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Biomedical subjects

G Gold

Publications and source records attributed to G Gold.

At least 37 records · Page 2Linked to original sources

Immediate causes of death of demented and non-demented elderly.

OBJECTIVE: To investigate the immediate causes of death, in autopsied demented and non-demented elderly. DESIGN: Retrospective clinicopathologic correlations. SETTING: Acute and intermediate care geriatric hospital. PARTICIPANTS: 342 hospitalized demented and non-demented elderly (mean age 84.94 +/- 6.9 years) who underwent consecutive postmortem examinations: 120 demented patients with either vascular dementia (VaD, n = 34), mixed dementia (MD, n = 65) or Alzheimer's disease (AD, n=21) neuropathologically confirmed and 222 nondemented elderly. RESULTS: Primary causes of death were similar in both demented and non-demented patients; the commonest were cardiovascular disease and bronchopneumonia. Cardiac causes of death and especially cardiac failure were more frequent in VaD than in AD or MD (respectively P = 0.027 and 0.005). Dementia was an underlying but never a primary cause of death. CONCLUSIONS: Immediate causes of death are similar in elderly demented and non-demented patients.

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Imidazoline receptor antisera-selected (IRAS) cDNA: cloning and characterization.

The imidazoline-1 receptor (IR1) is considered a novel target for drug discovery. Toward cloning an IR1, a truncated cDNA clone was isolated from a human hippocampal lambda gt11 cDNA expression library by relying on the selectivity of two antisera directed against candidate IR proteins. Amplification reactions were performed to extend the 5' and 3' ends of this cDNA, followed by end-to-end PCR and conventional cloning. The resultant 5131-basepair molecule, designated imidazoline receptor-antisera-selected (IRAS) cDNA, was shown to encode a 1504-amino acid protein (IRAS-1). No relation exists between the amino acid sequence of IRAS-1 and proteins known to bind imidazolines (e.g., it is not an alpha2-adrenoceptor or monoamine oxidase subtype). However, certain sequences within IRAS-1 are consistent with signaling motifs found in cytokine receptors, as previously suggested for an IR1. An acidic region in IRAS-1 having an amino acid sequence nearly identical to that of ryanodine receptors led to the demonstration that ruthenium red, a dye that binds the acidic region in ryanodine receptors, also stained IRAS-1 as a 167-kD band on SDS gels and inhibited radioligand binding of native I1 sites in untransfected PC-12 cells (a source of authentic I1 binding sites). Two epitope-selective antisera were also generated against IRAS-1, and both reacted with the same 167-kD band on Western blots. In a host-cell-specific manner, transfection of IRAS cDNA into Chinese hamster ovary cells led to high-affinity I1 binding sites by criteria of nanomolar affinity for moxonidine and rilmenidine. Thus, IRAS-1 is the first protein discovered with characteristics of an IR1.

Amino Acid Motifs↗

Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters.

The possible relationship between changes in islet cell mass and in islet neogenesis-associated protein (INGAP)-cell mass induced by sucrose administration to normal hamsters was investigated. Normal hamsters were given sucrose (10% in drinking water) for 5 (S8) or 21 (S24) weeks and compared with control (C) fed hamsters. Serum glucose and insulin levels were measured and quantitative immunocytochemistry of the endocrine pancreas was performed. Serum glucose levels were comparable among the groups, while insulin levels were higher in S hamsters. There was a significant increase in beta-cell mass (P<0.02) and in beta-cell 5-bromo-2'-deoxyuridine index (P<0.01), and a significant decrease in islet volume (P<0.01) only in S8 vs C8 hamsters. Cytokeratin (CK)-labelled cells were detected only in S8 hamsters. INGAP-positive cell mass was significantly larger only in S8 vs C8 hamsters. Endocrine INGAP-positive cells were located at the islet periphery ( approximately 96%), spread within the exocrine pancreas ( approximately 3%), and in ductal cells (<1%) in all groups. INGAP positivity and glucagon co-localization varied according to topographic location and type of treatment. In C8 hamsters, 49.1+/-6. 9% cells were INGAP- and glucagon-positive in the islets, while this percentage decreased by almost half in endocrine extra-insular and ductal cells. In S8 animals, co-expression increased in endocrine extra-insular cells to 36.3+/-9.5%, with similar figures in the islets, decreasing to 19.7+/-6.9% in ductal cells. INGAP-positive cells located at the islet periphery also co-expressed CK. In conclusion, a significant increase of INGAP-positive cell mass was only observed at 8 weeks when neogenesis was present, suggesting that this peptide might participate in the control of islet neogenesis. Thus, INGAP could be a potentially useful tool to treat conditions in which there is a decrease in beta-cell mass.

Animals↗

Neuroanatomic correlates of visual agnosia in Alzheimer's disease: a clinicopathologic study.

OBJECTIVE: To examine the neuroanatomic correlates of visual agnosia in AD. METHODS: The authors performed an anterograde clinicopathologic study of 23 patients with clinically and neuropathologically confirmed AD in a 305-bed acute care geriatric hospital and a 165-bed acute care psychiatric hospital. The presence of apperceptive visual agnosia was assessed using the Ghent's overlapping figure test and the Gottschaldt's hidden figure test. Associative visual agnosia was examined using the conceptual items of the Columbia Mental Maturity Test. Correlations between neurofibrillary tangle (NFT) and senile plaque (SP) densities and visual agnosia were studied using forward stepwise logistic regression. RESULTS: A statistically significant relation was found between NFT densities in Brodmann's areas 18, 19, and 37, and associative visual agnosia, whereas NFT densities in the areas studied did not correlate with the presence of apperceptive visual agnosia. Senile plaque counts did not correlate with any of the neuropsychological parameters. CONCLUSIONS: These results support the existence of a dichotomy between associative and apperceptive agnosia, and show that only the former is related to the damage of secondary and high-order visual association areas in AD. In addition, the results suggest that SP densities do not represent a valuable pathologic correlate of visual agnosia in this disorder.

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Threonine phosphorylations induced by RX-871024 and insulin secretagogues in betaTC6-F7 cells.

Treatment of the pancreatic beta-cell line betaTC6-F7 with an imidazoline compound, RX-871024, KCl, or tolbutamide resulted in increased threonine phosphorylation of a 220-kDa protein (p220) concurrent with enhanced insulin secretion, which can be partially antagonized by diazoxide, an ATP-sensitive potassium (K(ATP)) channel activator. Although phosphorylation of p220 was regulated by cytoplasmic free calcium concentration ([Ca(2+)](i)), membrane depolarization alone was not sufficient to induce phosphorylation. Phosphorylation of p220 also was not directly mediated by protein kinase A, protein kinase C, or insulin exocytosis. Analysis of subcellular fractions indicated that p220 is a hydrophilic protein localized exclusively in the cytosol. Subsequently, p220 was purified to homogeneity, sequenced, and identified as nonmuscle myosin heavy chain-A (MHC-A). Stimulation of threonine phosphorylation of nonmuscle MHC-A by KCl treatment also resulted in increased phosphorylation of a 40-kDa protein, which was coimmunoprecipitated by antibody to MHC-A. Our results suggest that both nonmuscle MHC-A and the 40-kDa protein may play roles in regulating signal transduction, leading to insulin secretion.

Amino Acid Sequence↗

Free-standing health care facilities: financial arrangements, quality assurance and a pilot study.

Free-standing health care facilities now deliver many diagnostic and therapeutic services formerly provided only in hospitals. The financial arrangements available to these facilities differ according to whether the services are uninsured or insured. For an uninsured service, such as cosmetic surgery, the patient pays a fee directly to the service provider. For an insured service, such as cataract surgery, the provincial government uses tax revenues to fund the facility by paying it a facility fee and remunerates the physician who provided the service with a professional fee. No comprehensive, proactive quality assurance efforts have been implemented for either these facilities or the clinical practice provided within them. A pilot study involving therapeutic facilities in Ontario has suggested that a large-scale quality improvement effort could be undertaken in these facilities and rigorously evaluated.

Ambulatory Care Facilities↗

Pathologic correlates of apraxia in Alzheimer disease.

OBJECTIVE: To examine the neuroanatomical correlates of apraxia in Alzheimer disease. PATIENTS: Twenty-three patients with clinically overt Alzheimer disease. DESIGN: Anterograde study and neuropathologic case series. Clinical severity was assessed using the Global Deterioration Scale. Ideomotor praxis was examined on transitive and intransitive movements and meaningless gestures, and dressing ability was evaluated clinically. Constructive praxis was tested using a 3-dimensional figure copying task. Correlations between neurofibrillary tangle and senile plaque densities and praxis test performance were studied using stepwise logistic regression models. SETTING: Studies were conducted at the Psychiatric and Geriatric Hospitals of the University of Geneva School of Medicine, Geneva, Switzerland. MAIN OUTCOME MEASURES: Odds ratios to estimate the associations between neurofibrillary tangle and senile plaque densities in each neocortical area and the presence of ideomotor, dressing, and constructional apraxia. RESULTS: Statistically significant relationships were found between neurofibrillary tangle densities in the anterior cingulate cortex and ideomotor and dressing apraxia and between neurofibrillary tangle densities in the superior parietal, posterior cingulate, and occipital cortex and constructional apraxia. Senile plaque counts did not correlate with praxic performance. CONCLUSIONS: These results suggest that ideomotor and dressing apraxia are associated with mild damage of the anterior cingulate cortex, whereas constructional apraxia is related to the disruption of cortical pathways mediating visuospatial cognition in Alzheimer disease. Senile plaque densities do not represent a valuable pathologic correlate of apraxia in this disorder.

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Re-evaluating the role of vascular changes in the differential diagnosis of Alzheimer's disease and vascular dementia.

Alzheimer's disease (AD) and vascular dementia (VaD) are the two most common causes of dementia, and much effort has been devoted to their differential diagnosis. However, current epidemiological, clinical and neuropathological evidence points to a substantial overlap between AD and VaD and suggests that vascular pathology, the traditional cornerstone of the differential diagnosis between the two entities, may not represent as clear a line of demarcation as originally believed. It may be time to reevaluate the dichotomy between AD and VaD.

Alzheimer Disease↗

Cellular vulnerability in brain aging and Alzheimer's disease. Clinical correlates and molecular background.

The neuropathological changes associated with normal brain aging and Alzheimer's disease involve specific cortical circuits. Extensive hippocampal alterations are correlated with age-associated memory impairment, while substantial neurofibrillary tangle formation in neocortical association areas of the temporal lobe is a prerequisite for the development of Alzheimer's disease. Several lines of evidence indicate that there is no correlation between senile plaque densities and the degree of dementia in this disorder. The cortical involvement in the ninth and tenth decades of life is different from that observed in younger patients in that parietal and cingulate areas are affected early in the course of Alzheimer's disease, and neocortical senile plaques densities are strongly correlated with the severity of dementia. Moreover, Alzheimer's disease pathology is characterized in these very old patients by high neurofibrillary tangle densities in the anterior CA1 field, but not in the entorhinal cortex and inferior temporal cortex. These patterns of lesion distribution are discussed in respect to the neurochemical, genetic and metabolic factors which may influence the neuronal vulnerability in Alzheimer's disease.

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Vascular dementia. Differential diagnosis and therapeutic issues.

Although it has long been felt that dementia may be due to atherosclerosis, the concept has recently evolved to include multiple pathophysiological mechanisms related to deficiencies in cerebral blood supply. Epidemiological data has identified hypertension and stroke as the most potent risk factors for the development of vascular dementia (VaD). New diagnostic criteria have been proposed and new neuroimaging techniques have led to a better detection of cerebral vascular pathology. However, the differential diagnosis between Alzheimer's disease and VaD, the two most common causes of dementia, remains clinically challenging. Therapeutic interventions for VaD are limited, nevertheless several lines of evidence suggest a strong potential for preventive treatment through the control of vascular risk factors.

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[Dependency: possible risk or inevitable outcome?].

This is the burning issue of the hour. In attempting to resolve it within the context of advanced age, it is important to clarify the meaning of the words involved: Independence and autonomy are far from being synonyms. Independence refers to the ability to perform physical activities of daily living (bathing, eating, preparing meals, shopping, money management), whereas the second word, autonomy, refers more to the ability to make decisions, to reason, to express an appropriate opinion in a given situation. Hazard and inevitability are totally at variance. Hazard implies the likelihood of occurrence of an event harmful to health, or to the length or quality of life. Hazard is more or less predictable, whereas inevitability is the expression of a supernatural power controlling all events. To find out whether "dependency is a hazard or an inevitability", it is necessary to conduct a historical review of the extension in human longevity and in particular of the current "weight" of aging both on individuals and on society at large. In Geneva, the proportion of the over 65-year-olds grew from 5.1 percent in 1880 to 13.4 percent in 1990. During that time, the gain in life expectancy was 52.4 percent for Geneva males of 80 years of age and 93 percent for Geneva females of the same age. This drastic change in age groups was coupled with a noteworthy change in household sizes. In 1860, the number of persons per household was 4.5. In 1990, it was down to 2.2. Conversely, the number of inmates in Geneva's medico-social institutions went up from 649 to 1168 between 1982 and 1992. In this socio-economic and cultural perspective, the concept of "globality of the individual" throughout his lifetime explains: age-related physiological changes; the long-term repercussion of physical, professional or leisure activities; the consequences of the accumulation of such varied risk factors as overweight or its opposite, malnutrition, tobacco or stress. Such frailty caused by aging is an ideal breeding ground for disease. For now, what matters most is the functional consequence of disease. Is the disease acute or chronic? Two out of three deaths result from a chronic disease, which caused loss of function by organs (impairment), loss of function by the subject himself (disability) or loss of function by the individual in society (social handicap or disadvantage). Raising the question "Dependency: a hazard or an inevitability?" boils down to asking oneself about the place of disease in our society and its determinants, and about all aspects of medicine and especially of prevention. When detected, a susceptibility brings into play primary prevention, aimed at averting the onset of the disease. After a disease has set in, measures to prevent recurrence, or secondary prevention, are required. Lastly, prevention of dependency and of loss of autonomy is part of tertiary prevention. Except for violent traumatic accidents, the formulation of the above concepts proves that dependency is essentially "a hazard". Therefore, let us anticipate!

Activities of Daily Living↗

Competitive particle concentration fluorescence immunoassays for measuring anti-diabetic drug levels in mouse plasma.

Two competitive particle concentration fluorescence immunoassays were developed to measure blood levels of analogs of anti-diabetic drugs being tested in diabetic mice. Ligands that contained the active pharmacophores were conjugated to PPD for immunization and to beta-phycoerythrin for use as a tracer in the immunoassays. Approximately 90% of 262 compounds assayed were detectable at less than 120 nM in plasma which was well below the estimated therapeutic level of 1 microM for lowering blood glucose. These data were used to define the bioavailability of test compounds and assist in decisions of constructing active analogs. Of additional interest, we noted crossreactivity of one monoclonal antibody for 3 different compound classes that are all known to bind with varying affinities to peroxisome proliferator-activated receptors.

Animals↗

Monoclonal antibodies as surrogate receptors in a high throughput screen for compounds that enhance insulin sensitivity.

Monoclonal antibodies (MoAbs) were made to a known insulin sensitivity enhancer (ISE) compound, CS-045. The MoAbs were characterized with respect to binding other known thiazolidinedione ISE compounds using a CS-045 labeled with b-phycoerythrin in a competitive particle concentration fluorescence immunoassay (PCFIA). By comparing the rank order of IC50 values for each compound to its respective potency as an ISE, one MoAb (13E3) was selected for further characterization. This MoAb was also used as a surrogate receptor in a high throughput screen to identify novel compounds that compete for binding to CS-045. Some of the hits were found to have efficacy in reducing blood glucose. Subsequently, another group reported that several compounds with the core thiazolidinedione structure of the ISE compounds bound with high affinity to peroxisome proliferator-activating receptors (PPAR). Therefore, we used the MoAb assay to test these and other compounds that are known to bind to PPARgamma and noted crossreactivity with some of the compounds.

Animals↗