Apathy is one of the most challenging and prevalent behavioral symptoms of dementia. It is associated with increased disability and caregiver frustration as well as reduced quality of life, ...rehabilitation outcomes and survival after nursing home admission. A literature search to set criteria yielded 56 nonpharmacological intervention studies with outcomes relevant to apathy in dementia. Studies were rated according to quality and categorized into 7 groups: exercise, music, multisensory, animals, special care programming, therapeutic activities and miscellaneous. Despite a lack of methodological rigor, it is apparent that nonpharmacological interventions have the potential to reduce apathy. This review indicates that therapeutic activities, particularly those provided individually, have the best available evidence for effectiveness in dementia. Recommendations are provided for quality research.
Toll-like receptor 4 (TLR4), the signal-transducing molecule of the LPS receptor complex, plays a fundamental role in the sensing of LPS from Gram-negative bacteria. Activation of TLR4 signaling ...pathways by LPS is a critical upstream event in the pathogenesis of Gram-negative sepsis, making TLR4 an attractive target for novel antisepsis therapy. To validate the concept of TLR4-targeted treatment strategies in Gram-negative sepsis, we first showed that TLR4⁻/⁻ and myeloid differentiation primary response gene 88 (MyD88)⁻/⁻ mice were fully resistant to Escherichia coli-induced septic shock, whereas TLR2⁻/⁻ and wild-type mice rapidly died of fulminant sepsis. Neutralizing anti-TLR4 antibodies were then generated using a soluble chimeric fusion protein composed of the N-terminal domain of mouse TLR4 (amino acids 1-334) and the Fc portion of human IgG1. Anti-TLR4 antibodies inhibited intracellular signaling, markedly reduced cytokine production, and protected mice from lethal endotoxic shock and E. coli sepsis when administered in a prophylactic and therapeutic manner up to 13 h after the onset of bacterial sepsis. These experimental data provide strong support for the concept of TLR4-targeted therapy for Gram-negative sepsis.
The objective of this study was to review existing dementia screening tools with a view to informing and recommending suitable instruments to general practitioners (GPs) based on their performance ...and practicability for general practice.
A systematic search of pre-MEDLINE, MEDLINE, PsycINFO, and the Cochrane Library Database was undertaken. Only available full-text articles about dementia screening instruments written in English or with an English version were included. Articles using a translation of an English language instrument were excluded unless validated in a general practice, community, or population sample.
The General Practitioner Assessment of Cognition (GPCOG), Mini-Cog, and Memory Impairment Screen (MIS) were chosen as most suitable for routine dementia screening in general practice. The GPCOG, Mini-Cog, and MIS were all validated in community, population, or general practice samples, are easy to administer, and have administration times of 5 minutes or less. They also have negative predictive validity and misclassification rates, which do not differ significantly from those of the Mini-Mental Status Examination.
It is recommended that GPs consider using the GPCOG, Mini-Cog, or MIS when screening for cognitive impairment or for case detection.
The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible ...to Fas ligand-induced death signals,, indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPS, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis, whereas the long form, FLIPL, contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPS and FLIPL interact with the adaptor protein FADD, and the protease FLICE,, and potently inhibit apoptosis induced by all known human death receptors. FLIPL is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIPL protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis.
Abstract Background Patients with chronic kidney disease (CKD) often have mixed dyslipidemia and high cardiovascular disease risk. Although statins reduce LDL-C, adding a fibrate may further improve ...lipid parameters. Objective This multicenter, randomized study evaluated the short-term efficacy and safety profile of fenofibric acid (FA) + rosuvastatin (R) combination therapy for improving lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. The study also assessed estimated glomerular filtration rate after study drug washout. Methods Patients received FA 45 mg + R (5 mg for 8 weeks, then 10 mg for 8 additional weeks) or R monotherapy (5 mg for 8 weeks, then 10 mg for 8 additional weeks), followed by an 8-week washout period. Primary and secondary end points were percent changes in triglycerides and HDL-C, respectively, from baseline to week 8. Results FA 45 mg + R 5 mg, compared with R 5 mg, resulted in significant improvements in triglycerides (median % changes: week 8, −38.0% vs −22.4%, P < 0.001; week 16, −42.6% vs −29.7%, P < 0.001) and HDL-C (mean % changes: week 8, 16.9% vs 7.8%, P < 0.001; week 16, 17.3% vs 8.9%, P < 0.001). Adverse event rates were similar between groups (70.7% with FA + R vs 68.6% with R). Mean serum creatinine level at baseline was 1.36 mg/dL in the FA + R group and 1.38 mg/dL in the R group. The final treatment serum creatinine value, defined as the last nonmissing postbaseline value collected within 30 days after the last dose of study drug, was 1.52 mg/dL with FA + R (vs 1.41 mg/dL with R; P < 0.001), which then decreased to 1.39 mg/dL after the 8-week washout (vs 1.42 mg/dL with R). Conclusions The data suggest that, after 16 weeks of therapy, FA + R has an acceptable safety profile and improved TG and HDL-C efficacy versus R. FA + R combination therapy may thus further improve lipid parameters in patients with stage 3 CKD and mixed dyslipidemia. ClinicalTrials.gov identifier: NCT00680017.
Most people with dementia in Western societies will eventually be placed in a nursing home. This can be stressful to those with dementia and to their families. The adjustment to this new caring ...environment by both residents and their family caregivers and the factors that influence this are the focus of this review.
A literature search of Embase, Scopus, and Medline databases of articles published in English between 1990 and 2011 using specified search terms was performed to examine this transition. The 174 titles located were screened and reference lists hand searched resulting in the 49 relevant articles included in this review.
This decision and the subsequent adjustment period is a difficult time for people with dementia and their family caregivers. Admission has been linked to increased behavioral symptoms and in particular depression and agitation, decreasing cognition, frailty, and falls in people with dementia. For caregivers, guilt, depression, feelings of failure, and continuing burden but also improvement in quality of life have been variously reported. Research to determine what influences the trajectory of these different outcomes and the prevalence of positive outcomes for people with dementia is lacking. Successful transitions may be assisted by ensuring that the person with dementia has input into decision making, orientation procedures for the person with dementia and family member prior to and on admission, a "buddy" system for new arrivals, and a person-centered approach.
Adjustment to admission to residential care can be difficult for people with dementia and their family caregivers. Longitudinal research examining factors influencing the adjustment can provide a basis for intervention trials to improve this transition.
Viruses have evolved many distinct strategies to avoid the host's apoptotic response. Here we describe a new family of viral inhibitors (v-FLIPs) which interfere with apoptosis signalled through ...death receptors and which are present in several gamma-herpesviruses (including Kaposi's-sarcoma-associated human herpesvirus-8), as well as in the tumorigenic human molluscipoxvirus. v-FLIPs contain two death-effector domains which interact with the adaptor protein FADD, and this inhibits the recruitment and activation of the protease FLICE by the CD95 death receptor. Cells expressing v-FLIPs are protected against apoptosis induced by CD95 or by the related death receptors TRAMP and TRAIL-R. The herpesvirus saimiri FLIP is detected late during the lytic viral replication cycle, at a time when host cells are partially protected from CD95-ligand-mediated apoptosis. Protection of virus-infected cells against death-receptor-induced apoptosis may lead to higher virus production and contribute to the persistence and oncogenicity of several FLIP-encoding viruses.
Objectives:Disinhibited behaviors in dementia are associated with multiple negative outcomes. However, effective interventions are under-researched. This systematic review aims to provide an overview ...of intervention studies that report outcome measures of disinhibited behaviors in dementia.Design:Systematic searches of the databases MEDLINE, EMBASE, and PsychINFO, Social Work Abstracts and Cochrane Central Register of Controlled Trial databases were conducted for publications published between 2002 and March 2020. We included hand-searched reviews, original articles, case reports, cohort studies, and randomized controlled trials (RCTs). All studies were rated for research quality. Statistical and clinical significance were considered for individual studies. Effect sizes were included where provided or calculated where possible. Mean effect sizes were calculated for RCTs only.Participants:The systematic review included studies involving people living with dementia.Measurements:The Neuropsychiatric Inventory disinhibition subscale was used most often.Results:Nine pharmacological and 21 nonpharmacological intervention studies utilized different theoretical/clinical approaches. These included pain management, antidepressants, models of care, education and/or training, music-based approaches, and physical activity. The quality of research in RCTs was strong with a greater effect size in nonpharmacological compared to pharmacological approaches (mean Cohen’s d = 0.49 and 0.27, respectively). Disinhibition was a secondary outcome in all studies.Conclusion:Pharmacological (including pain management and antidepressants) and, more so, nonpharmacological (models of care, education/training, physical activity, and music) approaches were effective in reducing disinhibition.
Obliterative bronchiolitis (OB) is the most important cause of graft dysfunction post‐lung transplantation. It is likely that the small airway epithelium is a target of the alloimmune response, and ...that epithelial integrity is a crucial determinant of airway patency. Our goals are to elucidate epithelial cell kinetics in the heterotopic mouse trachea model and to determine potential mechanisms of cell death in allografts. Allografts and isografts were obtained by transplanting BALB/c tracheas into C57BL/6 and BALB/c immunosuppressed and nonimmunosuppressed hosts, respectively and harvested from day 3–20. Morphometry, BrdU and TUNEL labeling, and EM studies were performed. Columnar epithelium in isografts and allografts sloughs during day 0–3, but regenerates in both sets of grafts by day 10. Subsequently, allografts become inflamed and denuded, while isografts retain an intact epithelium. Prior to airway denudation, allografts exhibited significantly increased epithelial cell density, BrdU labeling index (LI), and TUNEL positive cells. Epithelial apoptosis was confirmed by electron microscopy. Allograft percent ciliated columnar epithelium and lumenal circumference were significantly decreased. Cyclosporin delayed airway fibrosis but did not alter the progression of the allograft through the phases of early ischemic injury, airway epithelial cell regeneration, and eventual cell death. These studies quantitatively demonstrate that the allograft epithelium actively regenerates in the alloimmune environment, but succumbs to increased apoptotic cell death, underscoring the importance of the airway epithelium as a self‐renewing source of alloantigen.
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