Search Results - (Author, Cooperation:E. Hirsch)

2018-08-31

Genetics Society of America (GSA)

2160-1836

Biology

2018-09-06

American Chemical Society (ACS)

0002-7863

1520-5126

Chemistry and Pharmacology

2018-05-25

American Physical Society (APS)

1098-0121

1095-3795

Physics

Superfluidity and superconductivity

2013-07-05

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Amino Acid Sequence ; Animals ; COS Cells ; Cercopithecus aethiops ; Class II Phosphatidylinositol 3-Kinases/metabolism ; Clathrin-Coated Vesicles/metabolism ; *Endocytosis ; HEK293 Cells ; HeLa Cells ; Humans ; Molecular Sequence Data ; Phosphatidylinositol Phosphates/*metabolism ; Phosphoric Monoester Hydrolases/metabolism ; Sorting Nexins/metabolism ; Time Factors

2014-06-12

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Enzyme Inhibitors/*pharmacology ; Immune Tolerance/*drug effects ; Neoplasms/*enzymology/*immunology ; Phosphatidylinositol 3-Kinases/*metabolism ; T-Lymphocytes, Regulatory/*drug effects

article

2005

Pädagogik ; Bildungsreform ; USA

Brookings papers on education policy, (2005) S. 175-207, 1096-2719

English

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

We examined the effect of pioglitazone, a peroxisome proliferator-activated receptor-γ (PPARγ)agonistofthethiazolidinedione class, on dopaminergic nerve cell death and glial activation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. The acute intoxication of C57BL/6 mice with MPTP led to nigrostriatal injury, as determined by tyrosine hydroxylase (TH) immunocytochemistry, and HPLC detection of striatal dopamine and metabolites. Damage to the nigrostriatal dopamine system was accompanied by a transient activation of microglia, as determined by macrophage antigen-1 (Mac-1) and inducible nitric oxide synthase (iNOS) immunoreactivity, and a prolonged astrocytic response. Orally administered pioglitazone (∼ 20 mg/kg/day) attenuated the MPTP-inducedglialactivation and prevented the dopaminergic cell loss in the substantia nigra pars compacta (SNpc). In contrast, there was little reduction of MPTP-induced dopamine depletion, with no detectable effect on loss of TH immunoreactivity and glial response in the striatum of pioglitazone-treated animals. Low levels of PPARγ expression were detected in the ventral mesencephalon and striatum, and were unaffected by MPTP or pioglitazone treatment. Since pioglitazone affects primarily the SNpc in our model, different PPARγ-independent mechanisms may regulate glial activation in the dopaminergic terminals compared with the dopaminergic cell bodies after acute MPTP intoxication.

Electronic Resource

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: Iron is abnormally accumulated in the substantia nigra pars compacta of patients with Parkinson's disease (PD). Because neuronal and glial iron uptake seems to be mediated by the binding of ferrotransferrin to a specific high-affinity receptor on the cell surface, the number of transferrin receptors could be altered in this disease. The regional distribution of specific binding sites for human 125I-diferric transferrin has been studied in the mesencephalon, on cryostat-cut sections from autopsy brains of control subjects and parkinsonian patients by in vitro autoradiography. Densities of binding sites were highest in the central gray substance (˜10 fmol/mg of tissue equivalent), intermediate in the catecholaminergic cell group A8, superior colliculus, and ventral tegmental area, and almost nonexistent in the substantia nigra. The density of 125I-transferrin binding sites was not significantly different between parkinsonian and control brains in any region analyzed. These results show that in the mesencephalon the regional density of transferrin binding sites is lowest in the dopaminergic cell groups, which are the most vulnerable to PD, and suggest that iron does not accumulate through an increased density of transferrin receptors at the level of the substantia nigra.

Electronic Resource

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: Parkinson's disease is characterized by massive degeneration of the melanized dopaminergic neurons in the substantia nigra. The functional capacity of the surviving nigral neurons is affected, as indicated by the subnormal levels of tyrosine hydroxylase (TH) mRNA in these neurons and the presence in the parkinsonian mesencephalon of melanized neurons lacking TH immunoreactivity. This is apparently in contradiction with the known overactivity of dopamine synthesis and release that occurs in the remaining dopaminergic terminals. To test the ability of the surviving neurons to express TH protein, a semiquantitative immunocytochemical method was developed. The relative amounts of TH were estimated with a computer-assisted image analysis system in the dopaminergic neurons of representative mesencephalic sections of control and parkinsonian brains and for comparison in brains from patients with Alzheimer's disease. In control brains, the mean TH content per neuron differed from one subject to another and between the different dopaminergic cell groups of the mesencephalon in the same subject. Within a given dopaminergic region, the level of TH was variable among neurons. In patients with Parkinson's disease, the ratio of TH protein content per neuron in the substantia nigra by reference to that of the central gray substance was reduced. In patients with Alzheimer's disease, the amount of TH was selectively reduced in the remaining dopaminergic neurons of the ventral tegmental area, a region characterized by a loss in dopaminergic neurons. The decrease in cellular TH content might therefore be related to the presence of the neurodegenerative process in the area considered. In patients with Parkinson's disease, the incapacity of the surviving neurons to express normal TH levels may reduce the efficiency of the hyperactivity mechanisms that develop in the remaining striatal dopaminergic terminals.

Electronic Resource

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: The contribution of neuromelanin (NM) to the pathogenesis of Parkinson's disease (PD) has long been suspected. In particular, a correlation has been reported between the estimated cell loss in the mesencephalic dopaminergic cell groups and the percentage of NM-pigmented neurons in these cell groups. To test whether the amount of pigment per cell is a critical factor or whether the presence of NM within a neuron is sufficient to account for the degeneration of dopaminergic neurons, the NM content was measured in each neuron from representative sections throughout the ventral mesencephalon of four control subjects and four patients with PD. Intraneuronal NM was quantified by a densitometric method, using known amounts of synthetic melanin as standards. In control brains, the distribution of melanized neurons in the nigral complex showed a high proportion of lightly melanized neurons in the ventral tegmental area and the pars α and γ of the substantia nigra (SN), whereas heavily melanized neurons were mostly located in the pars β and lateralis of the SN. An inverse relationship was observed between the percentage of surviving neurons in PD compared with controls and the amount of NM they contain, suggesting that the vulnerability of the dopaminergic neurons is related to their NM content. Factors other than NM may be involved in the differential vulnerability of catecholaminergic neurons in PD. In particular, the constant topography of the cell loss suggests that cell position within the nigral complex is a key factor.

Electronic Resource

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Abstract: The levels of different elements were studied by x-ray microanalysis in the substantia nigra and the central gray substance of patients with Parkinson's disease, progressive supranuclear palsy, and matched controls. In control brains, only iron, potassium, silicium, sodium, sulfur, and zinc were within the limit of detection of the technique. The abundance of each element was different, but their respective concentrations in the two brain regions were similar, except for sulfur levels which were higher on neuromelanin aggregates in the substantia nigra than in nigral regions lacking neuromelanin, and in the central gray substance. In Parkinson's disease, but not in progressive supranuclear palsy, nigral iron levels increased in regions devoid of neuromelanin and decreased on neuromelanin aggregates, but were unchanged in the central gray substance, when compared to control values. Concentrations of the other elements in the central gray substance and substantia nigra were not different from controls in brains from patients with Parkinson's disease and progressive supranuclear palsy. Analysis of Lewy bodies in the parkinsonian substantia nigra revealed high levels of iron and the presence of aluminum. Metal abundance was not affected in progressive supranuclear palsy, in spite of the nigral cell death. This suggests that the increased iron levels and the detection of aluminum observed in Parkinson's disease are not solely the consequence of the neuronal degeneration.

Electronic Resource

1471-4159

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Huntington's disease is an autosomal dominant disorder with degeneration of medium size striatal neurones. As the disease evolves, other neuronal populations are also progressively affected. A transgenic mouse model of the disease (R6/2) that expresses exon 1 of the human Huntington gene with approximately 150 CAG repeats has been developed, but GABA concentrations are reported to be normal in the striatum of these animals. In the present study, we analysed the status of GABAergic systems by means of glutamic acid decarboxylase (GAD)67 mRNA in situ hybridization in the brain of R6/2 transgenic mice and wild-type littermates. We show that GAD67 expression is normal in the striatum, cerebellum and septum but decreased in the frontal cortex, parietal cortex, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata of R6/2 mice. These data, which may, in part, account for the behavioural changes seen in these animals, indicate that at 12.5 weeks of age the pathological features seen in the mice differ from those seen in humans with Huntington's disease.

Electronic Resource

1468-2982

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

The efficacy and safety of long-acting propranolol (LA.P), 160 mg once-daily, in the prophylactic treatment of migraine have been tested against placebo in a multicentric, double-blind, randomized study. The two groups are compared in a parallel manner over a treatment period of 12 weeks, following a 4-week placebo run-in period. Fifty-five of the 74 patients who entered the trial were included at the end of the run-in period. Forty-one patients completed the study. None of the 14 patients who withdrew from the study did so because of side effects. The statistical analysis was done according to the “intention to treat” principle. LA.P was significantly more effective than placebo in reducing the frequency of migraine attacks (p=0.01 by variance analysis). LA.P reduced the average number of monthly crises by 48% on day 84. There was a slight but significant reduction of the systolic blood pressure and heart rate in the erect position, but there was no significant difference between LA.P and placebo regarding either the number of complaints or the number of side effects elicited out of a 17-item questionnaire. None of the observed side effects led to a withdrawal from treatment.

Electronic Resource

1749-6632

Blackwell Publishing Journal Backfiles 1879-2005

Natural Sciences in General

Electronic Resource

1460-9568

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

The pathophysiology of parkinsonian tremor remains a matter of debate with two opposing hypotheses proposing a peripheral and a central origin, respectively. A central origin of tremor could arise either from a rhythmic activity of the internal segment of the globus pallidus (GPi) or from a structure such as the thalamus, outside the basal ganglia. In this study, single-unit recordings were performed in three 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys within the GPi and within three territories of the motor thalamus (delimited by their afferent inputs from the GPi, the substantia nigra and the cerebellum, respectively). For each recorded neuron, we compared the variations in firing rate and pattern in tremor and no tremor periods. Tremor either occurred spontaneously or was induced by external stimulation. When the animals entered into a tremor period we observed: (i) an increase in the mean firing rate in about half of the recorded neurons of the motor thalamus; and (ii), a change from an irregular to a rhythmic discharge within the range of tremor frequency (5–7 Hz) in about 10% of the recorded neurons of the motor thalamus (pallidal and cerebellar territories) and the GPi. Most of the thalamic neurons that exhibited a rhythmic discharge during tremor were found to be sensitive to external stimulation. Because the changes in firing rate occurred predominantly in the motor thalamus and not in the GPi, and because a fast rhythmic discharge of 10–15 Hz was frequently observed in the GPi and not in the motor thalamus, we conclude that thalamic activity is not a simple reproduction of basal ganglia output. Moreover, we suggest that thalamic processing of basal ganglia outputs could participate in the genesis of tremor, and that this thalamic processing could be influenced by sensory inputs and/or changes in attentional level elicited by external stimulation.

Electronic Resource

1460-9568

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.

Electronic Resource

1460-9568

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

The effects of nigrostriatal denervation and L-dopa therapy on GABAergic neurons were analysed in patients with Parkinson's disease and in monkeys rendered parkinsonian by MPTP intoxication. The expression of the messenger RNA coding for the 67 kDa isoform of glutamic acid decarboxylase (GAD67 mRNA), studied by quantitative in situ hybridization, was used as an index of the GABAergic activity of the striatal neurons. A significant increase in GAD67 mRNA expression, generalized to all GABAergic neurons, was observed in MPTP-treated monkeys compared to control monkeys in the putamen and caudate nucleus (+44 and +67% respectively), but not in the ventral striatum. L-Dopa therapy significantly reduced GAD67 mRNA expression in the putamen and caudate nucleus to levels similar to those found in control monkeys. However, the return to normal of GAD67 mRNA expression was not homogeneous across all neurons since it was followed by an increase of labelling in one subpopulation of GABAergic neurons and a decrease in another. These data suggest that in MPTP-treated monkeys the degeneration of nigrostriatal dopaminergic neurons results in a generalized increase in GABAergic activity in all the GABAergic neurons of the striatum, which is partially reversed by L-dopa therapy. As the expression of GAD67 mRNA is less intense in the ventral than in the dorsal striatum, this increase in striatal GABAergic activity may be related to the severity of nigrostriatal denervation. In parkinsonian patients who had been chronically treated with L-dopa, GAD67 mRNA expression was significantly decreased in all GABAergic neurons, in the caudate nucleus (by 44%), putamen (by 43.5%) and ventral striatum (by 26%). The opposite variation of GAD67 mRNA in patients with Parkinson's disease, compared with MPTP-treated monkeys, might be explained by the combination of chronic nigrostriatal denervation and long-term L-dopa therapy.

Electronic Resource

0093-1896

General, Interdisciplinary

CRITICAL RESPONSE

0093-1896

General, Interdisciplinary

0043-8006

English, American Studies