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Biomedical subjects

Daniel Kuhn

Publications and source records attributed to Daniel Kuhn.

13 recordsLinked to original sources
PubMed2007

Dementia care mapping as a research tool.

INTRODUCTION: Dementia Care Mapping (DCM) was originally developed as a clinical tool but has attracted interest as a potential observational measure of quality of life (QOL) and well-being of long-term care residents with dementia. DCM coding involves continuous observation over a 6-h period, with observers recording a Behavior Category Code (BCC, a recording of activity/interaction) and a Well/Ill Being (WIB) score at 5 min intervals. METHOD: Descriptive data from several different research teams on the distribution and psychometric properties of DCM data were compiled and summarized. RESULTS: Issues and problems identified include: complex scoring algorithms, inter-rater reliability of the BCCs, limited variability of WIB values, associations between resident characteristics and DCM assessments, rater time burden, and comparability of results across study settings. CONCLUSIONS: Despite the identified limitations, DCM has promise as a research measure, as it may come closer to rating QOL from the perspective of persons with dementia than other available measures. Its utility will depend on the manner in which it is applied and an appreciation of the measure's strength and limitations. Possible changes that might improve the reliability, validity, and practicality of DCM as a research tool include coding the predominant event (rather than the 'best' event), shortening the observation period, and adding '0' as a neutral WIB coding option.

Activities of Daily Living↗
PubMed2006

From the similarity analysis of protein cavities to the functional classification of protein families using cavbase.

In this contribution, the classification of protein binding sites using the physicochemical properties exposed to their pockets is presented. We recently introduced Cavbase, a method for describing and comparing protein binding pockets on the basis of the geometrical and physicochemical properties of their active sites. Here, we present algorithmic and methodological enhancements in the Cavbase property description and in the cavity comparison step. We give examples of the Cavbase similarity analysis detecting pronounced similarities in the binding sites of proteins unrelated in sequence. A similarity search using SARS M(pro) protease subpockets as queries retrieved ligands and ligand fragments accommodated in a physicochemical environment similar to that of the query. This allowed the characterization of the protease recognition pockets and the identification of molecular building blocks that can be incorporated into novel antiviral compounds. A cluster analysis procedure for the functional classification of binding pockets was implemented and calibrated using a diverse set of enzyme binding sites. Two relevant protein families, the alpha-carbonic anhydrases and the protein kinases, are used to demonstrate the scope of our cluster approach. We propose a relevant classification of both protein families, on the basis of the binding motifs in their active sites. The classification provides a new perspective on functional properties across a protein family and is able to highlight features important for potency and selectivity. Furthermore, this information can be used to identify possible cross-reactivities among proteins due to similarities in their binding sites.

Algorithms↗
PubMed2006

An efficient method for the synthesis of peptide aldehyde libraries employed in the discovery of reversible SARS coronavirus main protease (SARS-CoV Mpro) inhibitors.

A method for the parallel solid-phase synthesis of peptide aldehydes has been developed. Protected amino acid aldehydes obtained by the racemization-free oxidation of amino alcohols with Dess-Martin periodinane were immobilized on threonyl resins as oxazolidines. Following Boc protection of the ring nitrogen to yield the N-protected oxazolidine linker, peptide synthesis was performed efficiently on this resin. A peptide aldehyde library was designed for targeting the SARS coronavirus main protease, SARS-CoV M(pro)(also known as 3CL(pro)), on the basis of three different reported binding modes and supported by virtual screening. A set of 25 peptide aldehydes was prepared by this method and investigated in inhibition assays against SARS-CoV M(pro). Several potent inhibitors were found with IC(50) values in the low micromolar range. An IC(50) of 7.5 muM was found for AcNSTSQ-H and AcESTLQ-H. Interestingly, the most potent inhibitors seem to bind to SARS-CoV M(pro) in a noncanonical binding mode.

Aldehydes↗
PubMed2005

A comparison of three methods of measuring dementia-specific quality of life: perspectives of residents, staff, and observers.

PURPOSE: This exploratory study compared three methods of assessing dementia specific quality of life, corresponding to the perspectives of residents, staff members, and trained observers. DESIGN AND METHODS: We collected data on 172 residents with dementia in four special care nursing facilities and three assisted living facilities. Analyses assessed the relationship of each quality-of-life method or perspective to the others and to resident characteristics such as cognitive and functional status. RESULTS: The relationship of staff quality-of-life measures to resident characteristics varied by care setting while no significant relationships were found for resident quality-of-life measures. Staff and observational measures were moderately correlated in both settings. Moderate correlations of resident measures with staff and observational measures were found in the assisted living sample. IMPLICATIONS: Each perspective is relatively independent and somewhat unique. Measures that focus on specific aspects of quality of life may be more appropriate to use with assisted living residents than with residents of special care facilities.

Aged, 80 and over↗
PubMed2004

Efficient similarity search in protein structure databases by k-clique hashing.

MOTIVATION: Graph-based clique-detection techniques are widely used for the recognition of common substructures in proteins. They permit the detection of resemblances that are independent of sequence or fold homologies and are also able to handle conformational flexibility. Their high computational complexity is often a limiting factor and prevents a detailed and fine-grained modeling of the protein structure. RESULTS: We present an efficient two-step method that significantly speeds up the detection of common substructures, especially when used to screen larger databases. It combines the advantages from both clique-detection and geometric hashing. The method is applied to an established approach for the comparison of protein binding-pockets, and some empirical results are presented. AVAILABILITY: Upon request from the authors.

Algorithms↗
PubMed2004

Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition.

By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.

Animals↗
PubMed2004

Comparison of dementia-specific quality of life measures in adult day centers.

This study evaluated five dementia-specific quality of life (DQOL) measures including client interviews, staff proxies, and observations with 54 clients in three adult day centers. Also, the relationship of cognitive and functional status to each of the DQOL measures was assessed. Client interviews correlated well with each other, but not with other measures. Staff proxies were strongly correlated with each other and moderately correlated with the observational measure. On average, clients rated their DQOL higher than staff. Analyses suggest that functional impairment is associated with poorer DQOL as indicated by staff and observer measures. Possible explanations and implications are explored.

Aged↗
PubMed2002

A new method to detect related function among proteins independent of sequence and fold homology.

A new method has been developed to detect functional relationships among proteins independent of a given sequence or fold homology. It is based on the idea that protein function is intimately related to the recognition and subsequent response to the binding of a substrate or an endogenous ligand in a well-characterized binding pocket. Thus, recognition of similar ligands, supposedly linked to similar function, requires conserved recognition features exposed in terms of common physicochemical interaction properties via the functional groups of the residues flanking a particular binding cavity. Following a technique commonly used in the comparison of small molecule ligands, generic pseudocenters coding for possible interaction properties were assigned for a large sample set of cavities extracted from the entire PDB and stored in the database Cavbase. Using a particular query cavity a series of related cavities of decreasing similarity is detected based on a clique detection algorithm. The detected similarity is ranked according to property-based surface patches shared in common by the different clique solutions. The approach either retrieves protein cavities accommodating the same (e.g. co-factors) or closely related ligands or it extracts proteins exhibiting similar function in terms of a related catalytic mechanism. Finally the new method has strong potential to suggest alternative molecular skeletons in de novo design. The retrieval of molecular building blocks accommodated in a particular sub-pocket that shares similarity with the pocket in a protein studied by drug design can inspire the discovery of novel ligands.

Algorithms↗
PubMedDate not supplied

Behavioral observations and quality life among persons with dementia in 10 assisted living facilities.

This study examined the quality of life of 131 persons with dementia living in 10 assisted livingfacilities in a Midwestern state, using the observational method known as Dementia Care Mapping (DCM). Trained observers collected detailed information on the types of interactions and activities taking place among residents and staff on a given day. Key differences were noted between residents living in small, dementia-specific sites (10 to 28 residents) and those living in large sites that were not dementia-specific (40 to 63 residents). The latter group fared better overall with respect to quality of life and diversity of interactions and activities. Additional methods of examining quality of life among persons with dementia will be helpful to explain these differences.

Assisted Living Facilities↗
PubMedDate not supplied

Development of the knowledge about memory loss and care (KAML-C) test.

The purpose of this study was to develop a test to assess the knowledge of family caregivers concerning memory loss, the early stages of Alzheimer's disease (AD), and related care issues. A total of 31 multiple-choice items were generated in three domains: medical information, caregiving, and legal/financial planning. The test was administered to experts in the field of dementia research and care, medical students, and family caregivers. Item analysis procedures were then used to reduce the test to 15 items. Results suggest that the Knowledge about Memory Loss and Care (KAML-C) test is a reliable and valid test for examining the knowledge level of family caregivers with a relative in the early stages of dementia.

Adult↗
PubMedDate not supplied

Information and service needs of persons with Alzheimer's disease and their family caregivers living in rural communities.

This study aimed to identify the information and service needs of persons with Alzheimer's disease (AD) and their family caregivers living in rural communities and to assess differences and similarities in each partner's perspective. In an outpatient clinic setting, a self-report survey was completed by 100 caregivers, while a similar survey was used to interview 100 persons with mild to moderate AD. The survey assessed respondents' interest in information or services related to 22 topics about AD and various aspects of coping with the disease. Although more caregivers than persons with AD reported interest in each topic, 8 of the top 10 topics endorsed by each group of respondents were the same. However, analysis of responses by dyads revealed substantial disagreement in terms of each partner's interest in information and services. Patient and family education, as well as referrals for services, must take into account each partner's unique perspective and needs.

Adaptation, Psychological↗