Parkinson's Disease: Clinical Signs and Symptoms, Neural Mechanisms, Positron Emission Tomography, and Therapeutic Interventions

Parkinson's disease is one of the most frequent neurodegenerative brain diseases. Its time course is slow and is characterized by progressive loss of dopaminergic and other brainstem neurons resulting in malfunctioning of the cerebral neuronal systems responsible for motor functions. The clinical signs are slowness of movement, muscle rigidity and rest-tremor amongst other features. The cause of the disease is unknown, but recently involvement of genetic factors is being researched. Positron emission tomography (PET) allows in vivo determination of striatai dopaminergic activity. This has increased our insight in the pathophysiology of the disease and permits direct study of disease progression at a biochemical level and equally to monitor whether potential neuroprotective interventions are indeed effective. Thus far no drug has emerged but promising substances are currently being studied

Untersuchung eines möglichen neuroprotektiven Effektes der Kainsäure- und Chinolinsäureläsion des Nucleus subthalamicus auf dopaminerge Neurone der Substantia nigra im 6-Hydroxydopamin- und im 3-Nitropropionsäure-Parkinson-Tiermodell der Ratte.

Das idiopathische Parkinson-Syndrom zählt zu den häufigsten neuro¬logischen Erkrankungen. Der ihm zugrundeliegende progressive Verlust dopaminerger nigrostriataler Neurone in der Pars compacta der Substantia nigra und das daraus resultierende Dopamindefizit innerhalb des Striatums führt nach der heutigen Kenntnis der Organi¬sation der Basalganglien zu einer enthemmten Aktivität des Ncl. Subthalamicus und nachfolgend zur Hyperaktivität inhibitorischer GABAerger Neuronen des medialen Pallidumsegments auf Thalamus¬kerngebiete. Somit sinkt die exzitatorische Funktion der Thalamus¬kern¬gebiete auf die motorischen Kortexareale. Neuerdings werden exzitatorische glutamaterge Neurone zwischen dem Ncl. Subthalamicus und der Substantia nigra postuliert, wobei unter Umständen die neurotoxische Eigenschaft des Glutamats auf metabolisch vorgeschädigte dopaminerge Neurone der Substantia nigra bei der Äthiologie des Morbus Parkinson eine Rolle spielen könnte. Schon seit einiger Zeit kommt klinisch die funktionelle Ausschaltung des Ncl. Subthalamicus oder des medialen Pallidumsegments mittels chronischer Hochfrequenzstimulation bzw. die thermokoagulatorische Läsion des medialen Pallidumsegments beim fortgeschrittenen Morbus Parkinson zum Einsatz. Der genaue Wirkmechanismus der oben angeführten Eingriffe ist noch nicht hinreichend geklärt. In der vorliegenden Arbeit wurde der neuroprotektive Effekt von Kainsäure- und Chinolinsäureläsionen des Ncl. Subthalamicus auf dopaminerge Neurone der Pars compacta der Substantia nigra im subakuten 6-Hydroxydopamin- und im 3-Nitropropionsäure-Modell des Morbus Parkinson untersucht. Hierbei konnten die Ergebnisse anderer Arbeitsgruppen nicht gestützt werden, wonach eine Läsion des Ncl. Subthalamicus neuroprotektive Effekte auf die Neuronenpopulationen der Substantia nigra zeigen soll. Eine Wiederholung der Experimente mit größerer Fallzahl erscheint zwingend notwendig, dies insbesondere, weil sich aus den Ergeb¬nissen der Arbeiten entscheidende klinisch-therapeutische Konse¬quenzen mit Folgen für die Prognose der Erkrankten ergeben könnten

Catechol-O-methyltransferase inhibition with tolcapone reduces the "wearing off" phenomenon and levodopa requirements in fluctuating parkinsonian patients.

BACKGROUND: More than 50% of patients with Parkinson's disease develop motor response fluctuations (the "wearing off" phenomenon) after more than five years of levodopa therapy. Inhibition of catechol-O-methyltransferase by tolcapone has been shown to increase levodopa bioavailability and plasma elimination half life, thereby prolonging the efficacy of levodopa. OBJECTIVES: The primary objective was to evaluate the efficacy of tolcapone in reducing "wearing off" in levodopa treated, fluctuating parkinsonian patients. Secondary objectives included assessment of reduction in levodopa requirements, improvement in patients' clinical status, duration of improvements, and tolerability of tolcapone. METHODS: In this multicentre, randomised, double blind, placebo controlled trial, 58 patients received placebo, 60 received 100 mg tolcapone three times daily (tid), and 59 received 200 mg tolcapone tid, in addition to levodopa/benserazide. RESULTS: After three months with 200 mg tolcapone tid, "off" time decreased by 26.2% of the baseline value, "on" time increased by 20.6% (P<O.01 v placebo), and the mean total daily levodopa dose decreased by 122 mg from the baseline dose of 676 mg (P<0.01). These responses were maintained up to nine months. With 100 mg tolcapone tid, "off" time decreased by 31.5% (P<0.05), "on" time increased by 21.3% (P<0.01), and the mean total daily levodopa dose decreased by 109 mg from the baseline dose of 668 mg (P<0.05). With 200 mg tolcapone tid, unified Parkinson's disease rating scale motor and total scores were significantly reduced, and quality of life (sickness impact profile) scores were significantly improved. Both dosages were well tolerated. Dyskinesia was the most often reported levodopa induced adverse event. Diarrhea was the most often reported non-dopaminergic adverse event and the most frequent reason for withdrawal from the study: four patients in the 100 mg tolcapone tid group and six in the 200 mg tid group withdrew because of diarrhea. CONCLUSION: Tolcapone prolongs "on" time in fluctuating parkinsonian patients while allowing a reduction in daily levodopa dosage, thereby improving the efficacy of long term levodopa therapy

Particle dynamics of a cartoon dune

The spatio-temporal evolution of a downsized model for a desert dune is observed experimentally in a narrow water flow channel. A particle tracking method reveals that the migration speed of the model dune is one order of magnitude smaller than that of individual grains. In particular, the erosion rate consists of comparable contributions from creeping (low energy) and saltating (high energy) particles. The saltation flow rate is slightly larger, whereas the number of saltating particles is one order of magnitude lower than that of the creeping ones. The velocity field of the saltating particles is comparable to the velocity field of the driving fluid. It can be observed that the spatial profile of the shear stress reaches its maximum value upstream of the crest, while its minimum lies at the downstream foot of the dune. The particle tracking method reveals that the deposition of entrained particles occurs primarily in the region between these two extrema of the shear stress. Moreover, it is demonstrated that the initial triangular heap evolves to a steady state with constant mass, shape, velocity, and packing fraction after one turnover time has elapsed. Within that time the mean distance between particles initially in contact reaches a value of approximately one quarter of the dune basis length

Neuronal precursor cells with dopaminergic commitment in the rostral migratory stream of the mouse

Neuroblasts born in the subventricular zone of adult mammals migrate via the rostral migratory stream into the granular cell layer or periglomerular layer of the olfactory bulb to differentiate into interneurons. To analyze if new neurons in the granular cell layer or periglomerular layer have different origins, we inserted a physical barrier into the rostral migratory stream, depleted cell proliferation with cytarabine infusions, labeled newborn cells with bromodeoxyuridine, and sacrificed mice after short-term (0, 2, or 14 days) or long-term (55 or 105 days) intervals. After short-term survival, the subventricular zone and rostral migratory stream rapidly repopulated with bromodeoxyuridine(+) cells after cytarabine-induced depletion. Nestin, glial fibrillary acidic protein and the PAX6 were expressed in bromodeoxyuridine(+) cells within the rostral migratory stream downstream of the physical barrier. After long-term survival after physical barrier implantation, bromodeoxyuridine(+) neurons were significantly reduced in the granular cell layer, but bromodeoxyuridine(+) and dopaminergic neurons in the periglomerular layer remained unaffected by the physical barrier. Thus, newborn neurons for the granular cell layer are mainly recruited from neural stem cells located in the subventricular zone, but new neurons for the periglomerular layer with dopaminergic predisposition can rise as well from neuronal stem or precursor cells in the rostral migratory stream

The Computational Complexity of Knot and Link Problems

We consider the problem of deciding whether a polygonal knot in 3-dimensional Euclidean space is unknotted, capable of being continuously deformed without self-intersection so that it lies in a plane. We show that this problem, {\sc unknotting problem} is in {\bf NP}. We also consider the problem, {\sc unknotting problem} of determining whether two or more such polygons can be split, or continuously deformed without self-intersection so that they occupy both sides of a plane without intersecting it. We show that it also is in NP. Finally, we show that the problem of determining the genus of a polygonal knot (a generalization of the problem of determining whether it is unknotted) is in {\bf PSPACE}. We also give exponential worst-case running time bounds for deterministic algorithms to solve each of these problems. These algorithms are based on the use of normal surfaces and decision procedures due to W. Haken, with recent extensions by W. Jaco and J. L. Tollefson.Comment: 32 pages, 1 figur

Anisotropic admixture in color-superconducting quark matter

The analysis of color-superconducting two-flavor deconfined quark matter at moderate densities is extended to include a particular spin-1 Cooper pairing of those quarks which do not participate in the standard spin-0 diquark condensate. (i) The relativistic spin-1 gap Delta' implies spontaneous breakdown of rotation invariance manifested in the form of the quasi-fermion dispersion law. (ii) The critical temperature of the anisotropic component is approximately given by the relation T_c'~ Delta'(T=0)/3. (iii) For massless fermions the gas of anisotropic Bogolyubov-Valatin quasiquarks becomes effectively gapless and two-dimensional. Consequently, its specific heat depends quadratically on temperature. (iv) All collective Nambu-Goldstone excitations of the anisotropic phase have a linear dispersion law and the whole system remains a superfluid. (v) The system exhibits an electromagnetic Meissner effect.Comment: v2: references added, angular dependence of the gap clarified, v3: extended discussion, typo in eq. (5) corrected, version accepted for publication in PR

Meson loop effects in the NJL model at zero and non-zero temperature

We compare two different possibilities to include meson-loop corrections in the Nambu-Jona-Lasinio model: a strict 1/N_c-expansion in next-to-leading order and a non-perturbative scheme corresponding to a one-meson-loop approximation to the effective action. Both schemes are consistent with chiral symmetry, in particular with the Goldstone theorem and the Gell-Mann-Oakes-Renner relation. The numerical part at zero temperature focuses on the pion and the rho-meson sector. For the latter the meson-loop-corrections are crucial in order to include the dominant rho -> pipi-decay channel, while the standard Hartree + RPA approximation only contains unphysical qqbar-decay channels. We find that m_\pi, f_\pi, and quantities related to the rho-meson self-energy can be described reasonably with one parameter set in the 1/N_c-expansion scheme, whereas we did not succeed to obtain such a fit in the non-perturbative scheme. We also investigate the temperature dependence of the quark condensate. Here we find consistency with chiral perturbation theory to lowest order. Similarities and differences of both schemes are discussed.Comment: 51 pages, 18 figures, to be published in Physics of Atomic Nuclei, the volume dedicated to the 90th birthday of A.B. Migdal, error in Eq. 4.22 correcte

Malignancy risk analysis in patients with inadequate fine needle aspiration cytology (FNAC) of the thyroid

Background Thyroid fine needle aspiration cytology (FNAC) is the standard diagnostic modality for thyroid nodules. However, it has limitations among which is the incidence of non-diagnostic results (Thy1). Management of cases with repeatedly non-diagnostic FNAC ranges from simple observation to surgical intervention. We aim to evaluate the incidence of malignancy in non-diagnostic FNAC, and the success rate of repeated FNAC. We also aim to evaluate risk factors for malignancy in patients with non-diagnostic FNAC. Materials and Methods Retrospective analyses of consecutive cases with thyroid non diagnostic FNAC results were included. Results Out of total 1657 thyroid FNAC done during the study period, there were 264 (15.9%) non-diagnostic FNAC on the first attempt. On repeating those, the rate of a non-diagnostic result on second FNAC was 61.8% and on third FNAC was 47.2%. The overall malignancy rate in Thy1 FNAC was 4.5% (42% papillary, 42% follicular and 8% anaplastic), and the yield of malignancy decreased considerably with successive non-diagnostic FNAC. Ultrasound guidance by an experienced head neck radiologist produced the lowest non-diagnostic rate (38%) on repetition compared to US guidance by a generalist radiologist (65%) and by non US guidance (90%). Conclusions There is a low risk of malignancy in patients with a non-diagnostic FNAC result, commensurate to the risk of any nodule. The yield of malignancy decreased considerably with successive non-diagnostic FNAC

Ti-Al composite wires with high specific strength

An alternative deformation technique was applied to a composite made of titanium and an aluminium alloy in order to achieve severe plastic deformation. This involves accumulative swaging and bundling. Furthermore, it allows uniform deformation of a composite material while producing a wire which can be further used easily. Detailed analysis concerning the control of the deformation process, mesostructural and microstructural features and tensile testing was carried out on the as produced wires. A strong grain refinement to a grain size of 250–500 nm accompanied by a decrease in h111i fibre texture component and a change from low angle to high angle grain boundary characteristics is observed in the Al alloy. A strong increase in the mechanical properties in terms of ultimate tensile strength ranging from 600 to 930 MPa being equivalent to a specific strength of up to 223 MPa/g/cm3 was achieved