David Hamerman

Toward an Understanding of Frailty

Health care providers who serve an aging population inherently associate the word frailty with patients whom they perceive as frail. Although frailty is not confined to elderly persons, it is more frequently observed in persons older than 85 years of age (the oldest old) (1). This is because limitations and diseases associated with aging are an inseparable part of frailty (2-5). As a result, frailty remains more a constellation of many conditions than a discrete clinical entity, and it certainly does not have a precise scientific meaning (6). Frailty is often identified by words that express a similar state, such as feeble, or, as the French describe it, fragilit (7). Speechly and Tinetti (8) contrasted frail with vigorous in a study of elderly community dwellers. These limitations in defining frailty make its actual prevalence uncertain. Strawbridge and colleagues (9) noted the breadth of the conceptual range of frailty: On the one hand, it might include one or more conditions associated with old age (and, thus, most older persons would be frail) (10); on the other hand, it might be limited to severely disabled persons (in which case only a small proportion of older persons would be frail). But even if frailty is not universal and represents a subset of the many persons who have attained advanced age and remain vigorous, it nevertheless assumes an importance out of proportion to its prevalence. There is a high toll in personal suffering, caregiver burden, costs of health care, medication use, and hospitalization, all of which signify enhanced health care demands by any measure of health resources utilization. Defining frailty may be like attempting to know the dancer from the dance; nevertheless, I attempt to present an understanding of frailty by describing many of its clinical correlates and considering evidence for its biological underpinnings. Frailty might emerge more sharply as a clinical entity if it were described in biological terms. Evidence indicates that many of the clinical states associated with frailty are related to the pathophysiologic effects of an altered metabolic balance, manifested by cytokine overexpression and hormonal decline. Currently studied serum markers that reflect this imbalance lack specificity thus far but may provide a way to identify frailty at its incipient stages and differentiate it from associated comorbid conditions. This would stimulate new therapeutic interventions and ultimately promote primary prevention. The potential to ameliorate frailty is an important health care goal that has enormous societal implications; it could add to the quality of the later years of life and perhaps extend the life span. Clinical Correlates Comprehensive reviews of frailty have been published recently (2, 3, 5, 7, 9, 11-13). A MEDLINE search revealed that frailty was cited in 335 articles (13) from 1989 to 1992 and in 563 articles (3) from 1992 to January 1996. Although Brown and coworkers (7) defined frailty as diminished ability to carry out the important practical and social activities of daily living, frailty is more often described in general terms: a product of excess demand imposed upon reduced capacity (3); a precarious balance easily perturbed (11); a condition in individuals lacking in strength who are delicately constituted or fragile (6); or a state that puts persons at risk for adverse health outcomes (2) or makes them inherently vulnerable to challenge from the environment (9, 14) or unable to integrate responses in the face of stress (15). Table 1 shows an evolving geriatric functional continuum in which frailty is a midpoint between independence and pre-death. Primary intervention is currently limited because manifestations of frailty before functional decline are not always apparent. In an intermediate stage, manifestations are already evident, prompting secondary interventions; for persons in whom frailty is destined to progress to an end stage, interventions are essentially palliative. The designation of frailty overlaps with a range of other clinical correlates that broadly represent functional decline (12): being underweight or having anorexia or cachexia (29-33), moving slowly or taking to bed (28), responding only partially to nutrients or failing to thrive (20-23), coping poorly or not at all (acopia) (27), demonstrating sarcopenia and weakness (18, 19) with limited mobility and a tendency to fall (8), or requiring limited assistance or being dependent (12, 13, 26) (Table 1). Cognitive impairments may also appear as a slowing of mentation rather than as an acute change or a state of confusion, such as delirium. Frailty is sometimes but not always associated with dementia. Table 1. A Geriatric Functional Continuum In the constellation of frailty, the health provider must make critical decisions that relate to medicalization of a condition that may not necessarily be disease based. For persons who seem frail, how extensive should the work-up, which is often poorly tolerated, be in an effort to uncover underlying, progressive disease (cancer is the most obvious in view of the invariable weight loss)? Should a condition that tips the balance (such as stroke or hip fracture after a fall) be considered an accountable, or organic, basis on which to diagnose frailty (8, 11, 20, 22, 24)? When can a frail person, his or her family, or, more often, his or her physician consider frailty nonorganic (22)a progressive loss of homeostatic and stabilizing mechanisms and a primary failure to thrive (25)and accept or recommend comfort care? Clearly, these choices will require individual considerations and a review of the place of the frail person within the geriatric continuum from apparently early to very late. Proposed interventions aimed at improving or stabilizing the existing quality of life raise medical decisions, ethical issues, and, particularly in this era, aspects of cost and benefit. Defining a rational way to intervene may also be difficult in many elderly patients where illness does not fit a classic disease model (35) and when the presentation is atypical (36). Involuntary weight loss without apparent disease or vague symptoms alone may indicate risk for death in some older persons (28, 29). In one study, persons in an intermediate care facility who took to bed because of fatigue or nonlocalizing weakness had significantly shorter survival than the group as a whole (28). Despite the many reviews that seek to define frailty more precisely by patient assessment and identification of risk factors in order to promote early intervention (37-39), the concept of frailty remains diffuse. To some extent, it is similar to the term anemia, which implies a clinical perception; symptoms; and physical, laboratory, and biological findings that reflect many underlying conditions. Table 2 lists several conditions that interact with frailty and increase the likelihood of its development. Prospects for intervention would have to take these interactive conditions into account. Fried (2) proposed a model pathway of frailty that depends on whether the intervention occurs in the incipient phase of the alteration (primary strategy), during the clinical syndrome (secondary strategy), or at the time of the adverse outcome (tertiary strategy). Buchner and Wagner (6) discuss risk factors predictive of future disability that can be modified to reduce subsequent risk (primary prevention) and interventions to retard an early state of disablement (secondary prevention). In a cohort of older persons living in the community, risk factors for frailty included leg and arm weakness, reduced vision or hearing, and anxiety (56). In Great Britain, the required annual health check for all patients 75 years of age or older revealed physical symptoms in about half, for which some action was taken (57). Certainly, a reservoir of unreported needs that can be addressed exists for elderly persons at home (58). Table 2. Interactive Conditions Associated with Frailty The benefits of comprehensive geriatric assessment generally seem more evident in frail populations (10, 11, 14, 59) as Rubenstein and colleagues (60) showed. In a groundbreaking study, they found that comprehensive geriatric assessment prolonged life in frail older men in a Veterans Administration facility (60). In the long run, however, the health outcomes that result from assessment of elderly frail persons are not likely to reduce morbidity (61) but rather to extend it (62, 63) because associated chronic, nonfatal conditions will be identified (63). In fact, as Boult and associates (64) point out, the current orientation aimed at reducing fatal conditions, such as cancer or coronary artery disease, would increase the number of older persons with functional limitations. In the next decade, reduction of chronic, nonfatal conditions would be a signal public health achievement in an aging society (63, 64). The prevalence of chronic disability and of many chronic degenerative diseases in the United States seemed to decrease from 1982 to 1994 (65). During the course of this continuing achievement, identification of the biological underpinnings of frailty would help dissociate this state from the constellation of associated and less remediable chronic conditions and facilitate early intervention. Biological Underpinnings Our understanding of a biological basis for many chronic conditions, such as osteoarthritis (66), osteoporosis (67, 68), and Alzheimer disease (69, 70), has advanced because of advocating personal health practices, defining genetic and biological markers, and evaluating diagnostic imaging techniques, where the ultimate intent is secondary or primary prevention. However, potential interventions for frailty based on understanding of its biological basis are confounded at the outset by the multifactorial nature of the condition, its manifestations within the spectrum of many chronic nonfatal conditions, the overlay of cognitive and mood al

Metachromasia; chemical theory and histochemical use.

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Interleukin 1 enhances synovial cell hyaluronate synthesis.

Abstract Interleukin 1 enhances proliferation of murine thymocytes in the presence of lectins, and is also known to stimulate the release of prostaglandins and neutral proteases from a variety of cell types. We have previously shown that a factor isolated from the culture media of disaggregated lining cells of the human synovial membrane was indistinguishable from monocyte-derived interleukin 1. We report here that interleukin 1 from either source stimulates hyaluronate synthesis by synovial membrane cells. Upon gel filtration or isoelectric focusing of synovial cell superna-tants, the hyaluronate-stimulatory activity co-fractionates with the interleukin 1 activity. Enhanced cell secretion of hyaluronate is a newly described metabolic effect of interleukin 1.

Communication Skills of House Officers: A Study in a Medical Clinic

The communication skills of house officers in medical clinic were studied. Ten communication skills were identified as being central to the doctor-patient relationship. Twenty interns and residents were observed in 60 clinic visits. Skills well-demonstrated by the house officers related to listening, history taking, assessing patient compliance, examining the patient, and prescribing therapy. Underdeveloped skills were those that involved obtaining the patients understanding of his illness, social history, and emotional response and the doctors explanation of the illness. To enhance performance of these skills, changes are recommended in four areas of ambulatory teaching: liaison psychiatry, faculty development, medical precepting, and the relationship between faculty and house officers.

Ombudsmen (medical-psychiatric) rounds. An approach to meeting patient-staff needs.

Ombudsmen rounds conducted jointly by a medical attending physician (ombudsman) and a psychiatrist bring the entire staff on each of the medical wards of Montefiore Hospital together weekly. An attempt is made to address both staff and patient needs on an inpatient medical service. Through group discussions and patient interviews, in which the patient has an opportunity to express his own feelings about his illness and his care, the staff becomes aware of the psychosocial issues that are universally evoked by illness and hospitalization. All staff members are also encouraged to relate their reactions to the patient and their interactions with each other. The ombudsmen-rounds concept maximizes the use of the internist and liaison psychiatrist, and makes psychosocial-medical teaching routine on the medical service in a contemporary teaching hospital where the practice of holistic medicine has been so difficult to implement.

Risk Factors Associated with Immobility

In nursing homes, immobility and related complications are major problems with profound health care and financial implications. We conducted a retrospective study to identify risk factors associated with immobility. We compared factors in 34 nonambulatory residents with those in 12 independent ambulatory residents who served as controls. Factors associated with immobility included contractures, severe dementia, poor vision, and history of hip /leg fractures. Factors not associated with immobility included age, osteoarthritis, mild to moderate dementia, weight gain, and broad categories of selected medications. The immobile patients were further analyzed by sub‐grouping into those with and without contractures. Contractures were significantly associated with severe dementia. The finding that immobility was not identified on problem lists for 85% (29) of the immobile residents and that for 29% (10) reasons for immobility could not be ascertained suggest that immobility is frequently not documented as a major problem in medical records nor adequately evaluated.

Hyaluronate in normal human synovial fluid.

Several methods were used in the present study to determine the hyaluronate content of normal synovial fluid. Weighing rather than pipetting the small samples of viscous fluid made it possible to measure hyaluronate in 0.25 Gm. of synovial fluid. Hyaluronate was precipitated in mucin clots formed by adding acid or a polyvalent cation to synovial fluid, and was measured indirectly by determining hexosamine in these clots. Since a part of the hexosamine of synovial fluid is not a component of hyaluronate, an important aspect of this work was the demonstration that no nonhyaluronate hexosamine was precipitated in mucin clots, and that no hyaluronate hexosamine remained in the supernatant after a mucin clot was formed. Hyaluronate content of synovial fluid was also measured by determining the fall in hexosamine after hyaluronidase digestion and dialysis of whole synovial fluid. Figures for hyaluronate in synovial fluid as determined by mucin clot technique, and by hyaluronidase digestion and dialysis of synovial fluid agreed, lending confidence in the validity of these methods.

Glycosaminoglycans Produced by Human Synovial Cell Cultures

Human synovial cells in culture are known to synthesize hyaluronic acid, but the production of sulfated glycosaminoglycans (GAG) has received less attention. Using 14C-glucosamine as a precursor, GAG content was studied in the medium, trypsin-solubilized pericellular layer, and cell residue fraction of cultured synovial cells derived from the synovial membranes of nonrheumatoid and rheumatoid joints. Over 90% of the total non-dialyzable counts appeared in the culture medium, for the most part in hyaluronic acid. The remaining nondialyzable counts were cell-associated, almost equally divided between the pericellular layer and cell residues. In these fractions, only part of the counts were in GAG susceptible to testicular hyaluronidase digestion, and GAG were significantly lower in the cell residue of the rheumatoid synovial cells compared to the nonrheumatoid cells. Analysis of the chondroitinase ABC and AC digestion products of these GAG indicated the presence of chondroitin-4 and -6 sulfates, and dermatan sulfate, but not heparan sulfate. Similar findings with respect to the identity of the GAG in nonrheumatoid and rheumatoid synovial cell culture media were obtained with 35SO4 as a precursor.

Growth Factors With Heparin Binding Affinity In Human Synovial Fluid

Abstract Synovial effusions were obtained from the knees of 15 subjects with joint trauma, menisceal or ligamentous injury, or osteoarthritis. Heparin-Sepharose affinity chromatography of these synovial fluids revealed, in general, three major peaks of mito-genic activity as measured by incorporation of 3H-thymidine into 3T3 cells. Gradient elution patterns showed activities at 0.5M NaCl, which is characteristic of platelet derived growth factor, and at 1.1M NaCl and 1.6M NaCl, indicative of acidic and basic fibroblast growth factors, respectively. The identities of these mitogenic fractions were confirmed by specific immunologic and receptor-binding assays. The presence of platelet derived, acidic and basic fibroblast growth factors in the synovial fluid may contribute to wound healing in the arthritic joint.

Cellular Origin of Hyaluronateprotein in the Human Synovial Membrane

Bright fluorescent staining, which indicates the presence of hyaluronateprotein, was observed in the lining cells of the synovial membrane following application of rabbit antiserum to hyaluronateprotein and a fluorescein-labeled antiserum to rabbit γ-globulin. Staining was shown to be specific and due to antigenic determinants on or closely associated with the protein moiety of hyaluronateprotein.