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

Statistical mechanics of an ideal Bose gas in a confined geometry

We study the behaviour of an ideal non-relativistic Bose gas in a three-dimensional space where one of the dimensions is compactified to form a circle. In this case there is no phase transition like that for the case of an infinite volume, nevertheless Bose-Einstein condensation signified by a sudden buildup of particles in the ground state can occur. We use the grand canonical ensemble to study this problem. In particular, the specific heat is evaluated numerically, as well as analytically in certain limits. We show analytically how the familiar result for the specific heat is recovered as we let the size of the circle become large so that the infinite volume limit is approached. We also examine in detail the behaviour of the chemical potential and establish the precise manner in which it approaches zero as the volume becomes large.Comment: 13 pages, 2 eps figures, revtex

Coarse-Graining and Renormalization Group in the Einstein Universe

The Kadanoff-Wilson renormalization group approach for a scalar self-interacting field theor generally coupled with gravity is presented. An average potential that monitors the fluctuations of the blocked field in different scaling regimes is constructed in a nonflat background and explicitly computed within the loop-expansion approximation for an Einstein universe. The curvature turns out to be dominant in setting the crossover scale from a double-peak and a symmetric distribution of the block variables. The evolution of all the coupling constants generated by the blocking procedure is examined: the renormalized trajectories agree with the standard perturbative results for the relevant vertices near the ultraviolet fixed point, but new effective interactions between gravity and matter are present. The flow of the conformal coupling constant is therefore analyzed in the improved scheme and the infrared fixed point is reached for arbitrary values of the renormalized parameters.Comment: 18 pages, REVTex, two uuencoded figures. (to appear in Phys. Rev. D15, July) Transmission errors have been correcte

Analytic approximation and an improved method for computing the stress-energy of quantized scalar fields in Robertson-Walker spacetimes

An improved method is given for the computation of the stress-energy tensor of a quantized scalar field using adiabatic regularization. The method works for fields with arbitrary mass and curvature coupling in Robertson-Walker spacetimes and is particularly useful for spacetimes with compact spatial sections. For massless fields it yields an analytic approximation for the stress-energy tensor that is similar in nature to those obtained previously for massless fields in static spacetimes.Comment: RevTeX, 8 pages, no figure

Study of a Swiss dopa-responsive dystonia family with a deletion in GCH1: redefining DYT14 as DYT5.

OBJECTIVE: To report the study of a multigenerational Swiss family with dopa-responsive dystonia (DRD). METHODS: Clinical investigation was made of available family members, including historical and chart reviews. Subject examinations were video recorded. Genetic analysis included a genome-wide linkage study with microsatellite markers (STR), GTP cyclohydrolase I (GCH1) gene sequencing, and dosage analysis. RESULTS: We evaluated 32 individuals, of whom 6 were clinically diagnosed with DRD, with childhood-onset progressive foot dystonia, later generalizing, followed by parkinsonism in the two older patients. The response to levodopa was very good. Two additional patients had late onset dopa-responsive parkinsonism. Three other subjects had DRD symptoms on historical grounds. We found suggestive linkage to the previously reported DYT14 locus, which excluded GCH1. However, further study with more stringent criteria for disease status attribution showed linkage to a larger region, which included GCH1. No mutation was found in GCH1 by gene sequencing but dosage methods identified a novel heterozygous deletion of exons 3 to 6 of GCH1. The mutation was found in seven subjects. One of the patients with dystonia represented a phenocopy. CONCLUSIONS: This study rules out the previously reported DYT14 locus as a cause of disease, as a novel multiexonic deletion was identified in GCH1. This work highlights the necessity of an accurate clinical diagnosis in linkage studies as well as the need for appropriate allele frequencies, penetrance, and phenocopy estimates. Comprehensive sequencing and dosage analysis of known genes is recommended prior to genome-wide linkage analysis

Method to compute the stress-energy tensor for the massless spin 1/2 field in a general static spherically symmetric spacetime

A method for computing the stress-energy tensor for the quantized, massless, spin 1/2 field in a general static spherically symmetric spacetime is presented. The field can be in a zero temperature state or a non-zero temperature thermal state. An expression for the full renormalized stress-energy tensor is derived. It consists of a sum of two tensors both of which are conserved. One tensor is written in terms of the modes of the quantized field and has zero trace. In most cases it must be computed numerically. The other tensor does not explicitly depend on the modes and has a trace equal to the trace anomaly. It can be used as an analytic approximation for the stress-energy tensor and is equivalent to other approximations that have been made for the stress-energy tensor of the massless spin 1/2 field in static spherically symmetric spacetimes.Comment: 34 pages, no figure

Theorems for asymptotic safety of gauge theories

We classify the weakly interacting fixed points of general gauge theories coupled to matter and explain how the competition between gauge and matter fluctuations gives rise to a rich spectrum of high- and low-energy fixed points. The pivotal role played by Yukawa couplings is emphasised. Necessary and sufficient conditions for asymptotic safety of gauge theories are also derived, in conjunction with strict no go theorems. Implications for phase diagrams of gauge theories and physics beyond the Standard Model are indicated

Antineoplastic activity of idazoxan hydrochloride

Idazoxan hydrochloride (IDA) is a 241 molecular weight imidazoline and adrenoreceptor ligand. It binds to mitochondrial membranes and promotes apoptosis of pancreatic beta cells. Since IDA has not been tested against tumor cells, the purpose of our study was to determine if IDA has antineoplastic activity. We used the conversion of a soluble tetrazolium salt to an insoluble formazan precipitate and differential staining cytotoxicity assays to determine if IDA was cytotoxic to cell lines of murine lung cancer and human prostate cancer, as well as to a variety of fresh human tumor samples. We used flow cytometry to analyze cell death and calreticulin expression. IDA is cytotoxic to both cell lines and against aliquots of specimens of breast, gastric, lung, ovarian and prostate cancers as well as non-Hodgkin’s lymphoma. It produces apoptotic cell death and promotes calreticulin expression, suggesting that IDA might be immunomodulatory in vivo. We anticipate that IDA will be clinically useful in cancer treatment

One-loop λϕ4\lambda \phi^4 theory in Robertson-Walker spacetimes: adiabatic regularization and analytic approximation

The renormalization of a scalar field theory with a quartic self-coupling (a $\lambda \phi^4$ theory) via adiabatic regularization in a general Robertson-Walker spacetime is discussed. The adiabatic counterterms are presented in a way that is most conducive to numerical computations. A variation of the adiabatic regularization method is presented which leads to analytic approximations for the energy-momentum tensor of the field and the quantum contribution to the effective mass of the mean field. Conservation of the energy-momentum tensor for the field is discussed and it is shown that the part of the energy-momentum tensor which depends only on the mean field is not conserved but the full renormalized energy-momentum tensor is conserved as expected and required by the semiclassical Einstein's equation. It is also shown that if the analytic approximations are used then the resulting approximate energy-momentum tensor is conserved. This allows a self-consistent backreaction calculation to be performed using the analytic approximations. The usefulness of the approximations is discussed.Comment: 12 pages in revtex, and no figure