Geriatrics and health care reform: opportunities in managed care for preserving excellence in the care of the elderly.
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Biomedical subjects
H Fillit
Publications and source records attributed to H Fillit.
Binding of heparan sulfate glycosaminoglycan to beta-amyloid peptide: inhibition by potentially therapeutic polysulfated compounds.
Heparin sulfate proteoglycans are believed to play an important role in amyloidosis as pathologic chaperones. They bind to amyloidogenic proteins and may mediate the deposition and fibrillogenesis of amyloid at specific tissue sites. In the present study, we demonstrate that heparin sulfate glycosaminoglycan and proteoglycan both bind to the beta-amyloid peptide involved in Alzheimer's disease. The interaction of heparan sulfate proteoglycan and glycosaminoglycan can be inhibited by other sulfated compounds such as heparin, dextran sulfate and pentosan polysulfate. These polysaccharides which are currently used clinically, their derivatives or analogs may be effective as therapeutic agents to prevent or slow the progression of amyloidogenesis in Alzheimer's disease or other amyloidogenic disorders.
Amyloid beta-Peptides↗
Autoantibodies to heparin from patients with antiphospholipid antibody syndrome inhibit formation of antithrombin III-thrombin complexes.
The antiphospholipid antibody syndrome (APS) is characteristically associated with thrombosis. Heparan sulfate (HS) is a physiologic endothelial cell surface modulator of normal anticoagulation, containing a specific oligosaccharide sequence that binds antithrombin III with high affinity and also is present in heparin, a related glycosaminoglycan. We hypothesized that a subset of antiphospholipid antibodies with high affinity for heparan sulfate/heparin epitopes may inhibit the function of HS, promoting a procoagulant state. Purified IgG from all seven patients with APS studied were reactive with heparin by enzyme-linked immunosorbent assay, whereas none of five controls had antiheparin reactivity. IgG antiheparin antibodies were purified from two APS patients by affinity chromatography on heparin-Sepharose. Specificity studies showed that low-affinity electrostatic interactions clearly did not account for the observed reactivity with heparin, and that APS IgG antiheparin antibodies were specifically reactive with a disaccharide present in the heparin pentasaccharide that binds antithrombin III. Furthermore, APS IgG antiheparin antibodies inhibited heparin-accelerated formation of antithrombin III-thrombin complexes. We conclude that antiheparan sulfate/heparin antibodies may be a cause of autoimmune vascular thrombosis in the antiphospholipid antibody syndrome.
Adult↗
Autoantibodies to vascular heparan sulfate proteoglycan in systemic lupus erythematosus react with endothelial cells and inhibit the formation of thrombin-antithrombin III complexes.
Vascular heparan sulfate proteoglycan (vHSPG) is an important functional component of the microvasculature. Previous studies have demonstrated autoimmunity to vHSPG in systemic lupus erythematosus (SLE). In the current studies, we further investigated the immunospecificity of anti-vHSPG antibodies in SLE sera by enzyme-linked immunoassay (ELISA). In direct binding assays, SLE sera contained IgG antibodies reactive with native vHSPG and with heparan sulfate (HS) glycosaminoglycan in significantly higher titers than controls. Employing purified SLE IgG in liquid-phase competitive immunoinhibition ELISAs, SLE IgG anti-HS antibodies cross-reacted with heparin and DNA, but not with other glycosaminoglycans or anionic phospholipid antigens. Immunochemical studies demonstrated that the immunodominant site on HS recognized by SLE IgG contained 2-O-sulfated uronic acid. Removal of N-sulfated and 6-O-sulfated residues primarily on N-acetyl-glucosamine had no effect on antigenicity, further demonstrating that nonspecific charge interactions which are the result of sulfation do not solely account for the antigenicity of HS. SLE IgG from patients with active SLE was further affinity purified on DNA-cellulose and HS-Sepharose columns for immunospecificity studies. After affinity purification of both anti-DNA and anti-HS antibodies, significant enhancement of direct binding reactivity with HS was noted. In addition, anti-DNA and anti-HS IgG antibody reacted with the cell surface of endothelial cells by a cellular ELISA (CELISA). Immunoinhibition studies of CELISA reactivity confirmed that affinity-purified SLE IgG anti-DNA anti-HS antibody were reactive with endothelial cell surface HS antigens. Furthermore, SLE IgG anti-DNA antibody reactivity with endothelial cells was not reduced by DNase treatment of the cells, but was significantly reduced by heparitinase digestion. Since HS plays an important role in the maintenance of normal anticoagulation on the endothelial cell surface by binding antithrombin III, we investigated the inhibition of heparin-accelerated thrombin-antithrombin III complex formation by SLE IgG. Purified IgG from patients with active SLE, but not from normal controls, inhibited heparin-accelerated formation of TAT complexes. These studies demonstrate the presence of IgG autoantibodies to HS in patients with SLE. Anti-HS antibodies recognize an antigenic site also present in heparin, but not other glycosaminoglycans, bind to the endothelial cell surface, and inhibit the formation of TAT complexes. SLE IgG anti-HS antibodies recognize a sulfated uronic acid epitope containing 2-O-sulfate which is important in certain functions of HS, including antithrombin III binding. Thus, anti-HS antibodies may promote a procoagulant state at the endothelial cell surface.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Challenges for acute care geriatric inpatient units under the present Medicare prospective payment system.
The Mount Sinai Medical Center's Geriatric Evaluation and Treatment Unit (GETU) is a 16-bed acute care geriatric unit that operates under the Medicare Prospective Payment System (PPS) in an academic medical center environment. The Medicare PPS and the needs of our local health care system have played a considerable role in the development and operation of our inpatient acute care geriatric unit. The GETU provides acute geriatric care and geriatric assessment and is a site for education and clinical research. The GETU serves a targeted group of acutely ill, hospitalized frail elderly with complex, interdisciplinary needs. The multidisciplinary GETU team was financed from generally available and justifiable hospital resources. Geriatric assessment is conducted under the Medicare PPS during the process of acute care without prolonging hospital length of stay. In fact, during the past 6 years, the introduction of geriatric care and assessment programs has been associated with a significant reduction in hospital length of stay and hospital costs for this complex and difficult population. It is our experience that an acute care geriatric unit functioning under traditional Medical Prospective Payment can have the dual effect of enhancing care and reducing hospital costs for the hospitalized frail elderly.
Academic Medical Centers↗
Acute care of dementia patients: specialized programs needed.
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Making geriatric assessment an asset to your primary care practice.
Geriatric assessment provides the physician with an individualized care plan for at-risk older patients with complex health problems. Its four basic components are physical, mental, functional, and social/economic health. Although the ideal assessment is performed by a team from a variety of disciplines, primary care physicians may perform a limited version in the office and then make appropriate referrals for further evaluation. Various screening instruments are helpful, but they have their limitations. Results provide you with a blueprint that aims to restore function, lower costs, and improve the patient's quality of life.
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Binding of secreted human neuroblastoma proteoglycans to the Alzheimer's amyloid A4 peptide.
Proteoglycans (PGs) may play a fundamental role in all forms of amyloidosis. In Alzheimer's disease, proteoglycans are found deposited in senile plaques and in neurofibrillary tangles. However, the cellular source of these deposited PGs and their role in amyloidosis in Alzheimer's disease is unknown. Proteoglycans were purified from conditioned medium of human neuroblastoma cells (SKNSH-SY 5Y). Two species of proteoglycans were identified by enzyme susceptibility including a heparan sulfate proteoglycan and a dermatan sulfate proteoglycan. A monoclonal antibody to the protein core of a vascular basement membrane heparan sulfate proteoglycan found in senile plaques in Alzheimer's disease cross-reacted with the proteoglycans secreted by human neuroblastoma cells. Binding between 35SO4-labelled neuroblastoma proteoglycans and the Alzheimer amyloid (A4) peptide was demonstrated by affinity chromatography. Specificity studies demonstrated that binding of human neuroblastoma proteoglycans to the amyloid peptide was specific for a heparan sulfate glycosaminoglycan, with some binding to a dermatan sulfate proteoglycan. Binding to A4 was also demonstrated by a chemically deglycosylated protein core preparation. No significant binding of neuroblastoma proteoglycans was found to two other basic peptides derived from the extracellular domain of the beta-amyloid precursor, demonstrating the specificity of proteoglycan binding to the A4 peptide. Human neuroblastoma proteoglycans may bind to the-Alzheimer amyloid A4 peptide in a region with a heparin binding consensus sequence [VHHQKL] which also contains the cleavage site of the beta-amyloid precursor protein. Neuronal proteoglycans may either regulate the secretion of the amyloid protein precursor or modify the binding of the amyloid protein precursor to other cellular adhesion molecules. Alterations in this binding may be related to the pathogenesis of amyloid deposition in Alzheimer's disease.
Alzheimer Disease↗
Studies of the cellular immune response to heparan sulfate proteoglycan in the tight skin mouse.
As in human scleroderma, tight skin (TSK/+) mice develop cutaneous hyperplasia with over-production of extracellular matrix, including collagen and proteoglycans, associated with autoimmunity to a number of autoantigens. The present study investigated the presence of cellular autoimmunity to basement membrane heparan sulfate proteoglycan (HSPG) in diseased TSK/+mice and their nondiseased littermates, pallid mice (+/pa). Lymphocyte proliferative responses to specific HSPG antigens, including intact HSPG, HSPG protein core (P. Core), and the glycosaminoglycan heparan sulfate (HS) were studied. Splenocytes from young TSK and control pallid mice reacted weakly to intact HSPG and HSPG P. Core antigens and did not respond to HS. However, lymphocytes from old TSK mice were reactive with HSPG and P. Core and demonstrated a de novo response to HS. The proliferative response to intact HSPG and HSPG P. Core in TSK mice was T cell dependent, but the response to HS was T cell independent. The T cell-dependent response was mediated by the CD4-positive subset and required the participation of class II major histocompatibility complex molecules. Cellular autoimmunity to HSPG, a critical cell surface and extracellular matrix component, may play a role in the disease suffered by TSK mice. Further studies are necessary to determine the mechanisms which link autoimmunity to HSPG with the pathology seen in TSK mice, particularly the overproduction of extracellular matrix and fibrosis.
Animals↗
Monoclonal antibodies to heparan sulfate inhibit the formation of thrombin-antithrombin III complexes.
As components of the cell surface and extracellular matrix, heparan sulfate proteoglycans play an important role in the function of most organs, including the vasculature. Autoimmunity to heparan sulfate (HS) glycosaminoglycan epitopes may play a role in tissue injury. Tight skin (TSK) mice suffer a disease resembling scleroderma, an autoimmune disease associated with alterations in the extracellular matrix of the skin and other organs, as well as vascular injury. Studies of autoimmunity to HS were performed in TSK mice employing a solid-phase radioimmunoassay for the detection of anti-HS antibody. An increase in the clonal frequency of hybridomas secreting anti-HS antibody was noted in TSK mice compared to that in control mice. Liquid-phase competitive inhibition specificity studies of IgM and IgG anti-HS monoclonal antibodies demonstrated little cross-reactivity with other glycosaminoglycans. Some cross-reactivity, albeit at lower affinity, with phosphorylated antigens including DNA, cardiolipin, and RNA polymerase were noted. Negatively charged sulfate groups and carboxyl groups played a role in the immunodominant site. Monoclonal antibodies to HS inhibited the binding of HS to antithrombin III and the formation of thrombin-antithrombin III complexes. These results demonstrate autoimmunity to HS in TSK mice. The results also indicate that HS is a high-affinity antigen of pathological significance for anti-DNA and anti-phospholipid antibodies. Thrombosis induced by polyclonal anti-phospholipid antibodies may be mediated by a subset of these antibodies with high affinity for HS. Anti-HS antibodies may promote a procoagulant state by the blockade of HS binding to antithrombin III, inhibiting the accelerated formation of thrombin-antithrombin III complexes.
Animals↗
Identification of antigenic epitopes in type IV collagen by use of synthetic peptides.
Peptides representing potential antigenic regions of the NC-1 and 7-S domains of the human alpha 1 and alpha 2, and bovine alpha 3 chains of type IV collagen were synthesized either chemically or by the recombinant DNA technique and tested by ELISA using antibodies raised in rabbits against the whole type IV collagen or the NC-1 domain. Sera from patients with Goodpasture syndrome (GP) or with acute poststreptococcal glomerulonephritis (APSGN) were also tested. The location of antigenic determinants was predicted from the primary and secondary structure of the chains, that is, aromaticity, hydrophilicity and presence of beta-turns. All synthetic peptides reacted with the antiserum to type IV collagen (anti-Col IV). Whereas all peptides arising from the NC-1 domain reacted with anti-NC-1, intact 7-S or peptides of the alpha 1 or alpha 2 chain of the 7-S domain did not react. However intact 7-S reacted with anti-Col IV. Two synthetic peptides from the NC-1 domain of alpha 1, (a.a. 71-90 and a.a. 176-190), one from the alpha 2 (a.a. 70-83) and four from the alpha 3 chain (a.a. 72-89, a.a. 104-117, a.a. 133-145, a.a. 185-203) reacted with anti-NC-1 and anti-COL IV. The above peptides, except alpha 3 (72-89) and alpha 3 (185-203), were tested and found to be reactive with sera from patients with GP.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Identification of alcoholism and depression in a geriatric medicine outpatient clinic.
OBJECTIVE: To examine the utility of brief screening instruments for alcoholism and depression in the frail elderly medical outpatient. DESIGN: Cross-sectional examination. SETTING: Coffey Geriatric Outpatient Clinic, The Mount Sinai School of Medicine, New York City. SUBJECTS: Convenience sample of 84 consenting male and female outpatients over 62 years of age. MEASUREMENTS: The Michigan Alcohol Screening Test (MAST), CAGE questionnaire, and the Geriatric Depression Scale (GDS). RESULTS: Four subjects (5%) scored positive for alcoholism on the MAST, all of whom had been previously identified by the geriatric clinic staff. In contrast, the CAGE only identified 1 (1.4%) alcoholic subject. Thirty-two percent of subjects scored positive for depression on the GDS, yet only one-third of these depressed patients had been previously identified by the geriatric team as depressed. Among the depressed outpatients, 19% were labeled anxious and received anxiolytics from the geriatric medical staff. CONCLUSIONS: Whereas brief alcohol screening instruments to detect alcoholism did not augment the geriatrician's clinical assessment, screening for depression with the GDS may be an important adjunct to the identification of depression in geriatric medical patients.
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Association of autoimmunity to vascular heparan sulfate proteoglycan and vascular disease in the aged.
In the very old, there is an increased prevalence of immunologically mediated vascular disease. Vascular heparan sulfate proteoglycan (vHSPG) is a molecule which plays an important structural and functional role in the vasculature. Autoimmunity to vHSPG may play a role in the pathogenesis of vascular disease. The presence of autoantibodies to vHSPG was investigated in sera from aged nursing home patients who have a high prevalence of vascular disease. The results showed an association of the presence of autoantibodies to vHSPG in the sera from patients in this aged population with vascular disease, particularly cerebrovascular disease, renal disease and diabetes. In addition, autoantibodies to vHSPG protein core were associated with cerebrovascular disease in this frail elderly population. These studies support the hypothesis that autoimmunity may play a role in vascular disease in the aged.
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The role of anthropometry in the assessment of malnutrition in the hospitalized frail elderly.
Although common among the hospitalized frail elderly, malnutrition is often unrecognized by clinicians, and its identification is fought with difficulty due to inadequate nutritional assessment methods and standards. This study compared the use of percent ideal body weight (%IBW) and anthropometry in the assessment of malnutrition in the hospitalized frail elderly. Approximaty 45% of patients studied had at least two anthropometric measurements below the 5th percentile, a level reflecting severe malnutrition. However, only 28% of patients were found to be less than 90% IBW, a level reflecting only mild to severe changes in body weight. Serum albumin was below normal (< 35 g/l) in 30% of patients. The total lymphocyte count was below normal (< 1,500 cells/mm3) in 53%, and was severely depressed (< 800 cells/mm3) in 24%. Thus, despite the use of stringent anthropometric criteria indicating severe malnutrition, anthropometry appeared more sensitive than %IBW as a measure of malnutrition in the hospitalized frail elderly. Furthermore, acute illness causes changes in commonly employed blood measures which make them unreliable in the assessment of malnutrition in this population. Anthropometry may prove to be the most stable, easily performed, and sensitive measure of malnutrition in the hospitalized frail elderly. However, further studies are clearly needed, including the development of appropriate anthropometric reference standards for the very old, a population that commonly suffers malnutrition.
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Autoantibodies to the protein core of vascular basement membrane heparan sulfate proteoglycan in systemic lupus erythematosus.
Vascular heparan sulfate proteoglycan (vHSPG) has an important role in the normal vasculature, including hemostasis, lipolysis and other vascular functions. These functions are mediated by both the glycosaminoglycan and protein core moieties of vHSPG. Autoimmunity to vHSPG has been demonstrated to play a role in vascular injury in animal models, and is present in patients with autoimmune vascular disease. However, most previous studies of human autoimmunity to vHSPG have only investigated heparan sulfate glycosaminoglycan epitopes. In the current investigations, autoantibodies to the protein core of vHSPG in sera from patients with systemic lupus erythematosus (SLE) were investigated. vHSPG protein core was prepared by chemical deglycosylation. Competitive immunoinhibition ELISA and immunoblotting immunoassays were established employing monoclonal antibodies to vHSPG protein core. SLE sera were demonstrated to contain IgG autoantibodies reactive with the vHSPG protein core by immunoblotting. Human autoantibodies to vHSPG protein core were not inhibited by heparan sulfate confirming their protein core reactivity. Competitive immunoinhibition studies employing a solid phase radioimmunoassay also confirmed the reactivity of human sera with vHPSG protein core. By ELISA, a significant increase in the occurrence of anti-vHSPG protein core antibodies was noted in SLE sera. While most previous investigations have demonstrated autoimmunity to heparan sulfate, the presence of IgG autoantibodies to vHSPG protein core demonstrates that the entire vHSPG proteoglycan is the target of autoimmunity in SLE.
Animals↗
The geriatric evaluation and treatment unit: a model site for acute care of the frail elderly, education, and research.
Geographically based inpatient geriatric units are an increasingly common organizational approach throughout the world for the care of the hospitalized frail elderly with complex, multidisciplinary acute care needs. The unit provides comprehensive and efficient quality care to these patients by bringing together, in a geographically based unit, specialists from a multiplicity of disciplines to provide needed services in a coordinated manner. To accomplish its goals, the unit employs experts in geriatric medicine, nursing, social work, psychiatry, and other disciplines in a team approach to comprehensive assessment. The education of medical students, medical housestaff, and geriatrics fellows is a critical function of the unit. The unit also serves as a site for research in improving the care of the hospitalized frail elderly.
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Research activities in the Department of Geriatrics and Adult Development.
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Aging↗
Vascular dementia: stroke prevention takes on new urgency.
Vascular dementia is a clinical syndrome of acquired intellectual impairment resulting from brain injury due to a cerebrovascular disorder. It is a complex diagnosis, and diagnostic criteria vary. In community practice, the physician can probably make the diagnosis based on the history and medical examination. CT demonstration of one or more infarcts increases the likelihood of this diagnosis. Hypertension is a major risk factor for vascular dementia. Others include smoking, hyperlipidemia, atrial fibrillation, diabetes, and a sedentary lifestyle. Cerebrovascular disease is an important cause of cognitive decline in older patients. Therefore, it is important to recognize risk factors for stroke and institute measures for prevention.
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