Depressive symptoms are associated with analgesic use in people with Alzheimer's disease: Kuopio ALSOVA study.

Neuropsychiatric symptoms of Alzheimer's disease (AD) such as depression may be associated with pain, which according to the literature may be inadequately recognized and managed in this population. This study aimed to identify the factors associated with analgesic use in persons with AD; in particular, how AD severity, functional status, neuropsychiatric symptoms of AD, co-morbidities and somatic symptoms are associated with analgesic use. 236 community-dwelling persons with very mild or mild AD at baseline, and their caregivers, were interviewed over five years as part of the prospective ALSOVA study. Generalized Estimating Equations (GEEs) were used to estimate unadjusted and adjusted odds ratios (ORs) for the factors associated with analgesic use over a five year follow-up. The proportion of persons with AD using any analgesic was low (13.6%) at baseline and remained relatively constant during the follow-up (15.3% at Year 5). Over time, the most prevalent analgesic changed from non-steroidal anti-inflammatories (8.1% of persons with AD at Year 1) to acetaminophen (11.1% at Year 5). Depressive symptoms (measured by the Beck Depression Inventory, BDI) were independently associated with analgesic use, after effects of age, gender, education, AD severity, comorbidities and somatic symptoms were taken into account. For every one unit increase in BDI, the odds of analgesic use increased by 4% (OR = 1.04, 95% confidence interval CI = 1.02-1.07). Caregiver depressive symptoms were not statistically significantly associated with analgesic use of the person with AD. Depressive symptoms were significantly associated with analgesic use during the five year follow-up period. Possible explanations warranting investigation are that persons with AD may express depressive symptoms as painful somatic complaints, or untreated pain may cause depressive symptoms. Greater awareness of the association between depressive symptoms and analgesic use may lead to safer and more effective prescribing for these conditions

User needs elicitation via analytic hierarchy process (AHP). A case study on a Computed Tomography (CT) scanner

Background: The rigorous elicitation of user needs is a crucial step for both medical device design and purchasing. However, user needs elicitation is often based on qualitative methods whose findings can be difficult to integrate into medical decision-making. This paper describes the application of AHP to elicit user needs for a new CT scanner for use in a public hospital. Methods: AHP was used to design a hierarchy of 12 needs for a new CT scanner, grouped into 4 homogenous categories, and to prepare a paper questionnaire to investigate the relative priorities of these. The questionnaire was completed by 5 senior clinicians working in a variety of clinical specialisations and departments in the same Italian public hospital. Results: Although safety and performance were considered the most important issues, user needs changed according to clinical scenario. For elective surgery, the five most important needs were: spatial resolution, processing software, radiation dose, patient monitoring, and contrast medium. For emergency, the top five most important needs were: patient monitoring, radiation dose, contrast medium control, speed run, spatial resolution. Conclusions: AHP effectively supported user need elicitation, helping to develop an analytic and intelligible framework of decision-making. User needs varied according to working scenario (elective versus emergency medicine) more than clinical specialization. This method should be considered by practitioners involved in decisions about new medical technology, whether that be during device design or before deciding whether to allocate budgets for new medical devices according to clinical functions or according to hospital department

Lysyl hydroxylase 3 localizes to epidermal basement membrane and Is reduced in patients with Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in COL7A1 resulting in reduced or absent type VII collagen, aberrant anchoring fibril formation and subsequent dermal-epidermal fragility. Here, we identify a significant decrease in PLOD3 expression and its encoded protein, the collagen modifying enzyme lysyl hydroxylase 3 (LH3), in RDEB. We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin. We demonstrate expression is in-part regulated by endogenous type VII collagen and that, in agreement with previous studies, even small reductions in LH3 expression lead to significantly less secreted LH3 protein. Exogenous type VII collagen did not alter LH3 expression in cultured RDEB keratinocytes and we show that RDEB patients receiving bone marrow transplantation who demonstrate significant increase in type VII collagen do not show increased levels of LH3 at the basement membrane. Our data report a direct link between LH3 and endogenous type VII collagen expression concluding that reduction of LH3 at the basement membrane in patients with RDEB will likely have significant implications for disease progression and therapeutic intervention

Complete genome sequence of a novel extrachromosomal virus-like element identified in planarian Girardia tigrina

BACKGROUND: Freshwater planarians are widely used as models for investigation of pattern formation and studies on genetic variation in populations. Despite extensive information on the biology and genetics of planaria, the occurrence and distribution of viruses in these animals remains an unexplored area of research. RESULTS: Using a combination of Suppression Subtractive Hybridization (SSH) and Mirror Orientation Selection (MOS), we compared the genomes of two strains of freshwater planarian, Girardia tigrina. The novel extrachromosomal DNA-containing virus-like element denoted PEVE (Planarian Extrachromosomal Virus-like Element) was identified in one planarian strain. The PEVE genome (about 7.5 kb) consists of two unique regions (Ul and Us) flanked by inverted repeats. Sequence analyses reveal that PEVE comprises two helicase-like sequences in the genome, of which the first is a homolog of a circoviral replication initiator protein (Rep), and the second is similar to the papillomavirus E1 helicase domain. PEVE genome exists in at least two variant forms with different arrangements of single-stranded and double-stranded DNA stretches that correspond to the Us and Ul regions. Using PCR analysis and whole-mount in situ hybridization, we characterized PEVE distribution and expression in the planarian body. CONCLUSIONS: PEVE is the first viral element identified in free-living flatworms. This element differs from all known viruses and viral elements, and comprises two potential helicases that are homologous to proteins from distant viral phyla. PEVE is unevenly distributed in the worm body, and is detected in specific parenchyma cells

Impaired Bone Health in Inflammatory Bowel Disease: A Case-Control Study in 80 Pediatric Patients

Peer reviewe

Identification of Domains and Amino Acids Essential to the Collagen Galactosyltransferase Activity of GLT25D1

Collagen is modified by hydroxylation and glycosylation of hydroxylysine residues. This glycosylation is initiated by the β1,O galactosyltransferases GLT25D1 and GLT25D2. The structurally similar protein cerebral endothelial cell adhesion molecule CEECAM1 was previously reported to be inactive when assayed for collagen glycosyltransferase activity. To address the cause of the absent galactosyltransferase activity, we have generated several chimeric constructs between the active human GLT25D1 and inactive human CEECAM1 proteins. The assay of these chimeric constructs pointed to a short central region and a large C-terminal region of CEECAM1 leading to the loss of collagen galactosyltransferase activity. Examination of the three DXD motifs of the active GLT25D1 by site-directed mutagenesis confirmed the importance of the first (amino acids 166–168) and second motif (amino acids 461–463) for enzymatic activity, whereas the third one was dispensable. Since the second DXD motif is incomplete in CEECAM1, we have restored the motif by introducing the substitution S461D. This change did not restore the activity of the C-terminal region, thereby showing that additional amino acids were required in this C-terminal region to confer enzymatic activity. Finally, we have introduced the substitution Q471R-V472M-N473Q-P474V in the CEECAM1-C-terminal construct, which is found in most animal GLT25D1 and GLT25D2 isoforms but not in CEECAM1. This substitution was shown to partially restore collagen galactosyltransferase activity, underlining its importance for catalytic activity in the C-terminal domain. Because multiple mutations in different regions of CEECAM1 contribute to the lack of galactosyltransferase activity, we deduced that CEECAM1 is functionally different from the related GLT25D1 protein

Combined effects of precipitation and nitrogen deposition on native and invasive winter annual production in California deserts

Primary production in deserts is limited by soil moisture and N availability, and thus is likely to be influenced by both anthropogenic N deposition and precipitation regimes altered as a consequence of climate change. Invasive annual grasses are particularly responsive to increases in N and water availabilities, which may result in competition with native forb communities. Additionally, conditions favoring increased invasive grass production in arid and semi-arid regions can increase fire risk, negatively impacting woody vegetation that is not adapted to fire. We conducted a seeded garden experiment and a 5-year field fertilization experiment to investigate how winter annual production is altered by increasing N supply under a range of water availabilities. The greatest production of invasive grasses and native forbs in the garden experiment occurred under the highest soil N (inorganic N after fertilization = 2.99 g m−2) and highest watering regime, indicating these species are limited by both water and N. A classification and regression tree (CART) analysis on the multi-year field fertilization study showed that winter annual biomass was primarily limited by November–December precipitation. Biomass exceeded the threshold capable of carrying fire when inorganic soil N availability was at least 3.2 g m−2 in piñon-juniper woodland. Due to water limitation in creosote bush scrub, biomass exceeded the fire threshold only under very wet conditions regardless of soil N status. The CART analyses also revealed that percent cover of invasive grasses and native forbs is primarily dependent on the timing and amount of precipitation and secondarily dependent on soil N and site-specific characteristics. In total, our results indicate that areas of high N deposition will be susceptible to grass invasion, particularly in wet years, potentially reducing native species cover and increasing the risk of fire

Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca2+ binding and protein dimerization

<p>Abstract</p> <p>Background</p> <p>As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, <it>Polyandrocarpa </it><it>misakiensis</it>, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from <it>P. misakiensis</it>. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except <it>Drosophila</it>, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood.</p> <p>Results</p> <p>When Phe⁶⁵of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr⁶⁹with Arg⁶⁹made dimers unstable. When Glu¹⁰⁶was changed to Gly¹⁰⁶, the resultant mutant protein completely lost Ca²⁺binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. <it>Polyandrocarpa </it><it>Eed</it>, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to <it>Polyandrocarpa </it>cells, only wild-type TC14-3 could induce <it>Eed </it>without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. <it>PmEed </it>knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3.</p> <p>Conclusion</p> <p>These results show that in <it>P. misakiensis</it>, the cytostatic activity of TC14-3 is mediated by <it>PmEed </it>and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca²⁺-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells.</p

Cleavage of the urokinase receptor (uPAR) on oral cancer cells : regulation by transforming growth factor - beta 1 (TGF-beta 1) and potential effects on migration and invasion

Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - beta 1 (TGF-beta 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real- time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-beta 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF-beta 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.Peer reviewe

Capsid and Infectivity in Virus Detection

The spectacular achievements and elegance of viral RNA analyses have somewhat obscured the importance of the capsid in transmission of viruses via food and water. The capsid’s essential roles are protection of the RNA when the virion is outside the host cell and initiation of infection when the virion contacts a receptor on an appropriate host cell. Capsids of environmentally transmitted viruses are phenomenally durable. Fortuitous properties of the capsid include antigenicity, isoelectric point(s), sometimes hemagglutination, and perhaps others. These can potentially be used to characterize capsid changes that cause or accompany loss of viral infectivity and may be valuable in distinguishing native from inactivated virus when molecular detection methods are used