Skin function and skin disorders in Parkinson's disease.

Cutaneous symptoms (seborrhoea and hyperhidrosis) in Parkinson's disease were investigated. In 70 treated patients with Parkinson's disease and 22 control subjects, non-invasive bioengineering methods (sebumetry, corneometry, pH) were carried out on the forehead, sternum and forearm. In addition, concomitant dermatoses and medication were recorded. 18.6% of the patients had seborrhoea on the forehead (>220 microg/cm2), 51.4% showed normal sebum values (100-220 microg/cm2) and 30% a sebostasis (<100 microg/cm2). Males has significantly higher sebum values than females. No relationship between the seborrhoea and the therapy for Morbus Parkinson was found. Patients with hyperhidrosis (n = 36) had significantly lower pH values (p < 0.05) on the forehead than those without hyperhidrosis. 22 patients (31.9%) reported a cold/hot flush and a further 13 (18.8%) had clinical rosacea. Seborrhoea is rare in treated Parkinsonian patients but hyperhidrosis is frequently found. Furthermore, a particular lack of vasostability (flush) appears to be an autonomic dysregulation in the skin related to Morbus Parkinson, which has not been studied to any extent to date.

A new procedure for evaluation of renal function without urine collection in rat.

BACKGROUND: A new procedure to improve the accuracy of inulin assessment and renal glomerular filtration rate (GFR) avoiding urine sampling was compared and validated versus the reference procedure (with urine sampling and Anthrone reaction) in conscious unrestrained male Wistar rats. METHODS: The hemodynamic study consisted of a priming dose of inulin (16 mg/kg) and para-aminohippurate (PAH; 8 mg/kg) followed by an infusion of inulin (36 mg/mL) and PAH (5.8 mg/mL) at a rate of 0.055 mL/min until steady-state conditions were reached (105 min). Inulin concentrations from samples were determined by a new enzymatic assay and Anthrone reaction. PAH concentrations were determined according to the standard method described by Smith et al. RESULTS: A high correlation was found between GFR and renal blood flow (RBF) values calculated using the alternative (without urine sampling) and the reference (with urine sampling) clearance techniques (r = 0.98, P < 0.001, and r = 0.97, P < 0.001, respectively). Moreover, a significant and positive correlation between the values obtained from enzymatic and Anthrone inulin assessments was found (r = 0.99, P < 0.001). Likewise, the values of the 95% confidence interval (mean +/- 2 SD) for the enzymatic inulin assay showed a good agreement with those achieved with Anthrone (1.14 +/- 0.21 and 1.14 +/- 0.19 mL. min-1. 100 g-1 rat body weight, respectively). CONCLUSIONS: This new approach has methodological and experimental advantages with respect to traditional procedures, making it a useful tool, not only for research purposes but also in the clinical setting.

The NOD Idd9 genetic interval influences the pathogenicity of insulitis and contains molecular variants of Cd30, Tnfr2, and Cd137.

Previous analyses of NOD mice have shown that some genes control the development of both insulitis and diabetes, while other loci influence diabetes without reducing insulitis. Evidence for the existence of a gene only influencing diabetes, Idd9 on mouse chromosome 4, is provided here by the development of a novel congenic mouse strain, NOD.B10 Idd9. NOD.B10 Idd9 mice display profound resistance to diabetes even though nearly all develop insulitis. Subcongenic analysis has demonstrated that alleles of at least three B10 genes, Idd9.1, Idd9.2, and Idd9.3 are required to produce Idd9-mediated diabetes resistance. Candidate genes with amino acid differences between the NOD and B10 strains have been localized to the 5.6 cM Idd9.2 interval (Tnfr2, Cd30) and to the 2.0 cM Idd9.3 interval (Cd137).

Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system.

A new quantitative cytometric technique, termed the ArrayScanTM, is described and used to measure NF-kappaB nuclear translocation induced by interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha). The amount of p65 staining is measured in both the nuclei defined by Hoechst 33342 labeling and in the surrounding cytoplasmic area within a preselected number of cells/well in 96-well plates. Using this technique in synchronously activated human chondrocytes or HeLa cells, NF-kappaB was found to move to the nucleus with a half-time of 7-8 min for HeLa and 12-13 min for chondrocytes, a rate in each case about 4-5 min slower than that of Ikappa Balpha degradation. IL-1 receptor antagonist and anti-TypeI IL-1 receptor antiserum on the one hand and anti-TNFalpha and monoclonal anti-TNF receptor 1 antibodies on the other hand could be shown to respectively inhibit IL-1 and TNFalpha stimulation in both cell types. In contrast, a polyclonal anti-TNF receptor 1 antiserum exhibited both a 50% agonism and a 50% antagonism to a TNFalpha stimulation in a dose-dependent fashion, indicating that subtle functional responses to complex agonist and antagonist stimuli could be measured. The effects of different proteasome inhibitors to prevent Ikappa Balpha degradation and subsequent NF-kappaB translocation could also be discriminated; Leu-Leu-Leu aldehyde was only a partial inhibitor with an IC50 of 2 microM, while clastolactacystin beta-lactone was a complete inhibitor with an IC50 of 10 microM. The nonselective kinase inhibitor K252a completely inhibited both IL-1 and TNFalpha stimulation in both cell types with an IC50 of 0.4 microM. This concentration, determined after a 20-min stimulation, was shown to be comparable with that obtained for inhibition of IL-6 production induced by a 100-fold lower IL-1 and TNFalpha concentration measured after 17 h of stimulation. These results suggest that the ArrayScanTM technology provides a rapid, sensitive, quantitative technique for measuring early events in the signal transduction of NF-kappaB.

Glutamine synthetase activity in patients with Parkinson's disease.

According to current concepts, the excitatory amino acid glutamate is involved in the pathogenesis of Parkinson's disease (PD). Overactivity of glutamatergic projection neurons and beneficial effect of antiglutamatergic substances in animal experiments suggest that excess supply of glutamate might contribute to the pathophysiology of PD. Reduced activity of the glutamate metabolizing enzyme glutamine synthetase (GS) leads to decreased uptake of glutamate and thus abundant glutamate. Here we report that PD patients and age-matched controls are comparable with respect to GS activity in peripheral blood mononuclear cells (PBMC). These results imply no systemic dysregulation of the enzyme GS in patients with PD.

Pharmacodynamics of levodopa coadministered with apomorphine in parkinsonian patients with end-of-dose motor fluctuations.

The modification of the pharmacodynamic response to a single oral dose of levodopa/benserazide by the coadministration of the dopamine agonist apomorphine was investigated in parkinsonian patients with end-of-dose motor fluctuations. The relation between levodopa plasma concentrations and motor response was examined in a double-blind, randomized, crossover design in 10 patients with idiopathic Parkinson's disease with end-of-dose motor fluctuations. Oral single-dose challenges with 100 mg of levodopa/25 mg of benserazide were carried out twice in each patient, under coadministration with apomorphine (1 mg/h) or 0.9% saline (placebo) subcutaneously. The sum scores (sigma score) of the Columbia University Rating Scale (CURS) were used as effect parameters for pharmacodynamic assessment. A sigmoidal Emax model was fitted to the data using a semiparametric pharmacokinetic-pharmacodynamic approach. Levodopa pharmacokinetics were not significantly modified by the coadministration of apomorphine. The area under the curve was 1599 +/- 615 ng.ml-1 h. (levodopa + saline) and 1821 +/- 625 ng.ml-1.h (levodopa + apomorphine). Cmax was 1094 +/- 476 ng.ml-1 (levodopa + saline) and 1129 +/- 435 ng.ml-1 (levodopa + apomorphine). Under both experimental regimens, the maximum clinical response to levodopa (Emax) yielded a decrease in the CURS sigma rating of about 20 score points. Estimates of the EC50 of levodopa decreased significantly from 430 +/- 163 ng.ml-1 (levodopa + saline) to 315 +/- 123 ng+ml-1 (levodopa + apomorphine) (95% confidence interval [CI] 0.51 -0.98, point estimator 0.75). The mean duration of the motor response rose from 1.9 +/- 0.5 h (levodopa + saline) to 3.0 +/- 0.9 h (levodopa + apomorphine (95% CI 1.23 to 2.06, point estimator 1.60). Thus, a reduction of the threshold levels for levodopa (EC50) was accompanied by approximately 50% gain in on-phase duration, but not in an increased magnitude of the motor response (Emax).

Soluble HLA class I and class II antigens in patients with multiple sclerosis.

Soluble HLA class I (sHLA-I) and soluble HLA class II (sHLA-II) antigen levels during different stages of disease were investigated in paired serum and cerebrospinal fluid (CSF) samples from 37 patients with multiple sclerosis (MS) using ELISA and Western blot analysis. Soluble HLA-II antigens in the serum of untreated patients with the relapsing-remitting type of MS (RRMS) were found to be significantly elevated in acute relapse as compared to values obtained from patients under steroid treatment, in remission or healthy controls. No significant differences in circulating sHLA-I levels could be detected. In contrast, a trend towards increased intrathecal production of sHLA-I molecules in the CSF was observed in untreated RRMS patients in acute relapse, whereas the levels of soluble HLA-II antigens in the CSF were below the detection limit of the ELISA method. Our observations underline the presence of systemic immune activation in MS patients, as reflected in elevated serum sHLA-II antigen levels, and reveal a dichotomy between sHLA class I and II antigen production in the peripheral blood versus CSF in acute MS. Serial measurements of sHLA-II antigen levels might represent a non-invasive method to assess disease activity in MS patients.

Quantification of IBZM dopamine receptor SPET in de novo Parkinson patients before and during therapy.

A number of neurodegenerative diseases have been evaluated with 123I-iodobenzamide (123I-IBZM) dopamine receptor scintigraphy, including Parkinson's disease. Differential diagnosis is based on the semi-quantitative determination of striatal uptake in the basal ganglia. Seven procedures for calculating basal ganglia uptake were compared and checked statistically in (1) 28 previously untreated de novo parkinsonian patients before and (2) 14 patients after (mean of 9 months) commencement of anti-Parkinson medication. Of the 21 hemi-parkinsonian patients, 16 demonstrated increased uptake contralaterally (mean right-to-left difference = 8%, sensitivity = 76%) using the most robust uptake procedure. The difference in uptake between the affected and contralateral sides (mean = 6%) was significant (P = 0.02). The mean (+/- S.D.) basal ganglia/frontal cortex (BG/FC) ratio was 1.55 +/- 0.14 (attenuation-corrected). Attenuation correction did not affect the relative ratio of basal ganglia uptake (P = 0.01). The anti-Parkinson medication did not result in any significant changes in the BG/FC ratio at follow-up, but responders could be differentiated from non-responders based on initial uptake (mean BG/FC ratio of 1.58 and 1.39 respectively). We conclude that 123I-IBZM can be used routinely to identify which Parkinson patients will benefit from dopaminergic medication.

The impact of migration policy on the labour market performance of migrants: a comparative case study.

PIP: Some anticipated differences were found between the labor market performance of migrant groups in Sweden and Switzerland. However, contrary to the results of studies in other countries, the authors' data suggest that migration policy has had only a small impact upon migrants' labor market performance. In their examination of the impact of migration policy upon the labor market performance of migrants in Sweden and Switzerland, the authors focus upon the income and employment of groups of foreign residents relative to natives and explore sociodemographic characteristics and educational policies. The Swedish and Swiss migration policies differ in their approaches to achieving desired ends. Swiss policy has been economically oriented, considering migrants as merely temporary guests and lacking any explicit integration policy. In contrast, however, Swedish policy stressed humanitarian and political aspects, rejecting migration for economic labor reasons and striving for the long-term integration of foreigners admitted to the country. Relative income performance differences between migrant groups and natives in the two countries were small in 1991, and migrants' performance in the two labor markets appears to have been determined especially by the interplay of microeconomic characteristics of migrants and the microeconomic state and transition of the host country's economy.^ieng

Association of serine protease with the rise of intracellular calcium in cytotoxic T lymphocytes.

The precise role of the granular enzyme A (granzyme A), a serine protease, in the lytic process of cytotoxic T lymphocytes (CTL) is not clear. We have recently constructed a CTL line transfected with the antisense gene of granzyme A (a-GrA). These a-GrA CTL had lower GrA activity as well as decreased lytic activities, as measured by 51Cr and by DNA degradation assays. Furthermore, at low effector:target ratio (1:8) in prolonged lytic assays, they could not lyse targets as rapidly as the control CTL. When we examined their ability to exocytose BLT (CBZ-L-lys-thiobenzyl)-esterase in the presence of anti-CD3 antibody, the a-GrA CTL exocytosed poorly compared to the parental CTL or control transfectant with a CAT gene. Most strikingly, a-GrA cells could not release intracellular stores of Ca2+ in response to anti-CD3 induction, although the Ca2+ flux was normal when they were stimulated with ionomycin. When the parental CTL was treated with a specific benzyllactam inhibitor of BLT-esterase or N-tosyl-L-phenylalanylchloromethyl ketone, the Ca2+ flux induced by anti-CD3 was also suppressed. We propose that granzyme A is involved in the signal transduction pathway that causes the rise of the intracellular calcium.

Unusual course of herpes simplex virus encephalitis after acyclovir therapy.

This is a report on a case of herpes simplex encephalitis (HSE) taking an unusual course after initially successful acyclovir therapy. The etiology of HSE was proven serologically, by repeated detection of herpes simplex virus (HSV)-specific DNA sequences in cerebrospinal fluid (CSF) with polymerase chain reaction (PCR) and was supported by cerebral imaging. After both the neurological symptoms and laboratory findings had improved initially under acyclovir therapy, the patient's clinical condition deteriorated accompanied by a renewed increase in CSF pleocytosis and protein content. Nuclear magnetic resonance (NMR) imaging confirmed the finding of bilateral, mainly temporal lesions compatible with a diagnosis of relapsing HSE. The patient responded well to a second cycle of antiviral therapy but required a third treatment cycle due to renewed deterioration later on. HSV-specific DNA sequences could not be demonstrated in several consecutive CSF samples taken after the first week of illness but increased inflammatory changes typical of HSE were seen on NMR during phases of deterioration. IgM-class antibodies against HSV were detected in CSF 4 weeks after onset of symptoms and stayed positive for at least 7 weeks. Reasons for the repeated deterioration and possible explanations for the absence of HSV DNA in spite of what could be seen as relapses are discussed.

Arginine 206 of the C5a receptor is critical for ligand recognition and receptor activation by C-terminal hexapeptide analogs.

C5a is a 74-amino-acid glycoprotein whose receptor is a member of the rhodopsin superfamily. While antagonists have been generated to many of these receptors, similar efforts directed at family members whose natural ligands are proteins have met with little success. The recent development of hexapeptide analogs of C5a has allowed us to begin elucidation of the molecular events that lead to activation by combining a structure/activity study of the ligand with receptor mutagenesis. Removal of the hexapeptide's C-terminal arginine reduces affinity by 100-fold and eliminates the ability of the ligand to activate the receptor. Both the guanidino side chain and the free carboxyl of the arginine participate in the interaction. The guanidino group makes the energy-yielding contact with the receptor, while the free carboxylate negates "electrostatic" interference with Arg-206 of the receptor. It is the apparent movement Arg-206 induced by this set of interactions that is responsible for activation, since conversion of Arg-206 to alanine eliminates the agonist activity of the hexapeptides. Surprisingly, activation is a nearly energy-neutral event and may reflect the binding process rather than the final resting site of the ligand.

Lamotrigine in Parkinson's disease--a double blind study.

Antiglutamatergic acting substances are considered to be useful tools for the treatment of hypokinesia in animal models for Parkinson's disease (PD). Moreover, most known antiglutamatergic compounds act postsynaptically and are either toxic or weak with regard to their clinical potency. The antiepileptic drug "Lamotrigine (LTG)" inhibits presynaptic glutamate release and may therefore provide a novel approach for PD therapy. Encouraging results from a pilot project led us to establish a placebo controlled trial including 20 patients with PD. The substance was generally well tolerated. There was a significant difference in the investigator's overall assessment of efficacy (6/10 vs. 2/10 improvement; p < 0.05) and a tendency for LTG to exhibit a beneficial effect in some registration parameters, but no significant differences in motor response were found between the two groups. We failed to confirm that LTG mediates a strong antiparkinsonian effect in this small study, but to clearly demonstrate slight or moderate beneficial effects larger groups are required.

Treatment strategies in Parkinson's disease after a quarter century experiences with L-DOPA therapy.

Parkinson's disease is treated in relation to its symptoms and stage in any individual plan of therapy. L-Dopa treatment is the most effective method of therapy and there is no evidence that would prohibit the early application of L-Dopa. The side-effects and motor complications during long-term L-Dopa treatment have led to give preference to combinations of L-Dopa with other anti-Parkinsonian agents. It is still controversial as to which combination of agents sould be used and whether L-Dopa long-term problems demand the initial introduction of a combination therapy. Another open question is whether neuroprotection is possible in Parkinson's disease with the drugs currently available. In advanced stages of Parkinson's disease treatment of concomitand mental symptoms and multifarious disorders of the autonomic nervous system are becoming of increasing significance.

Fluctuations in Parkinson's disease. Pathogenetic significance of levodopa's cerebral pharmacokinetics and pharmacodynamics.

The pathogenetic mechanisms which are responsible for the clinical manifestation of motor-fluctuations are poorly understood. Peripheral pharmacokinetics do obviously not play a significant role. For a better understanding of fluctuations exact knowledge and precise characterization of the levodopa induced motor-response (MR) might be useful. In a number of studies it has been demonstrated that this MR follows the "all or none" rule after a levodopa threshold concentration has been exceeded. Such a threshold is considered to exist in the plasma-compartiment as well as in the cerebral effect-compartiment. The specific character of the MR can be modified by the coadministration of dopamine-agonists. Dopamine-agonists lower the levodopa threshold and they reduce the time-lag between levodopa plasmaconcentration and MR. The duration of the MR can be prolonged but the intensity (amplitude) of the MR cannot be augmented. Most of these data to levodopa pharmacodynamics can be explained by a model which is presented in this paper and which is mainly based on cerebral pharmacokinetic mechanisms.

[Slow-release L-dopa vs. standard L-dopa in Parkinson patients in various stages of the disease. Studies of pharmacokinetics and motor effectiveness]. / L-Dopa- "slow release" vs. L-Dopa- "standard" bei Parkinson-Patienten in unterschiedlichen Krankheitsstadien. Untersuchungen zu Pharmakokinetik und motorischer Wirksamkeit.

Most strategies for the therapeutic management of L-dopa-dependent fluctuations in Parkinsonian patients aim at the continuous stimulation of postsynaptic dopaminergic receptors. Slow release- (s.r.-) preparations of L-dopa appear to present a promising and effective solution for this objective. Clinical experience with the available s.-r.-preparations has lead to the identification of some specific areas for their use. It has not been possible, however, to sharply define their entire range of application. The present study, therefore, compared single dose kinetics and pharmacodynamic effects of three dosages of L-dopa/bensearazid-s.r.-preparation (ASTA H995 125 mg, 250 mg, 275 mg) in a controlled, randomised, 4-fold, double blind, cross over design. The effects were studied in 12 Parkinsonian patients with vs. without motor fluctuations. Motor responses were monitored multimodally (according to the Columbia University Rating Scale, the Purdue Pegboard, and a modified version of the Webster Step Second Test). The pharmacokinetic effectiveness of the s.r.-approach could be demonstrated in both groups. It was possible to ascertain significant differences in kinetics between the various L-dopa-s.r.-dosages and L-dopa standard. No significant difference, however, appeared in the pharmacokinetic characteristic values (Cmax, Tmax, AUC0-->infinity, T1/2) between the fluctuating and non-fluctuating patients. A circumscribed motor effect was demonstrable only for those patients with fluctuations. As expected, motor responses were delayed and lasted longer in these patients after applying the L-dopa-s.r.-dosage. A three times greater dosage of L-dopa-s.r. was required in order to obtain a superior motor effect to the L-dopa-standard-preparation.(ABSTRACT TRUNCATED AT 250 WORDS)