Apathy and Its Response to Antipsychotic Review and Nonpharmacological Interventions in People With Dementia Living in Nursing Homes: WHELD, a Factorial Cluster Randomized Controlled Trial

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordObjectives Apathy is common, impactful, and difficult to manage in people with dementia. We evaluated the efficacy of nonpharmacological interventions, exercise, and social interaction, in combination with antipsychotic review, to reduce apathy in people with dementia living in nursing homes in a cluster randomized controlled trial (RCT). Methods Well-being and health for people with dementia (WHELD) program included a 2 × 2 × 2 factorial cluster RCT involving people with dementia living in 16 nursing homes in the United Kingdom. All homes received training in person-centered care, and were randomized to receive antipsychotic review, social interaction, and exercise, either alone or in combinations. Apathy was one of the secondary outcomes of the WHELD trial, and it was measured by the Neuropsychiatric Inventory–nursing home version at baseline and 9 months (n = 273). We used multilevel mixed effects linear regression models to assess the impact of the interventions on apathy. Results Prevalence of apathy was 44.0% (n = 120; 95% confidence interval [CI] 38.1%–49.9%) at baseline. Severity of apathy had significant positive correlations with dementia severity, neuropsychiatric symptoms, depressive symptoms, agitation, and the needs of the people with dementia (P < .001). Antipsychotic review reduced antipsychotic use, but it significantly increased apathy (β = 5.37; SE = 0.91; P < .001). However, antipsychotic review in combination with either social interaction (β = −5.84; SE = 1.15; P < .001) or exercise (β = −7.54; SE = 0.93; P < .001) significantly reduced apathy. Conclusions Antipsychotic review can play a significant role in improving apathy in people with dementia living in nursing homes, when combined with psychosocial interventions such as social interaction and exercise. Guidance must be adapted to reflect this subtlety in care.National Institute for Health Research (NIHR

Epidemiology of Pain in People With Dementia Living in Care Homes: Longitudinal Course, Prevalence, and Treatment Implications

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordIntroduction Knowledge regarding the longitudinal course, impact, or treatment implications of pain in people with dementia living in care homes is very limited. Methods We investigated the people with dementia living in 67 care homes in London and Buckinghamshire, United Kingdom. Pain, dementia severity, neuropsychiatric symptoms, depression, agitation, and quality-of-life were measured using appropriate instruments at baseline (N = 967) and after 9 months (n = 629). Results Baseline prevalence of pain was 35.3% (95% CI 32.3–38.3). Pain severity was significantly correlated with dementia severity, neuropsychiatric symptoms, depression, agitation, and quality of life at both time points. Regular treatment with analgesics significantly reduced pain severity. Pain was significantly associated with more antipsychotic prescriptions. Pain was significantly associated (OR 1.48; 95% CI 1.18–1.85) with all-cause mortality during follow-up. Conclusions Pain is an important determinant of neuropsychiatric symptoms, mortality, quality-of-life, and antipsychotic prescriptions. Improved identification, monitoring, and treatment of pain are urgent priorities to improve the health and quality-of-life for people with dementia.National Institute for Health Research (NIHR

Development of a UK core dataset for geriatric medicine research: a position statement and results from a Delphi consensus process

BACKGROUND: There is lack of standardisation in assessment tools used in geriatric medicine research, which makes pooling of data and cross-study comparisons difficult. METHODS: We conducted a modified Delphi process to establish measures to be included within core and extended datasets for geriatric medicine research in the United Kingdom (UK). This included three complete questionnaire rounds, and one consensus meeting. Participants were selected from attendance at the NIHR Newcastle Biomedical Research Centre meeting, May 2019, and academic geriatric medicine e-mailing lists. Literature review was used to develop the initial questionnaire, with all responses then included in the second questionnaire. The third questionnaire used refined options from the second questionnaire with response ranking. RESULTS: Ninety-eight responses were obtained across all questionnaire rounds (Initial: 19, Second: 21, Third: 58) from experienced and early career researchers in geriatric medicine. The initial questionnaire included 18 questions with short text responses, including one question for responders to suggest additional items. Twenty-six questions were included in the second questionnaire, with 108 within category options. The third questionnaire included three ranking, seven final agreement, and four binary option questions. Results were discussed at the consensus meeting. In our position statement, the final consensus dataset includes six core domains: demographics (age, gender, ethnicity, socioeconomic status), specified morbidities, functional ability (Barthel and/or Nottingham Extended Activities of Daily Living), Clinical Frailty Scale (CFS), cognition, and patient-reported outcome measures (dependent on research question). We also propose how additional variables should be measured within an extended dataset. CONCLUSIONS: Our core and extended datasets represent current consensus opinion of academic geriatric medicine clinicians across the UK. We consider the development and further use of these datasets will strengthen collaboration between researchers and academic institutions

Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients

Triptolide Inhibits the Proliferation of Prostate Cancer Cells and Down-Regulates SUMO-Specific Protease 1 Expression

Recently, traditional Chinese medicine and medicinal herbs have attracted more attentions worldwide for its anti-tumor efficacy. Celastrol and Triptolide, two active components extracted from the Chinese herb Tripterygium wilfordii Hook F (known as Lei Gong Teng or Thunder of God Vine), have shown anti-tumor effects. Celastrol was identified as a natural 26 s proteasome inhibitor which promotes cell apoptosis and inhibits tumor growth. The effect and mechanism of Triptolide on prostate cancer (PCa) is not well studied. Here we demonstrated that Triptolide, more potent than Celastrol, inhibited cell growth and induced cell death in LNCaP and PC-3 cell lines. Triptolide also significantly inhibited the xenografted PC-3 tumor growth in nude mice. Moreover, Triptolide induced PCa cell apoptosis through caspases activation and PARP cleavage. Unbalance between SUMOylation and deSUMOylation was reported to play an important role in PCa progression. SUMO-specific protease 1 (SENP1) was thought to be a potential marker and therapeutical target of PCa. Importantly, we observed that Triptolide down-regulated SENP1 expression in both mRNA and protein levels in dose-dependent and time-dependent manners, resulting in an enhanced cellular SUMOylation in PCa cells. Meanwhile, Triptolide decreased AR and c-Jun expression at similar manners, and suppressed AR and c-Jun transcription activity. Furthermore, knockdown or ectopic SENP1, c-Jun and AR expression in PCa cells inhibited the Triptolide anti-PCa effects. Taken together, our data suggest that Triptolide is a natural compound with potential therapeutic value for PCa. Its anti-tumor activity may be attributed to mechanisms involving down-regulation of SENP1 that restores SUMOylation and deSUMOyaltion balance and negative regulation of AR and c-Jun expression that inhibits the AR and c-Jun mediated transcription in PCa

Single cell dissection of plasma cell heterogeneity in symptomatic and asymptomatic myeloma

Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients

Physical mapping and BAC-end sequence analysis provide initial insights into the flax (Linum usitatissimum L.) genome

<p>Abstract</p> <p>Background</p> <p>Flax (<it>Linum usitatissimum </it>L.) is an important source of oil rich in omega-3 fatty acids, which have proven health benefits and utility as an industrial raw material. Flax seeds also contain lignans which are associated with reducing the risk of certain types of cancer. Its bast fibres have broad industrial applications. However, genomic tools needed for molecular breeding were non existent. Hence a project, Total Utilization Flax GENomics (TUFGEN) was initiated. We report here the first genome-wide physical map of flax and the generation and analysis of BAC-end sequences (BES) from 43,776 clones, providing initial insights into the genome.</p> <p>Results</p> <p>The physical map consists of 416 contigs spanning ~368 Mb, assembled from 32,025 fingerprints, representing roughly 54.5% to 99.4% of the estimated haploid genome (370-675 Mb). The N50 size of the contigs was estimated to be ~1,494 kb. The longest contig was ~5,562 kb comprising 437 clones. There were 96 contigs containing more than 100 clones. Approximately 54.6 Mb representing 8-14.8% of the genome was obtained from 80,337 BES. Annotation revealed that a large part of the genome consists of ribosomal DNA (~13.8%), followed by known transposable elements at 6.1%. Furthermore, ~7.4% of sequence was identified to harbour novel repeat elements. Homology searches against flax-ESTs and NCBI-ESTs suggested that ~5.6% of the transcriptome is unique to flax. A total of 4064 putative genomic SSRs were identified and are being developed as novel markers for their use in molecular breeding.</p> <p>Conclusion</p> <p>The first genome-wide physical map of flax constructed with BAC clones provides a framework for accessing target loci with economic importance for marker development and positional cloning. Analysis of the BES has provided insights into the uniqueness of the flax genome. Compared to other plant genomes, the proportion of rDNA was found to be very high whereas the proportion of known transposable elements was low. The SSRs identified from BES will be valuable in saturating existing linkage maps and for anchoring physical and genetic maps. The physical map and paired-end reads from BAC clones will also serve as scaffolds to build and validate the whole genome shotgun assembly.</p