COVID-19 in Assisted Living: Protecting a Critical Long-Term Care Resource.

The COVID-19 pandemic had a big impact on assisted living (AL), a vital setting in long-term care (LTC). Understanding the strengths and opportunities for improvement through practice, policy, and research are essential for AL to be prepared for the next pandemic and other challenges. AL communities experienced the pandemic in unique ways, because of varying regulatory environments, differences in familiarity with using and procuring personal protective equipment not typically used in AL (such as N95 masks), loss of family involvement, the homelike environment, and lower levels of licensed clinical staff. Being state rather than federally regulated, much less national data are available about the COVID-19 experience in AL. This article reviews what is known about cases and deaths, infection control, and the impact on residents and staff. For each, we suggest actions that could be taken and link them to the Assisted Living Workgroup Report (ALW) recommendations. Using the Center for Excellence in Assisted Living (CEAL) 15-year ALW report, we also review which of these recommendations have and have not been implemented by states in the preceding decade and half, and how their presence or absence may have affected AL pandemic preparedness. Finally, we provide suggestions for policy, practice, and research moving forward, including improving state-level reporting, staff vaccine requirements, staff training and work-life, levels of research-provider partnerships, dissemination of research, and uptake of a holistic model of care for AL.

Apical sodium-dependent bile acid transporter inhibition with volixibat improves metabolic aspects and components of non-alcoholic steatohepatitis in Ldlr-/-.Leiden mice.

Interruption of bile acid recirculation through inhibition of the apical sodium-dependent bile acid transporter (ASBT) is a promising strategy to alleviate hepatic cholesterol accumulation in non-alcoholic steatohepatitis (NASH), and improve the metabolic aspects of the disease. Potential disease-attenuating effects of the ASBT inhibitor volixibat (5, 15, and 30 mg/kg) were investigated in high-fat diet (HFD)-fed Ldlr-/-.Leiden mice over 24 weeks. Plasma and fecal bile acid levels, plasma insulin, lipids, and liver enzymes were monitored. Final analyses included liver histology, intrahepatic lipids, mesenteric white adipose tissue mass, and liver gene profiling. Consistent with its mechanism of action, volixibat significantly increased the total amount of bile acid in feces. At the highest dose, volixibat significantly attenuated the HFD-induced increase in hepatocyte hypertrophy, hepatic triglyceride and cholesteryl ester levels, and mesenteric white adipose tissue deposition. Non-alcoholic fatty liver disease activity score (NAS) was significantly lower in volixibat-treated mice than in the HFD controls. Gene profiling showed that volixibat reversed the inhibitory effect of the HFD on metabolic master regulators, including peroxisome proliferator-activated receptor-γ coactivator-1ß, insulin receptor, and sterol regulatory element-binding transcription factor 2. Volixibat may have beneficial effects on physiological and metabolic aspects of NASH pathophysiology.

Complex Regulation of the Pericellular Proteolytic Microenvironment during Tumor Progression and Wound Repair: Functional Interactions between the Serine Protease and Matrix Metalloproteinase Cascades.

Spatial and temporal regulation of the pericellular proteolytic environment by local growth factors, such as EGF and TGF-ß, initiates a wide repertoire of cellular responses coupled to a plasmin/matrix metalloproteinase (MMP) dependent stromal-remodeling axis. Cell motility and invasion, tumor metastasis, wound healing, and organ fibrosis, for example, represent diverse events controlled by expression of a subset of genes that encode various classes of tissue remodeling proteins. These include members of the serine protease and MMP families that functionally constitute a complex system of interacting protease cascades and titrated by their respective inhibitors. Several structural components of the extracellular matrix are upregulated by TGF-ß as are matrix-active proteases (e.g., urokinase (uPA), plasmin, MMP-1, -3, -9, -10, -11, -13, -14). Stringent controls on serine protease/MMP expression and their topographic activity are essential for maintaining tissue homeostasis. Targeting individual elements in this highly interactive network may lead to novel therapeutic approaches for the treatment of cancer, fibrotic diseases, and chronic wounds.

PAI-1: An Integrator of Cell Signaling and Migration.

Cellular migration, over simple surfaces or through complex stromal barriers, requires coordination between detachment/re-adhesion cycles, involving structural components of the extracellular matrix and their surface-binding elements (integrins), and the precise regulation of the pericellular proteolytic microenvironment. It is now apparent that several proteases and protease inhibitors, most notably urokinase plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1), also interact with several cell surface receptors transducing intracellular signals that significantly affect both motile and proliferative programs. These events appear distinct from the original function of uPA/PAI-1 as modulators of the plasmin-based proteolytic cascade. The multifaceted interactions of PAI-1 with specific matrix components (i.e., vitronectin), the low-density lipoprotein receptor-related protein-1 (LRP1), and the uPA/uPA receptor complex have dramatic consequences on the migratory phenotype and may underlie the pathophysiologic sequalae of PAI-1 deficiency and overexpression. This paper focuses on the increasingly intricate role of PAI-1 as a major mechanistic determinant of the cellular migratory phenotype.

PAI-1 mediates the TGF-beta1+EGF-induced "scatter" response in transformed human keratinocytes.

Cooperative interactions between growth factor signaling pathways are important elements in carcinoma progression. A model system combining transforming growth factor-beta1 (TGF-beta1) and EGF was developed to investigate mechanisms underlying induced epithelial-to-mesenchymal transition (EMT) in ras-transformed human (HaCaT II-4) keratinocytes. Dual stimulation with TGF-beta1+EGF resulted in keratinocyte "plasticity" and pronounced colony dispersal. The most highly expressed transcript, identified by mRNA profiling, encoded plasminogen activator inhibitor-1 (PAI-1; SERPINE1). PAI-1 negatively regulates plasmin-dependent matrix degradation, preserving a stromal scaffold permissive for keratinocyte motility. Mitogen-activated extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) and p38 signaling were required for maximal PAI-1 upregulation and TGF-beta1+EGF-stimulated cell locomotion, as pharmacologic disruption of MEK/p38 activity ablated both responses. Moreover, PAI-1 knockdown alone effectively inhibited TGF-beta1+EGF-dependent cell scattering, indicating a functional role for this SERPIN in the dual-growth factor model of induced motility. Moreover, EGFR signaling blockade or EGFR knockdown attenuated TGF-beta1-induced PAI-1 expression, implicating EGFR transactivation in TGF-beta1-stimulated PAI-1 expression, and reduced colony dispersal in TGF-beta1+EGF-treated cultures. Identification of such cooperative signaling networks and their effect on specific invasion-promoting target genes, such as PAI-1, may lead to the development of pathway-specific therapeutics that affect late-stage events in human tumor progression.

The role of nursing home admission and dementia status on care for diabetes mellitus.

OBJECTIVES: To study the role of nursing home (NH) admission and dementia status on the provision of five procedures related to diabetes mellitus. DESIGN: Retrospective cohort study using data from a large prospective study in which an expert panel determined the prevalence of dementia. SETTING: Fifty-nine Maryland NHs. PARTICIPANTS: Three hundred ninety-nine new admission NH patients with diabetes mellitus. MEASUREMENTS: Medicare administrative claims records matched to the NH medical record data were used to measure procedures related to diabetes mellitus received in the year before NH admission and up to a year after admission (and before discharge). Procedures included glycosylated hemoglobin, fasting blood glucose, dilated eye examination, lipid profile, and serum creatinine. RESULTS: For all but dilated eye examinations, higher rates of procedures related to diabetes mellitus were seen in the year after NH admission than in the year before. Residents without dementia received more procedures than those with dementia, although this was somewhat attenuated after controlling for demographic, health, and healthcare utilization variables. Persons without dementia experience greater increases in procedure rates after admission than those with dementia. CONCLUSION: The structured environment of care provided by the NH may positively affect monitoring procedures provided to elderly persons with diabetes mellitus, especially those without dementia. Medical decisions related to the risks and benefits of intensive treatment for diabetes mellitus to patients of varying frailty and expected longevity may lead to lower rates of procedures for residents with dementia.

TGF-beta1 + EGF-initiated invasive potential in transformed human keratinocytes is coupled to a plasmin/MMP-10/MMP-1-dependent collagen remodeling axis: role for PAI-1.

The phenotypic switching called epithelial-to-mesenchymal transition is frequently associated with epithelial tumor cell progression from a comparatively benign to an aggressive, invasive malignancy. Coincident with the emergence of such cellular plasticity is an altered response to transforming growth factor-beta (TGF-beta) as well as epidermal growth factor (EGF) receptor amplification. TGF-beta in the tumor microenvironment promotes invasive traits largely through reprogramming gene expression, which paradoxically supports matrix-disruptive as well as stabilizing processes. ras-transformed HaCaT II-4 keratinocytes undergo phenotypic changes typical of epithelial-to-mesenchymal transition, acquire a collagenolytic phenotype, and effectively invade collagen type 1 gels as a consequence of TGF-beta1 + EGF stimulation in a three-dimensional physiologically relevant model system that monitors collagen remodeling. Enhanced collagen degradation was coupled to a significant increase in matrix metalloproteinase (MMP)-10 expression and involved a proteolytic axis composed of plasmin, MMP-10, and MMP-1. Neutralization of any one component in this cascade inhibited collagen gel lysis. Similarly, addition of plasminogen activator inhibitor type 1 (SERPINE1) blocked collagen degradation as well as the conversion of both proMMP-10 and proMMP-1 to their catalytically active forms. This study therefore identifies an important mechanism in TGF-beta1 + EGF-initiated collagen remodeling by transformed human keratinocytes and proposes a crucial upstream role for plasminogen activator inhibitor type 1-dependent regulation in this event.

TGF-ß1-Induced Expression of the Anti-Apoptotic PAI-1 Protein Requires EGFR Signaling.

TGF-ß1 and its target gene encoding plasminogen activator inhibitor-1 (PAI-1) are major regulators of capillary outgrowth, vessel maturation and angiogenic network stability. The increasing realization of the complexity of PAI-1 action in the vascular system requires analysis of specific signaling events that impact its expression in a physiologically-relevant cell system. PAI-1 was required for tubular differentiation and maintenance of cellular survival in complex gels since targeted disruption of PAI-1 synthesis or activity with antisense constructs or function-blocking antibodies resulted in network regression. Indeed, serum-deprivation-induced apoptosis of tubulogenic T2 cells was concentration-dependently inhibited by addition of a stable PAI-1 mutant protein consistent with the established pro-survival role of PAI-1 in vascular endothelial cells. PAI-1 induction and ERK pathway activation in response to TGF-ß1 was attenuated by EGFR signaling blockade (with AG1478) or preincubation with the MMP/ADAM inhibitor GM6001. The combination of AG1478 + GM6001 completely ablated both responses suggesting that EGFR transactivation is important in PAI-1 gene control and may, at least partially, involve ligand shedding. TGF-ß1-stimulated PAI-1 induction was preceded, in fact, by EGFR phosphorylation on Y845 (a src kinase target residue). EGFR1 knockdown with lentiviral shRNA constructs, moreover, effectively decreased (by >75%) TGF-ß1-stimulated PAI-1 expression whereas infection with control (i.e. GFP) viruses had no effect. TGF-ß1 failed to induce PAI-1 synthesis in EGFR-deficient fibroblasts while introduction of a wild-type EGFR1 construct in EGFR(-/-) cells rescued the PAI-1 response to TGF-ß1 confirming, at a genetic level, the targeted knockdown data. The continued clarification of novel cooperative signaling cascades that impact expression of important angiogenic genes (e.g. PAI-1) may provide therapeutically useful targets to manage the pathophysiology of human neoplastic and vascular diseases.

PAI-1 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma.

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-beta synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-beta/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype. In one physiologically relevant model of human cutaneous SCC progression, TGF-beta1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs), among the most prominent of which is MMP-10-an MMP known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC. One testable hypothesis proposes that TGF-beta1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies.

Short-stay nursing home rehabilitation patients: transitional care problems pose research challenges.

A clinical intervention pilot study to improve depression care for short-stay nursing home Medicare-reimbursed rehabilitation patients funded by the National Institute on Aging was conducted. Despite solid theoretical and clinical grounding and the support of a large nursing home company, several roadblocks to implementation were encountered, including involving patients and families, communication between providers, involving community primary care physicians, staff time constraints, and conducting research with short-stay patients. Although frustrating from a research standpoint, these roadblocks closely reflect problems identified by the American Geriatrics Society as impeding the delivery of high-quality transitional care in geriatrics. These research roadblocks are described as they were encountered in the clinical setting, and each is placed within the larger context of challenges associated with care transitions, especially for older persons with complex health needs receiving nursing home rehabilitation. Finally, recommendations are offered for researchers conducting much-needed research within geriatric transitional care settings, including starting early in the care transition chain and assisting patients and families with providing continuity across care settings.

SERPINE1 (PAI-1) is deposited into keratinocyte migration "trails" and required for optimal monolayer wound repair.

Cutaneous tissue injury, both in vivo and in vitro, initiates activation of a "wound repair" transcriptional program. One such highly induced gene encodes plasminogen activator inhibitor type-1 (PAI-1, SERPINE1). PAI-1-GFP, expressed as a fusion protein under inducible control of +800 bp of the wound-activated PAI-1 promoter, prominently "marked" keratinocyte migration trails during the real-time of monolayer scrape-injury repair. Addition of active recombinant PAI-1 to wounded wild-type keratinocyte monolayers as well as to PAI-1(-/-) MEFs and PAI-1(-/-) keratinocytes significantly stimulated directional motility above basal levels in all cell types. PAI-1 expression knockdown or antibody-mediated functional inhibition, in contrast, effectively attenuated injury repair. The defect in wound-associated migratory activity as a consequence of antisense-mediated PAI-1 down-regulation was effectively reversed by addition of recombinant PAI-1 immediately after scrape injury. One possible mechanism underlying the PAI-1-dependent motile response may involve fine control of the keratinocyte substrate detachment/re-attachment process. Exogenous PAI-1 significantly enhanced keratinocyte spread cell "footprint" area while PAI-1 neutralizing antibodies, but not control non-immune IgG, effectively inhibited spreading with apoptotic hallmarks evident within 24 h. Importantly, PAI-1 not only stimulated keratinocyte adhesion and wound-initiated planar migration but also rescued keratinocytes from plasminogen-induced substrate detachment/anoikis. The early transcriptional response of the PAI-1 gene to monolayer trauma and its prominence in the injury repair genetic signature are consistent with its function as both a survival factor and regulator of the time course of epithelial migration as part of the cutaneous injury response program.

Regulation of extracellular matrix remodeling following transforming growth factor-beta1/epidermal growth factor-stimulated epithelial-mesenchymal transition in human premalignant keratinocytes.

During tumor progression, malignant cells exploit critical developmental and tissue remodeling programs, often promoting a plastic phenotype referred to as an epithelial-mesenchymal transition (EMT). Autocrine/paracrine signaling due to tumor microenvironment cytokines, such as members of the transforming growth factor-beta (TGF-beta) and epidermal growth factor (EGF) families, largely regulates the morphological and invasive phases of the EMT phenotype. Notably, epithelial cell initiation often coincides with a switch in the response of these cells to TGF-beta and is concomitant with EGF receptor amplification. Modeling these events, we have observed that premalignant human keratinocytes, HaCaTs, acquire a highly motile and scattered phenotype indicative of EMT following stimulation with TGF-beta1 and EGF. TGF-beta1 and EGF have been shown to upregulate a number of matrix metalloproteinases (MMP) in epithelial cells, which may in turn play a role in developing metastatic potential in these cells. We have established that an increase in MMP-10 expression occurs following treatment of HaCaT cells with a combination of TGF-beta1 and EGF. This increase in MMP-10 expression paralleled the development of a collagenolytic phenotype that was sensitive to components of the plasminogen activation system, including the plasminogen activator inhibitor type-1 (PAI-1). Significantly high levels of MMP-10 have been detected in squamous cell carcinomas of the head and neck, esophagus, oral cavity and skin. Importantly, TGF-beta1 in addition to upregulating MMP-10 has been shown to upregulate PAI-1 expression in HaCaT cells. Taken together, these observations suggest that TGF-beta1 and EGF play a complex role in modulating proteolytic and transitional events such as EMT that may facilitate the progression of human premalignant epithelial cells toward a more invasive phenotype.

PAI-1 is a Critical Upstream Regulator of the TGF-beta1/EGF-Induced Invasive Phenotype in Mutant p53 Human Cutaneous Squamous Cell Carcinoma.

The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma (SCC) often reflects increased autocrine/paracrine TGF-beta synthesis and epidermal growth factor receptor (EGFR) amplification. Cooperative TGF-beta/EGFR signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in acquisition of an invasive phenotype. TGF-beta1+EGF stimulation increases the production of several matrix metalloproteinases (MMPs) in human SCC. Among the most prominent is MMP-10 which is known to be elevated in SCC in situ. Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity. Paradoxically, PAI-1, the major physiological inhibitor of plasmin generation, is also up-regulated under these conditions and is an early event in progression of incipient epidermal SCC. A model is proposed in which TGF-beta1+EGF-dependent MMP-10 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion. Increased PAI-1 expression serves to temporally and spatially modulate plasmin-initiated pericellular proteolysis, further facilitating epithelial invasive potential. Defining the complex signaling mechanisms that maintain this elegant balance is critical to developing potential therapeutics for the treatment of human cutaneous malignancies.

The uPA receptor and the somatomedin B region of vitronectin direct the localization of uPA to focal adhesions in microvessel endothelial cells.

Vitronectin is a plasma protein which can deposit into the extracellular matrix where it supports integrin and uPA dependent cell migration. In earlier studies, we have shown that the plasma protein, vitronectin, stimulates focal adhesion remodeling by recruiting urokinase-type plasminogen activator (uPA) to focal adhesion sites [Wilcox-Adelman, S. A., Wilkins-Port, C. E., McKeown-Longo, P. J., 2000. Localization of urokinase-type plasminogen activator to focal adhesions requires ligation of vitronectin integrin receptors. Cell. Adhes. Commun.7, 477-490]. In the present study, we used a variety of vitronectin constructs to demonstrate that the localization of uPA to adhesion sites requires the binding of both vitronectin integrin receptors and the uPA receptor (uPAR) to vitronectin. A recombinant fragment of vitronectin containing the connecting sequence (VN(CS)) was able to support integrin-dependent adhesion, spreading and focal adhesion assembly by human microvessel endothelial cells. Cells adherent to this fragment were not able to localize uPA to focal adhesions. A second recombinant fragment containing both the amino-terminal SMB domain and the CS domain was able to restore the localization of uPA to adhesion sites. This fragment, which contains a uPAR binding site, also resulted in the localization of uPAR to adhesion sites. uPAR blocking antibodies as well as phospholipase C treatment of cells inhibited uPA localization to adhesion sites confirming a role for uPAR in this process. The SMB domain alone was unable to direct either uPAR or uPA to adhesion sites in the absence of the CS domain. Our results indicate that vitronectin-dependent localization of uPA to adhesion sites requires the sequential binding of vitronectin integrins and uPAR to vitronectin.

Informal caregiver involvement and illness detection among cognitively impaired nursing home residents.

BACKGROUND: The participation of informal caregivers in the care of nursing home (NH) residents has the potential to positively impact care, especially for cognitively impaired residents whose own ability to advocate for their care is often limited. This study examined relationships between the level of informal caregiver involvement (ICI) in the NH and the degree to which residents' common medical conditions were detected by facility staff. METHODS: One hundred pairs of cognitively impaired residents and their primary informal caregivers were enrolled from three facilities in the Baltimore, Maryland area. Data collection involved interviews with informal caregivers and facility staff, as well as a medical evaluation and chart review of residents. A measure of illness detection was created by comparing a medical examination of the resident with chart review information. ICI was measured via staff rating and informal caregiver self-report. RESULTS: Correlations between illness detection and ICI were significant, with r = -.46 (p <.001) and r = -.39 (p <.001), for staff rating and self-reports, respectively. In regression models taking into account resident characteristics (age, race, gender, comorbidities, payment status, duration of stay, and cognitive impairment) and facility differences, higher ICI and being female predicted higher rates of illness detection. CONCLUSIONS: Though the cross-sectional nature of the study prevents the analysis of causal relationships, the involvement level of informal caregivers in the NH care of cognitively impaired residents was statistically related to higher rates of illness detection. Ramifications for the role of informal caregivers in long-term care are discussed.

Mortality and adverse health events in newly admitted nursing home residents with and without dementia.

OBJECTIVES: To evaluate the association between dementia and mortality, adverse health events, and discharge disposition of newly admitted nursing home residents. It was hypothesized that residents with dementia would die at a higher rate and develop more adverse health events (e.g., infections, fevers, pressure ulcers, falls) than residents without dementia because of communication and self-care difficulties. DESIGN: An expert clinician panel diagnosed an admission cohort from a stratified random sample of 59 Maryland nursing homes, between 1992 and 1995. The cohort was followed for up to 2 years or until discharge. SETTING: Fifty-nine Maryland nursing homes. PARTICIPANTS: Two thousand one hundred fifty-three newly admitted residents aged 65 and older not having resided in a nursing home for 8 or more days in the previous year. MEASUREMENTS: Mortality, infection, fever, pressure ulcers, fractures, and discharge home. RESULTS: Residents with dementia had significantly lower overall rates of infection (relative risk (RR)=0.77, 95% confidence interval (CI)=0.70-0.85) and mortality (RR=0.61, 95% CI=0.53-0.71) than those without dementia, whereas rates of fever, pressure ulcers, and fractures were similar for the two groups. These results persisted when rates were adjusted for demographic characteristics, comorbid conditions, and functional status. During the first 90 days of the nursing home stay, residents with dementia had significantly lower rates of mortality if not admitted for rehabilitative care under a Medicare qualifying stay (RR=0.25, 95% CI=0.14-0.45), were less often discharged home (RR=0.33, 95% CI=0.28-0.38), and tended to have lower fever rates (RR=0.78, 95% CI=0.63-0.96) than residents without dementia. CONCLUSION: Newly admitted nursing home residents with dementia have a profile of health events that is distinct from that of residents without dementia, indicating that the two groups have different long-term care needs. Results suggest that further investigation of whether residents with dementia can be well managed in alternative residential settings would be valuable.

Families filling the gap: comparing family involvement for assisted living and nursing home residents with dementia.

PURPOSE: The purpose of this study was to compare the sociodemographics, self-rated health, and involvement levels of family caregivers of residents with dementia in residential care/assisted living (RC/AL) versus nursing home settings. DESIGN AND METHODS: We conducted telephone interviews with the family caregivers most involved with 353 residents of 34 residential care and 10 nursing home facilities. We measured involvement by caregiver self-report of monthly out-of-pocket spending, involvement and burden ratings, and the frequency of engaging in eight specific care activities. Open-ended questions elicited areas in which caregivers preferred different involvement and ways the facility could facilitate involvement. RESULTS: Nursing home caregivers rated their health poorer than RC/AL caregivers, but there were no sociodemographic differences between the two. RC/AL caregivers rated both their perception of involvement and burden higher and engaged more frequently in monitoring the resident's health, well-being, and finances than did nursing home caregivers, although the reported time spent per week on care did not differ. IMPLICATIONS: RC/AL and nursing home caregivers to residents with dementia may tailor their care to fit the needs of the resident and setting. Results are discussed in relation to the Congruence Model of Person-Environment Fit.

Identifying changeable barriers to family involvement in the nursing home for cognitively impaired residents.

PURPOSE: Barriers to family involvement in the nursing home with the potential for change through intervention are examined, including transportation, caregiver health, relationships with staff, and resident characteristics. DESIGN AND METHODS: Data were collected for 93 family caregiver-resident pairs by means of telephone interviews and chart review. Regression modeling was used to identify relationships between involvement (caregiver visit frequency) and the changeable barriers after the known variables of distance, kinship, payment source, length of stay, and cognitive function were taken into account. RESULTS: Lower visit frequency was found for caregivers reporting problems with transportation, poor relationships with staff, and a smaller network of supportive family and friends. Higher caregiver anxiety was related to higher visit frequency. IMPLICATIONS: Several barriers to family involvement are shown to be as or more influential than ones identified in previous research, thus providing empirical support for interventions currently used as well as suggesting new areas for intervention.

The receptor for urokinase-type plasminogen activator regulates fibronectin matrix assembly in human skin fibroblasts.

Previous studies have indicated that the receptor for urokinase-type plasminogen activator, uPAR, can form functional complexes with integrin receptors thereby modulating integrin activity. In the present study, the role of uPAR in the regulation of alpha5beta1-dependent polymerization of the fibronectin matrix was investigated. Incubation of fibroblast monolayers with the P-25 peptide, a uPAR ligand, resulted in a 12-15-fold increase in the accumulation of exogenous fibronectin in the cell layer. The exogenous fibronectin co-localized in the extracellular matrix with endogenous cell-derived fibronectin, and its deposition into the matrix was inhibited by blocking antibodies against the beta1 integrin receptor. The P-25-dependent increase in fibronectin assembly was associated with a 7-8-fold increase in the expression of matrix assembly sites as well as a 37-fold increase in the rate of transfer of cell surface-bound fibronectin into a detergent-insoluble matrix. The effects of P-25 on the matrix assembly were attenuated by incubating cells with either phospholipase C or with antibodies against uPAR, confirming a role for uPAR in the P-25-dependent increase in matrix assembly. P-25-treated cells exhibited a 10-fold increase in the binding of the 120-kDa cell-binding fragment of fibronectin suggesting an increase in alpha5beta1 affinity for fibronectin. Consistent with this, treatment of cells with P-25 also resulted in a 6-10-fold increase in the binding of two different monoclonal antibodies that recognize the active conformation of the beta1 integrin. These results indicate that P-25 increases matrix assembly by altering the activation state of the alpha5beta1 integrin receptor and suggest that changes in integrin activation affect both the number of matrix assembly sites as well as the rate of transfer of cell-bound fibronectin into a detergent-insoluble matrix. These data provide direct evidence that uPAR and integrin receptors synergistically regulate the levels of fibronectin in the extracellular matrix.