Three new observational scales for use in Dutch nursing homes: scales from the Resident Assessment Instrument for Activities of Daily Living, cognition and depression

The reliability and validity of three MDS scales for ADL, cognition and depression are described. The scales consist of items of the Minimum Data Set of the Resident Assessment Instrument and are available just after an MDS assessment. Data collection took place in nine Dutch nursing homes (N = 227) and consisted of three MDS assessments within one month to determine reliability. Several criterion measures were assessed in order to determine convergent validity. Intra- and inter-rater reliability and internal consistency were determined as well as correlation coefficients of the criterion measures and the MDS scales. All three MDS scales appear reliable, especially the ADL-Hierarchy has very good psychometric properties (intra- and inter-rater Intra Class Correlation were 0.81 and 0.83, respectively). Convergent validity of the ADL-Hierarchy and the Cognitive Performance Scale is good, the Depression Rating Scale appears valid in residents with moderate cognitive disorders at the most, but the results are more difficult to interpret in residents with severe cognitive disorders. The MDS scales appear useful in clinical practice and for research purposes in the Dutch nursing homes.     

Chronic pain in dementia and in disorders with a high risk for congnitive impairment

Ageing increases the risk for the etiology of chronic pain and dementia. hence, the increase in the number of elderly people implies that the number of elderly with dementia suffering from chronic pain will increase as well. A key question relates to if and how patients with dementia perceive pain. the inadequateness of pain assessment, particularly in a more advanced stage, is also reflected in a decreased use of analgesics by elderly people with dementia. Insight into possible changes in pain experience as have been observed in the few available clinical studies, could be enhanced by knowledge about the neuropathology which may differ per subtype of dementia. It is striking that pain has not been examined in degenerative diseases of the central nervous system with a high risk for cognitive impairment such as Parkinson's disease and multiple sclerosis. In these disorders, pain is a prominent clinical symptom and to date it is not known whether the experience of pain will change in a stage in which patients become cognitively impaired. Finally, a number of instruments which are most appropriate to assess pain in communicative and non-communicative patients are discussed.     

Developmental Defects and Male Sterility in Mice Lacking the Ubiquitin-Like DNA Repair Gene mHR23B

mHR23B encodes one of the two mammalian homologs of Saccharomyces cerevisiae RAD23, a ubiquitin-like fusion protein involved in nucleotide excision repair (NER). Part of mHR23B is complexed with the XPC protein, and this heterodimer functions as the main damage detector and initiator of global genome NER. While XPC defects exist in humans and mice, mutations for mHR23A and mHR23B are not known. Here, we present a mouse model for mHR23B. Unlike XPC-deficient cells, mHR23B(-/-) mouse embryonic fibroblasts are not UV sensitive and retain the repair characteristics of wild-type cells. In agreement with the results of in vitro repair studies, this indicates that mHR23A can functionally replace mHR23B in NER. Unexpectedly, mHR23B(-/-) mice show impaired embryonic development and a high rate (90%) of intrauterine or neonatal death. Surviving animals display a variety of abnormalities, including retarded growth, facial dysmorphology, and male sterility. Such abnormalities are not observed in XPC and other NER-deficient mouse mutants and point to a separate function of mHR23B in development. This function may involve regulation of protein stability via the ubiquitin/proteasome pathway and is not or only in part compensated for by mHR23A.     

The Resistance of Human APOBEC3H to HIV-1 NL4-3 Molecular Clone Is Determined by a Single Amino Acid in Vif

Some human APOBEC3 cytidine deaminases have antiviral activity against HIV-1 and other retroviruses. The single deaminase domain APOBEC3H (A3H) enzyme is highly polymorphic and multiple A3H haplotypes have been identified. A3H haplotype II (A3H-hapII) possesses the strongest activity against HIV-1. There remains, however, uncertainty regarding the extent to which A3H-hapII is sensitive to HIV-1 Vif mediated degradation. We tested, therefore, the two different reference Vif proteins widely used in previous studies. We show that A3H-hapII is resistant to NL4-3 Vif while it is efficiently degraded by LAI Vif. Co-immunoprecipitation assays demonstrate that LAI Vif, but not NL4-3 Vif associates with A3H-hapII. Chimeras between NL4-3 and LAI Vif identify the amino acid responsible for the differential degradation activity: A histidine at position 48 in Vif confers activity against A3H-hapII, while an asparagine abolishes its anti-A3H activity. Furthermore, the amino acid identity at position 48 only affects the degradation of A3H-hapII, whereas recognition of and activity against human A3D, A3F and A3G are only minimally affected. NL4-3 encoding 48H replicates better than NL4-3 WT (48N) in T cell-lines stably expressing A3H hapII, whereas there is no fitness difference in the absence of APOBEC3. These studies provide an explanation for the conflicting reports regarding A3H resistance to Vif mediated degradation.     

The inositol polyphosphate 5-phosphatases: traffic controllers, waistline watchers and tumour suppressors?

Phosphoinositide signals regulate cell proliferation, differentiation, cytoskeletal rearrangement and intracellular trafficking. Hydrolysis of PtdIns(4,5)P2 and PtdIns(3,4,5)P3, by inositol polyphosphate 5-phosphatases regulates synaptic vesicle recycling (synaptojanin-1), hematopoietic cell function [SHIP1(SH2-containing inositol polyphosphate 5-phosphatase-1)], renal cell function [OCRL (oculocerebrorenal syndrome of Lowe)] and insulin signalling (SHIP2). We present here a detailed review of the characteristics of the ten mammalian 5-phosphatases. Knockout mouse phenotypes and underexpression studies are associated with significant phenotypic changes, indicating non-redundant roles, despite, in many cases, overlapping substrate specificity and tissue expression. The extraordinary complexity in the control of phosphoinositide signalling continues to be revealed.