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S Gauthier

Publications and source records attributed to S Gauthier.

At least 73 records · Page 4Linked to original sources
PubMed1998

Relation between severity of Alzheimer's disease and costs of caring.

BACKGROUND: Data from the Canadian Study of Health and Aging (CSHA) were used to examine the relation between severity of Alzheimer's disease, as measured by the Mini-Mental State Examination (MMSE), and costs of caring. METHODS: The CSHA was a community-based survey of the prevalence of dementia, including subtypes such as Alzheimer's disease, among elderly Canadians. Survey subjects with a diagnosis of possible or probable Alzheimer's disease were grouped into disease severity levels of mild (MMSE score 21-26), mild to moderate (MMSE score 15-20), moderate (MMSE score 10-14) and severe (MMSE score below 10). Components of care available from the CSHA were use of nursing home care, use of medications, use of community support services by caregivers and unpaid caregiver time. Costs were calculated from a societal perspective and are expressed in 1996 Canadian dollars. RESULTS: The annual societal cost of care per patient increased significantly with severity of Alzheimer's disease. The cost per patient was estimated to be $9451 for mild disease, $16,054 for mild to moderate disease, $25,724 for moderate disease and $36,794 for severe disease. Institutionalization was the largest component of cost, accounting for as much as 84% of the cost for people with severe disease. For subjects living in the community, unpaid caregiver time and use of community services were the greatest components of cost and increased with disease severity. INTERPRETATION: The societal cost of care of Alzheimer's disease increases drastically with increasing disease severity. Institutionalization is responsible for the largest cost component.

Alzheimer Disease↗
PubMed1998

Interhemispheric disconnection syndrome in Alzheimer's disease.

It is commonly acknowledged that patients with Alzheimer's disease show memory and cognitive deficits that result from their cerebral histopathological abnormalities. We report new evidence showing that they also manifest deficits in interhemispheric integration of information, probably reflecting a corpus callosum dysfunction. Patients were given a battery of motor, somatosensory, and visual tests that had to be carried out by using either one or both hemispheres. Tasks were chosen such that subjects with Alzheimer's disease performed normally when using intrahemispheric processing. They, however, performed poorly when interhemispheric communication was required. This observation attests to the presence of a disconnection syndrome and suggests that these interhemispheric tasks can serve as diagnostic tools for the early assessment of their dementia.

Alzheimer Disease↗
PubMed1998

Mapping of genetic modulators of natural resistance to infection with Salmonella typhimurium in wild-derived mice.

Despite antibiotic therapy and vaccination programs, microbial diseases continue to be the leading cause of morbidity and mortality worldwide. The genetic basis of the host response to infection is complex, and its understanding has been facilitated through the study of mouse models of human infectious diseases. Genetic variation in resistance of mice to infection with Salmonella typhimurium has been recognized for over 50 years and shown to be a multifactorial trait. We have studied the genetic basis of resistance or susceptibility to infection with S. typhimurium in the wild-derived inbred mouse Mus musculus molossinus (MOLF/Ei). MOLF/Ei mice are extremely susceptible to infection with S. typhimurium despite the presence of resistance alleles at Nramp1 and Lps. To identify genes that modulate the expression of natural resistance or susceptibility to infection with S. typhimurium in MOLF/Ei, we have performed a genome-wide study using an F2 intercross between C56BL/6J and MOLF/Ei inbred mice. We have mapped three QTLs that significantly affect survival time following lethal infection with S. typhimurium. The Salmonella-resistant phenotype was linked to Nramp1 on proximal chromosome 1 (maximum lod score of 18.8 at D1Mcg4) and to a newly mapped region on mouse chromosome 11 (maximum lod score of 7.0 at D11Mit5). The third QTL conferred recessive susceptibility and was located on mouse chromosome 1, approximately 25 cM distal to Nramp1 (maximum lod score of 4.8 at D1Mit100).

Animals↗
PubMed1998

Current diagnostic methods and outcome variables for clinical investigation of Alzheimer's disease.

The diagnosis of Alzheimer's disease (AD) is done by a careful history, requiring reliable informants and serial observations. The main differential diagnosis is depression, delirium, and inappropriate use of psychotropic drugs. Other common causes of dementia such as vascular, Lewy body disease, frontal lobe degeneration, can be distinguished by the pattern of symptoms and findings on the physical examination. A minimal amount of laboratory investigation is usually required. The natural history of AD, with progressive involvement of cognition, activities of daily living and behaviour, justifies the need of outcome variables addressing these specific symptomatic domains. These are complemented by global clinical assessment tools for disease staging and disease progression. A new challenge is to select from outcome variables used in clinical investigations the most appropriate tools for regular clinical practice.

Aged↗
PubMed1998

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors.

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.

Androgens↗
PubMed1998

Ethical guidelines of the Alzheimer Society of Canada.

Alzheimer's disease raises numerous ethical issues which vary and evolve over the course of the illness. In recognition of the need for ongoing discussion of these issues, the Alzheimer Society of Canada established a Task Force on Ethics in 1995. Through a process of "discourse ethics" and consultation on a national scale, the Task Force produced a series of guidelines dealing with the issues of: communicating the diagnosis, driving, respecting individual choice, quality of life, participation in research, genetic testing, the use of restraints, and end-of-life care. This manuscript presents a summary of these guidelines as well as a summary of the ideas on which they were based. It was the hope of the Society that the publication of these guidelines will serve to facilitate discussion of the ethics of care of those with Alzheimer's disease.

Alzheimer Disease↗
PubMed1998

First International Pharmacoeconomic Conference on Alzheimer's Disease: report and summary.

The First International Pharmacoeconomic Conference on Alzheimer's Disease (AD) was held in Amsterdam in July 1998. The meeting was held under the auspices of the International Working Group for Harmonization of Dementia Drug Guidelines (http://dementia.ion.ucl.ac.uk/harmon), bringing together academics, clinicians, purchasers, and representatives from industry. Presentations were given on the methodology of pharmacoeconomic studies in AD, particularly focusing on caregiver burden, quality of life (QOL), and resource utilization. Three economic models of AD were presented based on data from the United States, Canada, and the United Kingdom. In two studies, these data were then used to model the cost-effectiveness and effect on cost of treatment with donepezil. Both studies suggested a possible cost advantage for the use of donepezil, when compared with no placebo or treatment, particularly when donepezil is used appropriately in mild-to-moderate AD. These data need to be interpreted with care, as none of the cost or utility information were collected during the clinical trials. Additional data from a 2-year clinical trial of selegiline and vitamin E suggest that cognitive measures may be poor predictors of economic outcome, which is better measured directly. Both economic models of donepezil rely on short-term cognitive data to predict long-term outcome, a methodf that may not be useful in predicting economic savings. The issues facing pharmacoeconomists, researchers, clinicians, and families in the future were addressed in a series of workshops using a method of strategic futuring. The workshops attempted to see 7 years into the future for a range of areas, including consumer and caregiver use of pharmacoeconomic data; early detection and prevention; Japanese perspectives; activities of daily life and what will be daily life activities; caregiver burden; QOL at the end of life; new uses for new information and communication technology in clinical research; and physicians' use of pharmacoeconomic data. A range of exciting futures were predicted, although common themes that arose when considering barriers to achieving these futures included cost, education, political will, confidentiality, privacy, and ethics. The first conference was deemed to have been a success, having attracted more than 160 delegates and many distinguished speaker. A second conference is planned for the year 2000. Over the next 2 years, research needs to be broadened particularly in the methodological areas of resource utilization, QOL, and caregiver burden. Data from clinical trials with relevant economic and QOL outcomes will be needed by purchasers if drug treatments for dementia are to gain widespread use. It is also hoped that the models described at the meeting may become more freely available to politicians, purchasers, clinicians, and caregivers to help them make better decisions about treatment.

Aged↗
PubMed1998

Clinical trials and therapy.

Parallel-group studies have established the efficacy of cholinesterase inhibitors in Alzheimer's disease, at least for short-term cognitive and clinical global enhancement. Noncognitive outcomes are currently under scrutiny. Time to reach clinical milestones may be a more useful trial design for new studies aiming to delay appearance or progression of disease.

Alzheimer Disease↗
PubMed1998

Update on diagnostic methods, natural history and outcome variables in Alzheimer's disease.

The diagnosis of Alzheimer's disease (AD) currently relies on history obtained from family or friends and on mental status assessment matched to National Institute of Neurological and Communicative Disorders and Stroke criteria. Progression over time may or may not be typical, suggesting alternate diagnoses such as Lewy body or frontotemporal dementias. Apolipoprotein E genotype does not appear to be useful as a diagnostic marker. The usefulness of brain imaging in AD must be reexamined. Critical events in the natural history of AD, such as institutionalization and loss of ability for self-care, could be used as end points. Loss of ability for instrumental tasks, such as driving, traveling alone, or managing finances, would be preferable for early-stage stabilization studies. Different symptomatic domains of AD (mood, cognition, functional autonomy, behavior, motoricity) can be quantified using specific outcome measures. Although cognitive loss has been considered a core symptom of AD from a regulatory perspective, loss of functional autonomy and behavioral disinhibition are considered more important by clinicians and families. Recently, the availability of new scales has led to an interest in all of these domains. Results from symptomatic drug studies suggest a differential effect of cholinesterase inhibitors on cognition versus muscarinic agonists on functional autonomy and behavior. Hence there is a need to measure these domains separately and, eventually, to attempt combination therapy. Quality of life is a difficult but important dimension of AD therapeutic research, and it requires further methodological research.

Alzheimer Disease↗
PubMed1998

Comparison of the effects of the new orally active antiestrogen EM-800 with ICI 182 780 and toremifene on estrogen-sensitive parameters in the ovariectomized mouse.

The nonsteroidal antiestrogen EM-800 is approximately 10-fold more potent than ICI 182 780, the most potent known steroidal antiestrogen, at inhibiting estrone-stimulated uterine weight in ovariectomized mice (half-maximal inhibitory daily s.c. doses of 0.2 and 2.0 microg, respectively). At maximal doses, however, both compounds lead to a similar maximal 90% inhibition of estrone-stimulated uterine weight. A 10-fold higher activity of EM-800 compared with ICI 182 780 was also observed on estrone-stimulated vaginal weight, with maximal inhibitions of 96% and 90%, respectively, achieved by the two compounds. In addition, EM-800 injected s.c. or administered orally led to a marked loss of uterine and vaginal estrogen receptor levels measured by binding assay, whereas ICI 182 780 exerted no inhibitory effect on this parameter under the experimental conditions used. Comparable effects were observed when estrogen receptor protein levels were measured by enzyme immunoassay. After oral administration, EM-800 exerted maximal 83% and 88% inhibitions of uterine and vaginal weight, respectively, whereas maximal inhibitions limited to 51% and 67% were achieved with toremifene. This limited inhibition by toremifene of the stimulatory effect of estrone on uterine and vaginal weight is probably due to the intrinsic estrogenic activity of the compound. The present data also show that the steroidal antiestrogen ICI 182 780 has less than 3% the activity of EM-800 when administered by the oral route. In fact, EM-800 administered orally is 2- to 3-fold more potent than ICI 182 780 injected s.c.

Animals↗
PubMed1998

Effect of twenty-four-week treatment with the antiestrogen EM-800 on estrogen-sensitive parameters in intact and ovariectomized mice.

Treatment with the antiestrogen EM-800, at the daily oral dose of 3 microg, 10 microg, 30 microg, or 100 microg for 24 weeks, caused a marked inhibition of uterine and vaginal weight in both intact and ovariectomized mice. Maximal 64% and 41% inhibitions of uterine weight were achieved in intact and ovariectomized animals, respectively. Similar inhibitory effects of EM-800 were observed on vaginal weight with maximal inhibitions of 71% and 35%, in intact and ovariectomized animals, respectively. The pure antiestrogenic activity of EM-800 on the hypothalamo-pituitary-ovarian axis is illustrated by the 76-91% increases in ovarian weight observed in intact animals treated with the 10-100 microg doses of the antiestrogen. Serum 17beta-estradiol was 93% increased at the 100 microg daily dose of EM-800, whereas serum androstenedione, testosterone, and dihydrotestosterone were 141-713% increased over control at the same dose of the antiestrogen. Serum LH was increased by treatment with EM-800 in intact animals, whereas no effect was observed on the elevated gonadotropin levels in ovariectomized animals. At all doses used in intact animals, the antiestrogen caused a complete disappearance of the glandular elements of the mammary gland, the atrophy being comparable with that observed in ovariectomized mice. The mammary gland of EM-800-treated animals was exclusively composed of an atrophied ductal system lined by atrophied epithelial cells with an absence of lobulo-glandular elements. No effect of the compound was observed on the histology of the mammary gland in ovariectomized animals, thus showing the pure antiestrogenic effect of EM-800 on the mammary gland, as shown also for the uterus, vagina, and hypothalamo-pituitary axis. At histopathology, all doses of EM-800 in intact animals led to a moderate to severe uterine and vaginal atrophy. The uterine atrophy affected both the myometrium and the endometrium. Interestingly, the uterine atrophy achieved in intact animals treated with EM-800 was greater than that observed after ovariectomy alone, thus clearly demonstrating the pure antiestrogenic activity of EM-800. The present data show the highly potent and pure antiestrogenic activity of EM-800 on all parameters measured after 6 months of treatment in both intact and ovariectomized mice, a maximal effect being reached at the daily 10 microg dose of the antiestrogen in intact animals.

Androstenedione↗
PubMed1998

Sleep disturbances and eeg slowing in alzheimer's disease.

Changes in sleep structure, and especially REM sleep, and in EEG activation were studied in relation to the cholinergic deficit found in Alzheimer's Disease (AD). With respect to sleep architecture, only REM sleep percent was reduced in AD patients compared to controls as a result of a decrease in mean REM episode duration. Different results were obtained in patients with progressive supranuclear palsy (PSP). These results are discussed with respect to the role of brainstem and forebrain cholinergic populations in REM sleep generation in humans. More importantly, it was shown by means of spectral analyses that EEG slowing is much more prominent in REM sleep than in wakefulness in AD. Furthermore, there is a distinct topographical pattern of REM sleep EEG slowing in AD patients which is in agreement with findings from neuroradiological and neuropathological studies. Using the ratio of slow over fast frequencies from the temporal regions, a correct classification of 90.4% of subjects was obtained for the REM sleep EEG. This discrimination rate is the best marker of AD so far using a single measure. Quantitative REM sleep EEG was also used to evaluate patients' biological response to cholinergic treatments. Finally, we present here preliminary data on the progression of EEG slowing in wakefulness and in REM sleep. After six months on a placebo, there was only a decrease in alpha activity in wakefulness over all regions studied. No changes were observed for REM sleep.

Aged↗
PubMed1998

Prevention of Alzheimer's disease.

Delaying the emergence of Alzheimer's disease (AD) symptoms by 5 to 10 years would have a significant public health impact in the long term. Data generated from large scale epidemiological studies on risk as well as protective factors for AD are leading to treatment strategies that can be tested in transgenic animal models as well as human populations at higher genetic risk.

Aged↗
PubMed1997

Long-term inhibitory effects of a novel anti-estrogen on the growth of ZR-75-1 and MCF-7 human breast cancer tumors in nude mice.

The effects of the novel anti-estrogen EM-343 on the growth of 2 hormone-responsive human breast cancer tumors have been examined in athymic nude mice. At the low daily dose of 5 microg, EM-343 administered subcutaneously for 6 months completely blocked the stimulatory effect of endogenous estrogens on the growth of ZR-75-1 and MCF-7 tumors implanted in nude mice. In addition, uterine weight decreased by 60% while ovarian weight increased by 37%. Estrogen receptor (ER) levels measured by [3H]-labeled estrogen binding were markedly reduced (by 96%, 96% and 92%) in ZR-75-1 and MCF-7 tumors, and in the mouse uterus, respectively. Accompanying the decrease in ER, progesterone receptor levels were reduced by 79%, 87% and 76%, respectively, in the above-mentioned tissues following EM-343 treatment. Our data show the pure anti-estrogenic properties of EM-343 and its high potency as an inhibitor of growth of human ZR-75-1 and MCF-7 breast tumors in nude mice.

Animals↗
PubMed1997

Comparative effects of 28-day treatment with the new anti-estrogen EM-800 and tamoxifen on estrogen-sensitive parameters in intact mice.

Following 28 days of oral administration, in intact mice, the novel non-steroidal anti-estrogen EM-800 was at least 30-fold more potent than tamoxifen in inhibiting uterine weight. Moreover, the maximal inhibitory effect achieved with tamoxifen on uterine weight was only 40% that with EM-800. The pure anti-estrogenic activity of EM-800 on the hypothalamo-pituitary-gonadal axis is illustrated by the increase in ovarian weight, while tamoxifen, due to its estrogenic activity, decreased ovarian weight. EM-800 is 10- to 30-fold more potent than tamoxifen in inhibiting uterine and vaginal estrogen receptors. Since 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is the key enzyme in estradiol formation, the potent inhibitory effect of EM-800 on uterine 17beta-HSD could play an additional role by decreasing the availability of estradiol in the uterine tissue, while tamoxifen, on the contrary, stimulates activity of the enzyme. The atrophic changes in both the endometrial and myometrial layers achieved with EM-800 almost reached those observed 28 days after ovariectomy. EM-800 also resulted in a marked decrease in the number of ovarian developing follicles and corpora lutea, while the number of atretic follicles was increased. Tamoxifen treatment, on the other hand, produced an increase in both the number and crowding of the endometrial glands and a mild atrophy of the myometrial layer. Tamoxifen caused atrophic changes of the vaginal epithelium, especially at the highest doses, though the atrophy was much less pronounced than that following EM-800 treatment or ovariectomy. In addition to being at least 30-fold more potent than tamoxifen in inhibiting uterine weight, the novel anti-estrogen causes atrophy of the endometrium, stimulates the hypothalamo-pituitary-gonadal axis and inhibits uterine 17beta-HSD activity, while tamoxifen exerts opposite and estrogen-like effects on these parameters.

17-Hydroxysteroid Dehydrogenases↗
PubMed1997

Alzheimer's disease: current knowledge, management and research.

Alzheimer's disease is a common neurological condition, appearing as early as age 40 but increasing dramatically in incidence over age 85. Different genetic factors are at play, modified by events over a lifetime. Clinical diagnosis is possible through careful history taking with a reliable informant and a minimum number of laboratory tests. A relatively predictable natural history can be observed, with progression through stages of cognitive loss, functional impairment and behavioural disinhibition or apathy. New medications such as donepezil offer hope for improving or stabilizing symptoms. Such treatment can be administered by primary care physicians with experience in the diagnosis and management of Alzheimer's disease. Disease stabilization, or even prevention, may be possible in the future.

Adult↗
PubMed1997

Characterization of the effects of the novel non-steroidal antiestrogen EM-800 on basal and estrogen-induced proliferation of T-47D, ZR-75-1 and MCF-7 human breast cancer cells in vitro.

Since estrogens play a predominant role in the development and growth of human breast cancer, antiestrogens represent a logical approach to the treatment of this disease. The present study compares the effects of the novel nonsteroidal anti-estrogen EM-800 and related compounds with those of a series of anti-estrogens on basal and 17 beta-estradiol (E2)-induced cell proliferation in human breast cancer cell lines. In the absence of added E2, EM-800 and related compounds failed to change basal cell proliferation, thus showing the absence of intrinsic estrogenic activity in the ER-positive T-47D, ZR-75-1 and MCF-7 cell lines. The stimulation of T-47D cell proliferation induced by 0.1 nM E2 was competitively blocked by a simultaneous incubation with EM-652, EM-800, OH-tamoxifen, OH-toremifene, ICI 182780, ICI 164384, droloxifene, tamoxifen and toremifene at apparent Ki values of 0.015, 0.011-0.017, 0.040-0.054, 0.043, 0.044, 0.243 and 0.735 nM, approx. 10 nM and > 10 nM, respectively. Similar data were obtained in ZR-75-1 and/or MCF-7 cells. Moreover, EM-652 was 6-fold more potent than OH-Tamoxifen in inhibiting the proportion of cycling MCF-7 cells. Our data show that EM-800 and EM-652 are the most potent known antiestrogens in human breast cancer cells in vitro and that they are devoid of the estrogenic activity of OH-tamoxifen and droloxifene suggested by stimulation of cell growth in the absence of estrogens in ZR-75-1 and MCF-7 cells.

Benzopyrans↗