Diurnal variability of C-reactive protein in obstructive sleep apnea

OBJECTIVE: The objective of this study is to examine the diurnal variability of C-reactive protein (CRP) in obstructive sleep apnea (OSA). METHODS AND MEASUREMENTS: Participants included 44 women and men with untreated OSA (mean apnea/hypopnea index = 37.5, SD +/- 28) and 23 healthy adults with no OSA. Sleep was monitored with polysomnography in the University of California San Diego General Clinical Research Center. Over a 24-h period, blood was collected every 2 h, and CRP levels were determined. RESULTS: Adjusting for age, gender, and body mass index, a significant group by time interaction showed that patients with OSA had higher CRP levels during the daytime (8:00 a.m.-8:00 p.m.) versus the nighttime (10:00 p.m. until 6:00 p.m.; p < 0.001). Non-apneics showed no significant change in CRP levels during the 24 h. CONCLUSIONS: The findings indicate that sleep apnea patients have disproportionately elevated CRP levels in the day versus the nighttime, possibly as a result of carryover effects of nighttime arousal into the daytime.

Tight Genetic Linkage of Prezygotic Barrier Loci Creates a Multifunctional Speciation Island in Petunia

Most flowering plants depend on animal vectors for pollination and seed dispersal. Differential pollinator preferences lead to premating isolation and thus reduced gene flow between interbreeding plant populations [1, 2, 3 and 4]. Sets of floral traits, adapted to attract specific pollinator guilds, are called pollination syndromes [5]. Shifts in pollination syndromes have occurred surprisingly frequently [6], considering that they must involve coordinated changes in multiple genes affecting multiple floral traits. Although the identification of individual genes specifying single pollination syndrome traits is in progress in many species, little is known about the genetic architecture of coadapted pollination syndrome traits and how they are embedded within the genome [7]. Here we describe the tight genetic linkage of loci specifying five major pollination syndrome traits in the genus Petunia: visible color, UV absorption, floral scent production, pistil length, and stamen length. Comparison with other Solanaceae indicates that, in P. exserta and P. axillaris, loci specifying these floral traits have specifically become clustered into a multifunctional “speciation island” [ 8 and 9]. Such an arrangement promotes linkage disequilibrium and avoids the dissolution of pollination syndromes by recombination. We suggest that tight genetic linkage provides a mechanism for rapid switches between distinct pollination syndromes in response to changes in pollinator availabilities.

Nitric oxide induces cell death in canine cruciate ligament cells by activation of tyrosine kinase and reactive oxygen species

BACKGROUND: There is increasing evidence suggesting that development of progressive canine cranial cruciate ligament (CCL) rupture involves a gradual degeneration of the CCL itself, initiated by a combination of factors, ranging from mechanical to biochemical. To date, knowledge is lacking to what extent cruciate disease results from abnormal biomechanics on a normal ligament or contrary how far preliminary alterations of the ligament due to biochemical factors provoke abnormal biomechanics. This study is focused on nitric oxide (NO), one of the potential biochemical factors. The NO-donor sodium nitroprusside (SNP) has been used to study NO-dependent cell death in canine cranial and caudal cruciate ligament cells and to characterize signaling mechanisms during NO-stimulation. RESULTS: Sodium nitroprusside increased apoptotic cell death dose- and time-dependently in cruciate ligamentocytes. Cells from the CCL were more susceptible to apoptosis than CaCL cells. Caspase-3 processing in response to SNP was not detected. Testing major upstream and signal transducing pathways, NO-induced cruciate ligament cell death seemed to be mediated on different levels. Specific inhibition of tyrosine kinase significantly decreased SNP-induced cell death. Mitogen activated protein kinase ERK1 and 2 are activated upon NO and provide anti-apoptotic signals whereas p38 kinase and protein kinase C are not involved. Moreover, data showed that the inhibition reactive oxygen species (ROS) significantly reduced the level of cruciate ligament cell death. CONCLUSIONS: Our data support the hypothesis that canine cruciate ligamentocytes, independently from their origin (CCL or CaCL) follow crucial signaling pathways involved in NO-induced cell death. However, the difference on susceptibility upon NO-mediated apoptosis seems to be dependent on other pathways than on these tested in the present study. In both, CCL and CaCL, the activation of the tyrosine kinase and the generation of ROS reveal important signaling pathways. In perspective, new efforts to prevent the development and progression of cruciate disease may include strategies aimed at reducing ROS.

Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin, and blood leukocytes

BACKGROUND The correlation between noninvasive markers with endoscopic activity according to the modified Baron Index in patients with ulcerative colitis (UC) is unknown. We aimed to evaluate the correlation between endoscopic activity and fecal calprotectin (FC), C-reactive protein (CRP), hemoglobin, platelets, blood leukocytes, and the Lichtiger Index (clinical score). METHODS UC patients undergoing complete colonoscopy were prospectively enrolled and scored clinically and endoscopically. Samples from feces and blood were analyzed in UC patients and controls. RESULTS We enrolled 228 UC patients and 52 healthy controls. Endoscopic disease activity correlated best with FC (Spearman's rank correlation coefficient r = 0.821), followed by the Lichtiger Index (r = 0.682), CRP (r = 0.556), platelets (r = 0.488), blood leukocytes (r = 0.401), and hemoglobin (r = -0.388). FC was the only marker that could discriminate between different grades of endoscopic activity (grade 0, 16 [10-30] μg/g; grade 1, 35 [25-48] μg/g; grade 2, 102 [44-159] μg/g; grade 3, 235 [176-319] μg/g; grade 4, 611 [406-868] μg/g; P < 0.001 for discriminating the different grades). FC with a cutoff of 57 μg/g had a sensitivity of 91% and a specificity of 90% to detect endoscopically active disease (modified Baron Index ≥ 2). CONCLUSIONS FC correlated better with endoscopic disease activity than clinical activity, CRP, platelets, hemoglobin, and blood leukocytes. The strong correlation with endoscopic disease activity suggests that FC represents a useful biomarker for noninvasive monitoring of disease activity in UC patients.

The Individualized Genetic Barrier Predicts Treatment Response in a Large Cohort of HIV-1 Infected Patients

The success of combination antiretroviral therapy is limited by the evolutionary escape dynamics of HIV-1. We used Isotonic Conjunctive Bayesian Networks (I-CBNs), a class of probabilistic graphical models, to describe this process. We employed partial order constraints among viral resistance mutations, which give rise to a limited set of mutational pathways, and we modeled phenotypic drug resistance as monotonically increasing along any escape pathway. Using this model, the individualized genetic barrier (IGB) to each drug is derived as the probability of the virus not acquiring additional mutations that confer resistance. Drug-specific IGBs were combined to obtain the IGB to an entire regimen, which quantifies the virus' genetic potential for developing drug resistance under combination therapy. The IGB was tested as a predictor of therapeutic outcome using between 2,185 and 2,631 treatment change episodes of subtype B infected patients from the Swiss HIV Cohort Study Database, a large observational cohort. Using logistic regression, significant univariate predictors included most of the 18 drugs and single-drug IGBs, the IGB to the entire regimen, the expert rules-based genotypic susceptibility score (GSS), several individual mutations, and the peak viral load before treatment change. In the multivariate analysis, the only genotype-derived variables that remained significantly associated with virological success were GSS and, with 10-fold stronger association, IGB to regimen. When predicting suppression of viral load below 400 cps/ml, IGB outperformed GSS and also improved GSS-containing predictors significantly, but the difference was not significant for suppression below 50 cps/ml. Thus, the IGB to regimen is a novel data-derived predictor of treatment outcome that has potential to improve the interpretation of genotypic drug resistance tests.

Cutaneous reactive angiomatosis with combined histological pattern mimicking a cellulitis

Cutaneous reactive angiomatoses (CRA) encompass a distinct group of rare benign reactive vascular proliferations that include reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. The etiology of these conditions, often associated with either localized or systemic diseases, is poorly understood. We report a 72-year-old woman who presented giant diffuse cellulitis-like plaques on the right lower limb and the pelvis and a reduction of her general condition with fever. Light microscopy studies revealed combined features of reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis. A small arteriovenous fistula of the right lower leg was thought to act as trigger. Systemic corticosteroids resulted in the clinical remission of the skin lesions. Our observation provides strong evidence that reactive angioendotheliomatosis, diffuse dermal angiomatosis and reactive intralymphatic histiocytosis, previously regarded as distinct forms of CRA, may show overlapping histopathological features and most likely represent facets of the same disease.

Television viewing, C-reactive protein, and depressive symptoms in older adults

There is emerging evidence for a link between sedentary behavior and mental health, although the mechanisms remain unknown. We tested if an underlying inflammatory process explains the association between sedentary behavior and depressive symptoms. We conducted a two year follow-up of 4964 (aged 64.5 ± 8.9 years) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported TV viewing time was assessed at baseline as a marker of leisure time sedentary behavior. The eight-item Centre of Epidemiological Studies Depression (CES-D) scale was administered to measure depressive symptoms at follow-up. At baseline, TV time was associated with C-reactive protein (CRP), adjusted geometric mean CRP values were 2.94 mg/L (<2 h/d TV); 3.04 mg/L (2–4 h/d TV); 3.29 mg/L (4–6 h/d TV); 3.23 mg/L (>6 h/d TV). We observed both a direct association of TV time on CES-D score at follow-up (B = 0.08, 95% CI, 0.05, 0.10) and indirect effects (B = 0.07, 95% CI, 0.05, 0.08). The indirect effects were largely explained through lack of physical activity, smoking, and alcohol, but not by CRP or body mass index.

Language as a barrier and facilitator for women's career progress

Purpose When applying for leadership positions or acting as leaders, women are still perceived with a ‘lack of fit’, thus hired less likely and evaluated less favorably than their male counterparts. In many languages, different language forms can be used to refer to both women and men: masculine forms (e.g., CEO in German: ‘Geschäftsführer’) and alternative forms (e.g., feminine‐masculine word pairs, CEO in German ‘Geschäftsführerin/Geschäftsführer’). We assumed that the use of masculine forms endorses the ‘lack of fit’ for women in leadership, whereas alternative forms reduce it. Design/Methodology Two studies tested the hypotheses by manipulating language forms (masculine forms vs. alternative forms) and gender of the target to hire/evaluate (female vs. male). Results The results indicated as predicted that masculine forms lead to the ‘lack of fit’ for women in the leadership context, whereas alternative forms reduce it. Women were less likely to be employed for leadership positions (Study 1) and evaluated less favorably as leaders (Study 2) than their male counterparts with masculine forms. However, with alternative forms no differences in employment decisions and evaluations of women and men were found. Limitations These two studies were conducted with student‐samples. Further research is needed to replicate effects with relevant samples as HRmanagers and to investigate underlying mechanisms. Research/Practical Implications Organizations may use alternative forms instead of masculine forms in job advertisements for leadership positions to overcome barriers for women in leadership. Originality/Value These are the first studies in testing the effects of language forms in the leader selection and evaluation.

Wnt activation of immortalized brain endothelial cells as a tool for generating a standardized model of the blood brain barrier in vitro

Reproducing the characteristics and the functional responses of the blood-brain barrier (BBB) in vitro represents an important task for the research community, and would be a critical biotechnological breakthrough. Pharmaceutical and biotechnology industries provide strong demand for inexpensive and easy-to-handle in vitro BBB models to screen novel drug candidates. Recently, it was shown that canonical Wnt signaling is responsible for the induction of the BBB properties in the neonatal brain microvasculature in vivo. In the present study, following on from earlier observations, we have developed a novel model of the BBB in vitro that may be suitable for large scale screening assays. This model is based on immortalized endothelial cell lines derived from murine and human brain, with no need for co-culture with astrocytes. To maintain the BBB endothelial cell properties, the cell lines are cultured in the presence of Wnt3a or drugs that stabilize β-catenin, or they are infected with a transcriptionally active form of β-catenin. Upon these treatments, the cell lines maintain expression of BBB-specific markers, which results in elevated transendothelial electrical resistance and reduced cell permeability. Importantly, these properties are retained for several passages in culture, and they can be reproduced and maintained in different laboratories over time. We conclude that the brain-derived endothelial cell lines that we have investigated gain their specialized characteristics upon activation of the canonical Wnt pathway. This model may be thus suitable to test the BBB permeability to chemicals or large molecular weight proteins, transmigration of inflammatory cells, treatments with cytokines, and genetic manipulation.

Targeting the Blood-brain Barrier with a Non-canonical Iron-mimicry Mechanism

Treatment of central nervous system (CNS) diseases is limited by the blood-brain barrier (BBB), a selective vascular interface restricting passage of most molecules from blood into brain. Specific transport systems have evolved allowing circulating polar molecules to cross the BBB and gain access to the brain parenchyma. However, to date, few ligands exploiting such systems have proven clinically viable in the setting of CNS diseases. We reasoned that combinatorial phage-display screenings in vivo would yield peptides capable of crossing the BBB and allow for the development of ligand-directed targeting strategies of the brain. Here we show the identification of a peptide mediating systemic targeting to the normal brain and to an orthotopic human glioma model. We demonstrate that this peptide functionally mimics iron through an allosteric mechanism and that a non-canonical association of (i) transferrin, (ii) the iron-mimic ligand motif, and (iii) transferrin receptor mediates binding and transport of particles across the BBB. We also show that in orthotopic human glioma xenografts, a combination of transferrin receptor over-expression plus extended vascular permeability and ligand retention result in remarkable brain tumor targeting. Moreover, such tumor targeting attributes enables Herpes simplex virus thymidine kinase-mediated gene therapy of intracranial tumors for molecular genetic imaging and suicide gene delivery with ganciclovir. Finally, we expand our data by analyzing a large panel of primary CNS tumors through comprehensive tissue microarrays. Together, our approach and results provide a translational avenue for the detection and treatment of brain tumors.

MODELING REACTIVE GAS UPTAKE, TRANSPORT, AND TRANSFORMATION IN AGGREGATED SOILS

Gas diffusion research in soils covers, to a large extent, the transport behavior of practically insoluble gases. We extend the mathematical description of gas transport to include reactive gaseous components that hydrolyze in water such as SO2 and CO2. The path between the free atmosphere and the microporous niches is modeled by assuming penetration through gas-filled macropores, air-water phase transfer, and diffusion and speciation in the liquid phase. For hydrolyzable gases, the rate of mass transfer into and the total absorption capacity of the soil solution may be high. Both the capacity and the transfer rate are influenced by the soil-solution pH; for high pH, they become extremely high for SO2. The soil absorption of such gases is also influenced by soil structure. Well-aerated, near-neutral soils are a potentially important sink for SO2.

Dilution of non-reactive tracers in variably saturated sandy structures

Based on a dye tracer experiment in a sand tank we addressed the problem of local dispersion of conservative tracers in the unsaturated zone. The sand bedding was designed to have a defined spatial heterogeneity with a strong anisotropy. We estimated the parameters that characterize the local dispersion and dilution from concentration maps of a high spatial and temporal resolution obtained by image analysis. The plume spreading and mixing behavior was quantified on the basis of the coefficient of variation of the concentration and of the dilution index. The heterogeneous structure modified the flow pattern depending on water saturation. The shape of the tracer plumes revealed the structural signature of the sand bedding at low saturation only. In this case pronounced preferential flow was observed. At higher flow rates the structure remained hidden by a spatially almost homogeneous behavior of the plumes. In this context, we mainly discuss the mechanism of re-distributing a finite mass of inert solutes over a large volume, due to macro- and micro-heterogeneities of the structure. (C) 2001 Elsevier Science Ltd. AU rights reserved.