Off-Label Biologic Regimens in Psoriasis: A Systematic Review of Efficacy and Safety of Dose Escalation, Reduction, and Interrupted Biologic Therapy

Objectives: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment) with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment

Maximum (prior) brain size, not atrophy, correlates with cognition in community-dwelling older people: a cross-sectional neuroimaging study

<p>Abstract</p> <p>Background</p> <p>Brain size is associated with cognitive ability in adulthood (correlation ~ .3), but few studies have investigated the relationship in normal ageing, particularly beyond age 75 years. With age both brain size and fluid-type intelligence decline, and regional atrophy is often suggested as causing decline in specific cognitive abilities. However, an association between brain size and intelligence may be due to the persistence of this relationship from earlier life.</p> <p>Methods</p> <p>We recruited 107 community-dwelling volunteers (29% male) aged 75–81 years for cognitive testing and neuroimaging. We used principal components analysis to derived a 'general cognitive factor' (g) from tests of fluid-type ability. Using semi-automated analysis, we measured whole brain volume, intracranial area (ICA) (an estimate of maximal brain volume), and volume of frontal and temporal lobes, amygdalo-hippocampal complex, and ventricles. Brain atrophy was estimated by correcting WBV for ICA.</p> <p>Results</p> <p>Whole brain volume (WBV) correlated with general cognitive ability (g) (r = .21, P < .05). Statistically significant associations between brain areas and specific cognitive abilities became non-significant when corrected for maximal brain volume (estimated using ICA), i.e. there were no statistically significant associations between atrophy and cognitive ability. The association between WBV and g was largely attenuated (from .21 to .03: i.e. attenuating the variance by 98%) by correcting for ICA. ICA accounted for 6.2% of the variance in g in old age, whereas atrophy accounted for < 1%.</p> <p>Conclusion</p> <p>The association between brain regions and specific cognitive abilities in community dwelling people of older age is due to the life-long association between whole brain size and general cognitive ability, rather than atrophy of specific regions. Researchers and clinicians should therefore be cautious of interpreting global or regional brain atrophy on neuroimaging as contributing to cognitive status in older age without taking into account prior mental ability and brain size.</p

PPARγ population shift produces disease-related changes in molecular networks associated with metabolic syndrome

Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of adipocyte differentiation and has an important role in metabolic syndrome. Phosphorylation of the receptor's ligand-binding domain at serine 273 has been shown to change the expression of a large number of genes implicated in obesity. The difference in gene expression seen when comparing wild-type phosphorylated with mutant non-phosphorylated PPARγ may have important consequences for the cellular molecular network, the state of which can be shifted from the healthy to a stable diseased state. We found that a group of differentially expressed genes are involved in bi-stable switches and form a core network, the state of which changes with disease progression. These findings support the idea that bi-stable switches may be a mechanism for locking the core gene network into a diseased state and for efficiently propagating perturbations to more distant regions of the network. A structural analysis of the PPARγ–RXRα dimer complex supports the hypothesis of a major structural change between the two states, and this may represent an important mechanism leading to the differential expression observed in the core network

A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis

Extracellular matrix interactions have essential roles in normal physiology and many pathological processes. Although the importance of extracellular matrix interactions in metastasis is well documented, systematic approaches to identify their roles in distinct stages of tumorigenesis have not been described. Here we report a novel-screening platform capable of measuring phenotypic responses to combinations of extracellular matrix molecules. Using a genetic mouse model of lung adenocarcinoma, we measure the extracellular matrix-dependent adhesion of tumour-derived cells. Hierarchical clustering of the adhesion profiles differentiates metastatic cell lines from primary tumour lines. Furthermore, we uncovered that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin. We show that these molecules correlate with human disease and that their interactions are mediated in part by α3β1 integrin. Thus, our platform allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets.National Institutes of Health (U.S.) (Grant K99-CA151968)National Institutes of Health (U.S.). Ruth L. Kirschstein National Research Service AwardStand Up To Cancer (SU2C/AACR)David H. Koch Institute for Integrative Cancer Research at MIT (CTC Project)Harvard Stem Cell Institute (SG-0046-08-00)National Cancer Center (Postdoctoral Fellowship)National Cancer Institute (U.S.) (U54CA126515)National Cancer Institute (U.S.) (U54CA112967)Howard Hughes Medical InstituteMassachusetts Institute of Technology. Ludwig Center for Molecular Oncolog

CRISPR Interference Directs Strand Specific Spacer Acquisition

Background: CRISPR/Cas is a widespread adaptive immune system in prokaryotes. This system integrates short stretches of DNA derived from invading nucleic acids into genomic CRISPR loci, which function as memory of previously encountered invaders. In Escherichia coli, transcripts of these loci are cleaved into small RNAs and utilized by the Cascade complex to bind invader DNA, which is then likely degraded by Cas3 during CRISPR interference. Results: We describe how a CRISPR-activated E. coli K12 is cured from a high copy number plasmid under non-selective conditions in a CRISPR-mediated way. Cured clones integrated at least one up to five anti-plasmid spacers in genomic CRISPR loci. New spacers are integrated directly downstream of the leader sequence. The spacers are non-randomly selected to target protospacers with an AAG protospacer adjacent motif, which is located directly upstream of the protospacer. A cooccurrence of PAM deviations and CRISPR repeat mutations was observed, indicating that one nucleotide from the PAM is incorporated as the last nucleotide of the repeat during integration of a new spacer. When multiple spacers were integrated in a single clone, all spacer targeted the same strand of the plasmid, implying that CRISPR interference caused by the first integrated spacer directs subsequent spacer acquisition events in a strand specific manner. Conclusions: The E. coli Type I-E CRISPR/Cas system provides resistance against bacteriophage infection, but also enables removal of residing plasmids. We established that there is a positive feedback loop between active spacers in a cluster – i

Does socioeconomic disparity in cancer incidence vary across racial/ethnic groups?

Objective Very few studies have simultaneously examined incidence of the leading cancers in relation to socioeconomic status (SES) and race/ethnicity in populations including Hispanics and Asians. This study aims to describe SES disparity in cancer incidence within each of four major racial/ethnic groups (non-Hispanic white, black, Hispanic, and Asian/Pacific Islander) for five major cancer sites, including female breast cancer, colorectal cancer, cervical cancer, lung cancer, and prostate cancer. Methods Invasive cancers of the five major sites diagnosed from 1998 to 2002 (n = 376,158) in California were included in the study. Composite area-based SES measures were used to quantify SES level and to calculate cancer incidence rates stratified by SES. Relative index of inequality (RII) was generated to measure SES gradient of cancer incidence within each racial/ethnic group. Results Significant variations were detected in SES disparities across the racial/ethnic groups for all five major cancer sites. Female breast cancer and prostate cancer incidence increased with increased SES in all groups, with the trend strongest among Hispanics. Incidence of cervical cancer increased with decreased SES, with the largest gradient among non-Hispanic white women. Lung cancer incidence increased with decreased SES with the exception of Hispanic men and women, for whom SES gradient was in the opposite direction. For colorectal cancer, higher incidence was associated with lower SES in non-Hispanic whites but with higher SES in Hispanics and Asian/Pacific Islander women. Conclusions Examining SES disparity stratified by race/ethnicity enhances our understanding of the complex relationships between cancer incidence, SES, and race/ethnicity

Cytomegalovirus infection in pediatric rheumatic diseases: a review

Human cytomegalovirus (HCMV) is familiar to pediatric rheumatologists mainly as a cause of opportunistic disease in pharmacologically immune suppressed patients. However, HCMV also has a variety of immuno-modulatory effects, through which it may influence the course of rheumatic conditions. In this article we discuss the interplay between HCMV and the immune system, and review the clinical manifestations, diagnosis, and treatment of HCMV infection in children with rheumatic disease

The effects of aging of scientists on their publication and citation patterns

The average age at which U.S. researchers get their first grant from NIH has increased from 34.3 in 1970, to 41.7 in 2004. These data raise the crucial question of the effects of aging on the scientific creativity and productivity of researchers. Those who worry about the aging of scientists usually believe that the younger they are the more creative and productive they will be. Using a large population of 13,680 university professors in Quebec, we show that, while scientific productivity rises sharply between 28 and 40, it increases at a slower pace between 41 and 50 and stabilizes afterward until retirement for the most active researchers. The average scientific impact per paper decreases linearly until 50-55 years old, but the average number of papers in highly cited journals and among highly cited papers rises continuously until retirement. Our results clearly show for the first time the natural history of the scientific productivity of scientists over their entire career and bring to light the fact that researchers over 55 still contribute significantly to the scientific community by producing high impact papers.Comment: 12 pages, 4 figure

Parallel molecular routes to cold adaptation in eight genera of New Zealand stick insects.

The acquisition of physiological strategies to tolerate novel thermal conditions allows organisms to exploit new environments. As a result, thermal tolerance is a key determinant of the global distribution of biodiversity, yet the constraints on its evolution are not well understood. Here we investigate parallel evolution of cold tolerance in New Zealand stick insects, an endemic radiation containing three montane-occurring species. Using a phylogeny constructed from 274 orthologous genes, we show that stick insects have independently colonized montane environments at least twice. We compare supercooling point and survival of internal ice formation among ten species from eight genera, and identify both freeze tolerance and freeze avoidance in separate montane lineages. Freeze tolerance is also verified in both lowland and montane populations of a single, geographically widespread, species. Transcriptome sequencing following cold shock identifies a set of structural cuticular genes that are both differentially regulated and under positive sequence selection in each species. However, while cuticular proteins in general are associated with cold shock across the phylogeny, the specific genes at play differ among species. Thus, while processes related to cuticular structure are consistently associated with adaptation for cold, this may not be the consequence of shared ancestral genetic constraints

Situational awareness, relational coordination and integrated care delivery to hospitalized elderly in the Netherlands: A comparison between hospitals

__Abstract__ Background: It is known that interprofessional collaboration is crucial for integrated care delivery, yet we are still unclear about the underlying mechanisms explaining effectiveness of integrated care delivery to older patients. In addition, we lack research comparing integrated care delivery between hospitals. Therefore, this study aims to (i) provide insight into the underlying components 'relational coordination' and 'situational awareness' of integrated care delivery and the role of team and organizational context in integrated care delivery; and (ii) compare situational awareness, relational coordination, and integrated care delivery of different hospitals in the Netherlands. Methods. This cross-sectional study took place in 2012 among professionals from three different hospitals involved in the delivery of care to older patients. A total of 215 professionals filled in the questionnaire (42% response rate).Descriptive statistics and paired-sample t-tests were used to investigate the level of situational awareness, relational coordination, and integrated care delivery in the three different hospitals. Correlation and multilevel analyses were used to investigate the relationship between background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery. Results: No differences in background characteristics, team context, organizational context, situational awareness, relational coordination and integrated care delivery were found among the three hospitals. Correlational analysis revealed that situational awareness (r = 0.30; p < 0.01), relational coordination (r = 0.17; p < 0.05), team climate (r = 0.29; p < 0.01), formal internal communication (r = 0.46; p < 0.01), and informal internal communication (r = 0.36; p < 0.01) were positively associated with integrated care delivery. Stepwise multilevel analyses showed that formal internal communication (p < 0.001) and situational awareness (p < 0.01) were associated with integrated care delivery. Team climate was not significantly associated with integrated care delivery when situational awareness and relational coordination were included in the equation. Thus situational awareness acted as mediator between team climate and integrated care delivery among professionals delivering care to older hospitalized patients. Conclusions: The results of this study show the importance of formal internal communication and situational awareness for quality of care delivery to hospitalized older patients