Dissociation of bound IFN gamma from IFN gamma R-IgG3 was 2-fold slower than from the sIFN gamma R produced in insect cells.

Animals↗
PubMed1995

Experimental therapy of systemic lupus erythematosus: the treatment of NZB/W mice with mouse soluble interferon-gamma receptor inhibits the onset of glomerulonephritis.

Female NZB/W F1 mice develop an autoimmune disease similar to human systemic lupus erythematosus (SLE), and ultimately die of glomerulonephritis. Starting at the age of 16 weeks NZB/W F1 mice were treated for a period of 19 weeks with soluble interferon-gamma receptor (sIFN-gamma R), anti-IFN-gamma monoclonal antibody (mAb) or IFN-gamma. All mice treated with sIFN-gamma R or anti-IFN-gamma mAb were alive 4 weeks after the treatment was discontinued, whereas 50% of mice died in the placebo groups and 78% of the mice died in the IFN-gamma-treated group. Histologically, there was severe membrano-proliferative glomerulonephritis in IFN-gamma- and placebo-treated mice, and minimal or no mesangioproliferative disease in mice receiving sIFN-gamma R or anti-IFN-gamma mAb. The renal mononuclear infiltrate (T lymphocytes and monocytes), expression of major histocompatibility complex class II antigen and glomerular immunoglobulin and complement deposition were reduced in those mice. These data suggest that an IFN-gamma inhibitor, such as the soluble IFN-gamma R, can be used for SLE therapy in the early stages of the disease.

Animals↗
PubMed1995

Primary pulmonary hypertension in a HIV+ patient.

Recent reports have suggested a possible association between HIV infection and primary pulmonary hypertension (PPH). We report the case of a HIV+ patient, without manifestations of the acquired immune deficiency syndrome (AIDS), who presented with signs of elevated pulmonary arterial pressure.

Adult↗
PubMed1994

Design and synthesis of potent and highly selective thrombin inhibitors.

Thrombin, a serine protease, plays a central role in the initiation and propagation of thrombotic events. An extensive search for new thrombin inhibitors was performed, using an unconventional approach. Screening of small basic molecules for binding in the recognition pocket of thrombin led to the discovery of (aminoiminomethyl)piperidine (amidinopiperidine) as a weak, but intrinsically selective, thrombin inhibitor. Elaboration of this molecule provided compounds which inhibit thrombin with Ki's in the range of 20-50 nM and with selectivities of 1000-4000 against trypsin. These inhibitor compounds show a new and unexpected binding mode to thrombin. Modification of the central building block and then of one of the hydrophobic substituents led to the discovery of a new family of thrombin inhibitors which has reverted to the former binding mode to thrombin. This last class of compounds shows inhibitory activities in the picomolar range, low toxicity, and a short plasma half life which favors its use for an intravenous application. From this series of thrombin inhibitors, 19f(Ro 46-6240) was selected for clinical development as an antithrombotic agent for intravenous administration.

Amino Acids↗
PubMed1994

Investigation of gestural and pantomime performance in chronic schizophrenic inpatients.

The present study compared the performance on apraxia tests and additional motor tasks between medicated chronic schizophrenic inpatients (n = 21) and healthy subjects (n = 21). Praxis testing did not reveal a clear-cut apractic syndrome in the patient group. The most striking difference between patients and healthy controls was the more frequent use of body parts as object (BPO) by schizophrenic patients (P < 0.0003). There was no significant difference in psychopathology between subgroups classified according to their BPO performance, although a tendency towards a difference in duration of illness and the actual hospitalization period existed between BPO subgroups. Schizophrenic patients performed more poorly than controls in frontal motor tasks: sequencing, including oral sequential movements, and reciprocal innervation. Frontal motor task performance tended to be related to the negative dimension of schizophrenia in accordance with previous studies. The data do not support the assumption that BPO performance is part of a multidimensional concrete attitude in schizophrenic patients. Nevertheless, this peculiarity in motor behaviour might be a link between neurophysiology and psychopathological phenomenology in schizophrenia. We therefore suggest further investigation focusing the performance of object-related pantomime movements in schizophrenic patients.

Adult↗
PubMed1994

Inhibition of clot-bound and free (fluid-phase thrombin) by a novel synthetic thrombin inhibitor (Ro 46-6240), recombinant hirudin and heparin in human plasma.

Clot-bound thrombin remains active and is less accessible to heparin-antithrombin III than fluid-phase thrombin. To determine whether clot-bound human thrombin is more susceptible to inactivation by direct thrombin inhibitors, the activity of a novel synthetic competitive thrombin inhibitor Ro 46-6240, recombinant hirudin and unfractionated heparin were compared with fluid-phase thrombin and clot-bound thrombin. Fibrinopeptide A generated in human plasma was used as an index of thrombin activity. Hirudin was the most potent inhibitor of fluid-phase and clot-bound thrombin. However, Ro 46-6240 inhibited clot-bound thrombin three times more potently than fluid-phase thrombin (IC50 19 vs 56 ng/ml) while hirudin was two times (IC50 8 vs 3 ng/ml) and heparin six times (IC50 1,205 vs 200 ng/ml) less active against clot-bound thrombin compared with fluid-phase thrombin. The relative selectivity for clot-bound thrombin is not a unique property of Ro 46-6240 since two other synthetic thrombin inhibitors tested inhibited clot-bound thrombin more effectively than fluid-phase thrombin and a third was equally active against both forms of thrombin. In contrast, the affinities of two chromogenic substrates were similar for both forms of thrombin. This study shows that direct thrombin inhibitors inhibit clot-bound thrombin more potently than heparin and suggests that an apparent selectivity for clot-bound thrombin can be achieved with some synthetic thrombin inhibitors. Further studies have to show whether the high potency of these direct thrombin inhibitor translates into antithrombotic efficacy in clinical situations with pre-existing clots.

Binding, Competitive↗
PubMed1994

Ro 42-1611 (arteflene), a new effective antimalarial: chemical structure and biological activity.

The discovery of the natural peroxides qinghaosu (arteannuin A, artemisinin) (1) and yingzhaosu A (3) from traditional Chinese herbal medicines was a major advance in the search for new antimalarials (Fig. 1). Whereas qinghaosu can be produced from natural sources and has been well studied, yingzhaosu A has never been available for full evaluation as anti-malarial. We have designed a synthesis of the novel ring system present in yingzhaosu A, the 2,3-dioxabicyclo[3.3.1]nonane and prepared a series of yingzhaosu A analogues which were tested against Plasmodium berghei in mice. Structure-activity rules could be established and used for lead optimization. The best anti-malarial activity was observed for analogues having a keto group within the ring system and an aliphatic or aromatic lipophilic tail as ring substituent. The optimized analogues possessed activity comparable to qinghaosu. In spite of the presence of a peroxide ring, the new compounds were chemically stable against common reagents. In contrast to qinghaosu and its derivatives, they were also stable against hydrolytic decomposition and could therefore be expected to show improved pharmacokinetic properties. As one of the best compounds, Ro 42-1611 (arteflene) (26n, Fig. 2) was selected for detailed preclinical evaluation. Ro 42-1611 (arteflene) was found negative in a battery of mutagenicity tests. It had low acute toxicity after oral or subcutaneous administration. In a 4-week oral tolerance study in rats, doses of up to 400 mg/kg/day were well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗