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

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

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

Neuropsychological patterns following lesions of the anterior insula in a series of forty neurosurgical patients

In the present study we investigated the effects of lesions affecting mainly the anterior insula in a series of 22 patients with lesions in the left hemisphere (LH), and 18 patients with lesions involving the right hemisphere (RH). The site of the lesion was established by performing an overlap of the probabilistic cytoarchitectonic maps of the posterior insula. Here we report the patients\u2019 neuropsychological profile and an analysis of their pre-surgical symptoms. We found that pre-operatory symptoms significantly differed in patients depending on whether the lesion affected the right or left insula and a strict parallelism between the patterns emerged in the pre-surgery symptoms analysis, and the patients\u2019 cognitive profile. In particular, we found that LH patients showed cognitive deficits. By contrast, the RH patients, with the exception of one case showing an impaired performance at the visuo-spatial planning test were within the normal range in performing all the tests. In addition, a sub-group of patients underwent to the post-surgery follow-up examination