Are Geriatrics-Focused Primary Care Clinics Better at Diagnosing Dementia Than Traditional Clinics? A Matched Cohort Study.

BACKGROUND: Dementia and mild cognitive impairment (MCI) are prevalent but underdiagnosed. OBJECTIVE: To compare new dementia/MCI diagnosis rates in geriatrics-focused primary care clinics and traditional primary care clinics. DESIGN: Secondary analysis of a prospective matched cohort study that spanned 2017-2021. PARTICIPANTS: Community-dwelling Veterans over 65 receiving primary care in a geriatrics-focused medical home (GeriPACT) or traditional primary care home (PACT) at one of 57 Veterans Affairs sites. We excluded individuals with a documented diagnosis of dementia or MCI in the year prior to enrollment. MAIN MEASURES: Diagnoses obtained from EHR. Cognitive status was assessed using modified Telephone Interview for Cognitive Status (mTICS) tool. KEY RESULTS: The 470 participants included in this analysis were predominantly white, non-Hispanic males with an average age of 80.3 years. 9.4% of participants received a diagnosis of dementia/MCI after 24 months: 11.5% in GeriPACT and 7.2% in PACT. Adjusted OR for dementia/MCI diagnosis based on GeriPACT exposure was 1.47 (95% CI 0.65-3.29). Low mTICS score (≤ 27) (OR 4.89, 95% CI 2.36-10.13) and marital status (married/partnered) (OR 1.89, CI 0.99-3.59) were independent predictors of dementia/MCI diagnosis. When stratified by cognitive status: diagnosis rates were 20.8% in GeriPACT and 16.7% in PACT among those who scored lower on the cognitive assessment (mTICS ≤ 27); 7.4% in GeriPACT and 3.6% in PACT among those who scored higher (mTICS > 27). The OR for new dementia/MCI diagnosis in GeriPACT was 1.19 (95% CI 0.49-2.91) among those with a low mTICS score and 1.85 (95% CI 0.70-4.88) among those with a higher mTICS score. CONCLUSIONS: Observed rates of new dementia/MCI diagnosis were higher in GeriPACT, but with considerable uncertainty around estimates. Geriatrics-focused primary care clinics may be a promising avenue for improving the detection of dementia in older adults, but further larger studies are needed to confirm this relationship.

Effect of interferon-ß1b on CXCR4-dependent chemotaxis in T cells from multiple sclerosis patients.

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease triggered by infiltration of activated T cells into the central nervous system. Interferon (IFN)-ß is an established, safe and effective treatment for patients with relapsing-remitting MS (RRMS). The cytokine can inhibit leucocyte infiltration into the central nervous system; however, little is known about the precise molecular mechanisms. Previously, in vitro application of IFN-ß1b was shown to reduce CXCL12/CXCR4-mediated monocyte migration. Here, we analysed the effects of IFN-ß1b on CXCR4-dependent T cell function. In vitro exposure to IFN-ß1b (1000 U/ml) for 20 h reduced CXCR4-dependent chemotaxis of primary human T cells from healthy individuals and patients with RRMS. Investigating the IFN-ß1b/CXCR4 signalling pathways, we found no difference in phosphorylation of ZAP70, ERK1/2 and AKT despite an early induction of the negative regulator of G-protein signalling, RGS1 by IFN-ß1b. However, CXCR4 surface expression was reduced. Quantitative real time-PCR revealed a similar reduction in CXCR4-mRNA, and the requirement of several hours' exposure to IFN-ß1b supports a transcriptional regulation. Interestingly, T cells from MS patients showed a lower CXCR4 expression than T cells from healthy controls, which was not reduced further in patients under IFN-ß1b therapy. Furthermore, we observed no change in CXCL12-dependent chemotaxis in RRMS patients. Our results demonstrate clearly that IFN-ß1b can impair the functional response to CXCR4 by down-regulating its expression, but also points to the complex in vivo effects of IFN-ß1b therapy.

Racial differences in osteoarthritis pain and function: potential explanatory factors.

OBJECTIVE: This study examined factors underlying racial differences in pain and function among patients with hip and/or knee osteoarthritis (OA). METHODS: Participants were n=491 African Americans and Caucasians enrolled in a clinical trial of telephone-based OA self-management. Arthritis Impact Measurement Scales-2 (AIMS2) pain and function subscales were obtained at baseline. Potential explanatory variables included arthritis self-efficacy, AIMS2 affect subscale, problem- and emotion-focused pain coping, demographic characteristics, body mass index, self-reported health, joint(s) with OA, symptom duration, pain medication use, current exercise, and AIMS2 pain subscale (in models of function). Variables associated with both race and pain or function, and which reduced the association of race with pain or function by >or=10%, were included in final multivariable models. RESULTS: In simple linear regression models, African Americans had worse scores than Caucasians on AIMS2 pain (B=0.65, P=0.001) and function (B=0.59, P<0.001) subscales. In multivariable models race was no longer associated with pain (B=0.03, P=0.874) or function (B=0.07, P=0.509), indicating these associations were accounted for by other covariates. Variables associated with worse AIMS2 pain and function were: worse AIMS2 affect scores, greater emotion-focused coping, lower arthritis self-efficacy, and fair or poor self-reported health. AIMS2 pain scores were also significantly associated with AIMS2 function. CONCLUSION: Factors explaining racial differences in pain and function were largely psychological, including arthritis self-efficacy, affect, and use of emotion-focused coping. Self-management and psychological interventions can influence these factors, and greater dissemination among African Americans may be a key step toward reducing racial disparities in pain and function.

Cover crop mixture diversity, biomass productivity, weed suppression, and stability.

The diversity-productivity, diversity-invasibility, and diversity-stability hypotheses propose that increasing species diversity should lead, respectively, to increased average biomass productivity, invasion resistance, and stability. We tested these three hypotheses in the context of cover crop mixtures, evaluating the effects of increasing cover crop mixture diversity on aboveground biomass, weed suppression, and biomass stability. Twenty to forty cover crop treatments were replicated three or four times at eleven sites using eighteen species representing three cover crop species each from six pre-defined functional groups: cool-season grasses, cool-season legumes, cool-season brassicas, warm-season grasses, warm-season legumes, and warm-season broadleaves. Each species was seeded as a pure stand, and the most diverse treatment contained all eighteen species. Remaining treatments included treatments representing intermediate levels of cover crop species and functional richness and a no cover crop control. Cover crop seeding dates ranged from late July to late September with both cover crop and weed aboveground biomass being sampled prior to winterkill. Stability was assessed by evaluating the variability in cover crop biomass for each treatment across plots within each site. While increasing cover crop mixture diversity was associated with increased average aboveground biomass, we assert that this was the result of the average biomass of the pure stands being drawn down by low biomass species rather than due to niche complementarity or increased resource use efficiency. At no site did the highest biomass mixture produce more than the highest biomass pure stand. Furthermore, while increases in cover crop mixture diversity were correlated with increases in weed suppression and biomass stability, we argue that this was largely the result of diversity co-varying with aboveground biomass, and that differences in aboveground biomass rather than differences in diversity drove the differences observed in weed suppression and stability.

The National Registry of Veterans with amyotrophic lateral sclerosis.

BACKGROUND: The Department of Veterans Affairs (VA) Cooperative Studies Program has established a National Registry of Veterans with Amyotrophic Lateral Sclerosis (ALS). This article describes the objectives, methods, and sample involved in the registry. METHODS: United States military veterans with ALS were identified through national VA electronic medical record databases and nationwide publicity efforts for an enrollment period of 4 1/2 years. Diagnoses were confirmed by medical record reviews. Registrants were asked to participate in a DNA bank. Follow-up telephone interviews are conducted every 6 months to track participants' health status. RESULTS: As of September 30, 2007, 2,400 veterans had consented to participate in the registry, 2,068 were included after medical record review, 995 were still living and actively participating, and 1,573 consented to participate in the DNA bank. 979 participants had been enrolled in the registry for at least 1 year, 497 for at least 2 years, and 205 for at least 3 years. Fourteen studies have been approved to use registry data for epidemiological, observational, and interventional protocols. CONCLUSION: This registry has proven to be a successful model for identifying large numbers of patients with a relatively rare disease and enrolling them into multiple studies, including genetic protocols.

The 5' stem-loop regulates expression of collagen alpha1(I) mRNA in mouse fibroblasts cultured in a three-dimensional matrix.

The stability of collagen alpha1(I) mRNA is regulated by its 5' stem-loop, which binds a cytoplasmic protein in a cap-dependent manner, and its 3'-untranslated region (UTR), which binds alphaCP. When cultured in a three-dimensional gel composed of type I collagen, mouse fibroblasts had decreased collagen alpha1(I) mRNA steady-state levels, which resulted from a decreased mRNA half-life. In cells cultured in gel, hybrid mouse-human collagen alpha1(I) mRNA with a wild-type 5' stem-loop decayed faster than the same mRNA with a mutated stem-loop. When the 5' stem-loop was placed in a heterologous mRNA, the mRNA accumulated to a lower level in cells grown in gel than in cells grown on plastic. This suggests that the 5' stem-loop down-regulates collagen alpha1(I) mRNA. Protein binding to the 5' stem-loop was reduced in cells grown in gel, which was associated with destabilization of the collagen alpha1(I) mRNA. In addition to the binding of a cytoplasmic protein, there was also a nuclear binding activity directed to the collagen alpha1(I) 5' stem-loop. The nuclear binding was increased in cells grown in gel, suggesting that it may negatively regulate expression of collagen alpha1(I) mRNA. Binding of alphaCP, a protein involved in stabilization of collagen alpha1(I) mRNA, was unchanged by the culture conditions.

Characterization of the interaction between alphaCP(2) and the 3'-untranslated region of collagen alpha1(I) mRNA.

Activated hepatic stellate cells produce increased type I collagen in hepatic fibrosis. The increase in type I collagen protein results from an increase in mRNA levels that is mainly mediated by increased mRNA stability. Protein-RNA interactions in the 3'-UTR of the collagen alpha1(I) mRNA correlate with stabilization of the mRNA during hepatic stellate cell activation. A component of the binding complex is alphaCP(2). Recombinant alphaCP(2) is sufficient for binding to the 3'-UTR of collagen alpha1(I). To characterize the binding affinity of and specificity for alphaCP(2), we performed electrophoretic mobility shift assays using the poly(C)-rich sequence in the 3'-UTR of collagen alpha1(I) as probe. The binding affinity of alphaCP(2) for the 3'-UTR sequence is approximately 2 nM in vitro and the wild-type 3' sequence binds with high specificity. Furthermore, we demonstrate a system for detecting protein-nucleotide interactions that is suitable for high throughput assays using molecular beacons. Molecular beacons, developed for DNA-DNA hybridization, are oligonucleotides with a fluorophore and quencher brought together by a hairpin sequence. Fluorescence increases when the hairpin is disrupted by binding to an antisense sequence or interaction with a protein. Molecular beacons displayed a similar high affinity for binding to recombinant alphaCP(2) to the wild-type 3' sequence, although the kinetics of binding were slower.

DAP12 and KAP10 (DAP10)-novel transmembrane adapter proteins of the CD3zeta family.

Transmembrane adapter proteins are molecules that associate with receptors and mediate intracellular signals following interaction of the receptor with its ligand. Many such molecules have been characterized in detail, particularly the small TM adapters of the CD3zeta class at the core of the T cell receptor. Recently, two new genetically linked members of this class of transmembrane adapters have been identified called DAP12 (KARAP) and KAP10 (DAP10), respectively. In this review, we discuss this new class of TM adapters using the wealth of knowledge concerning CD3zeta and FcRgamma to highlight similarities and differences with DAP12 and KAP10. In addition, novel receptor families which interact with these TM adapters have also been identified. The role of these receptors and their inhibitory isoforms are discussed.

Soluble HLA-A2.1 restricted peptides that are recognized by influenza virus specific cytotoxic T lymphocytes.

The influenza A virus matrix protein derived peptide with amino acids 57-68 (Lys-Gly-Ileu-Leu-Gly-Phe-Val-Phe-Thr-Leu-Thr-Val) is recognized by influenza virus HLA-A2 restricted CTL. Because of the large number of hydrophobic residues this peptide is very insoluble. Substitution with a number of polar amino acids resulted in a soluble peptide (Lys-Lys-Ala-Leu-Gly-Phe-Val-Phe-Thr-Leu-Asp-Lys) that was very effective in sensitizing HLA-A2 positive target cells. Further substitution of threonine in position 65 with lysine resulted in a soluble antagonist peptide that inhibited sensitization. Both agonist and antagonist peptides retained 20% of their biological activity when tyrosine was added at the N terminus. Soluble radio-iodinated peptides can now be prepared that will be useful reagents to study the interaction of peptides and class I molecules.

Regulation of collagen alpha1(I) expression in hepatic stellate cells.

The regulation of collagen alpha1(I) expression in hepatic stellate cells (HSCs) occurs in a complex fashion that is just beginning to be determined. The presence of regulatory sequences in both the 5' and 3' regions of the mRNA appear to be critical to its regulation in HSCs and are involved in the increased expression of collagen in activated HSCs. The 3' UTR contains a C-rich site that binds alphaCP, a known RNA-binding protein that is responsible for the increased stability of the mRNA in activated HSCs. Given that alphaCP is present in both activated and quiescent HSCs, there must be a mechanism for modifying alpha(CP to bind to the RNA in activated but not quiescent HSCs. The 5' region contains an evolutionary conserved stem-loop region that encompasses the translation initiation codon. This stem-loop can bind protein(s) in activated HSCs in an RNA cap-dependent manner. Such binding, together with the binding of alphaCP to the 3' UTR, can facilitate translation of collagen alpha1(I) mRNA, resulting in increased mRNA steady-state levels and collagen synthesis. A role of alphaCP in activating translation initiation has also been demonstrated. These two mechanisms work together to upregulate collagen alpha1(I) production in activated but not quiescent HSCs.

Assessment of coagulation system activation using spot urine measurements.

Coagulation system activation is most commonly assessed by measuring levels of one or more proteins in peripheral blood. Because faulty blood-drawing can cause activation of the coagulation system, artifactual elevations of such markers have been reported. We have therefore investigated the possibility of using randomly collected ('spot') urine samples as a non-invasive means of assessing the state of coagulation system activation. Using a commercially available enzyme-linked immunosorbent assay kit designed to measure plasma levels of fragment 1 + 2, we found immunoreactive fragment 2 in healthy control subjects, and significantly increased levels in diabetic and non-diabetic pregnant subjects, and patients with venous thromboembolism, prostate cancer, and diabetes. Measurements of excretion of immunoreactive fragment 2 are worth further study as an adjunct or alternative to plasma-based assays designed to detect or quantify coagulation system activation.

Degradation pathway of pralidoxime chloride in concentrated acidic solution.

The degradation products of pralidoxime chloride (1) (X- = Cl-) in concentrated aqueous solutions (less than or equal to 50% w/v) were identified using one or more methods: HPLC, polarography, voltammetry, MS and/or NMR. The products found were the 2-cyano-, 2-carboxamido- and 2-carboxy-1-methyl-pyridinium chlorides, 1-methyl pyridinium chloride, cyanide ion, ammonia and carbon dioxide. 1-Methyl-2-pyridone was indirectly identified by the presence of cyanide ion. The degradation rate increased with increasing pH values between pH 1 and 3.2 and with increasing concentrations between 1 and 50% w/v pralidoxime chloride. The results suggest that 1 (X- = Cl-) is dehydrated by a hydroxyl-ion catalyzed reaction ot the nitrile 2 which is hydrolyzed to either the pyridone 6 and cyanide ion or to 2-carboxamido-1-methyl-pyridinium chloride 3. The amide is hydrolyzed to give the 2-carboxy derivative 4 which finally is decarboxylated to give 1-methylpyridinium chloride 5.

Determination of water in penicillins using fast Karl Fischer reagents and electronic end-point optimization.

When using conventional Karl Fischer reagents for titration of water in penicillins, decomposition products (i.e. penicilloic acid) are shown to be partly cotitrated. Water in ampicillin, bacampicillin, carboxybenzylpenicillin and cloxacillin was titrated with slow and fast reagents and the differences in the results obtained were compared with the content of penicilloic acid determined mercurimetrically. A simple electronic control unit has been developed to optimize the speed of titration.

Analysis of film coating thickness and surface area of pharmaceutical pellets using fluorescence microscopy and image analysis.

A method is presented which enables geometrical characterisation of pharmaceutical pellets and their film coating. It provides a high level of details on the single pellet level. Image analysis was used to determine the coating thickness (h) applied on the pellets and the surface area (A) of the pellet cores. Different definitions of A and h are evaluated. Hierarchical analysis of variance was used to resolve different sources contributing to the total variance. The variance within pellets and the variance between pellets were found as significant sources of variation. Special emphasis was put on evaluation of A/h due to its influence on the release rate of an active drug substance from the pellet core. The pellet images were thus used to predict variations in the release rate using a mathematical model as a link between the image data and the release rate. General aspects of image analysis are discussed. The method would be useful in calibration of near infrared spectra to h in process analytical chemistry.

A synthesis of occupational behavior and sensory integration concepts in theory and practice, part 2: clinical applications.

This is the second of two papers addressing the occupational behavior and sensory integration approaches to occupational therapy for children. In the previous paper, basic concepts from these two approaches were discussed as presenting different, yet complementary, perspectives. The use of play was identified as central to occupational therapy practice from either perspective. Concepts from both approaches were integrated into a general systems model of play development in infancy and early childhood. This paper discusses play and sensory integration as interdependent developmental phenomena that are a function of interactions between the environment (input) and the child's internal processing (throughput). When input-throughput interactions do not permit the growth of competence, dysfunction occurs. Consideration of possible input and throughput deficits are suggested for assessment of individual children, and treatment guidelines are drawn from both the sensory integration and occupational behavior literature.

A synthesis of occupational behavior and sensory integration concepts in theory and practice, Part 1. Theoretical foundations.

This series of two articles presents a model of play development for use in pediatric occupational therapy. Proposing to unify the theoretical approaches of sensory integration and occupational behavior, the model uses play as the unifying link between these two apparently different approaches. This first article reviews the major concepts of sensory integration and occupational behavior, in addition to discussing the differences and similarities between the two. General systems concepts are used as a framework upon which a model of play development is constructed. Three hierarchical levels of play are described--sensorimotor, constructive, and social--with each broken down into several developmental steps.

The geriatric patient in surgery. Experience with patients over the age of 85 years.

Between 1982 and 1989 hospitalized treatment was applied to 615 patients aged between 85 and 101 years. The average age was 88.8 years. Operations were performed on 406 of them (66.1%). The surgical lethality amounted 16.5%. The lethality in conjunction with emergency operation was as high as 30.8% or as low as 10.7% in the context of elective operations. X-ray findings recorded from heart and lung as well as ECG provided reliable criteria for assessment of the surgical risk.