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Biomedical subjects

R Henderson

Publications and source records attributed to R Henderson.

At least 37 records · Page 2Linked to original sources
PubMed2001

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy): an Australian perspective.

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy (CADASIL) is a recently described cause of stroke or stroke-like episodes. It is caused by mutations in the Notch3 gene on chromosome 19p. We sought to demonstrate mutations of the Notch3 gene in Australian patients suspected of having CADASIL. Patients from several families were referred to the study. A diagnosis was determined clinically and by neuroimaging. Those suspected of having CADASIL had sequencing of exons 3 and 4 of the Notch3 gene. Eight patients, two of whom were siblings, were suspected of having CADASIL. Five patients (including the siblings) had mutations. Because of strong clustering of Notch3 mutations in CADASIL, this has potential as a reliable test for the disease in Australian patients.

Aged↗
PubMed2001

Regulation of metallothionein II messenger ribonucleic acid measures exogenous estrogen receptor-beta activity in SAOS-2 and LNCaPLN3 cells.

Estrogen receptor-beta (ERbeta) is a recently discovered member of the steroid hormone superfamily. Because its distribution is distinct from that of the classical estrogen receptor, and it is expressed in several nonclassical estrogen target tissues (e.g. prostate and bladder), its role in mediating the action of estrogen is unclear. One approach to elucidating the function of this receptor is to identify genes that it regulates. Using differential display, we profiled the messenger RNAs regulated by 17beta-estradiol in SAOS-2 and LNCaPLN3 cells overexpressing ERbeta. Follow-up studies used cells expressing either ERalpha or ERbeta. One gene, metallothionein II, was regulated by both receptor subtypes in LNCaPLN3 cells, but only by ERbeta in SAOS-2 cells. Because cycloheximide blocks this response, induction is probably mediated through regulation of at least one other protein. Identification of endogenous genes that are regulated differentially by ERalpha and ERbeta will be valuable tools in elucidating the function of ERbeta and the mechanisms by which these two receptors regulate transcription.

Cycloheximide↗
PubMed2000

Crystallographic analysis of protein conformational changes in the bacteriorhodopsin photocycle.

A variety of neutron, X-ray and electron diffraction experiments have established that the transmembrane regions of bacteriorhodopsin undergo significant light-induced changes in conformation during the course of the photocycle. A recent comprehensive electron crystallographic analysis of light-driven structural changes in wild-type bacteriorhodopsin and a number of mutants has established that a single, large protein conformational change occurs within 1 ms after illumination, roughly coincident with the time scale of formation of the M(2) intermediate in the photocycle of wild-type bacteriorhodopsin. Minor differences in structural changes that are observed in mutants that display long-lived M(2), N or O intermediates are best described as variations of one fundamental type of conformational change, rather than representing structural changes that are unique to the optical intermediate that is accumulated. These observations support a model for the photocycle of wild-type bacteriorhodopsin in which the structures of the initial state and the early intermediates (K, L and M(1)) are well approximated by one protein conformation in which the Schiff base has extracellular accessibility, while the structures of the later intermediates (M(2), N and O) are well approximated by the other protein conformation in which the Schiff base has cytoplasmic accessibility.

Bacteriorhodopsins↗
PubMed2000

Molecular mechanism of vectorial proton translocation by bacteriorhodopsin.

Bacteriorhodopsin, a membrane protein with a relative molecular mass of 27,000, is a light driven pump which transports protons across the cell membrane of the halophilic organism Halobacterium salinarum. The chromophore retinal is covalently attached to the protein via a protonated Schiff base. Upon illumination, retinal is isomerized. The Schiff base then releases a proton to the extracellular medium, and is subsequently reprotonated from the cytoplasm. An atomic model for bacteriorhodopsin was first determined by Henderson et al, and has been confirmed and extended by work in a number of laboratories in the last few years. Here we present an atomic model for structural changes involved in the vectorial, light-driven transport of protons by bacteriorhodopsin. A 'switch' mechanism ensures the vectorial nature of pumping. First, retinal unbends, triggered by loss of the Schiff base proton, and second, a protein conformational change occurs. This conformational change, which we have determined by electron crystallography at atomic (3.2 A in-plane and 3.6 A vertical) resolution, is largely localized to helices F and G, and provides an 'opening' of the protein to protons on the cytoplasmic side of the membrane.

Bacteriorhodopsins↗
PubMed2000

Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes.

The ventromedial nucleus of the hypothalamus (VMH) in mice first emerges as a histologically distinct cell cluster around embryonic day 17 (E17). The earliest known marker for cells destined to form the VMH is the orphan nuclear receptor, steroidogenic factor 1 (SF-1), which can be detected in the hypothalamic primordium by E11. Strikingly, the VMH is absent in newborn SF-1 knockout mice, suggesting that SF-1 is essential for the development of VMH neurons. We reported previously that the VMH can be identified before it emerges as a histologically distinct nucleus (i.e., at E13) by the exclusion of cells that are immunoreactive for both gamma-aminobutyric acid (GABA) and the synthetic enzyme, glutamic acid decarboxylase (GAD67). Subsequently, by E15, the developing VMH is demarcated further by cells that are immunoreactive for neuropeptide Y, estrogen receptor alpha (ERalpha), and galanin. It is noteworthy that the normal exclusion of GABA from the developing VMH is not seen in SF-1 knockout mice, and cells that are immunoreactive for neuropeptide Y, ERalpha, and galanin also are distributed aberrantly in this region. Thus, the absence of SF-1 profoundly affects the cellular architecture of the VMH from early stages in its formation. These data suggest that, directly or indirectly, SF-1 plays important roles in determining the distribution of cells in the mediobasal hypothalamus.

Animals↗
PubMed2000

The three-dimensional structure of halorhodopsin to 5 A by electron crystallography: A new unbending procedure for two-dimensional crystals by using a global reference structure.

Electron microscopy does not, in principle, require highly ordered crystals to determine a high-resolution structure. Nevertheless, crystals of any type help to constrain the molecules into a more limited range of orientations and positions, from which it is easier to carry out structure determination. We describe an improved procedure for determination of crystalline disorder, which we have applied to poorly ordered two-dimensional crystals of the chloride pump halorhodopsin from Halobacterium salinarum. The new image analysis procedure involves the use of a reference projection calculated from a global three-dimensional map to carry out the initial cross-correlation analysis. Coupled with a greater number of images taken with field emission gun microscopes, this has allowed us to calculate a three-dimensional structure for halorhodopsin, in which the seven transmembrane helices and certain molecular features, such as the beta-ionone ring of retinal, are now resolved.

Bacteriorhodopsins↗
PubMed2000

Choice of conditional models in bivariate survival.

We consider bivariate survival problems in which interest is in the conditional distribution of one survival variable given an uncensored observation of the other. The work is motivated by an analysis of time to cancer diagnosis then subsequent survival amongst a group of organ transplant recipients. The effect of conditioning is illustrated for five standard bivariate models. The consequences of adopting a misspecified marginal approach in which the conditioning variable is considered to be a fixed covariate are investigated.

Age Factors↗
PubMed2000

Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2.

BACKGROUND: The indications for pegylated liposomal doxorubicin (doxil) are expanding. We, therefore, wished to assess the safety of delivering doses exceeding 500 mg/m2 of doxil to patients with solid tumors. PATIENTS AND METHODS: Subjects accrued to eight phase I and II protocol studies conducted at two institutions, were assessed for cardiac function at baseline and at specified intervals by MUGA scans. In this retrospective analysis, the findings of 42 patients, from the total of 237 entered, who had reached or exceeded cumulative doses of 500 mg/m2 (range 500-1500 mg/m2) were reviewed. Changes in left ventricular ejection fraction (LVEF), and in clinical cardiac status were analyzed. Six patients, three who had received prior doxorubicin, also underwent endomyocardial biopsies after cumulative doses of 490-1320 mg/m2. RESULTS: None of the 42 patients had clinical congestive heart failure (CHF) secondary to cardiomyopathy. Post doxil MUGA scans were available for 41 of the 42 patients. Five had a drop of 10% or more in LVEF; three of these had received prior doxorubicin. Billingham endomyocardial biopsy scores ranged from 0-1 in five patients, while the sixth had a score of 1.5 after both 900 mg/m2 and 1320 mg/m2 doxil. Of a remaining 195 patients, 1 episode of CHF was recorded in a patient who had received 312 mg/m2 doxil over 120 mg/m2 of mitoxantrone and chest radiation. CONCLUSIONS: Cumulative doses in excess of 500 mg/m2 of doxil appear to carry a considerably lesser risk of cardiomyopathy as judged by serial LVEF's and clinical follow-up, than is generally associated with free doxorubicin. Heart biopsies have provided reassuring data in a small number of patients, even if pretreated with doxorubicin. However, since three doxorubicin pretreated patients were among the five experiencing drops in LVEF, more data are warranted on such patients.

Adult↗
PubMed2000

Healthcare provider characteristics and perceived confidence from HIV/AIDS education.

This study reports findings from six training projects designed to keep health providers up-to-date on emerging developments and approaches in HIV/AIDS care. Participants were 3,779 individuals who described themselves, their professional background, and their specific experience in the HIV/AIDS field. These characteristics were compared with their self-reported confidence in managing clients, counseling clients, providing services, and the training topics. A repeated-measures design examining level and change of confidence showed little support for links between provider characteristics and confidence due to HIV/AIDS training experience. Thus, knowing a provider's background does not necessarily provide diagnostic information about who might most benefit in improved confidence from HIV/AIDS educational training. These results suggest that HIV/AIDS training programs may be targeted broadly-to a wide range of healthcare providers of diverse backgrounds-with little or no impact on overall levels and changes in provider confidence.

Attitude of Health Personnel↗
PubMed2000

Joint modelling of longitudinal measurements and event time data.

This paper formulates a class of models for the joint behaviour of a sequence of longitudinal measurements and an associated sequence of event times, including single-event survival data. This class includes and extends a number of specific models which have been proposed recently, and, in the absence of association, reduces to separate models for the measurements and events based, respectively, on a normal linear model with correlated errors and a semi-parametric proportional hazards or intensity model with frailty. Special cases of the model class are discussed in detail and an estimation procedure which allows the two components to be linked through a latent stochastic process is described. Methods are illustrated using results from a clinical trial into the treatment of schizophrenia.

Journal Article↗
PubMed2000

Intratracheal instillation as an exposure technique for the evaluation of respiratory tract toxicity: uses and limitations.

The evaluation of respiratory tract toxicity from airborne materials frequently involves exposure of animals via inhalation. This provides a natural route of entry into the host and, as such, is the preferred method for the introduction of toxicants into the lungs. However, for various reasons, this technique cannot always be used, and the direct instillation of a test material into the lungs via the trachea has been employed in many studies as an alternative exposure procedure. Intratracheal instillation has become sufficiently widely used that the Inhalation Specialty Section of the Society of Toxicology elected to develop this document to summarize some key issues concerning the use of this exposure procedure. Although there are distinct differences in the distribution, clearance, and retention of materials when administered by instillation compared to inhalation, the former can be a useful and cost-effective procedure for addressing specific questions regarding the respiratory toxicity of chemicals, as long as certain caveats are clearly understood and certain guidelines are carefully followed.

Aerosols↗
PubMed2000

Predictive accuracy and explained variation in Cox regression.

We suggest a new measure of the proportion of the variation of possibly censored survival times explained by a given proportional hazards model. The proposed measure, termed V, shares several favorable properties with an earlier V1 but also improves the handling of censoring. The statistic contrasts distance measures between individual 1/0 survival processes and fitted survival curves with and without covariate information. These distance measures, Dx and D, respectively, are themselves informative as summaries of absolute rather than relative predictive accuracy. We recommend graphical comparisons of survival curves for prognostic index groups to improve the understanding of obtained values for V, Dx, and D. Their use and interpretation is exemplified for a Yorkshire lung cancer study on survival. From this and an overview for several well-known clinical data sets, we show that the likely amount of relative or absolute predictive accuracy is often low even if there are highly significant and relatively strong prognostic factors.

Adult↗
PubMed2000

Trainee characteristics and perceptions of HIV/AIDS training quality.

HIV/AIDS education and training have played a vital role in keeping health providers up to date on emerging developments and approaches. This study reports findings from seven HIV/AIDS education and training projects. Participants in more than 600 training sessions described themselves, their professional background, and their general reasons for taking the training. Immediately following the training, they also rated the quality of their educational experience along several dimensions. Trainee characteristics were related to assessments of training quality, using a regression decision-tree analytic approach. Although effect sizes were generally small, quality ratings of the HIV/AIDS training experiences were associated with certain projects, basic trainee demographic characteristics, professional background, and experience in the HIV field. Greater understanding about participant characteristics can provide clues about how these training experiences are perceived and processed and may inform decision making about instructional HIV/AIDS curricula.

Adult↗