Malignant melanoma of the conjunctiva metastasising to the parotid gland.
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Aged↗
Biomedical subjects
S Rose
Publications and source records attributed to S Rose.
Counselling and psychotherapy: media distortion.
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Counseling↗
6-Hydroxydopamine lesioning differentially affects alpha-synuclein mRNA expression in the nucleus accumbens, striatum and substantia nigra of adult rats.
The effect of a unilateral 6-hydroxydopamine (6-OHDA) lesion and/or repeated administration of levodopa (L-DOPA) to normal and 6-OHDA-lesioned rats on alpha-synuclein mRNA expression was investigated by in situ hybridization histochemistry. A 6-OHDA lesion of the nigro-striatal pathway alone, confirmed by the loss of nigral tyrosine hydroxylase mRNA expression, markedly decreased alpha-synuclein mRNA in the lesioned substantia nigra (SN). In contrast, the levels of alpha-synuclein mRNA in the denervated striatum and nucleus accumbens were not altered. Chronic administration of L-DOPA to normal or 6-OHDA-lesioned rats had no effect on alpha-synuclein mRNA expression in the SN, striatum or nucleus accumbens. These data confirm that alpha-synuclein is localized in the nigro-striatal tract but that its gene expression is not regulated by dopamine.
Animals↗
Involvement of inducible nitric oxide synthase in inflammation-induced dopaminergic neurodegeneration.
The loss of dopaminergic neurones in the substantia nigra with Parkinson's disease may result from inflammation-induced proliferation of microglia and reactive macrophages expressing inducible nitric oxide synthase (iNOS). We have investigated the effects of the supranigral administration of lipopolysaccharide on iNOS-immunoreactivity, 3-nitrotyrosine formation and tyrosine hydroxylase-immunoreactive neuronal number, and retrogradely labelled fluorogold-positive neurones in the ventral mesencephalon in male Wistar rats. Following supranigral lipopolysaccharide injection, 16-18 h previously, there was intense expression of NADPH-diaphorase and iNOS-immunoreactivity in non-neuronal, macrophage-like cells. This was accompanied by intense expression of glial fibrillary acidic protein-immunoreactive astrocytosis in the substantia nigra. There were also significant reductions in the number of tyrosine hydroxylase(50-60%)- and fluorogold (65-75%)-positive neurones in the substantia nigra. In contrast, tyrosine hydroxylase-immunoreactivity in the ventral tegmental area was not altered. Pre-treatment of animals with the iNOS inhibitor, S-methylisothiourea (10 mg kg(-1), i.p.), led to a significant reduction of lipopolysaccharide-induced cell death. Similar reduction of tyrosine hydroxylase-immunoreactivity and fluorogold-labelled neurones in the substantia nigra following lipopolysaccharide administration suggests dopaminergic cell death rather than down-regulation of tyrosine hydroxylase. We conclude that the expression of iNOS- and 3-nitrotyrosine-immunoreactivity and reduction of cell death by S-methylisothiourea suggest the effects of lipopolysaccharide may be nitric oxide-mediated, although other actions of lipopolysaccharide (independent of iNOS induction) cannot be ruled out.
Animals↗
Alterations in striatal neuropeptide mRNA produced by repeated administration of L-DOPA, ropinirole or bromocriptine correlate with dyskinesia induction in MPTP-treated common marmosets.
Chronic administration of L-DOPA to MPTP-treated common marmosets induces marked dyskinesia while repeated administration of equivalent antiparkisonian doses of ropinirole and bromocriptine produces only mild involuntary movements. The occurrence of dyskinesia has been associated with an altered balance between the direct and indirect striatal output pathways. Using in situ hybridisation histochemistry, we now compare the effects of these drug treatments on striatal preproenkephalin-A (PPE-A) and adenosine A(2a) receptor mRNA expression as markers of the indirect pathway and striatal preprotachykinin (PPT) mRNA and preproenkephalin-B (PPE-B, prodynorphin) mRNA expression as markers of the direct pathway.The equivalent marked losses of specific [3H]mazindol binding in the striatum of all drug treatment groups confirmed the identical nature of the nigral cell loss produced by MPTP treatment. MPTP-induced destruction of the nigro-striatal pathway markedly increased the level of PPE-A mRNA in the caudate nucleus and putamen and decreased the levels of PPT and PPE-B mRNA relative to normal animals. Repeated treatment with L-DOPA for 30 days produced marked dyskinesia but had no effect on the MPTP-induced increase in PPE-A mRNA in the caudate nucleus and putamen. In contrast, L-DOPA treatment normalised the MPTP-induced decrease in the level of PPT and PPE-B mRNA. Repeated treatment with ropinirole produced little or no dyskinesia but markedly reversed the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen. However, it had no effect on the decrease in PPT or PPE-B mRNA. Similarly, bromocriptine treatment which induced only mild dyskinesia attenuated the MPTP-induced elevation in PPE-A mRNA in the caudate nucleus and putamen with no effect on reduced striatal PPT or PPE-B mRNA. Neither MPTP treatment nor treatment with L-DOPA, bromocriptine or ropinirole had any effect on adenosine A(2a) receptor mRNA in the striatum. These patterns of alteration in striatal PPE-A and PPT and PPE-B mRNA produced by L-DOPA, bromocriptine and ropinirole show differential involvement of markers of the direct and indirect striatal output pathways related to improvement of locomotor activity and mirror the relative abilities of the drugs to induce dyskinesia.
Animals↗
[Developing evidence based guidelines on cardiac rehabilitation - phase 1: a qualitative review].
BACKGROUND: Guidelines are a means to support effective clinical practice and can be used to implement evidence-based medicine in rehabilitative practice. In 1998 a study on cardiac rehabilitation, funded by Bundesversicherungsanstalt für Angestellte, BfA, concluded that the AHCPR's Guideline on Cardiac Rehabilitation published in 1995 could be used as a reference guideline for the rehabilitation of coronary patients. The AHCPR Guideline and other systematic reviews showed cardiac rehabilitation to be an effective means in coronary care. However, no detailed information is given with regard to the structural and processual details that are required for a multidimensional and comprehensive cardiac rehabilitation scheme. To define those central characteristics, therapeutic interventions that had been proven to be effective for cardiac rehabilitation were analysed. The information derived from these analyses will then be used to develop a more detailed evidence-based guideline. METHODS: The analysis was based on the research cited in the AHCPR Guideline. Additionally, a systematic search of the literature identified (randomised) controlled studies published after 1995 for the analysis. Using criteria that had been developed prior to our review, one third (n = 53) of the 159 studies identified were considered suitable for further analysis. Characteristics of the study design, the interventions and the outcomes reported were extracted on a standardised data sheet. In order to facilitate comparisons, studies were arranged according to main intervention and target groups. As it is not possible to present the results in their entirety, this publication focuses on the main aspects which illustrate the method applied. RESULTS: 32 of the 53 studies included dealt with patients after myocardial infarction (MI). In these 32 studies a total of 40 interventions (in 2,912 patients) were investigated. 28 of these interventions dealt with exercise training or exercise training combined with other physical training (i. e. strength training). 7 interventions dealt with counselling only, and 5 interventions had exercise training and counselling as integral parts. Exercise training starts mainly three to four weeks after MI, for 30 - 60 minutes three to 5 times a week. Usually, training intensity is set at 65 - 80 % of the maximum heart rate (or 70 % of the maximum oxygen consumption) reached in standardised exercise testing. All interventions lead to gains in exercise tolerance. Compared to untreated control groups the net benefit ranges from + 11 % to + 30 %. The higher the intensity of the training, the larger the net benefit. The majority of the studies on the effectiveness of exercise training after MI do not report outcomes like psychological well-being, return to work or modification of risk factors. DISCUSSION: Despite limitations in report quality and methodology in some of the studies included, a detailed analysis of the interventions investigated can be used to substantiate optimal cardiac rehabilitation. It is possible to quantify important characteristics of the main elements and to define lower and upper limits of treatment. While formulating these limits, it is intended to maintain compatibility with the BfA Classification of therapeutic measures in medical rehabilitation (KTL). As a next step the data from the KTL statistics will be used to assess the scope of German rehabilitative care to define areas which do not comply with the limits defined in the guideline. The results will be consented with experts from science and clinical practice in order to develop an evidence-based, empirically founded, practicable and acceptable guideline for cardiac rehabilitation.
Coronary Disease↗
Acetyllysine-binding and function of bromodomain-containing proteins in chromatin.
Acetylated histones are generally associated with active chromatin. The bromodomain has recently been identified as a protein module capable of binding to acetylated lysine residues, and hence is able to mediate the recruitment of factors to acetylated chromatin. Functional studies of bromodomain-containing proteins indicate how this domain contributes to the activity of a number of nuclear factors including histone acetyltransferases and chromatin remodelling complexes. Here, we review the characteristics of acetyllysine-binding by bromodomains, discuss associated domains found in these proteins, and address the function of the bromodomain in the context of chromatin. Finally, the modulation of bromodomain binding by neighbouring post-translational modifications within histone tails might provide a mechanism through which combinations of covalent marks could exert control on chromatin function.
Acetyltransferases↗
Antibodies to C-C chemokine receptor 5 in normal human IgG block infection of macrophages and lymphocytes with primary R5-tropic strains of HIV-1.
In the present study, we demonstrate that normal human IgG for therapeutic use (i.v. Ig) contains natural Abs directed against the CCR5 coreceptor for HIV-1. Abs to CCR5 were isolated from i.v. Ig using an affinity matrix consisting of a synthetic peptide corresponding to the N-terminus of CCR5 coupled to Sepharose. Natural anti-CCR5 Abs inhibited the binding of RANTES to macrophages, demonstrating their interaction with the coreceptor of R5-tropic HIV-1. Affinity-purified anti-CCR5 Ig further inhibited infection of lymphocytes and monocytes/macrophages with primary and laboratory-adapted strains of HIV-1, but did not inhibit infection with X4-tropic HIV. Our results suggest that anti-CCR5 Abs from healthy immunocompetent donors may be suitable for development of novel passive immunotherapy regimens in specific clinical settings in HIV infection.
Animals↗
Prevalence of type 2 diabetes in children in Birmingham.
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Adolescent↗
6-hydroxydopamine increases hydroxyl free radical production and DNA damage in rat striatum.
Oxidative damage is considered to be an important factor of 6-hydroxydopamine (6-OHDA) toxicity. To address this issue, microdialysis probes were implanted into the striatum of Wistar rats and perfused with 6-OHDA. Salicylate was included in the perfusion fluid to measure 2,3-dihydroxybenzoic acid (2,3-DHBA) as a marker of hydroxyl radical formation using HPLC with electrochemical detection. Additionally, striatal tissue was analysed for DNA base alterations using gas chromatography-mass spectrometry. 6-OHDA administration resulted in a rapid and substantial 6.6-fold increase in 2,3-DHBA formation and also increased levels of the modified DNA bases 5-hydroxycytosine, hypoxanthine and 2,6-diamino-4-hydroxy-5-formamidopyrimidine. Hydroxyl radical formation and DNA base alterations are early phenomena of 6-OHDA toxicity and provide clues to the processes that may be involved in the initiation of cell death in Parkinson's disease.
Adrenergic Agents↗
Structure-activity investigation of the inhibition of 3-hydroxypyridin-4-ones on mammalian tyrosine hydroxylase.
3-Hydroxypyridin-4-ones are currently one of the main candidates for the development of orally active iron chelators. Small bidentate ligands tend to inhibit iron-containing metalloenzymes and therefore can cause undesirable side effects. A range of 3-hydroxypyridin-4-ones with different R2 substituents was selected for the investigation of the structure-activity relationship between the chemical nature of the ligand and the inhibition of mammalian tyrosine hydroxylase. Results indicated that lipophilicity was the dominant factor in controlling the ability of this class of chelator to inhibit mammalian tyrosine hydroxylase. Ligands with hydrophilic R2 substituents tended to be weak inhibitors. No significant correlation was found in this study between iron-binding affinity, extended R2 chain length, and enzyme inhibitory activity. In contrast, both the LogP values of the entire molecule and of the R2 segment correlated well with inhibitory activity.
Animals↗
Induction of natural autoantibody activity following treatment of human immunoglobulin with dissociating agents.
Treatment of normal polyclonal human IgG and of F(ab')2 fragments of IgG with 6.0 M urea, 1.3 M sodium thiocyanate or with acidic buffers (pH 2.0), resulted in a dramatic and selective enhancement of the preexisting antibody reactivity with self antigens. Enhanced antibody activity revealed by the dissociating agents was inhibited by the addition of an excess of the relevant soluble antigen. Human monoclonal IgG, including four different IgG1m(1) V(H)3+ and V(K)3+ paraproteins differing only in their CDRs, exhibited different changes in reactivity following urea treatment indicating major involvement of CDR sequences. The calculated dissociation constant of the binding reaction of normal IgG to the self antigen actin was 10(-6) M, whether IgG had been treated or not, indicating that the treatment increased the proportion of available self-reactive molecules instead of increasing the affinity of the preexisting natural autoantibodies. Enhanced autoreactivity was not due to aggregation of Ig, unmasking of the antibody site by removal of low MW antigens, nor to the denaturation of natural Id-anti-Id complexes. Taken together, these results suggest that treatment of Ig with dissociating agent results in the exposure of basic polyreactive antibody structures. The enhancement of reactivity may be of relevance in physiology of mucosal immunity and in therapeutic immunomodulation.
Actins↗
Real-time detection of Brucella abortus, Brucella melitensis and Brucella suis.
Real-time PCR-based assays specific for Brucella abortus, Brucella melitensis and Brucella suis were developed. The assays utilize an upstream primer that is derived from 3' end of the genetic element IS 711, whereas the downstream primers and probes are designed from signature sequences specific to a species or a biovar. The PCR reactions were monitored for fluorescence resonance energy transfer by including two adjacent labeled probes that hybridize to the amplicons as they are formed. The upstream probes were labeled with fluorescein at 3' end while Cy5 was attached to the 5' end of the downstream probes. An increase in the ratio of fluorescein to Cy5 fluorescence during the cycling was indicative of positive amplification event. The assays were accomplished in less than 30 min using a LightCycler in real-time mode. The assays were tested on known strains as well as field isolates and were found to be specific for all known biovars of B. abortus, B. melitensis and biovar 1 of B. suis. Therefore, specificity, sensitivity, speed and real-time detection make these assays attractive for use in epidemiological and ecological studies.
Brucella↗
[Status of hearing aid use by children in schools for the hearing impaired and deaf].
To evaluate and possibly improve the hearing aid fittings of children attending the Westphalian School for the Hearing Impaired or the Westphalian School for the Deaf, regular pedaudiologic consulting hours were established at both schools. During a 2-year period, 115 children were examined once, 35 children twice, and 5 children three times. The examinations comprised ear microscopy, audiometry, and a check of the hearing aids with a 0.6-cm3 coupler (children up to 7 years) or 2-cm3 coupler, respectively. The following criteria were used to assess the quality of the hearing aid setting: status of the external auditory canal and middle ear, acceptance of wearing the hearing aid, status of the ear mold, technical status of the hearing aid, and its setting. The results were related to four variables: gender, type of school, age, and mean hearing loss. Overall, just 40.9% of all children showed satisfactory hearing aid performance at the first examination and just 37.1% at the second. A significant influence of the variables on the hearing aid performance was documented for hearing loss only. The higher the hearing loss, the more likely the children were to have good hearing aid status. Analysis of the different parameters revealed that an incorrect setting was the main problem, with a rate of 20.9%; the rate of the other parameters varied from 6.1% to 15.7%. Thus, no parameter was of major relevance to the results. The results of the second examination were poorer in most parameters than those of the first. These alarming results, which are probably not only of regional significance, demonstrate that the hearing aid status of children attending schools for the hearing impaired or for the deaf is in urgent need of improvement.
Adolescent↗
Beta-blockers in syncope: the jury is still out.
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Adrenergic beta-Antagonists↗
The central aromatic amino acid DOPA decarboxylase inhibitor, NSD-1015, does not inhibit L-DOPA-induced circling in unilateral 6-OHDA-lesioned-rats.
The centrally acting aromatic amino acid dopa decarboxylase (AADC) inhibitor, 3-hydroxybenzyl hydrazine (NSD-1015), is widely used to study the neurotransmitter-like actions of L-DOPA. However, the effects of NSD-1015 on L-DOPA-induced motor activity are unclear as both increases and decreases have been reported. We now investigate the effects of NSD-1015 on L-DOPA-induced contralateral circling behaviour in 6-OHDA-lesioned rats and on striatal levels of L-DOPA, 3-O-methyl-DOPA (3-OMD), dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) using microdialysis techniques. NSD-1015 (50-200 mg/kg i.p.) inhibited AADC activity both in the liver and striatum of normal rats. Administration of NSD-1015 (50-200 mg/kg i.p.), delayed the onset of circling produced by administration of L-DOPA (25 mg/kg i.p.) and carbidopa (12.5 mg/kg i. p.), suggesting blockade of central AADC activity. However, the duration of the L-DOPA-induced circling was prolonged and overall no inhibition of circling behaviour occurred. L-DOPA (25 mg/kg i.p.) plus carbidopa (12.5 mg/kg i.p.) increased extracellular levels of L-DOPA, 3-OMD, dopamine, DOPAC and HVA in the 6-OHDA-lesioned striatum. Pretreatment of rats with the central AADC inhibitor, NSD-1015 (100 mg/kg i.p.), potentiated the increase in dialysate levels of L-DOPA and 3-OMD. However, it did not reduce striatal dopamine levels in the 6-OHDA-lesioned hemisphere, which were elevated following L-DOPA administration. The increases in DOPAC and HVA levels were abolished by NSD-1015 pretreatment. These results suggest that, while NSD-1015 blocks central AADC activity, it also acts as a monoamine oxidase inhibitor so maintaining striatal dopamine concentration by reducing dopamine metabolism. NSD-1015, therefore, may not be an appropriate tool for the study of brain AADC activity and for assessing the neuromodulatory role of L-DOPA.
3,4-Dihydroxyphenylacetic Acid↗
Involvement of intrinsic cholinergic and GABAergic innervation in the effect of NMDA on striatal dopamine efflux and metabolism as assessed by microdialysis studies in freely moving rats.
Microdialysis perfusion was used to study the participation of striatal cholinergic and gamma-aminobutyric acid-ergic (GABAergic) neurotransmission in basal and N-methyl-D-aspartate (NMDA) receptor-modulated dopamine release and metabolism in the striatum of the freely moving rat. Reverse dialysis of atropine (1-50 microM) induced a concentration-related increase in dopamine efflux and decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) efflux. (+)-Bicuculline (10-100 microM) similarly increased dopamine efflux, but was without consistent effect on metabolite efflux. Reverse dialysis of NMDA (1 mM) evoked an approximately twofold increase in dopamine efflux and decreased DOPAC and HVA efflux to 30-40% of basal levels. The effect of NMDA on dopamine efflux was completely abolished by coadministration of tetrodotoxin (TTX; 1 microM) or atropine (10 microM), and markedly potentiated (approximately fourfold) by coadministration of (+)-bicuculline (50 microM). The NMDA-induced decrease in dopamine metabolite efflux was inhibited by coadministration of TTX or (+)-bicuculline, but was unaffected by atropine. Our data suggest that dopamine release in the striatum is subject to both cholinergic and GABAergic tonic inhibitory mechanisms mediated through muscarinic and GABAA receptors, respectively. Furthermore, NMDA-stimulated dopamine release also involves obligatory cholinergic facilitation and an inhibitory GABAergic component mediated through these respective receptors.
3,4-Dihydroxyphenylacetic Acid↗
6-hydroxydopamine increases the hydroxylation and nitration of phenylalanine in vivo: implication of peroxynitrite formation.
In the present study, we investigated the effect of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) on hydroxyl free radical and peroxynitrite formation in vivo using D-phenylalanine as a novel mechanistic probe. In vivo microdialysis was carried out in the striatum of freely moving male Wistar rats. The microdialysis probes were perfused with artificial cerebrospinal fluid containing 5 mM D-phenylalanine (flow rate 2 microL/min). After obtaining a stable baseline 6-OHDA was delivered into the striatum via reverse microdialysis for 60 min. HPLC measurements of the effluent were performed using photodiode array detection for determination of phenylalanine derived o-tyrosine and m-tyrosine (as hydroxylation markers) as well as of nitrotyrosine and nitrophenylalanine (as nitration markers). The basal levels of the hydroxylation derived products of phenylalanine were approximately 100-fold higher than those of the nitration derived products. 6-OHDA (0.1, 1, 10 mM) significantly increased o- and m-tyrosine up to nine- and 13-fold, respectively, whereas levels of 3-nitrotyrosine and 4-nitrophenylalanine were significantly increased up to 422- and 358-fold, respectively. The results demonstrate that phenylalanine is a sensitive in vivo marker for 6-OHDA-induced hydroxylation and nitration reactions which are clearly concentration dependent. We conclude that peroxynitrite formation is involved in 6-OHDA-induced neurochemical effects.
Adrenergic Agents↗