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Biomedical subjects

P Ridgway

Publications and source records attributed to P Ridgway.

At least 19 recordsLinked to original sources

Occupational exposure to organic solvents and long-term nervous system damage detectable by brain imaging, neurophysiology or histopathology.

The purpose of the present review is to assess the evidence published in scientific literature that industrial organic solvents as a generic group have the ability to induce long-term nervous system damage in workers that can be detected by techniques other than neuropsychological testing. The main body of evidence considered in this review was 40 studies involving the use of brain imaging, neurophysiological testing, gross autopsy or histopathology in groups of workers with long-term solvent exposure. Case reports involving both solvent abuse and occupational exposure, and experimental animal data have also been reviewed as supporting data. A number of the studies in groups of workers provide evidence of the presence of marginal atrophic abnormalities in the brain or deficits in nerve conduction velocity in solvent-exposed workers. However, there are limitations in the design of many of these studies, the strength of association between exposure and effect is not consistently strong, no dose-response relationship can be detected, the reported changes lack specificity and there is no coherence between the human and experimental animal data. Overall, it is not possible to draw reliable conclusions with respect to the presence or absence of nervous system damage related to the common properties of organic solvents.

Animals↗

Statistical evaluation of the revised fixed-dose procedure.

The fixed-dose procedure (FDP) was introduced as OECD Test Guideline 420 in 1992, as an alternative to the conventional median lethal dose (LD50) test for the assessment of acute oral toxicity (OECD Test Guideline 401). The FDP uses fewer animals and causes less suffering than the conventional test, while providing information on the acute toxicity to allow substances to be ranked according to the EU hazard classification system. Recently the FDP has been revised, with the aim of providing further reductions and refinements, and classification according to the criteria of the Globally Harmonized Hazard Classification and Labelling scheme (GHS). This paper describes the revised FDP and analyses its properties, as determined by a statistical modelling approach. The analysis shows that the revised FDP classifies substances for acute oral toxicity generally in the same, or a more stringent, hazard class as that based on the LD50 value, according to either the GHS or the EU classification scheme. The likelihood of achieving the same classification is greatest for substances with a steep dose-response curve and median toxic dose (TD50) close to the LD50. The revised FDP usually requires five or six animals with two or fewer dying as a result of treatment in most cases.

Algorithms↗

Tetracycline-regulated gene expression switch in Xenopus laevis.

Xenopus is a well-characterized model system for the investigation of biological processes at the molecular, cellular, and developmental level. The successful application of a rapid and reliable method for transgenic approaches in Xenopus has led to renewed interest in this system. We have explored the applicability of tetracycline-regulated gene expression, first described by Gossen and Bujard in 1992, to the Xenopus system. By optimizing conditions, tetracycline repressor induced expression of a luciferase reporter gene was readily and reproducibly achieved in both the Xenopus oocyte and developing embryo. This high level of expression was effectively abrogated by addition of low levels of tetracycline. The significance of this newly defined system for studies of chromatin dynamics and developmental processes is discussed.

Animals↗

CAF-1 and the inheritance of chromatin states: at the crossroads of DNA replication and repair.

Chromatin is no longer considered to be a static structural framework for packaging DNA within the nucleus but is instead believed to be an interactive component of DNA metabolism. The ordered assembly of chromatin produces a nucleoprotein template capable of epigenetically regulating the expression and maintenance of the genome. Factors have been isolated from cell extracts that stimulate early steps in chromatin assembly in vitro. The function of one such factor, chromatin-assembly factor 1 (CAF-1), might extend beyond simply facilitating the progression through an individual assembly reaction to its active participation in a marking system. This marking system could be exploited at the crossroads of DNA replication and repair to monitor genome integrity and to define particular epigenetic states.

Animals↗

The binding of a Fos/Jun heterodimer can completely disrupt the structure of a nucleosome.

An important first step in the chromatin remodelling process is the initial binding of a transcriptional activator to a nucleosomal template. We have investigated the ability of Fos/Jun (a transcriptional activator involved in the signal transduction pathway) to interact with its cognate binding site located in the promoter region of the mouse fos-related antigen-2 (fra-2) promoter, when this site was reconstituted into a nucleosome. Two different nucleosome assembly systems were employed to assemble principally non-acetylated or acetylated nucleosomes. The ability of Fos/Jun to interact with an acetylated or an unacetylated nucleosome differed markedly. Fos/Jun bound to an unacetylated nucleosome with only a 4- to 5-fold reduction in DNA binding affinity compared with naked DNA. Strikingly, the binding of Fos/Jun to a single high-affinity site incorporated into an acetylated nucleosome resulted in the complete disruption of nucleosomal structure without histone displacement. Moreover, this disruption was sufficient to facilitate the subsequent binding of a second transcription factor.

Acetylation↗

Transcriptional regulation of the PCNA promoter by p53.

We have examined the ability of p53 to affect transcription from the PCNA promoter in a number of cell types. In HeLa cells, p53 activates the PCNA promoter whereas in CV1, CHO, L929, and Saos-2 cells the same promoter is strongly repressed. By using stepwise deletions of the PCNA promoter, we have identified two potential regions of the promoter which are important for the ability of p53 to activate transcription in HeLa cells.

Animals↗

Residential programs for persons with severe mental illness: a nationwide survey of state-affiliated agencies.

About 1,500 agencies responded to a nationwide survey of community residential programs affiliated with state departments of mental health that was conducted in 1986-87. The agencies served more than 59,000 individuals who had psychiatric disabilities in more than 16,000 residential settings. The results reveal rapid growth in the number of programs since 1980 and the availability of a broad range of residential programs. Group homes and supervised apartments were the most common types of residential programs identified in the survey. The most commonly offered services were social and recreational activities, medication supervision, and on-site crisis intervention. Programs also offered such services as client advocacy and case management. Most program staff did not have professional training in a mental health field.

Adolescent↗

Comparison of outcomes for clients seeking and assigned to supported housing services.

As part of state-supported interventions to reduce risk of rehospitalization, seriously disabled psychiatric patients who had been involuntarily hospitalized twice in the previous three years were assigned to receive supported housing services in an Oregon community. Compared with 22 voluntary clients in the same supported housing program, the 21 involuntary (assigned) clients rated higher on risk factors such as history of suicide attempts, self-neglect, homelessness, and medication noncompliance, The involuntary clients showed a much higher utilization of supported housing services and case management, psychiatric, and shelter services during the nine months after entry into the program, and they had a higher one-year rehospitalization rate. However, they used substantially fewer inpatient days in the six months after entry in the program than in the six months before.

Adult↗

Tachyphylaxis to beta-adrenoceptor agonists in guinea pig airway smooth muscle in vivo and in vitro.

Beta-Adrenoceptor tachyphylaxis was induced by incubating spirally cut guinea pig tracheas with isoproterenol (2.4 x 10(-7) M) for 20 min. This incubation reduced the relaxant effects of catecholamines but not of dibutyryl cyclic AMP, theophylline or sodium nitrite. Tracheas incubated with norepinephrine, phosphodiesterase inhibitors or cyclic nucleotides became tachyphylactic to isoproterenol. Pretreatment with indomethacin prevented induction of tachyphylaxis. Incubation with adenosine, methoxamine or sodium nitrite did not induce beta-adrenoceptor tachyphylaxis. When we gave isoproterenol intramuscularly to guinea pigs, airway sensitivity to aerosolized histamine was unchanged but the toxicity of parenterally administered histamine was increased. A prolonged treatment with isoproterenol reduced airway sensitivity to histamine aerosols; this reduced sensitivity was reversed by indomethacin. Thus, beta-adrenoceptor tachyphylaxis may not explain increased toxicity of parenteral histamine after isoproterenol treatment. Elevated levels of cyclic AMP and an increased synthesis of prostaglandins may result in diminished response to beta-receptor stimulation.

Adrenergic beta-Agonists↗