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Biomedical subjects

K Ritchie

Publications and source records attributed to K Ritchie.

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

Caveolae and the caveolins in human disease.

There has been an exponential growth in caveolae research since the early 1990s. The caveolae membrane system comprises unique lipid and protein domains, and fulfills a role in a wide range of processes. At the plasma membrane caveolae serve to compartmentalise and integrate a wide range of signal transduction processes. A key structural and functional protein for caveolae is caveolin. Caveolin proteins possess a 'scaffolding' domain which for caveolins-1 and -3 appear central to many of the reported signal regulation functions for caveolae. Caveolae or caveolin protein are increasingly implicated in the molecular pathology of a number of diseases. Opportunities exist for basic and applied investigators working within the pharmaceutical sciences to exploit the caveolae membrane system to identify novel pharmacological targets and therapeutic strategies, including the delivery of pharmacologically active caveolin based peptides.

Caveolae↗
PubMed2001

Classification criteria for mild cognitive impairment: a population-based validation study.

OBJECTIVE: To evaluate the predictive validity and temporal stability of diagnostic criteria for mild cognitive impairment (MCI). BACKGROUND: MCI has been proposed as a nosologic entity referring to elderly persons with subclinical cognitive deficits due to incipient dementia. Classification criteria, which have been derived from small, selected clinical groups, are currently disputed, and have not yet been assessed within the general population. METHODS: Subjects meeting current criteria for MCI and also age-associated cognitive decline (AACD-a similar concept that is assumed to be related to normal cognitive aging processes rather than incipient dementia) were identified within each of three waves of a longitudinal population study, which included a standardized neurologic examination. RESULTS: In the general population, the prevalence of MCI was estimated to be 3.2% and AACD 19.3%. MCI was a poor predictor of dementia within a 3-year period, with an 11.1% conversion rate. Subjects with MCI also constituted an unstable group, with almost all subjects changing category each year. Discriminant function analysis failed to isolate a homogeneous clinical group. Subjects classified as AACD, contrary to the theoretical assumptions underlying the disorder, represented a more stable group, with a 28.6% conversion rate to dementia over 3 years (relative risk = 21.2). CONCLUSION: MCI criteria perform poorly when applied to a representative population sample. The authors propose modifications to current diagnostic criteria to increase their capacity to detect incipient dementia.

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PubMed2001

Current concepts in mild cognitive impairment.

The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.

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PubMed2001

Disability and mild cognitive impairment: a longitudinal population-based study.

OBJECTIVE: To determine whether mild cognitive deficit is associated with parallel changes in ability to perform activities of daily living. BACKGROUND: While considerable research has been conducted on the effect of senile dementia and other neurodegenerative disorders on ability to perform everyday activities, little is known about the much larger group of elderly persons suffering from mild cognitive deficits. METHODS: Disability prevalence was estimated in 368 persons over the age of 65 years recruited from the general population via a general practitioner network. Subjects were followed over a 3-year period using computerized cognitive assessment and observations of everyday functioning. Standardized neurological assessment in the third year permitted the identification of subjects who have evolved towards dementia. RESULTS: An overall disability prevalence was found in the general population of 26.3%, with 30.8% in subjects with sub-clinical cognitive impairment. Longitudinal follow-up showed cognitive decline over time without dementia to be paralleled by changes in activity performance, with visuospatial deficits having the most marked effect on overall functioning. High intelligence quotient (IQ) and education are seen to reduce the degree of activity loss, but only when senile dementia is not present. CONCLUSIONS: Difficulties in the performance of everyday activities were found more frequently in non-demented subjects with mild cognitive deficits than in the general population. High pre-morbid levels of ability are seen to have a protective effect. A diagnosis of dementia should not therefore be required by persons with cognitive impairment applying for home help.

Activities of Daily Living↗
PubMed2001

Elastic thickness compressibilty of the red cell membrane.

We have used an ultrasensitive force probe and optical interferometry to examine the thickness compressibility of the red cell membrane in situ. Pushed into the centers of washed-white red cell ghosts lying on a coverglass, the height of the microsphere-probe tip relative to its closest approach on the adjacent glass surface revealed the apparent material thickness, which began at approximately 90 nm per membrane upon detection of contact (force approximately 1-2 pN). With further impingement, the apparent thickness per membrane diminished over a soft compliant regime that spanned approximately 40 nm and stiffened on approach to approximately 50 nm under forces of approximately 100 pN. The same force-thickness response was obtained on recompression after retraction of the probe, which demonstrated elastic recoverability. Scaled by circumferences of the microspheres, the forces yielded energies of compression per area which exhibited an inverse distance dependence resembling that expected for flexible polymers. Attributed to the spectrin component of the membrane cytoskeleton, the energy density only reached one thermal energy unit (k(B)T) per spectrin tetramer near maximum compression. Hence, we hypothesized that the soft compliant regime probed in the experiments represented the compressibility of the outer region of spectrin loops and that the stiff regime < 50 nm was the response of a compact mesh of spectrin backed by a hardcore structure. To evaluate this hypothesis, we used a random flight theory for the entropic elasticity of polymer loops to model the spectrin network. We also examined the possibility that additional steric repulsion and apparent thickening could arise from membrane thermal-bending excitations. Fixing the energy scale to k(B)T/spectrin tetramer, the combined elastic response of a network of ideal polymer loops plus the membrane steric interaction correlated well with the measured dependence of energy density on distance for a statistical segment length of approximately 5 nm for spectrin (i.e., free chain end-to-end length of approximately 29 nm) and a hardcore limit of approximately 30 nm for underlying structure.

Biomechanical Phenomena↗
PubMed2001

Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly.

BACKGROUND: Anaesthesia could provoke persistent alterations in specific cognitive domains in the elderly where ageing-related neuronal changes may exacerbate pharmacotoxic effects. AIMS: To evaluate anaesthesia effects on the incidence of cognitive dysfunction after orthopaedic surgery in elderly patients. METHOD: A total of 140 patients over the age of 64 years completed a full range of computerised cognitive tests. The study takes into account effects of pre-operative cognitive dysfunction, depressive symptomatology and ability to perform activities of daily living. RESULTS: Postoperative cognitive decline persisted for up to 3 months in 56% of subjects. Dysfunction was limited to verbal, visuo-spatial and semantic abilities and secondary and implicit memory. Age, low educational level, pre-operative cognitive impairment or depression are risk factors. CONCLUSIONS: Cognitive functions are not equally affected, type of impairment being determined by the risk factors described above and anaesthesia type.

Activities of Daily Living↗
PubMed2001

Discrepancies between apolipoprotein E phenotyping and genotyping in the elderly.

We estimated the frequencies of phenotype (isoelectric focusing; IEF) vs. genotype (PCR/Hhal) discordance in a sample of an aged population (> 65 years). Both phenotype and genotype techniques have been used in the study of apolipoprotein E (apoE) polymorphism in 125 elderly subjects. The discordance between phenotype and genotype was unresolved in 11 (8.8%) of the 125 unrelated subjects studied. We observed a significant association between the presence of the E4 allele and both Alzheimer's disease (chi2 = 13, p < 0.001) and increased cholesterol concentration (Mann Whitney, p < 0.03). These relationships were not affected by the techniques used. Our results indicate that transcriptional modulation and post-transductional modifications in normal ageing and in aged-related diseases may explain in part discrepancies between gene analysis and protein characterisation.

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PubMed2000

Gastric-juice ammonia assay for diagnosis of Helicobacter pylori infection and the relationship of ammonia concentration to gastritis severity.

OBJECTIVES: To determine the test characteristics of gastric-juice ammonia concentration as measured by an ion-selective electrode and a rapid ammonia detection device for the diagnosis of Helicobacter pylori infection and to assess the relationship between gastric-juice ammonia concentration and the severity of gastritis. METHODS: Patients undergoing upper endoscopy had collection of gastric juice that was tested for ammonia using an ion-selective electrode and a rapid ammonia assay device that uses a pH-indicating membrane. A receiver operating characteristic curve was calculated for ammonia concentration. Severity of gastritis was graded using the Sydney classification (1) and correlated to gastric-juice ammonia concentration. Patients also underwent H. pylori testing by IgG serology, rapid urease testing, and histological special stain. Ammonia testing results were compared with a reference standard of two of three positive tests and with a second reference standard of a positive serology. RESULTS: 73 patients underwent endoscopy and collection of gastric juice. The receiver operating characteristic curve indicated an optimal cutoff value of 5 mM, yielding a sensitivity of 67%, specificity of 93%, positive predictive value of 67%, and negative predictive value of 93% (compared with the combined reference standard). The rapid NH3-testing device yielded a sensitivity of 83%, specificity 63%, positive predictive value 31%, and negative predictive value 95%. The severity of neutrophilic (p = 0.001) and mononuclear cell (p = 0.003) infiltration were significantly correlated with gastric-juice ammonia concentration. CONCLUSIONS: Measurement of gastric-juice ammonia concentration by ion-selective electrode or rapid detection device is a relatively insensitive and nonspecific means of H. pylori diagnosis. Gastritis severity increases with gastric-juice ammonia concentration.

Ammonia↗
PubMed2000

[Anesthesia and postoperative cognitive dysfunction in the elderly: a review of clinical and epidemiological observations].

Amnesic effects of anesthesia were first reported two hundred years ago, but the term postoperative cognitive dysfunction (POCD) has appeared only recently, covering a larger range of neuropsychological modifications resulting from surgical intervention. The clinical description of POCD is highly variable, ranging from concentration impairment to delirium. Significant short-term POCD is common in elderly persons, and can persist several months, varying both in time and intensity and affecting the full-range of cognitive functions (visual and auditory attention, primary and secondary memory, implicit memory, and visuospatial functioning). Incidence rates vary widely according to surgery type but also between studies for a given surgical procedure, as a result of methodological difficulties and limitations. Variability is largely attributable to the absence of a standardized POCD definition, the heterogeneity of procedures to measure cognitive deficits and the methods used for statistical analyses, but is also related to the disparity in targeted populations. The wide variation in study design and target populations precludes the application of formal meta-analysis procedures. We review the definition, epidemiology, etiology, pathophysiology and the clinical and public health implications of POCD. The effects of anesthetics are described in relation to ageing-related physiological changes. It is concluded that the complex interaction of etiological factors makes it difficult to determine at this point of time to what extent POCD may be attributed specifically to anesthetic agents.

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PubMed1999

Energy landscapes of receptor-ligand bonds explored with dynamic force spectroscopy.

Atomic force microscopy (AFM) has been used to measure the strength of bonds between biological receptor molecules and their ligands. But for weak noncovalent bonds, a dynamic spectrum of bond strengths is predicted as the loading rate is altered, with the measured strength being governed by the prominent barriers traversed in the energy landscape along the force-driven bond-dissociation pathway. In other words, the pioneering early AFM measurements represent only a single point in a continuous spectrum of bond strengths, because theory predicts that these will depend on the rate at which the load is applied. Here we report the strength spectra for the bonds between streptavidin (or avidin) and biotins-the prototype of receptor-ligand interactions used in earlier AFM studies, and which have been modelled by molecular dynamics. We have probed bond formation over six orders of magnitude in loading rate, and find that the bond survival time diminished from about 1 min to 0.001 s with increasing loading rate over this range. The bond strength, meanwhile, increased from about 5 pN to 170 pN. Thus, although they are among the strongest noncovalent linkages in biology (affinity of 10(13) to 10(15) M(-1)), these bonds in fact appear strong or weak depending on how fast they are loaded. We are also able to relate the activation barriers derived from our strength spectra to the shape of the energy landscape derived from simulations of the biotin-avidin complex.

Biotin↗
PubMed1999

Prodromal cognitive disorder in Alzheimer's disease.

INTRODUCTION: To trace the prodromal evolution of Alzheimer's disease using a comprehensive computerized cognitive battery and an evaluation of performance of everyday activities. MATERIALS AND METHODS: A general population cohort of 397 normal elderly persons hypothesized to have an increased risk of developing Alzheimer's disease was examined over a 3-year period. Twenty-two subjects developed AD in the third year and their performance was compared retrospectively with 150 subjects who had remained free of senile dementia and other psychiatric disorders throughout the period of the study. RESULTS: Adjusting for effects of age, education and incident illness, significant differences were found between the two groups on a wide range of tests 2 years before diagnosis. For half of these tests the decline was largely limited to persons with low levels of education. Education effects closer to the time of diagnosis were limited to a small number of verbal tasks. CONCLUSION: Patterns of cognitive impairment may be detected in cases of AD 2 years before formal clinical diagnosis, although high education level prolongs competence, principally on verbal tasks. The results suggest that a number of brief cognitive tests may have face validity and high discriminability independent of education level in the evaluation of cognitive complaints in early stage AD in the general practice setting.

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PubMed1999

Strength of a weak bond connecting flexible polymer chains.

Bond dissociation under steadily rising force occurs most frequently at a time governed by the rate of loading (Evans and Ritchie, 1997 Biophys. J. 72:1541-1555). Multiplied by the loading rate, the breakage time specifies the force for most frequent failure (called bond strength) that obeys the same dependence on loading rate. The spectrum of bond strength versus log(loading rate) provides an image of the energy landscape traversed in the course of unbonding. However, when a weak bond is connected to very compliant elements like long polymers, the load applied to the bond does not rise steadily under constant pulling speed. Because of nonsteady loading, the most frequent breakage force can differ significantly from that of a bond loaded at constant rate through stiff linkages. Using generic models for wormlike and freely jointed chains, we have analyzed the kinetic process of failure for a bond loaded by pulling the polymer linkages at constant speed. We find that when linked by either type of polymer chain, a bond is likely to fail at lower force under steady separation than through stiff linkages. Quite unexpectedly, a discontinuous jump can occur in bond strength at slow separation speed in the case of long polymer linkages. We demonstrate that the predictions of strength versus log(loading rate) can rationalize conflicting results obtained recently for unfolding Ig domains along muscle titin with different force techniques.

Animals↗
PubMed1999

Quality-of-life assessment in the old using the WHOQOL 100: differences between patients with senile dementia and patients with cancer.

INTRODUCTION: The measurement of quality of life is an increasingly important issue, particularly in regard to treatment of severe and chronic diseases. The aim of this pilot study was to assess potentially divergent profiles of quality of life in persons with two different pathologies: moderate dementia and cancer. METHOD: This pilot study was carried out in the neurology and cancer services of the medical school in Montpellier, France (Hôpital Gui de Chaulliac and CRLC Val d'Aurelle). The cumulative self-reporting test WHOQOL 100 (World Health Organization Quality of Life with 100 questions) was administered in 57 patients with either moderate senile dementia (27 cases with a Mini-Mental State Examination score >15; mean age of 73) or cancer (30 cases, mainly women with breast cancer; mean age of 53). The stability of responses was tested in a 2-week period. RESULTS: Results of the study showed clear and significant differences between the two groups in the domains of mobility and psychology. Further, eight questions and six facets with a significant difference in responses were found. Responses seemed more stable in the domains of autonomy, social relationship, and religion for the cancer group, and in autonomy and psychology for the dementia group. The age difference may be an important factor in the different quality of life measured but did not significantly influence responses to the test questions. CONCLUSION: The WHOQOL 100 seems a powerful instrument to assess quality of life in diseases such as cancer and moderate dementia. In this study, interesting differences in responses to the test questions between the two pathologic conditions were identified. Items that were unreliable on retesting are singled out. These results will be applied and reevaluated in the development of future, illness-specific and shorter versions of the WHOQOL 100.

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PubMed1999

Depressive illness, depressive symptomatology and regional cerebral blood flow in elderly people with sub-clinical cognitive impairment.

BACKGROUND: Depressive illness in dementia is often assumed to be a unitary clinical phenomenon. AIM: To describe changes in patterns of depressive symptomatology with time, and associated changes in cerebral blood flow to the frontal and temporal regions. METHOD AND RESULTS: 397 elderly people with sub-clinical cognitive dysfunction were observed over 3 years. Sixteen percent of them developed dementia during the study The prevalence of depressive symptomatology was higher in this group than in the general population, especially in women, who also had higher recovery rates. A changing profile of depressive symptoms was found in depressed elderly people progressing to dementia, with fewer affective symptoms and increases in agitation and motor slowing. These changes were paralleled by greater reductions in left temporal regional cerebral blood flow than in non-depressed subjects with Alzheimer's disease. CONCLUSION: In dementia, there may be two separate and interacting depressive syndromes whose differentiation may be clinically important.

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PubMed1999

The effects of wine and tobacco consumption on cognitive performance in the elderly: a longitudinal study of relative risk.

BACKGROUND: Evidence relating to the potentially protective effect of smoking and alcohol consumption in relation to senescent cognitive decline and Alzheimer's disease is inconclusive. METHODS: The relationship between wine and tobacco consumption and cognitive change was assessed within a longitudinal study of normal elderly people showing recent instability in cognitive functioning using an extensive battery of cognitive tests. RESULTS: While moderate wine consumption was found to be associated with a fourfold diminishing of the risk of Alzheimer's disease (OR = 0.26), as found in other studies, this effect was found to disappear when institutionalization was taken into account. Wine consumption was associated with an increased risk of decline over time in attention and in secondary memory. No protective effect for Alzheimer's disease was found for smoking, although smoking was associated with a decreased risk for decline over time in attentional and visuospatial functioning. No clear combined effect of smoking and drinking was found, even though smoking was found to increase the risk of decline in language performance when adjusted on wine consumption. CONCLUSIONS: There is no evidence to suggest that wine and tobacco consumption may protect against Alzheimer's disease.

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