Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1

Peer reviewedPublisher PD

Does the level of expressed emotion (LEE) questionnaire have the same factor structure for adolescents as it has for adults?

Background The level of expressed emotion (LEE) is a four-factor questionnaire that measures expressed emotion (EE) as perceived by the recipient. These factors are: perceived lack of emotional support, perceived intrusiveness, perceived irritation, and perceive criticism. The four factors of the LEE has previously been found to be related to psychological disorders and has good psychometric properties for adults. However, it has not previously been studied in adolescent populations. Methods A total of 311 adolescents participated in this study. Using structural equation modeling, confirmatory factor analyses were conducted to examine if the LEE also had the same four-factor structure for adolescents as it does for adults. Results The confirmatory factor analyses demonstrated that the LEE's four-factor structure also applied to adolescents. The internal consistency of the scales were good and all the inter-correlations between the scales were significant. Additionally, the factors were significantly correlated to adolescent depressive and anxiety symptom score dimensions. Conclusion These findings seem to indicate that the LEE may be a good instrument in the measurement of adolescents perceived EE

Assessing Susceptibility from Early-Life Exposure to Carcinogens

Cancer risk assessment methods currently assume that children and adults are equally susceptible to exposure to chemicals. We reviewed available scientific literature to determine whether this was scientifically supported. We identified more than 50 chemicals causing cancer after perinatal exposure. Human data are extremely limited, with radiation exposures showing increased early susceptibility at some tumor sites. Twenty-seven rodent studies for 18 chemicals had sufficient data after postnatal and adult exposures to quantitatively estimate potential increased susceptibility from early-life exposure, calculated as the ratio of juvenile to adult cancer potencies for three study types: acute dosing, repeated dosing, and lifetime dosing. Twelve of the chemicals act through a mutagenic mode of action. For these, the geometric mean ratio was 11 for lifetime exposures and 8.7 for repeat exposures, with a ratio of 10 for these studies combined. The geometric mean ratio for acute studies is 1.5, which was influenced by tissue-specific results [geometric mean ratios for kidney, leukemia, liver, lymph, mammary, nerve, reticular tissue, thymic lymphoma, and uterus/vagina > 1 (range, 1.6–8.1); forestomach, harderian gland, ovaries, and thyroid < 1 (range, 0.033–0.45)]. Chemicals causing cancer through other modes of action indicate some increased susceptibility from postnatal exposure (geometric mean ratio is 3.4 for lifetime exposure, 2.2 for repeat exposure). Early exposures to compounds with endocrine activity sometimes produce different tumors after exposures at different ages. These analyses suggest increased susceptibility to cancer from early-life exposure, particularly for chemicals acting through a mutagenic mode of action

Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

<p>Abstract</p> <p>Background</p> <p>Vaginal atrophy (VA) is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT). The ovariectomized (OVX) rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology.</p> <p>Methods</p> <p>We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene.</p> <p>Results</p> <p>A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation.</p> <p>Conclusion</p> <p>At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.</p

Niche stiffness underlies the ageing of central nervous system progenitor cells.

Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations1. One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs)2. A relatively overlooked potential source of this loss of function is the stem cell 'niche'-a set of cell-extrinsic cues that include chemical and mechanical signals3,4. Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.The work was supported by European Research Council (ERC) grant 772798 (to K.J.C.) and 772426 (to K.F.); the UK Multiple Sclerosis Society (to R.J.M.F.); Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/M008827/1 (to K.J.C and R.J.M.F.) and BB/N006402/1 (to K.F.); the Adelson Medical Research Foundation (R.J.M.F. and D.H.R.); an EMBO Long-Term Fellowship ALTF 1263-2015 and European Commission FP7 actions LTFCOFUND2013, GA-2013-609409 (to I.P.W.); and a core support grant from the Wellcome Trust and Medical Research Council (MRC) to the Wellcome Trust–MRC Cambridge Stem Cell Institute

Pharmacological Investigations of the Dissociative ‘Legal Highs’ Diphenidine, Methoxphenidine and Analogues

1,2-Diarylethylamines including lanicemine, lefetamine, and remacemide have clinical relevance in a range of therapeutic areas including pain management, epilepsy, neurodegenerative disease and depression. More recently 1,2-diarylethylamines have been sold as ‘legal highs’ in a number of different forms including powders and tablets. These compounds are sold to circumvent governmental legislation regulating psychoactive drugs. Examples include the opioid MT-45 and the dissociative agents diphenidine (DPH) and 2-methoxy-diphenidine (2-MXP). A number of fatal and non-fatal overdoses have been linked to abuse of these compounds. As with many ‘legal highs’, little is known about their pharmacology. To obtain a better understanding, the effects of DPH, 2-MXP and its 3- and 4-MeO- isomers, and 2-Cl-diphenidine (2-Cl-DPH) were investigated using binding studies at 46 central nervous system receptors including the N-methyl-D-aspartate receptor (NMDAR), serotonin, dopamine, norepinephrine, histamine, and sigma receptors as well as the reuptake transporters for serotonin, dopamine and norepinephrine. Reuptake inhibition potencies were measured at serotonin, norepinephrine and dopamine transporters. NMDAR antagonism was established in vitro using NMDAR-induced field excitatory postsynaptic potential (fEPSP) experiments. Finally, DPH and 2-MXP were investigated using tests of pre-pulse inhibition of startle (PPI) in rats to determine whether they reduce sensorimotor gating, an effect observed with known dissociative drugs such as phencyclidine (PCP) and ketamine. The results suggest that these 1,2-diarylethylamines are relatively selective NMDAR antagonists with weak off-target inhibitory effects on dopamine and norepinephrine reuptake. DPH and 2-MXP significantly inhibited PPI. DPH showed greater potency than 2-MXP, acting with a median effective dose (ED50) of 9.5 mg/kg, which is less potent than values reported for other commonly abused dissociative drugs such as PCP and ketamine

A Re-conceptualization of Access for 21st Century Healthcare

Many e-health technologies are available to promote virtual patient–provider communication outside the context of face-to-face clinical encounters. Current digital communication modalities include cell phones, smartphones, interactive voice response, text messages, e-mails, clinic-based interactive video, home-based web-cams, mobile smartphone two-way cameras, personal monitoring devices, kiosks, dashboards, personal health records, web-based portals, social networking sites, secure chat rooms, and on-line forums. Improvements in digital access could drastically diminish the geographical, temporal, and cultural access problems faced by many patients. Conversely, a growing digital divide could create greater access disparities for some populations. As the paradigm of healthcare delivery evolves towards greater reliance on non-encounter-based digital communications between patients and their care teams, it is critical that our theoretical conceptualization of access undergoes a concurrent paradigm shift to make it more relevant for the digital age. The traditional conceptualizations and indicators of access are not well adapted to measure access to health services that are delivered digitally outside the context of face-to-face encounters with providers. This paper provides an overview of digital “encounterless” utilization, discusses the weaknesses of traditional conceptual frameworks of access, presents a new access framework, provides recommendations for how to measure access in the new framework, and discusses future directions for research on access

Exploring CRM effectiveness: an institutional theory perspective

This study identifies the potential contribution that institutional theory can make to understanding the success of marketing practices. Based on institutional theory, we argue that the effectiveness of marketing practices decreases when firms are motivated to adopt such practices under the influence of institutional pressures originating in firms' environments. However, alignment between a practice and a firm's marketing strategy may buffer against these negative effects. We apply these insights to the case of customer relationship management (CRM). CRM is considered an important way to enhance customer loyalty and firm performance, but it has also been criticized for being expensive and for not living up to expectations. Empirical data from 107 organizations confirm that, in general, adopting CRM for mimetic motives is likely to result in fewer customer insights as a result of using this practice. Our study suggests that institutional theory has much to offer to the investigation of the effectiveness of marketing practices