Rejection: Some Causes, Symptoms, and Treatment

One of the many causes of personality problems is the feeling of rejection. It may result in the individual\u27s becoming hypersensitive, resentful, or demanding, particularly if this experience has occurred in the impressionable age of youth. It is my purpose in this paper to set forth some of the symptoms and responses that occur in the individual who has this feeling, and what avenues are open in the treatment of such maladjusted individuals

Dynamic Changes in Brain Mesenchymal Perivascular Cells Associate with Multiple Sclerosis Disease Duration, Active Inflammation, and Demyelination

Vascular changes, including blood brain barrier destabilization, are common pathological features in multiple sclerosis (MS) lesions. Blood vessels within adult organs are reported to harbor mesenchymal stromal cells (MSCs) with phenotypical and functional characteristics similar to pericytes. We performed an immunohistochemical study of MSCs/pericytes in brain tissue from MS and healthy persons. Post-mortem brain tissue from patients with early progressive MS (EPMS), late stage progressive MS (LPMS), and healthy persons were analyzed for the MSC and pericyte markers CD146, platelet-derived growth factor receptor beta (PDGFRβ), CD73, CD271, alpha-smooth muscle actin, and Ki67. The MS samples included active, chronic active, chronic inactive lesions, and normal-appearing white matter. MSC and pericyte marker localization were detected in association with blood vessels, including subendothelial CD146+PDGFRβ+Ki67+ cells and CD73+CD271+PDGFRβ+Ki67– cells within the adventitia and perivascular areas. Both immunostained cell subpopulations were termed mesenchymal perivascular cells (MPCs). Quantitative analyses of immunostainings showed active lesions containing increased regions of CD146+PDGFRβ+Ki67+ and CD73+CD271+PDGFRβ+Ki67– MPC subpopulations compared to inactive lesions. Chronic lesions presented with decreased levels of CD146+PDGFRβ+Ki67+ MPC cells compared to control tissue. Furthermore, LPMS lesions displayed increased numbers of blood vessels harboring greatly enlarged CD73+CD271+ adventitial and perivascular areas compared to control and EPMS tissue. In conclusion, we demonstrate the presence of MPC subgroups in control human brain vasculature, and their phenotypic changes in MS brain, which correlated with inflammation, demyelination and MS disease duration. Our findings demonstrate that brain-derived MPCs respond to pathologic mechanisms involved in MS disease progression and suggest that vessel-targeted therapeutics may benefit patients with progressive MS

Mass spectrometry imaging of cassette-dosed drugs for higher throughput pharmacokinetic and biodistribution analysis

Cassette dosing of compounds for preclinical drug plasma pharmacokinetic analysis has been shown to be a powerful strategy within the pharmaceutical industry for increasing throughput while decreasing the number of animals used. Presented here for the first time is data on the application of a cassette dosing strategy for label-free tissue distribution studies. The aim of the study was to image the spatial distribution of eight nonproprietary drugs (haloperidol, bufuralol, midazolam, clozapine, terfenadine, erlotinib, olanzapine, and moxifloxacin) in multiple tissues after oral and intravenous cassette dosing (four compounds per dose route). An array of mass spectrometry imaging technologies, including matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI), liquid extraction surface analysis tandem mass spectrometry (LESA-MS/MS), and desorption electrospray ionization mass spectrometry (DESI-MS) was used. Tissue analysis following intravenous and oral administration of discretely and cassette-dosed compounds demonstrated similar relative abundances across a range of tissues indicating that a cassette dosing approach was applicable. MALDI MSI was unsuccessful in detecting all of the target compounds; therefore, DESI MSI, a complementary mass spectrometry imaging technique, was used to detect additional target compounds. In addition, by adapting technology used for tissue profiling (LESA-MS/MS) low spatial resolution mass spectrometry imaging (∼1 mm) was possible for all targets across all tissues. This study exemplifies the power of multiplatform MSI analysis within a pharmaceutical research and development (R&D) environment. Furthermore, we have illustrated that the cassette dosing approach can be readily applied to provide combined, label-free pharmacokinetic and drug distribution data at an early stage of the drug discovery/development process while minimizing animal usage

Physical activity of subjects aged 50–64 years involved in the European Prospective Investigation into Cancer and Nutrition (EPIC)

Objective: To describe physical activity of participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Design: A cross-sectional analysis of baseline data of a European prospective cohort study. Subjects: This analysis was restricted to participants in the age group 50-64 years, which was represented in all EPIC centres. It involved 236 386 participants from 25 centres in nine countries. In each EPIC centre, physical activity was assessed by standardised and validated questions. Frequency distribution of type of professional activity and participation in non-professional activities, and age-adjusted means, medians and percentiles of time dedicated to non-professional activities are presented for men and women from each centre. Results: Professional activity was most frequently classified as sedentary or standing in all centres. There was a wide variation regarding participation in different types of non-professional activities and time dedicated to these activities across EPIC centres. Over 80% of all EPIC participants engaged in walking, while less than 50% of the subjects participated in sport. Total time dedicated to recreational activities was highest among the Dutch participants and lowest among men from Malmo (Sweden) and women from Naples (Italy). In all centres, total time dedicated to recreational activity in the summer was higher than in the winter. Women from southern Europe spent the most time on housekeeping. Conclusions: There is a considerable variation of physical activity across EPIC centres. This variation was especially evident for recreational activities in both men and women

Large carnivore expansion in Europe is associated with human population density and land cover changes

Aim: The recent recovery of large carnivores in Europe has been explained as resulting from a decrease in human persecution driven by widespread rural land abandonment, paralleled by forest cover increase and the consequent increase in availability of shelter and prey. We investigated whether land cover and human population density changes are related to the relative probability of occurrence of three European large carnivores: the grey wolf (Canis lupus), the Eurasian lynx (Lynx lynx) and the brown bear (Ursus arctos). Location: Europe, west of 64° longitude. Methods: We fitted multi-temporal species distribution models using >50,000 occurrence points with time series of land cover, landscape configuration, protected areas, hunting regulations and human population density covering a 24-year period (1992–2015). Within the temporal window considered, we then predicted changes in habitat suitability for large carnivores throughout Europe. Results: Between 1992 and 2015, the habitat suitability for the three species increased in Eastern Europe, the Balkans, North-West Iberian Peninsula and Northern Scandinavia, but showed mixed trends in Western and Southern Europe. These trends were primarily associated with increases in forest cover and decreases in human population density, and, additionally, with decreases in the cover of mosaics of cropland and natural vegetation. Main conclusions: Recent land cover and human population changes appear to have altered the habitat suitability pattern for large carnivores in Europe, whereas protection level did not play a role. While projected changes largely match the observed recovery of large carnivore populations, we found mismatches with the recent expansion of wolves in Central and Southern Europe, where factors not included in our models may have played a dominant role. This suggests that large carnivores’ co-existence with humans in European landscapes is not limited by habitat availability, but other factors such as favourable human tolerance and policy

Peptide ion channel toxins from the bootlace worm, the longest animal on Earth

Polypeptides from animal venoms have found important uses as drugs, pharmacological tools, and within biotechnological and agricultural applications. We here report a novel family of cystine knot peptides from nemertean worms, with potent activity on voltage-gated sodium channels. These toxins, named the α-nemertides, were discovered in the epidermal mucus of Lineus longissimus, the ‘bootlace worm’ known as the longest animal on earth. The most abundant peptide, the 31-residue long α-1, was isolated, synthesized, and its 3D NMR structure determined. Transcriptome analysis including 17 species revealed eight α-nemertides, mainly distributed in the genus Lineus. α-1 caused paralysis and death in green crabs (Carcinus maenas) at 1 µg/kg (~300 pmol/kg). It showed profound effect on invertebrate voltage-gated sodium channels (e.g. Blattella germanica Nav1) at low nanomolar concentrations. Strong selectivity for insect over human sodium channels indicates that α-nemertides can be promising candidates for development of bioinsecticidal agents

Self-Construal and Concerns Elicited by Imagined and Real Health Problems 1

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74826/1/j.1559-1816.2007.00283.x.pd

Uridine-derived ribose fuels glucose-restricted pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy1,2. This is mediated in part by a complex tumour microenvironment3, low vascularity4, and metabolic aberrations5,6. Although altered metabolism drives tumour progression, the spectrum of metabolites used as nutrients by PDA remains largely unknown. Here we identified uridine as a fuel for PDA in glucose-deprived conditions by assessing how more than 175 metabolites impacted metabolic activity in 21 pancreatic cell lines under nutrient restriction. Uridine utilization strongly correlated with the expression of uridine phosphorylase 1 (UPP1), which we demonstrate liberates uridine-derived ribose to fuel central carbon metabolism and thereby support redox balance, survival and proliferation in glucose-restricted PDA cells. In PDA, UPP1 is regulated by KRAS-MAPK signalling and is augmented by nutrient restriction. Consistently, tumours expressed high UPP1 compared with non-tumoural tissues, and UPP1 expression correlated with poor survival in cohorts of patients with PDA. Uridine is available in the tumour microenvironment, and we demonstrated that uridine-derived ribose is actively catabolized in tumours. Finally, UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models. Our data identify uridine utilization as an important compensatory metabolic process in nutrient-deprived PDA cells, suggesting a novel metabolic axis for PDA therapy

Modeling factors influencing the demand for emergency department services in ontario: a comparison of methods

<p>Abstract</p> <p>Background</p> <p>Emergency departments are medical treatment facilities, designed to provide episodic care to patients suffering from acute injuries and illnesses as well as patients who are experiencing sporadic flare-ups of underlying chronic medical conditions which require immediate attention. Supply and demand for emergency department services varies across geographic regions and time. Some persons do not rely on the service at all whereas; others use the service on repeated occasions. Issues regarding increased wait times for services and crowding illustrate the need to investigate which factors are associated with increased frequency of emergency department utilization. The evidence from this study can help inform policy makers on the appropriate mix of supply and demand targeted health care policies necessary to ensure that patients receive appropriate health care delivery in an efficient and cost-effective manner. The purpose of this report is to assess those factors resulting in increased demand for emergency department services in Ontario. We assess how utilization rates vary according to the severity of patient presentation in the emergency department. We are specifically interested in the impact that access to primary care physicians has on the demand for emergency department services. Additionally, we wish to investigate these trends using a series of novel regression models for count outcomes which have yet to be employed in the domain of emergency medical research.</p> <p>Methods</p> <p>Data regarding the frequency of emergency department visits for the respondents of Canadian Community Health Survey (CCHS) during our study interval (2003-2005) are obtained from the National Ambulatory Care Reporting System (NACRS). Patients' emergency department utilizations were linked with information from the Canadian Community Health Survey (CCHS) which provides individual level medical, socio-demographic, psychological and behavioral information for investigating predictors of increased emergency department utilization. Six different multiple regression models for count data were fitted to assess the influence of predictors on demand for emergency department services, including: Poisson, Negative Binomial, Zero-Inflated Poisson, Zero-Inflated Negative Binomial, Hurdle Poisson, and Hurdle Negative Binomial. Comparison of competing models was assessed by the Vuong test statistic.</p> <p>Results</p> <p>The CCHS cycle 2.1 respondents were a roughly equal mix of males (50.4%) and females (49.6%). The majority (86.2%) were young-middle aged adults between the ages of 20-64, living in predominantly urban environments (85.9%), with mid-high household incomes (92.2%) and well-educated, receiving at least a high-school diploma (84.1%). Many participants reported no chronic disease (51.9%), fell into a small number (0-5) of ambulatory diagnostic groups (62.3%), and perceived their health status as good/excellent (88.1%); however, were projected to have high Resource Utilization Band levels of health resource utilization (68.2%). These factors were largely stable for CCHS cycle 3.1 respondents. Factors influencing demand for emergency department services varied according to the severity of triage scores at initial presentation. For example, although a non-significant predictor of the odds of emergency department utilization in high severity cases, access to a primary care physician was a statistically significant predictor of the likelihood of emergency department utilization (OR: 0.69; 95% CI OR: 0.63-0.75) and the rate of emergency department utilization (RR: 0.57; 95% CI RR: 0.50-0.66) in low severity cases.</p> <p>Conclusion</p> <p>Using a theoretically appropriate hurdle negative binomial regression model this unique study illustrates that access to a primary care physician is an important predictor of both the odds and rate of emergency department utilization in Ontario. Restructuring primary care services, with aims of increasing access to undersupplied populations may result in decreased emergency department utilization rates by approximately 43% for low severity triage level cases.</p