DNA incisions stimulate genetic instability of triplet repeat sequences related to human hereditary neurological diseases

The molecular mechanisms responsible for the expansion and deletion of trinucleotide repeat sequences (TRS) are the focus of our studies. Several hereditary neurological diseases including Huntington's disease, myotonic dystrophy, and fragile X syndrome are associated with the instability of TRS. Using the well defined and controllable model system of Escherichia coli, the influences of three types of DNA incisions on genetic instability of CTG•CAG repeats were studied: DNA double-strand breaks (DSB), single-strand nicks, and single-strand gaps. The DNA incisions were generated in pUC19 derivatives by in vitro cleavage with restriction endonucleases. The cleaved DNA was then transformed into E. coli parental and mutant strains. Double-strand breaks induced deletions throughout the TRS region in an orientation dependent manner relative to the origin of replication. The extent of instability was enhanced by the repeat length and sequence (CTG•CAG vs. CGG•CCG). Mutations in recA and recBC increased deletions, mutations in recF stabilized the TRS, whereas mutations in ruvA had no effect. DSB were repaired by intramolecular recombination, versus an intermolecular gene conversion or crossover mechanism. 30 nt gaps formed a distinct 30 nt deletion product, whereas single strand nicks and gaps of 15 nts did not induce expansions or deletions. Formation of this deletion product required the CTG•CAG repeats to be present in the single-stranded region and was stimulated by E. coli DNA ligase, but was not dependent upon the RecFOR pathway. Models are presented to explain the DSB induced instabilities and formation of the 30 nucleotide deletion product. In addition to the in vitro creation of DSBs, several attempts to generate this incision in vivo with the use of EcoR I restriction modification systems were conducted. ^

Monitoring Neurological disease in Phonation

It is well known that many neurological diseases leave a fingerprint in voice and speech production. The dramatic impact of these pathologies in life quality is a growing concert. Many techniques have been designed for the detection, diagnose and monitoring the neurological disease. Most of them are costly or difficult to extend to primary services. The present paper shows that some neurological diseases can be traced a the level of voice production. The detection procedure would be based on a simple voice test. The availability of advanced tools and methodologies to monitor the organic pathology of voice would facilitate the implantation of these tests. The paper hypothesizes some of the underlying mechanisms affecting the production of voice and presents a general description of the methodological foundations for the voice analysis system which can estimate correlates to the neurological disease. A case of study is presented from spasmodic dysphonia to illustrate the possibilities of the methodology to monitor other neurological problems as well.

Neurological Disease Detection and Monitoring from Voice Production

The dramatic impact of neurological degenerative pathologies in life quality is a growing concern. It is well known that many neurological diseases leave a fingerprint in voice and speech production. Many techniques have been designed for the detection, diagnose and monitoring the neurological disease. Most of them are costly or difficult to extend to primary attention medical services. Through the present paper it will be shown how some neurological diseases can be traced at the level of phonation. The detection procedure would be based on a simple voice test. The availability of advanced tools and methodologies to monitor the organic pathology of voice would facilitate the implantation of these tests. The paper hypothesizes that some of the underlying mechanisms affecting the production of voice produce measurable correlates in vocal fold biomechanics. A general description of the methodological foundations for the voice analysis system which can estimate correlates to the neurological disease is shown. Some study cases will be presented to illustrate the possibilities of the methodology to monitor neurological diseases by voice

Estimating tremor in Vocal Fold Biomechanics for Neurological Disease characterisation

Neurological Diseases (ND) are affecting larger segments of aging population every year. Treatment is dependent on expensive accurate and frequent monitoring. It is well known that ND leave correlates in speech and phonation. The present work shows a method to detect alterations in vocal fold tension during phonation. These may appear either as hypertension or as cyclical tremor. Estimations of tremor may be produced by auto-regressive modeling of the vocal fold tension series in sustained phonation. The correlates obtained are a set of cyclicality coefficients, the frequency and the root mean square amplitude of the tremor. Statistical distributions of these correlates obtained from a set of male and female subjects are presented. Results from five study cases of female voice are also given.

The neurological basis of conscious color perception in a blind patient

We have studied patient PB, who, after an electric shock that led to vascular insufficiency, became virtually blind, although he retained a capacity to see colors consciously. For our psychophysical studies, we used a simplified version of the Land experiments [Land, E. (1974) Proc. R. Inst. G. B. 47, 23–58] to learn whether color constancy mechanisms are intact in him, which amounts to learning whether he can assign a constant color to a surface in spite of changes in the precise wavelength composition of the light reflected from that surface. We supplemented our psychophysical studies with imaging ones, using functional magnetic resonance, to learn something about the location of areas that are active in his brain when he perceives colors. The psychophysical results suggested that color constancy mechanisms are severely defective in PB and that his color vision is wavelength-based. The imaging results showed that, when he viewed and recognized colors, significant increases in activity were restricted mainly to V1-V2. We conclude that a partly defective color system operating on its own in a severely damaged brain is able to mediate a conscious experience of color in the virtually total absence of other visual abilities.

Thalamocortical dysrhythmia: A neurological and neuropsychiatric syndrome characterized by magnetoencephalography

Spontaneous magnetoencephalographic activity was recorded in awake, healthy human controls and in patients suffering from neurogenic pain, tinnitus, Parkinson's disease, or depression. Compared with controls, patients showed increased low-frequency θ rhythmicity, in conjunction with a widespread and marked increase of coherence among high- and low-frequency oscillations. These data indicate the presence of a thalamocortical dysrhythmia, which we propose is responsible for all the above mentioned conditions. This coherent θ activity, the result of a resonant interaction between thalamus and cortex, is due to the generation of low-threshold calcium spike bursts by thalamic cells. The presence of these bursts is directly related to thalamic cell hyperpolarization, brought about by either excess inhibition or disfacilitation. The emergence of positive clinical symptoms is viewed as resulting from ectopic γ-band activation, which we refer to as the “edge effect.” This effect is observable as increased coherence between low- and high-frequency oscillations, probably resulting from inhibitory asymmetry between high- and low-frequency thalamocortical modules at the cortical level.

An unliganded thyroid hormone receptor causes severe neurological dysfunction

Congenital hypothyroidism and the thyroid hormone (T3) resistance syndrome are associated with severe central nervous system (CNS) dysfunction. Because thyroid hormones are thought to act principally by binding to their nuclear receptors (TRs), it is unexplained why TR knock-out animals are reported to have normal CNS structure and function. To investigate this discrepancy further, a T3 binding mutation was introduced into the mouse TR-β locus by homologous recombination. Because of this T3 binding defect, the mutant TR constitutively interacts with corepressor proteins and mimics the hypothyroid state, regardless of the circulating thyroid hormone concentrations. Severe abnormalities in cerebellar development and function and abnormal hippocampal gene expression and learning were found. These findings demonstrate the specific and deleterious action of unliganded TR in the brain and suggest the importance of corepressors bound to TR in the pathogenesis of hypothyroidism.

Ion channel genes and human neurological disease: Recent progress, prospects, and challenges

What do epilepsy, migraine headache, deafness, episodic ataxia, periodic paralysis, malignant hyperthermia, and generalized myotonia have in common? These human neurological disorders can be caused by mutations in genes for ion channels. Many of the channel diseases are “paroxysmal disorders” whose principal symptoms occur intermittently in individuals who otherwise may be healthy and active. Some of the ion channels that cause human neurological disease are old acquaintances previously cloned and extensively studied by channel specialists. In other cases, however, disease-gene hunts have led the way to the identification of new channel genes. Progress in the study of ion channels has made it possible to analyze the effects of human neurological disease-causing channel mutations at the level of the single channel, the subcellular domain, the neuronal network, and the behaving organism.

Summary of proceedings and testimony from the Public Forum for the Development of a National Research Strategy for Neurological and Communicative Disorders /

"June 1, 1979."

National research strategy for neurological and communicative disorders.

"June 1, 1979."

Behavioral and neurological evaluation of workers exposed to carbon disulfide (CS2) /

Mode of access: Internet.

Neuroscience at the new millennium : priorities and plans for the National Institute of Neurological Disorders and Stroke, fiscal years 2000-2001.

"August 1999."

Conference on neurological disorders and commercial drivers. Final report.

Federal Highway Administration, Office of Motor Carriers, Washington, D.C.

Behavioral and neurological effects of methyl chloride : behavioral and neurological evaluation of workers exposed to industrial solvents : methyl chloride /

"Contract no. CDC 99-74-20."

Neurological bulletin. Clinical studies of nervous and mental diseases in the Neurological Department of Columbia University.

Editor: Frederick Tilney.