Changes in social engagement and depression predict incident loneliness among seriously ill home care clients.

ABSTRACTObjective:This study identified the predictors of incident loneliness in a group of seriously ill older adults (aged 65+) receiving home care. METHOD: Existing data collected with the Resident Assessment Instrument for Home Care (RAI-HC) were utilized. A cohort of clients (N = 2,499) with two RAI-HC assessments and no self-reported loneliness at time 1 were included. Self-reported loneliness, upon reassessment, was the outcome of interest. Clients with a prognosis of less than six months or severe health instability were included. RESULTS: The average length of time between assessments was 5.9 months (standard deviation = 4.10). During that time, 7.8% (n = 181) of the sample developed loneliness. In a multivariate regression model, worsening symptoms of depression, a decline in social activities, and not living with a primary caregiver all increased the risk of loneliness. SIGNIFICANCE OF RESULTS: These results highlight how changes in psychosocial factors over time can contribute to loneliness, which can inform clinicians as they seek to identify those who may be at risk for loneliness.

The Influence of Physical and Psychosocial Factors on Disruptive Pain Among Seriously Ill Home Care Patients.

OBJECTIVES: To estimate the prevalence and correlates of disruptive pain in a sample of seriously ill home care patients in the Canadian province of Ontario. METHODS: The design was a cross-sectional analysis of secondary data from 2757 patients aged 65+. RESULTS: Overall, 69.0% (n = 1902) had any level of pain and 41.6% (n = 1146) indicated that their pain disrupted their usual activities. In the univariate analysis of demographics, the risk of disruptive pain decreased significantly with increasing age ( P < .0001) and was significantly less common among men ( P = .0015). Multivariate analysis showed that unsteady gait (relative risk [RR] = 1.37; 95% confidence interval [CI], 1.18-1.59), arthritis (RR = 1.35; 95% CI, 1.23-1.49), symptoms of depression (RR = 1.24; 95% CI, 1.13-1.37), and declines in social activity that the patient rated as distressing (RR = 1.19; 95% CI, 1.08-1.31) were independently associated with disruptive pain. CONCLUSION: Disruptive pain is highly prevalent in this group, and the key factors associated with this outcome represent physical as well as psychosocial domain areas.

Treatment of chronic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking.

A novel strategy for anti-viral intervention of hepatitis B virus (HBV) through the disruption of the proper folding and transport of the hepadnavirus glycoproteins is described. Laboratory reared woodchucks chronically infected with woodchuck hepatitis virus (WHV) were treated with N-nonyl-deoxynojirimycin (N-nonyl-DNJ), an inhibitor of the endoplasmic reticulum (ER) alpha-glucosidases. The woodchucks experienced significant dose dependent decreases in enveloped WHV, resulting in undetectable amounts in some cases. The reduction in viremia correlated with the levels of hyperglucosylated glycan in the serum of treated animals. This correlation supports the mechanism of action associated with the drug and highlights the extreme sensitivity of the virus to this type of glycan inhibitor. At N-nonyl-DNJ concentrations that prevented WHV secretion, the glycosylation of most serum glycoproteins appeared unaffected, suggesting great selectivity for this class of therapeutics. Indeed, this may account for the low toxicity of the compound over the treatment period. We provide the first evidence that glucosidase inhibitors can be used in vivo to alter specific steps in the N-linked glycosylation pathway and that this inhibition has anti-viral effects.

A Deterioration in Hearing Is Associated With Functional and Cognitive Impairments, Difficulty With Communication, and Greater Health Instability.

Objectives: To examine the relationship between hearing deterioration and several health-related outcomes among home care clients in Ontario. Design: Longitudinal analysis was completed for clients with at least two comprehensive assessments. Hearing status, based on a single item, ranged from zero (no impairment) to three (highly impaired). Hearing deterioration was defined as at least a 1-point decline between subsequent assessments. Results: Seven percent experienced a 1-point deterioration in hearing and roughly 1% had a 2/3-point decline. After adjusting for other covariates, increasing age (odds ratio = 1.94; 95% confidence intervals [CIs] = [1.45, 2.61]) and a diagnosis of Alzheimer's disease (1.37; CI = [1.04, 1.80]) and other dementias (1.32; CI = [1.07, 1.63]) increased the risk of a 2/3-point deterioration. Conclusion: These findings can assist home care professionals and policy makers in creating and refining interventions to meet the needs of older adults with hearing difficulties.

Aromatic cross-links in insect cuticle: detection by solid-state 13C and 15N NMR.

Cross-polarization magic-angle-spinning nuclear magnetic resonance spectroscopy has been used to determine insect cuticle composition and cross-link structure during sclerotization or tanning. Unsclerotized cuticle from newly ecdysed pupae of the tobacco hornworm, Manduca sexta L., had a high protein content with lesser amounts of lipid and chitin. Concentrations of chitin, protein, and catechol increased substantially as dehydration and sclerotization progressed. Analysis of intact cuticle specifically labeled with carbon-13 and nitrogen-15 revealed direct covalent linkages between ring nitrogens of protein histidyl residues and ring carbons derived from the catecholamine dopamine. This carbon-nitrogen adduct was present in chitin isolated from cuticle by alkaline extraction and is probably bound covalently to chitin. These data support the hypothesis that the stiffening of insect cuticle during sclerotization results primarily from the deposition of protein and chitin polymers and their crosslinking by quinonoid derivatives of catecholamines.

Older Adults With a Combination of Vision and Hearing Impairment Experience Higher Rates of Cognitive Impairment, Functional Dependence, and Worse Outcomes Across a Set of Quality Indicators.

OBJECTIVES: Hearing and vision impairment were examined across several health-related outcomes and across a set of quality indicators (QIs) in home care clients with both vision and hearing loss (or dual sensory impairment [DSI]). METHOD: Data collected using the Resident Assessment Instrument for Home Care (RAI-HC) were analyzed in a sample of older home care clients. The QIs represent the proportion of clients experiencing negative outcomes (e.g., falls, social isolation). RESULTS: The average age of clients was 82.8 years ( SD = 7.9), 20.5% had DSI and 8.5% had a diagnosis of Alzheimer's disease (AD). Clients with DSI were more likely to have a diagnosis of dementia (not AD), have functional impairments, report loneliness, and have higher rates across 20 of the 22 QIs, including communication difficulty and cognitive decline. Clients with highly impaired hearing, and any visual impairment, had the highest QI rates. DISCUSSION: Individuals with DSI experience higher rates of adverse events across many health-related outcomes and QIs. Understanding the unique contribution of hearing and vision in this group can promote optimal quality of care.

Combined impairments in vision, hearing and cognition are associated with greater levels of functional and communication difficulties than cognitive impairment alone: Analysis of interRAI data for home care and long-term care recipients in Ontario.

OBJECTIVES: The objective of the current study was to understand the added effects of having a sensory impairment (vision and/or hearing impairment) in combination with cognitive impairment with respect to health-related outcomes among older adults (65+ years old) receiving home care or residing in a long-term care (LTC) facility in Ontario, Canada. METHODS: Cross-sectional analyses were conducted using existing data collected with one of two interRAI assessments, one for home care (n = 291,824) and one for LTC (n = 110,578). Items in the assessments were used to identify clients with single sensory impairments (e.g., vision only [VI], hearing only [HI]), dual sensory impairment (DSI; i.e., vision and hearing) and those with cognitive impairment (CI). We defined seven mutually exclusive groups based on the presence of single or combined impairments. RESULTS: The rate of people having all three impairments (i.e., CI+DSI) was 21.3% in home care and 29.2% in LTC. Across the seven groups, individuals with all three impairments were the most likely to report loneliness, to have a reduction in social engagement, and to experience reduced independence in their activities of daily living (ADLs) and instrumental ADLs (IADLs). Communication challenges were highly prevalent in this group, at 38.0% in home care and 49.2% in LTC. In both care settings, communication difficulties were more common in the CI+DSI group versus the CI-alone group. CONCLUSIONS: The presence of combined sensory and cognitive impairments is high among older adults in these two care settings and having all three impairments is associated with higher rates of negative outcomes than the rates for those having CI alone. There is a rising imperative for all health care professionals to recognize the potential presence of hearing, vision and cognitive impairments in those for whom they provide care, to ensure that basic screening occurs and to use those results to inform care plans.

Glycosylation inhibitors in biology and medicine.

Glycosidase inhibitors are moving increasingly out of the laboratory and into the clinic as potential agents for the treatment of diseases including diabetes, AIDS and cancer. These compounds, originally isolated from natural sources and utilized for unraveling the glycosylation pathways involved in post-translational modification of glycoproteins, have multiple effects that are only now being fully appreciated. In addition to their ability to inhibit processing exoglycosidases, lysosomal glycosidases and the intestinal disaccharidases involved in carbohydrate digestion, these compounds appear to have additional activities, including immunomodulatory properties and inhibition of glycolipid synthesis, which continue to expand their range of potential uses.

Synthesis of the enantiomers of 6-epicastanospermine and 1,6-diepicastanospermine from D- and L-gulonolactone.

The synthesis of the enantiomers of 6-epicastanospermine and of 1,6-diepicastanospermine from the enantiomeric gulonolactones is reported and the structure of the former is established as (1S,6R,7R,8R,8aR)-1,6,7,8-tetrahydroxyoctahydroindolizine. The inhibitory activities of the diastereomers against the amyloglucosidase-catalysed hydrolysis of p-nitrophenyl alpha-D-glucopyranoside were investigated, and the effects of 6-epicastanospermine and of 1,6-diepicastanospermine on 14 human liver glycosidases are reported.

Studies on selectin-carbohydrate interactions.

Recruitment of neutrophils to sites of inflammation is now believed to occur through an initial rolling interaction at the luminal surface of activated endothelium and is mediated by a class of mammalian lectins referred to as the selectins. Selectins recognize carbohydrate determinants on co-receptors. It is generally believed that many selectin molecules must bind to many carbohydrate receptor molecules i.e. multivalent binding, to enable sufficient binding strength to elicit the rolling response between the neutrophil and the endothelial cell. One of the approaches to the generation of more potent molecular antagonists of the selectin-mediated cell-cell interaction is to mimic the multivalent interaction in a single compound. Recent experiments utilising conjugated forms of sialyl Lewisx-BSA have explored this feasibility (Welply et al., 1994). In that study, monovalent sLex (sialic acid alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc), the minimum binding determinant for E-selectin, as well as monovalent sialyllactosamine (sialic acid alpha 2-3Gal beta 1-4GlcNAc), a non-binding structure, and the corresponding multivalent BSA-conjugated forms were tested for their ability to inhibit binding of HL-60 cells to immobilised E-selectin. As expected, only sLex and sLex-BSA were found to do so. sLex16-BSA (16 mol tetrasaccharide/mol BSA) showed a dose-dependent inhibition of HL-60 binding with a measured IC50 of 1 microM; demonstrating close to a three-order of magnitude enhancement of inhibitory activity compared to free sLex. This result indicated that multivalent forms of sLex are capable of binding to E-selectin with higher affinity than do monovalent glycans. In another study, fluorescent forms of monovalent sLex were synthesized and used to measure a true thermodynamic dissociation constant for the monovalent sLex:E-selectin interaction of 120 +/- 31 microM (Jacob et.al., 1995).

Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma.

Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF-beta and FGF signaling as well as Wnt/beta-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.

Degradation of glyphosate by Pseudomonas sp. PG2982 via a sarcosine intermediate.

The bacterium Pseudomonas PG2982 metabolizes glyphosate (N-(phosphonomethyl)glycine) by converting it to glycine, a one-carbon unit, and phosphate. Here we show that this conversion involves the intermediate formation of sarcosine. When cells are incubated with [14C]glyphosate, the 14C can be entrapped in glycine or sarcosine. With added sarcosine, 14C from all three carbons of glyphosate is recovered solely in sarcosine. In experiments with glycine, radioactivity from the carboxymethyl moiety of glyphosate is trapped in glycine as well as serine, whereas radioactivity from the phosphonomethyl carbon is only incorporated into serine. These results are consistent with a pathway involving the conversion of glyphosate to sarcosine by cleavage of its carbon-phosphorus (C-P) bond, followed by the oxidation of sarcosine to glycine and formaldehyde.

Solid-state 13C and 15N nuclear magnetic resonance studies of alanine metabolism in Aerococcus viridans (Gaffkya homari).

Transport and metabolism of D- and L-alanine by Aerococcus viridans (Gaffkya homari) have been studied using cross-polarization magic-angle spinning 13C and 15N NMR spectroscopy of lyophilized whole cells, isolated cell walls, and crude extracts. For equimolar concentrations in the growth medium, about 10 times more D-alanine than L-alanine is transported into the cells. Examination of cells labeled with D-[13C]alanine and L-[epsilon-15N]lysine by double cross-polarization magic-angle spinning 15N NMR indicates that only about 20% of the D-alanine present in cell-wall peptidoglycan comes directly from the growth medium. The rest is produced by de novo synthesis. Most of the labeled D-alanine is found within peptidoglycan precursors or inverted to L-alanyl residues of soluble proteins.

Modulation of cell-surface transferrin receptor by the imino sugar N-butyldeoxynojirimycin.

The imino sugar, N-butyldeoxynojirimycin, is an inhibitor of the glycoprotein-processing enzyme glucosidase I and exhibits anti-(human immunodeficiency virus) activity in vitro. We have investigated the effect(s) of this compound on cell-surface glycoproteins by flow cytometry. We observed selective modulation of the transferrin receptor in response to treatment with 0.5 mM N-butyldeoxynojirimycin resulting in reduced cell-surface transferrin-receptor expression. The receptor modulation was dose dependent, resulted in reduced 59Fe uptake by treated cells and was fully reversible within 24 h of culture in the absence of the compound. Pulse/chase analysis in conjunction with endoglycosidase-H digestion demonstrated that transferrin-receptor glycosylation was altered following N-butyldeoxynojirimycin treatment, which is compatible with glucosidase inhibition. In addition, modulation of transferrin receptor in response to N-butyldeoxynojirimycin was not confined to a single cell line, but was also observed with certain human lymphoid and myeloid cell lines. Mechanism(s) of action of the imino sugar resulting in reduced cell-surface transferrin-receptor expression are discussed.

Direct measurement of peptidoglycan cross-linking in bacteria by 15N nuclear magnetic resonance.

Cross-polarization magic angle spinning 9.12-MHz 15N nuclear magnetic resonance was used to measure the extent of peptidoglycan cross-linking within intact bacterial cells and isolated cell walls of Aerococcus viridans ATCC 10400 grown in the presence of L-[epsilon-15N]lysine. A value of 49% for the cross-linking index was found for normal cells, while for those grown in the presence of low levels of penicillin G (0.1 micrograms/ml), the cross-linking index was reduced to 35%.

Solid-state 15N NMR studies of the effects of penicillin on cell-wall metabolism of Aerococcus viridans (Gaffkya homari).

Lyophilized whole cells and isolated cell walls from Aerococcus viridans (Gaffkya homari) grown on a synthetic medium containing benzylpenicillin, and either L-[epsilon-15N]lysine or 15N-ammonium ion as the only source of label, have been studied using cross-polarization magic-angle spinning 15N nuclear magnetic resonance. The lysine is incorporated directly into protein and cell-wall peptidoglycan and was used to measure cell-wall cross-links. The ammonium ion acts as a non-specific label monitoring general metabolism. Inhibition of cell-wall cross linking by penicillin occurs, but may not be the exclusive cause of cell death and lysis in this microorganism. Instead, the disruption of the mechanism for control of peptidoglycan synthesis probably is a contributing factor.

Direct measurement of poly(beta-hydroxybutyrate) in a pseudomonad by solid-state 13C NMR.

Four narrow lines are observed in the high-resolution cross-polarization magic-angle spinning 13C NMR spectra of intact, lyophilized samples of Pseudomonas sp. LBr, in addition to the broader lines normally associated with bacterial cellular material. These narrow lines arise from poly(beta-hydroxybutyrate). The cellular carbon contained in this storage material can be measured quantitatively and nondestructively from the solid-state NMR spectra. We find that cells starved for phosphorus store up to 50% of their total carbon as poly(beta-hydroxybutyrate). When such cells are used to inoculate medium containing a source of phosphorus, all of the poly(beta-hydroxybutyrate) is metabolized by the time the culture has reached midlogarithmic growth phase.

Polysulfated derivatives of beta-cyclodextrin and myo-inositol as potent inhibitors of the interaction between L-selectin and peripheral addressin: implying a requirement for highly clustered sulfate groups.

We have utilized an in vitro assay that measures the binding of an L-selectin-human Fc chimera (LS-Fc) to [35S]sulfate labelled peripheral addressin (PNAd), a 120 kDa glycoprotein ligand for L-selectin in porcine lymph nodes, to evaluate inhibitory properties of a small group of sulfated derivatives of beta-cyclodextrin (beta-CD), sLe(x) and myo-inositol to their non-sulfated counterparts were studied. We found that hepta-sulfated beta-CD (IC50 = 0.2 mM) strongly inhibited the binding of L-selectin to PNAd. In contrast, the monosulfated beta-CD was a poor inhibitor, displaying < 10% inhibition at 0.5 mM and beta-CD was not active as an inhibitor. Similarly, inositol hexakissulfate, a compound containing six sulfate groups on the inositol ring displayed an inhibition of about 61% at 0.5 mM concentration, whereas the non-sulfated myoinositol was not inhibitory. These findings provide evidence that clustering of sulfate groups enhances affinity of molecules for binding to L-selectin.

Interaction of bovine carbonic anhydrase with (neutral) aniline, phenol, and methanol.

We have investigated the interaction of bovine carbonic anhydrase with neutral aniline, phenol, and methanol molecules. The measurements are of optical spectra and solvent water and methanol proton magnetic relaxation rates of solutions of Co2+-substituted enzyme. We recently proposed a model [Koenig, S. H., Brown, R. D., & Jacob, G. S. (1980) Proceedings of the Symposium on Biophysics and Physiology of Carbon Dioxide, Springer-Verlag, West Berlin and Heidelberg], based on the interaction of enzyme with monovalent anions, that accounts for the pH dependences observed for a wide variety of phenomena, including the apparent pKa for enzymatic activity. We now extend the model to include the observed effects of neutral molecules. Aniline and phenol, though isoelectronic, shift the observed pKa values in opposite directions, and both appear to bind at the aromatic binding site to which sulfonamide inhibitors and aromatic esters are known to bind. The resulting binary complexes behave as altered enzymes, with different values of the pKa for activity, but otherwise are similar to the native enzyme. In terms of our model, aniline and phenol alter the relative affinities of water and anions for the same coordination position of the metal ion at the active site. The effect is opposite in sign for the two nolecules becuase of the differing proton affinities of the NH2 and OH moieties of the phenol ring in each case. By extension, our results indicate that data from experiments using aromatic buffers such as imidazole and lutidine should be analyzed with some care; effects previously attributed to buffer molecules to the aromatic binding site in the active region of the enzyme. The interaction of methanol with carbonic anhydrase is quite different, and very weak. Methanol does displace water at the metal, but to first order there is little, if any, preferential binding of methanol compared to water. Observations by others that alcohols inhibit esterase activity with inhibition constants on the order of 1 M are not attributable to binding of alcohol to enzyme but rather, in our view, result from the increased solubility of aromatic ester substrates in the alcohol-modified solvent.