Serum Ferritin as a Prognostic Biomarker for Survival in Relapsed or Refractory Metastatic Colorectal Cancer.
This study investigated the prognostic impact of serum ferritin for survival in patients with relapsed or refractory metastatic colorectal cancer (mCRC). This retrospective cohort study reviewed clinicopathological characteristics and laboratory biomarkers in 120 mCRC patients being treated with Korean Medicine (KM). The overall survival (OS) of patients was calculated using the Kaplan-Meier method, and statistical significance was assessed using the log-rank test. Univariate and multivariate analyses of Cox proportional hazards regression were used to evaluate the prognostic impact for survival in relapsed or refractory mCRC patients. Of the patients, 62.5% had liver metastases, 74.1% underwent greater than second-line chemotherapy, and 80.8% underwent surgery. Median OS was 7.6 months for all patients after the initiation of KM treatment, which was begun 13.7 months, on average, after mCRC diagnosis. Concerning prognostic factors such as the presence of liver metastasis (p = 0.024), high carcinoembryonic antigen level (CEA > 5 ng/mL, p = 0.044), elevated C-reactive protein (CRP ≥ 10.0 mg/L, p = 0.000), high absolute monocyte count (AMC > 413.3 cells/μL, p = 0.034), elevated serum ferritin (ferritin ≥ 150 ng/mL, p = 0.002), low hemoglobin level (Hb < 12 g/dL, p = 0.026) and low albumin (albumin < 3.5 g/dL, p = 0.003) were associated with increased hazard ratios and poor survival. According to the multivariate proportional hazards model with backward and forward manners, albumin (albumin < 3.5 g/dL; hazard ratio (HR) 2.218, 95% confidence interval (CI) 1.135 - 3.990, p = 0.019), CRP (CRP ≥ 10.0 mg/L; HR 2.506, 95% CI 1.644 - 3.822, p = 0.000), CEA (CEA > 5 ng/mL; HR 2.040, 95% CI 1.203 - 3.460, p = 0.008), and serum ferritin (ferritin ≥ 150 ng/mL; HR 1.763, 95% CI 1.169 - 2.660, p = 0.007) were independent prognostic biomarkers of survival in mCRC patients. These results indicate that serum ferritin acts as an independent prognostic biomarker for survival in relapsed or refractory mCRC patients.


The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).
Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.


Estimation of CT cone-beam geometry using a novel method insensitive to phantom fabrication inaccuracy: implications for isocenter localization accuracy.
Mechanical instabilities that occur during gantry rotation of on-board cone-beam computed tomography (CBCT) imaging systems limit the efficacy of image-guided radiotherapy. Various methods for calibrating the CBCT geometry and correcting errors have been proposed, including some that utilize dedicated fiducial phantoms. The purpose of this work was to investigate the role of phantom fabrication imprecision on the accuracy of a particular CT cone-beam geometry estimate and to test a new method to mitigate errors in beam geometry arising from imperfectly fabricated phantoms. The authors implemented a fiducial phantom-based beam geometry estimation following the one described by Cho et al. [Med Phys 32(4), 968-983 (2005)]. The algorithm utilizes as input projection images of the phantom at various gantry angles and provides a full nine parameter beam geometry characterization of the source and detector position and detector orientation versus gantry angle. A method was developed for recalculating the beam geometry in a coordinate system with origin at the source trajectory center and aligned with the axis of gantry rotation, thus making the beam geometry estimation independent of the placement of the phantom. A second CBCT scan with the phantom rotated 180 degrees about its long axis was averaged with the first scan to mitigate errors from phantom imprecision. Computer simulations were performed to assess the effect of 2D fiducial marker positional error on the projections due to image discretization, as well as 3D fiducial marker position error due to phantom fabrication imprecision. Experimental CBCT images of a fiducial phantom were obtained and the algorithm used to measure beam geometry for a Varian Trilogy with an on-board CBCT. Both simulations and experimental results reveal large sinusoidal oscillations in the calculated beam geometry parameters with gantry angle due to displacement of the phantom from CBCT isocenter and misalignment with the gantry axis, which are eliminated by recalculating the beam geometry in the source coordinate system. Simulations and experiments also reveal an additional source of oscillations arising from fiducial marker position error due to phantom fabrication imprecision that are mitigated by averaging the results with those of a second CBCT scan with phantom rotated. With a typical fiducial marker position error of 0.020 mm (0.001 in.), source and detector position are found in simulations to be within 250 microm of the true values, and detector and gantry angles less than 0.2 degrees. Detector offsets are within 100 microm of the known value. Experimental results verify the efficacy of the second scan in mitigating beam geometry errors, as well as large apparent source/detector isocenter offsets arising from phantom fabrication imprecision. The authors have developed and validated a novel fiducial phantom-based CBCT beam geometry estimation algorithm that does not require precise positioning of the phantom at machine isocenter and is insensitive to positional imprecision of fiducial markers within the phantom due to fabrication errors. The method can accurately locate source and detector isocenters even when using an imprecise phantom, which is very important for measurement of isocenter coincidence of the therapy and on-board imaging systems.


Epicortical Brevetoxin Treatment Promotes Neural Repair and Functional Recovery after Ischemic Stroke.
Emerging literature suggests that after a stroke, the peri-infarct region exhibits dynamic changes in excitability. In rodent stroke models, treatments that enhance excitability in the peri-infarct cerebral cortex promote motor recovery. This increase in cortical excitability and plasticity is opposed by increases in tonic GABAergic inhibition in the peri-infarct zone beginning three days after a stroke in a mouse model. Maintenance of a favorable excitatory-inhibitory balance promoting cerebrocortical excitability could potentially improve recovery. Brevetoxin-2 (PbTx-2) is a voltage-gated sodium channel (VGSC) gating modifier that increases intracellular sodium ([Na+]i), upregulates N-methyl-D-aspartate receptor (NMDAR) channel activity and engages downstream calcium (Ca2+) signaling pathways. In immature cerebrocortical neurons, PbTx-2 promoted neuronal structural plasticity by increasing neurite outgrowth, dendritogenesis and synaptogenesis. We hypothesized that PbTx-2 may promote excitability and structural remodeling in the peri-infarct region, leading to improved functional outcomes following a stroke. We tested this hypothesis using epicortical application of PbTx-2 after a photothrombotic stroke in mice. We show that PbTx-2 enhanced the dendritic arborization and synapse density of cortical layer V pyramidal neurons in the peri-infarct cortex. PbTx-2 also produced a robust improvement of motor recovery. These results suggest a novel pharmacologic approach to mimic activity-dependent recovery from stroke.


Skin rejuvenation and wrinkle reduction using a fractional radiofrequency system.
Skin resurfacing has evolved rapidly over the past 15 years from ablative techniques to nonablative methods and most recently fractional ablative resurfacing. The purposes of this study were to analyze the degree of tissue ablation, coagulation, and heating; and to evaluate the clinical efficacy and safety of a fractional radiofrequency (RF) device, for the treatment of wrinkles with fractional skin ablation and coagulation. Individuals scheduled for abdominoplasty received fractional RF treatment to the abdomen area, using different tips at varying energy densities and coverage rates. Biopsies were performed ex vivo following abdominoplasty and tissue samples were routinely processed and stained, using hematoxylin and eosin). Another group of subjects received 3 facial treatments, scheduled at 3 to 4 week intervals. Clinical improvement and response to therapy were evaluated with standardized photography and clinical assessment by the subjects and investigators. Histological findings immediately posttreatment revealed demarcated zones of ablation/coagulation/necrosis and subnecrosis up to a depth of 450 microm. Higher energy levels generated deeper effects. We noticed a tunable balance between ablation and coagulation/necrosis. These effects were coverage mode and energy density dependent. Subjects undergoing facial treatment had minimal pain, no permanent side effects, or significant downtime. Investigators' assessment for improvement in skin texture correlated with subjects' evaluation and was greater than 40% for approximately 50% of subjects. Eighty percent of the subjects were satisfied with the results. Higher energy levels and lower coverage rates produced better aesthetic results along with less pain. The clinical observations and histological findings suggest that fractionated ablative skin resurfacing using a fractional radiofrequency device resulted in a safe, tolerable and effective improvement in skin texture and reduction of wrinkles. The depth of tissue ablation, coagulation and necrosis and the relative proportions of these phenomena were found to be controllable and could be modulated to optimize treatment of variable dermatologic conditions.


A novel method for quantitation of acylglycines in human dried blood spots by UPLC-tandem mass spectrometry.
Several acylcarnitines used as primary markers on dried blood filter papers (DBS) for newborn screening lack specificity and contribute to a higher false positive rate. The analysis of urine acylglycines is useful in the diagnosis of inborn errors of metabolism (IEM) including medium chain acyl-CoA dehydrogenase deficiency (MCADD), isovaleric acidemia, and beta-ketothiolase deficiency (BKTD). Currently, no method for analyzing acylglycines from DBS has been published. Acylglycines were extracted from two 3.2 mm DBS punches and butylated using Butanol-HCl. Ultra Performance Liquid Chromatography (UPLC-MS/MS) with run time of 10 min permits resolution and quantitation of 15 acylglycines; including several isobaric. Method development was completed. Reference intervals (n = 573) were established for four birth weight groups. Furthermore, samples from patients with a confirmed IEM (n = 11), and false positive screens (n = 78) were analyzed to validate the interpretation obtained from the newly established reference intervals. Calibration curves were linear from 0.005 to 25.0 μM. Ion suppression was evaluated as minimal (2 to 10%). Samples from known patients were used to validate the reference intervals. For C5OH-related disorders, tiglylglycine (TG), TG/acetylglycine (AG) ratio, 3methylcrotonylglycine (3MCG) and 3MCG/AG ratio increased specificity. Propionylglycine (PG) and PG/acetylglycine ratio were two discriminatory markers in the investigation of C3-related disorders. Hexanoylglycine (HG), octanoylglycine (OG), suberylglycine (SG), and the ratios HG/AG, OC/AG and SG/AG were excellent markers of MCADD deficiency. This method shows potential application as a second tier screen in order to reduce the false positive rate for a number of IEM targeted by newborn screening.


A Case for the Standardized Assessment of Testamentary Capacity.
With an increasingly aged, frail population that holds a disproportionate amount of wealth, clinicians (especially those with expertise in older adults) may be asked with more frequency to offer a clinical opinion on testamentary capacity (TC), the mental capacity to make a will. This paper reviews the legal criteria as well as the empirical research on assessment tools for determining testamentary capacity (TC). We also review the relevance of instruments used for the assessment of other decisional capacities in order to evince the potential value of developing a standardized assessment of TC for clinician experts. The legal criteria, often referred to as a "test", for determining requisite TC (Banks v. Goodfellow) have remained much the same since 1870 with minimal clinical input and, as such, there has been little development in TC assessment instruments. Decisional instruments designed to assess Consent to Treatment may have relevance for TC. We make the case for a semi-structured interview that includes standardized criteria for the legal test for TC, supplemented by a validated brief neuropsychological assessment, which together comprise a Contemporaneous Assessment Instrument (CAI) for TC.


SREBP inhibition ameliorates renal injury after unilateral ureteral obstruction.
Tubulointerstitial fibrosis is a major feature associated with declining kidney function in chronic kidney disease of diverse etiology. No effective means as yet exists to prevent the progression of fibrosis. We have shown that the transcription factor sterol-regulatory element-binding protein 1 (SREBP-1) is an important mediator of the profibrotic response to transforming growth factor-β (TGF-β) and angiotensin II, both key cytokines in the fibrotic process. Here, we examined the role of SREBP in renal interstitial fibrosis in the unilateral ureteral obstruction (UUO) model. The two isoforms of SREBP (-1 and -2) were activated by 3 days after UUO, with SREBP-1 showing a more sustained activation to 21 days. We then examined whether SREBP1/2 inhibition with the small-molecule inhibitor fatostatin could attenuate fibrosis after 14 days of UUO. SREBP activation was confirmed to be inhibited by fatostatin. Treatment decreased interstitial fibrosis, TGF-β signaling, and upregulation of α-smooth muscle actin (SMA), a marker of fibroblast activation. Fatostatin also attenuated inflammatory cell infiltrate and apoptosis. Associated with this, fatostatin preserved proximal tubular mass. The significant increase in atubular glomeruli observed after UUO, known to correlate with irreversible renal functional decline, was also decreased by treatment. In cultured primary fibroblasts, TGF-β1 induced the activation of SREBP-1 and -2. Fatostatin blocked TGF-β1-induced α-SMA and matrix protein upregulation. The inhibition of SREBP is thus a potential novel therapeutic target in the treatment of fibrosis in chronic kidney disease.


NorUrsodeoxycholic acid ameliorates cholemic nephropathy in bile duct ligated mice.
Severe cholestasis may cause cholemic nephropathy that can be modeled in common bile duct ligated (CBDL) mice. We aimed to explore the therapeutic efficacy and mechanisms of norursodeoxycholic acid (norUDCA) in cholemic nephropathy. In 8-week CBDL mice fed with norUDCA (prior or post CBDL) or chow we evaluated serum urea levels, urine cytology and urinary neutrophil gelatinase associated lipocalin (uNGAL), kidney and liver tissue quantification of fibrosis by hydroxyproline content and gene chip expression looking at key genes of inflammation and fibrosis. Moreover, we comprehensively analysed bile acid profiles in liver, kidney, serum and urine samples. NorUDCA-fed CBDL mice had significantly lower serum urea and uNGAL levels and less severe cholemic nephropathy as demonstrated by normal urine cytology, significantly reduced tubulointerstitial nephritis, and renal fibrosis as compared to controls. NorUDCA underwent extensive metabolism to produce even more hydrophilic compounds that were significantly enriched in kidneys. NorUDCA ameliorates cholemic nephropathy due to the formation of highly hydrophilic metabolites enriched in kidney. Consequently, norUDCA may represent a medical treatment for cholemic nephropathy. The term cholemic nephropathy describes renal dysfunction together with characteristic morphological alterations of the kidney in obstructive cholestasis that can be mimicked by ligation of the common bile duct in mice. Feeding the hydrophilic bile acid norUDCA to bile duct ligated mice leads to a significant amelioration of the renal phenotype due to the formation of highly hydrophilic metabolites enriched in the kidney and may therefore represent a medical treatment for cholemic nephropathy.


Regulation of Raf-1 by direct feedback phosphorylation.
The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Because of its integral role in cell signaling, Raf-1 activity must be precisely controlled. Previous studies have shown that phosphorylation is required for Raf-1 activation, and here, we identify six phosphorylation sites that contribute to the downregulation of Raf-1 after mitogen stimulation. Five of the identified sites are proline-directed targets of activated ERK, and phosphorylation of all six sites requires MEK signaling, indicating a negative feedback mechanism. Hyperphosphorylation of these six sites inhibits the Ras/Raf-1 interaction and desensitizes Raf-1 to additional stimuli. The hyperphosphorylated/desensitized Raf-1 is subsequently dephosphorylated and returned to a signaling-competent state through interactions with the protein phosphatase PP2A and the prolyl isomerase Pin1. These findings elucidate a critical Raf-1 regulatory mechanism that contributes to the sensitive, temporal modulation of Ras signaling.


Vitamin D: modulator of the immune system.
1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, is known to regulate calcium and phosphorus metabolism, thus being a key-player in bone-formation. However 1,25(OH)(2)D(3) also has a physiological role beyond its well-known role in skeletal homeostasis. Here, we describe 1,25(OH)(2)D(3) as an immunomodulator targeting various immune cells, including monocytes, macrophages, dendritic cells (DCs), as well as T-lymphocytes and B-lymphocytes, hence modulating both innate and adaptive immune responses. Besides being targets, immune cells express vitamin D-activating enzymes, allowing local conversion of inactive vitamin D into 1,25(OH)(2)D(3) within the immune system. Taken together, these data indicate that 1,25(OH)(2)D(3) plays a role in maintenance of immune homeostasis. Several epidemiological studies have linked inadequate vitamin D levels to a higher susceptibility of immune-mediated disorders, including chronic infections and autoimmune diseases. This review will discuss the complex immune-regulatory effects of 1,25(OH)(2)D(3) on immune cells as well as its role in infectious and autoimmune diseases, more in particular in tuberculosis and type 1 diabetes (T1D).


Urgent carotid surgery and stenting may be safe after systemic thrombolysis for stroke.
Early carotid surgery or stenting after thrombolytic treatment for stroke has become more common during recent years. It is unclear whether this carries an increased risk of postoperative complications and death. The aim of this nationwide population-based study was, therefore, to investigate the safety of urgently performed carotid procedures in patients treated with thrombolysis for stroke. Using the national Vascular and Stroke registries, we identified 3998 patients who had undergone carotid endarterectomy or carotid artery stenting for symptomatic carotid stenosis between May 2008 and December 2012. Among these, 2% (79 of 3998) had undergone previous thrombolysis for stroke. We conducted a retrospective review of registry data and individual case records with regard to postoperative complications, including surgical-site bleeding, stroke, and death. The outcome was compared with the results for the remaining patient cohort (3919 of 3998) undergoing carotid surgery and stenting during the study period. The median time between thrombolysis and the carotid procedure was 10 days. Seventy-one patients underwent carotid endarterectomy, and 6 patients underwent carotid artery stenting. The 30-day death and stroke rate for the thrombolysis cohort was 2.5% (2 of 79), and for the whole cohort, it was 3.8% (139 of 3626; P=0.55). The postoperative bleeding rates requiring reoperation were not significantly different between the groups (3.8% [3 of 79] in the thrombolysis group versus 3.3% [119 of 3626] in the whole cohort; P=0.79). There was no correlation between time from lysis to surgery or stenting and complications at 30 days postoperatively. Urgent carotid endarterectomy or carotid artery stenting after thrombolysis for stroke may be safe without increased risk of serious complications.


Resource-use efficiency explains grassy weed invasion in a low-resource savanna in north Australia.
Comparative studies of plant resource use and ecophysiological traits of invasive and native resident plant species can elucidate mechanisms of invasion success and ecosystem impacts. In the seasonal tropics of north Australia, the alien C4 perennial grass Andropogon gayanus (gamba grass) has transformed diverse, mixed tree-grass savanna ecosystems into dense monocultures. To better understand the mechanisms of invasion, we compared resource acquisition and usage efficiency using leaf-scale ecophysiological and stand-scale growth traits of A. gayanus with a co-habiting native C4 perennial grass Alloteropsis semialata. Under wet season conditions, A. gayanus had higher rates of stomatal conductance, assimilation, and water use, plus a longer daily assimilation period than the native species A. semialata. Growing season length was also ~2 months longer for the invader. Wet season measures of leaf scale water use efficiency (WUE) and light use efficiency (LUE) did not differ between the two species, although photosynthetic nitrogen use efficiency (PNUE) was significantly higher in A. gayanus. By May (dry season) the drought avoiding native species A. semialata had senesced. In contrast, rates of A. gayanus gas exchange was maintained into the dry season, albeit at lower rates that the wet season, but at higher WUE and PNUE, evidence of significant physiological plasticity. High PNUE and leaf (15)N isotope values suggested that A. gayanus was also capable of preferential uptake of soil ammonium, with utilization occurring into the dry season. High PNUE and fire tolerance in an N-limited and highly flammable ecosystem confers a significant competitive advantage over native grass species and a broader niche width. As a result A. gayanus is rapidly spreading across north Australia with significant consequences for biodiversity and carbon and retention.


Medullary breast carcinoma.
More then half a million cases each year makes breast cancer the most common malignancy in female. Medullary breast carcinoma (MBC) is a type of invasive ductal breast carcinoma that usually has favorable prognosis and is characterized by the high graded structure, high mitotic rate and heavy lymphoid infiltration. The last feature makes MBC an attractive subject for detailed studies in respect to development of novel immunological approaches for cancer treatment. In this review we have summarized the data on MBC morphology, antigenic repertoire and molecular biology features. The aim of this review was to illuminate the unique biological features and to outline theoretical basis for further investigations of MBC.


Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease.
Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.


High connectivity between reduced cortical thickness and disrupted white matter tracts in long-standing type 1 diabetes.
Previous studies have observed disruptions in brain white and gray matter structure in individuals with type 1 diabetes, and these structural differences have been associated with neurocognitive testing deficiencies. This study investigated the relationship between cerebral cortical thickness reductions and white matter microstructural integrity loss in a group of patients with type 1 diabetes and in healthy control subjects using diffusion tensor imaging (DTI). Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects underwent structural T1 and proton-density and DTI on a 3.0 Tesla scanner. Fractional anisotropy measurements were made on major cerebral white matter tracts, and DTI tractography was performed to identify cortical regions with high connectivity to these tracts. Posterior white matter tracts with reduced fractional anisotropy (optic radiations, posterior corona radiata, and the splenium region of the corpus callosum) were found to have high connectivity with a number of posterior cortical regions, including the cuneus, precuneus, fusiform, and posterior parietal cortical regions. A significant reduction in cortical thickness in the diabetic group was observed in the regions with high connectivity to the optic radiations and posterior corona radiata tracts (P < 0.05). The direct relationship between white and gray matter structural pathology has not been previously demonstrated in subjects with long-standing type 1 diabetes. The relationship between posterior white matter microstructural integrity disruption and lower cortical thickness demonstrated using a novel DTI connectivity technique suggests a common or interrelated pathophysiological mechanism in type 1 diabetes.


The Centers for Disease Control and Prevention: Findings From The National Healthy Worksite Program.
To evaluate employers' implementation of evidence-based interventions, and changes in employees' behaviors associated with participating in the national healthy worksite program (NHWP). NHWP recruited 100 small and mid-sized employers and provided training and support for 18 months. Outcome measures were collected with an employer questionnaire, an employee survey, and biometric data at baseline and 18 months later. The 41 employers who completed the NHWP implemented significantly more evidence-based interventions and had more comprehensive worksite health promotion programs after participating. Employees made significant improvements in physical activity and nutritional behaviors, but did not significantly improve employee weight. Training and technical support can help small and mid-sized employers implement evidence-based health interventions to promote positive employee behavior changes. A longer follow up period may be needed to assess whether NHWP led to improvements in clinical outcomes.


Neuron addition and loss in the song system: regulation and function.
Neurons continue to be produced and replaced throughout life in songbirds. Proliferation in the walls of the lateral ventricles gives rise to neurons that migrate long distances to populate many diverse telencephalic regions, including nuclei dedicated to the perception and production of song, a learned behavior. Many projection neurons are incorporated into the efferent motor pathway for song control. Replacement of these neurons is regulated, in part, by neuron death. Underlying mechanisms include gonadal steroids and BDNF, but are likely to involve other trophic factors as well. The functional significance of neuronal replacement remains unclear. However, recent experiments suggest a link between cell turnover and one or more specific attributes of song learning and production. Several hypotheses are critically examined, including the possibility that neuronal replacement provides motor flexibility to allow for error correction-a capacity needed for juvenile and adult song learning, but also likely to be important for the maintenance of song stereotypy. We highlight important gaps in our knowledge and discuss future directions that may bring us closer to solving the riddle of why neurons are produced and replaced in adulthood.


Fabrication of nanofibrous electrospun scaffolds from a heterogeneous library of co- and self-assembling peptides.
Self-assembling (SAPs) and co-assembling peptides (CAPs) are driving increasing enthusiasm as synthetic but biologically inspired biomaterials amenable of easy functionalization for regenerative medicine. On the other hand, electrospinning (ES) is a versatile technique useful for tailoring the nanostructures of various biomaterials into scaffolds resembling the extracellular matrices found in organs and tissues. The synergistic merging of these two approaches is a long-awaited advance in nanomedicine that has not been deeply documented so far. In the present work, we describe the successful ES of a library of diverse SAPs and CAPs into biomimetic nanofibrous mats. Our results suggest that suitable ES solutions are characterized by high concentrations of peptides, providing backbone physical chain entanglements, and by random coil/α-helical conformations while β-sheet aggregation may be detrimental to spinnability. The resulting peptide fibers feature interconnected seamless mats with nanofibers average diameters ranging from ∼100nm to ∼400nm. Also, peptide chemical nature and ES set up parameters play pivotal roles in determining the conformational transitions and morphological properties of the produced nanofibers. Far from being an exhaustive description of the just-opened novel field of ES-assembled peptides, this seminal work aims at shining a light on a still missing general theory for the production of electrospun peptidic biomaterials bringing together the spatial, biochemical and biomimetic of these two techniques into unique scaffolds for tissue engineering. Construction of peptide hydrogels has received considerable attention due to their potential as nanostructures amenable of easy functionalization and capable of creating microenvironments suited for culturing cells and triggering tissue regeneration. They display a superior biocompatibility unmatched by other known synthetic biomaterials so far. However, their applications are confined to body fillers because most of them do spontaneously form hydrogels, while effective tissue regeneration often requires well-defined fibrous scaffolds. In this work, we developed electrospun fibers of various peptides (cross-beta self-assembling, hierarchically assembling, functionalized, co-assembling) and we provided a deep understanding of the crucial phenomena to be taken into account when peptides fibers fabrication. These results open new venues for exploring novel regenerative applications of peptide nanofibrous scaffolds.


Effect identification in comparative effectiveness research.
The widespread adoption of electronic medical records means there are now vast data resources available for comparative effectiveness research (CER). In concert with conventional randomized controlled trials, CER holds great promise for advancing our understanding of how different therapeutic treatments yield different health outcomes in different settings and with different populations. But in a research culture fixated on estimating correlations and p-values, the threat of misinterpretation of results and improper CER inferences is troubling. Accordingly, this paper aims to shore up the inferential foundations of CER by introducing the fundamentals of effect identification, which is the process of identifying or teasing out empirically defensible causal effects from competing explanations. Three primary requirements of effect identification-positivity, exchangeability, and consistency- are explained and simple exampled are given. The take home message is that so-called big data from medical records may not yield better or more useful results. Advances will come only when the right question is addressed with the appropriate data and methods.


Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report.
The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.


Receptor tyrosine kinase inhibitor profiling using bead-based multiplex sandwich immunoassays.
Receptor tyrosine kinases (RTK) are important targets in drug discovery processes. Studying the phosphorylation pattern of RTKs enables the determination of their activation and inactivation states. Multiplex bead-based sandwich immunoassays are powerful tools for measuring the phosphorylation state of key regulators within cellular signalling networks. Here, we describe the analysis of the phosphorylation state of receptor tyrosine kinases using the epidermal growth factor receptor (EGFR) as an example. We provide a protocol for a bead-based sandwich immunoassay that enables a relative quantification of the EGFR and its generic tyrosine phosphorylation. We also present data from a kinase inhibitor experiment using 96-well cell-culture plates and a commercially available kit for the analysis of seven receptor tyrosine kinases.


Altering functional properties of fats using power ultrasound.
Ultrasound has been used for the last 50 y in different processing applications. Depending on the power and frequency of the sound waves, ultrasound techniques can be classified in different categories. Low-intensity ultrasound uses high frequencies in the range of 100 kHz to 10 MHz and is mostly used for therapeutic purpose (frequencies between 1 and 10 MHz) and to passively monitor the characteristics of materials (frequencies between 100 kHz and 10 MHz). High-intensity ultrasound (HIU), on the other hand, uses lower frequencies in the range of 20 to 100 kHz and it is commonly used for cleaning, disrupting, and restructuring materials. The objective of this study is to evaluate the effect of HIU on functional properties of anhydrous milk fat (AMF), palm kernel oil (PKO), and an all-purpose shortening (Sh). Results from this research shows that HIU induced primary and secondary nucleation in the lipid, generating smaller crystals and as a consequence harder materials. HIU affected hardness more efficiently when applied at higher crystallization temperatures (26 and 28 degrees C) as shown for AMF data, and when the sonication was applied after the first crystals were formed as observed for PKO and Sh systems. In addition to changes in hardness, AMF and Sh networks obtained after sonication were characterized by a steeper and sharper melting profile. This research shows that HIU can be used as an additional processing tool to tailor the functional properties of lipids with the potential to be used in the processing of trans-free shortenings.


Distinct regulatory cascades govern extraocular and pharyngeal arch muscle progenitor cell fates.
Genetic regulatory networks governing skeletal myogenesis in the body are well understood, yet their hierarchical relationships in the head remain unresolved. We show that either Myf5 or Mrf4 is necessary for initiating extraocular myogenesis. Whereas Mrf4 is dispensable for pharyngeal muscle progenitor fate, Tbx1 and Myf5 act synergistically for governing myogenesis in this location. As in the body, Myod acts epistatically to the initiating cascades in the head. Thus, complementary pathways, governed by Pax3 for body, and Tbx1 for pharyngeal muscles, but absent for extraocular muscles, activate the core myogenic network. These diverse muscle progenitors maintain their respective embryonic regulatory signatures in the adult. However, these signatures are not sufficient to ensure the specific muscle phenotypes, since the expected differentiated phenotype is not manifested when satellite cells are engrafted heterotopically. These findings identify novel genetic networks that may provide insights into myopathies which often affect only subsets of muscles.


Salvage therapy for recurrent and refractory ovarian cancer with high-dose chemotherapy and autologous bone marrow support: a Gynecologic Oncology Group pilot study.
Nine patients with recurrent or refractory epithelial ovarian carcinoma following previous chemotherapy were treated with high-dose carboplatin (300 mg/m2) and ifosfamide according to a dose escalation schedule (1.50, 1.75, 2.00 g/m2), each given intravenously daily for 5 days with autologous bone marrow support. Eight of the nine patients were evaluable for response. Five achieved complete response (CR), all of whom relapsed at 4, 5, 6, 8, and 23 months following treatment. Two partial responses persisted for 6 months, and one patient with stable disease progressed after 2 months and has since died of disease. The median duration of remission was 6 months. The treatment was well tolerated across the doses of ifosfamide with the exception of one treatment-related death which was due to acute renal failure and central nervous system toxicity from ifosfamide. It appears that the use of high-dose chemotherapy with autologous bone marrow support in the treatment of ovarian cancer produced a high rate of response of short duration in this small group of heavily pretreated women.


Sexual Attraction to Both Genders in Ambiphilic Men: Evidence from Implicit Cognitions.
Ambiphilic (or bisexual) men describe feelings of sexual attraction to both men and women. However, physiological measures of arousal have failed to show a consistent pattern of arousal to both genders. We measured men's automatic associations between the concept of sex (represented by words) and the concepts of men versus women (represented by images) via the Implicit Association Test (IAT) and a priming task. On the IAT, gynephilic men (N = 32) were faster for women-sex pairings, androphilic men (N = 18) were faster for men-sex pairings, while ambiphilic men (N = 20) showed no bias toward either gender. We then isolated the concepts of "men" and "women" by comparing them separately against neutral images. In contrast to both the gynephilic or androphilic men, ambiphilic men showed sexual associations to both men and women. On the priming task, ambiphilic men showed faster responses to sex words, but slower responses to not-sex words, when primed with pictures of either men or women compared to when primed by neutral images. The results from all the experimental tasks suggest that ambiphilic men have a pattern of sexual association that is different from both gynephilic and androphilic men and represents a sexual attraction to both men and women.


Firm's compliance behaviour towards food fortification regulations: Evidence from oil and salt producers in Bangladesh.
Impact of national food fortification programs is contingent on the extent to which there is compliance with national standards. However, this compliance is often sub-optimal and is not consistently measured. One of the challenges to more regular measurement is an over-reliance on quantitative assessments of micronutrient levels for compliance, which are costly. In resource constrained environments, this contributes to weaknesses in regulatory monitoring. We offer an alternative, systems-based approach to determine compliance, presenting a unique score that can capture firms' compliance behaviour, based on whether and how firms actually carry out stages of the fortification process. The key utility of such a measure being its use to monitor fortification propensity and assess changes in response to interventions. Further, we present an empirical application of this measure, providing novel evidence on firms' compliance towards food fortification regulations in Bangladesh, investigating the institutional and firm-level factors that correlate with compliance behaviour towards food fortification regulations among edible oil and salt producers.


Oral immunization with bacteriophage MS2-L2 VLPs protects against oral and genital infection with multiple HPV types associated with head & neck cancers and cervical cancer.
Human papillomaviruses (HPVs) are the most common sexually transmitted infections. HPVs are transmitted through anogenital sex or oral sex. Anogenital transmission/infection is associated with anogenital cancers and genital warts while oral transmission/infection is associated with head and neck cancers (HNCs) including recurrent respiratory papillomatosis. Current HPV vaccines protect against HPV types associated with ∼90% of cervical cancers and are expected to protect against a percentage of HNCs. However, only a few studies have assessed the efficacy of current vaccines against oral HPV infections. We had previously developed a mixed MS2-L2 candidate HPV vaccine based on bacteriophage MS2 virus-like particles (VLPs). The mixed MS2-L2 VLPs consisted of a mixture of two MS2-L2 VLPs displaying: i) a concatemer of L2 peptide (epitope 20-31) from HPV31 & L2 peptide (epitope 17-31) from HPV16 and ii) a consensus L2 peptide representing epitope 69-86. The mixed MS2-L2 VLPs neutralized/protected mice against six HPV types associated with ∼87% of cervical cancer. Here, we show that the mixed MS2-L2 VLPs can protect mice against additional HPV types; at the genital region, the VLPs protect against HPV53, 56, 11 and at the oral region, the VLPs protect against HPV16, 35, 39, 52, and 58. Thus, mixed MS2-L2 VLPs protect against eleven oncogenic HPV types associated with ∼95% of cervical cancer. The VLPs also have the potential to protect, orally, against the same oncogenic HPVs, associated with ∼99% of HNCs, including HPV11, which is associated with up to 32% of recurrent respiratory papillomatosis. Moreover, mixed MS2-L2 VLPs are thermostable at room temperature for up to 60 days after spray-freeze drying and they are protective against oral HPV infection.


Functional gamma chain-associated T cell receptors on cerebrospinal fluid-derived natural killer-like T cell clones.
We have derived 33 independent T cell clones from the cerebrospinal fluid (CSF) of a patient with subacute sclerosing panencephalitis using a single T cell cloning method. 6% (2 of 33) of these clones express the T cell receptor gamma (TCR-gamma) protein and are called CSF TCR-gamma clones. Phenotypic analyses of the CSF TCR-gamma clones indicate that they are WT-31-, CD3+, CD4-, and CD8-. The TCR-gamma protein exists on the cell surface as part of an 85-kD disulphide-linked dimer noncovalently associated with the CD3 polypeptides. The CSF TCR-gamma clones have NK-like activity that can be inhibited by anti-CD3 mAbs. Both CSF TCR-gamma clones proliferated in response to anti-CD3 mAbs coupled to Sepharose beads and/or IL-2. Furthermore, stimulation of one of these clones with anti-CD3 mAbs results in a rapid rise in intracellular calcium. These data suggest that T cells bearing the CD3-TCR-gamma protein complex are functional and play a role in the human immune response.


Insulin-like growth factor-I enhances cell-based repair of articular cartilage.
Composites of chondrocytes and polymerised fibrin were supplemented with insulin-like growth factor-I (IGF-I) during the arthroscopic repair of full-thickness cartilage defects in a model of extensive loss of cartilage in horses. Repairs facilitated with IGF-I and chondrocyte-fibrin composites, or control defects treated with chondrocyte-fibrin composites alone, were compared before death by the clinical appearance and repeated analysis of synovial fluid, and at termination eight months after surgery by tissue morphology, collagen typing, and biochemical assays. The structure of cartilage was evaluated histologically by Toluidine Blue reaction and collagen type-I and type-II in situ hybridisation and immunohistochemistry. Repair tissue was biochemically evaluated by DNA assay, proteoglycan quantitation and characterisation, assessment of collagen by reverse-phase high-performance liquid chromatography, and collagen typing using cyanogen bromide digestion and peptide separation by polyacrylamide gel electrophoresis. The results at eight months showed that the addition of IGF-I to chondrocyte grafts enhanced chondrogenesis in cartilage defects, including incorporation into surrounding cartilage. Gross filling of defects was improved, and the tissue contained a higher proportion of cells producing type-II collagen. Measurements of collagen type II showed improved levels in IGF-I-treated defects, supporting in situ hybridisation and immunohistochemical assessments of the defects. IGF-I improves the repair capabilities of chondrocyte-fibrin grafts in large full-thickness repair models.


Emotion regulation of others' positive and negative emotions is related to distinct patterns of heart rate variability and situational empathy.
Although emotion regulation has been proposed to be crucial for empathy, investigations on emotion regulation have been primarily limited to intrapersonal processes, leaving the interpersonal processes of self-regulation rather unexplored. Moreover, studies showed that emotion regulation and empathy are related with increased autonomic activation. How emotion regulation and empathy are related at the autonomic level, and more specifically during differently valenced social situations remains an open question. Healthy adults viewed a series of short videos illustrating a target who was expressing positive, negative, or no emotions during a social situation (Positive, Negative, or Neutral Social Scenes). Prior to each video, participants were instructed to reappraise their own emotions (Up-regulation, Down-regulation, or No-regulation). To assess autonomic activation, RR intervals (RRI), high frequency (HF) components of heart rate variability (HRV), and electrodermal activity phasic responses (EDRs) were calculated. Situational empathy was measured through a visual analogue scale. Participants rated how empathic they felt for a specific target. Up- and Down-regulation were related to an increase and a decrease in situational empathy and an increase in RRI and HF, respectively, compared to the control condition (No-regulation). This suggests increased activity of the parasympathetic branch during emotion regulation of situational empathic responses. Positive compared to Negative Social Scenes were associated with decreased situational empathy, in addition to a slightly but non-significantly increased HF. Altogether, this study demonstrates that emotion regulation may be associated with changes in situational empathy and autonomic responses, preferentially dominated by the parasympathetic branch and possibly reflecting an increase of regulatory processes. Furthermore, the current study provides evidence that empathy for different emotional valences is associated with distinct changes in situational empathy and autonomic responses.


Serum C-Reactive Protein as a Prognostic Biomarker in Amyotrophic Lateral Sclerosis.
Various factors have been proposed as possible candidates associated with the prognosis of amyotrophic lateral sclerosis (ALS); however, there is still no consensus on which biomarkers are reliable prognostic factors. C-reactive protein (CRP) is a biomarker of the inflammatory response that shows significant prognostic value for several diseases. To examine the prognostic significance of CRP in ALS. Patients' serum CRP levels were evaluated from January 1, 2009, to June 30, 2015, in a large cohort of patients with ALS observed by an Italian tertiary multidisciplinary center. Results were replicated in an independent cohort obtained from a population-based registry of patients with ALS. A post hoc analysis was performed of the phase 2 trial of NP001 to determine whether stratification by levels of CRP improves differentiation of responders and nonresponders to the drug. Serum CRP levels from the first examination were recorded to assess their effect on disease progression and survival. A total of 394 patients with ALS (168 women and 226 men; mean [SD] age at diagnosis, 60.18 [13.60] years) were observed in a tertiary multidisciplinary center, and the analysis was replicated in an independent cohort of 116 patients with ALS (50 women and 66 men; mean [SD] age at diagnosis, 67.00 [10.74] years) identified through a regional population-based registry. Serum CRP levels in the 394 patients with ALS correlated with severity of functional impairment, as measured by total score on the ALS Functional Rating Scale-Revised, at first evaluation (r = -0.14818; P = .004), and with patient survival (hazard ratio, 1.129; 95% CI, 1.033-1.234; P = .007). Similar results were found in the independent cohort (hazard ratio, 1.044; 95% CI, 1.016-1.056; P ≤ .001). Moreover, a post hoc analysis of the phase 2 trial of NP001 using the same CRP threshold showed that patients with elevated baseline CRP levels receiving the higher dose of NP001 had significantly less functional impairment after the treatment period compared with patients with normal baseline CRP, regardless of whether patients with normal CRP levels received NP001 or placebo (3.00 [3.62] vs -7.31 [6.23]; P = .04). These findings suggest that patients with ALS and elevated serum CRP levels progress more rapidly than do those with lower CRP levels and that this elevation may reflect a neuroinflammatory state potentially responsive to the immune regulators such as NP001.


Exercise preconditioning modulates genotoxicity induced by doxorubicin in multiple organs of rats.
The aim of this study was to investigate the effects of exercise in multiple organs of rats treated with doxorubicin. Male adult Wistar rats were distributed into the following groups: sedentary + NaCl; exercise + NaCl; sedentary + doxorubicin; and exercise + doxorubicin. Animals were sacrificed 2 days following injections. Central fragments from heart, liver, and kidney were collected and minced in 0.9% NaCl being cellular suspensions used for the single-cell gel (comet) assay. The results showed that exercise was able to prevent genotoxicity induced by doxorubicin in heart cells. By contrast, exercise was not able to prevent genotoxicity induced by doxorubicin in liver cells. The same occurred to kidney cells, i.e. no statistically significant differences (p > 0.05) were found when compared with groups not exposed to doxorubicin. Taken together, our results support the idea that exercise could contribute to the protective effect against genotoxicity induced by doxorubicin in heart cells.


Disparities in avoidable hospitalization by income in South Korea: data from the National Health Insurance cohort.
Avoidable hospitalizations can act as an indicator for primary health care quality, in particular ambulatory care sensitive conditions (ACSCs) as hospitalizations for these conditions are generally considered avoidable through successful management. This study aimed to examine whether differences exist between income levels in rates of avoidable hospitalization. The South Korea National Health Insurance claims data from 2002 to 2013 were used. All hospitalizations were included and categorized into avoidable and non-avoidable cases. The independent variable was income level classified into quartiles and the dependent variable rates of avoidable hospitalization. Analysis was conducted using the generalized estimating equation (GEE) Poisson model. Subgroup analysis was performed based on chronic versus acute disease status and urban versus rural region. A total of 1 310 492 cases were included, in which the crude rate of avoidable hospitalizations was 1444.5 per 100 000 person years. Compared to the Q4 highest income group set as reference, the Q3 (RR 1.07, 95% CI 1.04-1.09), Q2 (RR 1.16, 95% CI 1.13-1.19) and Q1 (RR 1.20, 95% CI 1.17-1.24) income groups showed higher rates of avoidable hospitalizations. Risks of avoidable hospitalizations for ACSCs was higher in lower than higher income groups, implying that socioeconomic status is related to disparities in avoidable hospitalizations. The findings suggest the importance of monitoring the vulnerable groups identified in managing avoidable hospitalizations.


FusC, a member of the M16 protease family acquired by bacteria for iron piracy against plants.
Iron is essential for life. Accessing iron from the environment can be a limiting factor that determines success in a given environmental niche. For bacteria, access of chelated iron from the environment is often mediated by TonB-dependent transporters (TBDTs), which are β-barrel proteins that form sophisticated channels in the outer membrane. Reports of iron-bearing proteins being used as a source of iron indicate specific protein import reactions across the bacterial outer membrane. The molecular mechanism by which a folded protein can be imported in this way had remained mysterious, as did the evolutionary process that could lead to such a protein import pathway. How does the bacterium evolve the specificity factors that would be required to select and import a protein encoded on another organism's genome? We describe here a model whereby the plant iron-bearing protein ferredoxin can be imported across the outer membrane of the plant pathogen Pectobacterium by means of a Brownian ratchet mechanism, thereby liberating iron into the bacterium to enable its growth in plant tissues. This import pathway is facilitated by FusC, a member of the same protein family as the mitochondrial processing peptidase (MPP). The Brownian ratchet depends on binding sites discovered in crystal structures of FusC that engage a linear segment of the plant protein ferredoxin. Sequence relationships suggest that the bacterial gene encoding FusC has previously unappreciated homologues in plants and that the protein import mechanism employed by the bacterium is an evolutionary echo of the protein import pathway in plant mitochondria and plastids.


Bacterial Heat Shock Protein GroEL (Hsp64) Exerts Immunoregulatory Effects on T Cells by Utilizing Apoptosis.
Aggregatibacter actinomycetemcomitans (Aa) expresses a 64-kDa GroEL protein belonging to the heat shock family of proteins. This protein has been shown to influence human host cells, but the apoptotic capacity of the GroEL protein regarding T cells is not yet known. The purpose of this study was to investigate the ability of A. actinomycetemcomitans GroEL (AaGroEL) protein to induce human peripheral blood T-cell apoptosis. Endogenous, purified AaGroEL protein was used as an antigen. In AaGroEL-treated T cells, the data indicated that phosphatidylserine exposure, an early apoptotic event, was dose- and time-dependent. The AaGroEL-treated T cells were also positive for active caspase-3 in a dose-dependent manner. The rate of AaGroEL-induced apoptosis was suppressed by the addition of the general caspase inhibitor Z-VAD-FMK. Furthermore, cleaved caspase-8 bands (40/36 kDa and 23 kDa) were identified in cells responding to AaGroEL. DNA fragmentation was also detected in the AaGroEL-treated T cells. Overall, we demonstrated that the endogenous GroEL from A. actinomycetemcomitans has the capacity to induce T-cell apoptosis.


COVID-19 pandemic lockdown and problematic eating behaviors in a student population.
Since mid-March 2020, over 3 billion people have been confined as a result of the COVID-19 pandemic. Problematic eating behaviors are likely to be impacted by the pandemic through multiple pathways. This study examined the relationships between stress related to lockdown measures and binge eating and dietary restriction in a population of French students during the first week of confinement. A sample of undergraduate students (N = 5,738) completed an online questionnaire 7 days after lockdown measures were introduced. The survey comprised variables related to lockdown measures and the COVID-19-pandemic, mood, stress, body image, binge eating and dietary restriction during the past 7 days, as well as intent to binge eat and restrict in the following 15 days. Stress related to the lockdown was associated with greater likelihood of binge eating and dietary restriction over the past week and intentions to binge eat and restrict over the next 15 days. Greater exposure to COVID-19-related media was associated with increased eating restriction over the past week. Binge eating and restriction (past and intentions) were associated with established risk factors, including female gender, low impulse regulation, high body dissatisfaction, and having a concurrent probable eating disorder. The higher the stress related to the first week of confinement, the higher the risk of problematic eating behaviors among students, particularly those characterized by eating-related concerns. Screening for risk factors and providing targeted interventions might help decrease problematic eating behaviors among those who are most vulnerable.


ANG1005, a Brain-Penetrating Peptide-Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases.
ANG1005, a novel taxane derivative, consists of three paclitaxel molecules covalently linked to Angiopep-2, designed to cross the blood-brain and blood-cerebrospinal barriers and to penetrate malignant cells via LRP1 transport system. Preclinical and clinical evidence of efficacy with ANG1005 has been previously shown. A multicenter, open-label phase II study in adult patients with measurable recurrent brain metastases from breast cancer (BCBM), with or without leptomeningeal carcinomatosis was conducted (n = 72 BCBM; n = 28 leptomeningeal carcinomatosis subset). ANG1005 was administered intravenously at 600 mg/m2 every 3 weeks. Tumor assessment was based on central nervous system (CNS) RECIST 1.1 for intracranial, and RECIST 1.1 for extracranial response. The primary endpoint was determination of intracranial objective response rate (iORR). Median age was 47.5 years. Safety profile was similar to that of paclitaxel with myelosuppression as the predominating toxicity. Average number of prior CNS-directed therapies was 2.8 and 94% of the patients had prior taxane treatment. Patient benefit (stable disease or better) was seen in 77% (intracranial) and 86% (extracranial) of the evaluable patients, with iORR of 15% (investigator) or 8% (independent radiology facility [IRF] review). In the leptomeningeal carcinomatosis subset, 79% of the patients had intracranial disease control and estimated median overall survival of 8.0 months (95% CI, 5.4-9.4). Even though the study preset rule for iORR per IRF was not met in this heavily pretreated population, a notable CNS and systemic treatment effect was seen in all patients including symptom improvement and prolonged overall survival compared to historical control for the subset of patients with leptomeningeal carcinomatosis (n = 28).


Association of Helicobacter pylori infection with cardiac syndrome X.
Cardiac syndrome X (CSX) includes chest pain, positive exercise stress test and/or radionuclide test for ischaemia and normal coronary angiography. There is no obvious aetiology for this syndrome. Some mechanisms such as endothelial dysfunction and oestrogen deficiency have been invoked. In this study, we surveyed the association of Helicobacter pylori (HP) infection with cardiac syndrome X. HP infection was detected by urea breath test (UBT) in patients with cardiac syndrome X, and compared with a sex- and age-matched control group. Patients with dyspepsia and coronary spasm were excluded. Statistical analysis was carried out using chi-square test. 40 patients (29 females and 11 males) with cardiac syndrome X aged between 30 and 65 years (mean 45.51 +/- 5.03 years) were compared with a control group (28 females and 12 males) aged between 31 and 64 years old (mean 44.93 +/- 5.16 years). 95 percent of patients were HP infected, while only 47.5 percent of members of the control group were infected (p-value is less than 0.001). Considering the high prevalence of HP infection in patients with CSX in our sample and probable causative effect of chronic infection in vascular diseases, we believe that there is a probable role for HP infection in the pathogenesis of CSX.


The Science of Salt: A focused review on salt-related knowledge, attitudes and behaviors, and gender differences.
The aim of the current review was to examine the scope of studies published in the Science of Salt Weekly that contained a measure of self-reported knowledge, attitudes, and behavior (KAB) concerning salt. Specific objectives were to examine how KAB measures are used to evaluate salt reduction intervention studies, the questionnaires used, and whether any gender differences exist in self-reported KAB. Studies were reviewed from the commencement of Science of Salt Weekly, June 2013 to the end of August 2017. Seventy-five studies had relevant measures of KAB and were included in this review, 13 of these were salt-reduction intervention-evaluation studies, with the remainder (62) being descriptive KAB studies. The KAB questionnaires used were specific to the populations studied, without evidence of a best practice measure. 40% of studies used KAB alone as the primary outcome measure; the remaining studies used more quantitative measures of salt intake such as 24-hour urine. Only half of the descriptive studies showed KAB outcomes disaggregated by gender, and of those, 73% showed women had more favorable KAB related to salt. None of the salt intervention-evaluation studies showed disaggregated KAB data. Therefore, it is likely important that evaluation studies disaggregate, and are appropriately powered to disaggregate all outcomes by gender to address potential disparities.


What makes a Salmonella strain epidemic? An expert opinion workshop.
An expert opinion workshop was held on the subject of the cause, identification and control of new and emerging Salmonella strains. Experts were invited to complete questionnaires, contribute to structured discussions and take part in cluster group tasks. Outputs of the workshop included that, with current surveillance methods, it might take up to 2.5 years from the first introduction of a new strain into the UK livestock population to its identification as a human epidemic strain. In order to reduce the time to detection and provide more effective control options, several recommendations were made, including better back-tracing of human cases to their source, which would require more effective communication between those responsible for human and veterinary surveillance.


The Shape of the Glucose Response Curve During an Oral Glucose Tolerance Test Heralds Biomarkers of Type 2 Diabetes Risk in Obese Youth.
The shape of the glucose response curve during an oral glucose tolerance test (OGTT), monophasic versus biphasic, identifies physiologically distinct groups of individuals with differences in insulin secretion and sensitivity. We aimed to verify the value of the OGTT-glucose response curve against more sensitive clamp-measured biomarkers of type 2 diabetes risk, and to examine incretin/pancreatic hormones and free fatty acid associations in these curve phenotypes in obese adolescents without diabetes. A total of 277 obese adolescents without diabetes completed a 2-h OGTT and were categorized to either a monophasic or a biphasic group. Body composition, abdominal adipose tissue, OGTT-based metabolic parameters, and incretin/pancreatic hormone levels were examined. A subset of 106 participants had both hyperinsulinemic-euglycemic and hyperglycemic clamps to measure in vivo insulin sensitivity, insulin secretion, and β-cell function relative to insulin sensitivity. Despite similar fasting and 2-h glucose and insulin concentrations, the monophasic group had significantly higher glucose, insulin, C-peptide, and free fatty acid OGTT areas under the curve compared with the biphasic group, with no differences in levels of glucagon, total glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pancreatic polypeptide. Furthermore, the monophasic group had significantly lower in vivo hepatic and peripheral insulin sensitivity, lack of compensatory first and second phase insulin secretion, and impaired β-cell function relative to insulin sensitivity. In obese youth without diabetes, the risk imparted by the monophasic glucose curve compared with biphasic glucose curve, independent of fasting and 2-h glucose and insulin concentrations, is reflected in lower insulin sensitivity and poorer β-cell function, which are two major pathophysiological biomarkers of type 2 diabetes in youth.


The propagule doesn't fall far from the tree, especially after short-interval, high-severity fire.
Subalpine forests that historically burned every 100-300 yr are expected to burn more frequently as climate warms, perhaps before trees reach reproductive maturity or produce a serotinous seedbank. Tree regeneration after short-interval (<30-yr) high-severity fire will increasingly rely on seed dispersal from unburned trees, but how dispersal varies with age and structure of surrounding forest is poorly understood. We studied wind dispersal of three conifers (Picea engelmannii, Abies lasiocarpa, and Pinus contorta var. latifolia, which can be serotinous and nonserotinous) after a stand-replacing fire that burned young (≤30 yr) and older (>100 yr) P. contorta forest in Grand Teton National Park (Wyoming, USA). We asked how propagule pressure varied with time since last fire, how seed delivery into burned forest varied with age and structure of live forest edges, what variables explained seed delivery into burned forest, and how spatial patterns of delivery across the burned area could vary with alternate patterns of surrounding live forest age. Seeds were collected in traps along 100-m transects (n = 18) extending from live forest edges of varying age (18, 30, and >100 yr) into areas of recent (2-yr) high-severity fire, and along transects in live forests to measure propagule pressure. Propagule pressure was low in 18-yr-old stands (~8 seeds/m2 ) and similarly greater in 30- and 100-yr-old stands (~32 seeds/m2 ). Mean dispersal distance was lowest from 18-yr-old edges and greatest from >100-yr-old edges. Seed delivery into burned forest declined with increasing distance and increased with height of trees at live forest edges, and was consistently higher for P. contorta than for other conifers. Empirical dispersal kernels revealed that seed delivery from 18-yr-old edges was very low (≤2.4 seeds/m2 ) and concentrated within 10 m of the live edge, whereas seed delivery from >100-yr-old edges was >4.9 seeds/m2 out to 80 m. When extrapolated throughout the burned landscape, estimated seed delivery was low (<49,400 seeds/ha) in >70% of areas that burned in short-interval fire (<30 yr). As fire frequency increases, immaturity risk will be compounded in short-interval fires because seed dispersal from surrounding young trees is limited.


Hormonal control of gubernaculum development during testis descent: gubernaculum outgrowth in vitro requires both insulin-like factor and androgen.
The gubernaculum connects the gonad to the inguinoscrotal region and is involved in testis descent. It rapidly develops in the male fetus, whereas development in the female fetus is lacking. Possible factors involved in gubernaculum development are androgens, anti-Müllerian hormone (AMH), and insulin-like factor (Insl3). Sexual dimorphism in gubernaculum development correlated with the mitotic activity of cells in the gubernacular bulbs from male and female fetuses. Androgen receptor expression was restricted to the mesenchymal core of the gubernacular bulb, whereas skeletal muscle was detected in its outer layer. In an organ culture system devised to further study gubernaculum development in vitro, morphology of gubernacular explants grown in the presence of testes was comparable with that of gubernacula developed in vivo. Testicular tissue or medium containing R1881, a synthetic androgen, had a growth stimulatory effect on gubernacular explants compared with ovarian tissue or basal medium only. Moreover, Amh-/-, Amh+/-, and Insl3+/- testes stimulated the growth of gubernacular explants to the same extent as control testes. Insl3-/- testes, however, did not produce such an activity. This study reveals an essential role for both androgen and Insl3 in the gubernaculum outgrowth during transabdominal testis descent.


Natural selection. V. How to read the fundamental equations of evolutionary change in terms of information theory.
The equations of evolutionary change by natural selection are commonly expressed in statistical terms. Fisher's fundamental theorem emphasizes the variance in fitness. Quantitative genetics expresses selection with covariances and regressions. Population genetic equations depend on genetic variances. How can we read those statistical expressions with respect to the meaning of natural selection? One possibility is to relate the statistical expressions to the amount of information that populations accumulate by selection. However, the connection between selection and information theory has never been compelling. Here, I show the correct relations between statistical expressions for selection and information theory expressions for selection. Those relations link selection to the fundamental concepts of entropy and information in the theories of physics, statistics and communication. We can now read the equations of selection in terms of their natural meaning. Selection causes populations to accumulate information about the environment.


Penetrating abdominal aortic trauma: a report of 129 cases.
The clinical presentation, resuscitation, and operative management of 129 patients with penetrating injuries to the abdominal aorta treated between 1960 and 1989 were reviewed. This is the largest reported civilian or military experience with this specific injury; our review of the literature was limited to reports focusing on the detailed analysis of the management and outcome of aortic trauma. Eighty-two percent of patients were in shock; 18 patients (14%) underwent emergency room thoracotomies, with no survivors. Of 46 patients requiring operating room thoracotomies, only 20% survived. All patients underwent exploration. Thirty percent had three or more visceral injuries; only 2% had no concurrent visceral injury. There were associated vascular injuries in 58% of patients, the inferior vena cava being the most frequent (37%). The most significant predictor of death was continued bleeding at operation. Ninety percent of patients with free intraperitoneal bleeding died, in contrast to 35% with a contained retroperitoneal hematoma (p less than 0.001). Aortic injuries were supraceliac in 25% of patients, between the celiac and renal arteries in 25%, and infrarenal in 50%. The respective mortality rates were 70%, 80%, and 47% (p less than 0.05). Repair of the aortic defect was possible in 103 patients (80%). The most common repair was lateral arteriorrhaphy in 53% of patients, followed by end-to-end anastomosis in 15% and prosthetic repairs in 8%. The overall mortality rate was 62%, which is similar to that of previous reports. Despite advances in trauma care, a functioning paramedic system, and the use of aggressive means to obtain aortic control, penetrating aortic trauma remains highly lethal.


Soluble interleukin-6 receptor in plasma and in lymphocyte culture supernatants of healthy individuals and patients with systemic lupus erythematosus and rheumatoid arthritis.
The soluble IL-6 receptor (sIL-6R) occurring in various body fluids of healthy persons and patients with various diseases is an agonist since its complex with IL-6 binds to gp130 making IL-6 receptor negative cells responsive for IL-6. The generation as well as the functional role of soluble IL-6 receptor is poorly understood. We measured the sIL-6R levels by ELISA sandwich technology in sera and in supernatants of lymphocyte cultures without and after incubations with dexamethasone. Our results indicate, that the sIL-6R levels in sera of patients with inactive systemic lupus erythematosus (SLE) and active rheumatoid arthritis (RA) were higher than those of the control group, active SLE and inactive RA. In vitro dexamethasone treatment stimulated generation of sIL-6R in both healthy persons and in active SLE, however it strongly suppressed sIL-6R in both RA groups. At mRNA level, we found that in SLE both the mRNA coding the cell-bound and an alternatively spliced variant corresponding to soluble IL-6R transcript increases, however the strong decrease of sIL6R protein in RA was not found at mRNA level.


The effects of omega-3 and omega-6 fatty acids on in vitro prostate cancer growth.
Dietary intake of essential fatty acids (EFA) may play a role in prostate cancer cell proliferation. Epidemiological studies have demonstrated that men whose dietary intake is high in omega-3 fatty acid (FA) composition have a lower incidence of clinical prostate cancer, suggesting that external factors such as diet may play an important role in development and growth of prostate cancer. Furthermore, in prostate cancer cell lines, omega-6 and omega-3 FAs have demonstrated promotional and inhibitory effects respectively. To investigate the effects of dietary fats on nontumorigenic prostate cell growth we conducted in vitro studies with human metastatic PC-3, LNCaP and TSU prostate cell lines, the rat metastatic Mat-Ly-Lu cell line and rat non-metastatic epithelial cell lines EPYP1, EPYP2 and EPYP3. Cell lines were treated with linoleic acid (LA), an omega-6 FA (n-6), as well as linolenic (LLA) and eicosapentaenoic (EPA) acids, which are both omega-3 FAs (n-3). All cell lines were treated with 10% and 0.5% serum supplemented media plus fatty acid for comparison. Our results demonstrate that linoleic acid(n-6) has promotional effects at doses of 1-100ng/ml in all cell lines with the exception of EPYPl. Experiments with linolenic acid (n-3) demonstrated consistent growth promotion in all cell lines examined with the exception of the EPYP2 cell line in which there was no significant effect. EPA had no effect in culture media supplemented with 10% serum, while in media containing 0.5% serum this FA demonstrated significant promotion in all human lines. Previous studies have indicated that EPA should inhibit human prostate cancer growth in vitro, however our results demonstrated promotion at low concentrations (lng/ml). At higher concentrations, EPA did inhibit prostate cell growth. These data indicate low levels of dietary fat, regardless of composition, may play a role in prostate cancer proliferation and could be an avenue for therapeutic intervention.


Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI).
To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast. 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:131-140.


Donor-free phosphenium-metal(0)-halides with unsymmetrically bridging phosphenium ligands.
Reactions of (cod)MCl2 (cod = 1,5 cyclooctadiene, M = Pd, Pt) with N-heterocyclic secondary phosphines or diphosphines produced complexes [(NHP)MCl]2 (NHP = N-heterocyclic phosphenium). The Pd complex was also accessible from a chlorophosphine precursor and Pd2(dba)3. Single-crystal X-ray diffraction studies established the presence of dinuclear complexes that contain μ-bridging NHP ligands in an unsymmetrical binding mode and display a surprising change in metal coordination geometry from distorted trigonal (M = Pd) to T-shaped (M = Pt). DFT calculations on model compounds reproduced these structural features for the Pt complex but predicted an unusual C2v-symmetric molecular structure with two different metal coordination environments for the Pd species. The deviation between this structure and the actual centrosymmetric geometry is accounted for by the prediction of a flat energy hypersurface, which permits large distortions in the orientation of the NHP ligands at very low energetic cost. The DFT results and spectroscopic studies suggest that the title compounds should be described as phosphenium-metal(0)-halides rather than conventional phosphido complexes of divalent metal cations and indicate that the NHP ligands receive net charge donation from the metals but retain a distinct cationic character. The unsymmetric NHP binding mode is associated with an unequal distribution of σ-donor/π-acceptor contributions in the two M-P bonds. Preliminary studies indicate that reactions of the Pd complex with phosphine donors provide a viable source of ligand-stabilized, zerovalent metal atoms and metal(0)-halide fragments.


Plant virus expression vectors set the stage as production platforms for biopharmaceutical proteins.
Transgenic plants present enormous potential as a cost-effective and safe platform for large-scale production of vaccines and other therapeutic proteins. A number of different technologies are under development for the production of pharmaceutical proteins from plant tissues. One method used to express high levels of protein in plants involves the employment of plant virus expression vectors. Plant virus vectors have been designed to carry vaccine epitopes as well as full therapeutic proteins such as monoclonal antibodies in plant tissue both safely and effectively. Biopharmaceuticals such as these offer enormous potential on many levels, from providing relief to those who have little access to modern medicine, to playing an active role in the battle against cancer. This review describes the current design and status of plant virus expression vectors used as production platforms for biopharmaceutical proteins.


Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy.
Gastric cancer (GC) is a heterogeneous disease comprising multiple subtypes that have distinct biological properties and effects in patients. We sought to identify new, intrinsic subtypes of GC by gene expression analysis of a large panel of GC cell lines. We tested if these subtypes might be associated with differences in patient survival times and responses to various standard-of-care cytotoxic drugs. We analyzed gene expression profiles for 37 GC cell lines to identify intrinsic GC subtypes. These subtypes were validated in primary tumors from 521 patients in 4 independent cohorts, where the subtypes were determined by either expression profiling or subtype-specific immunohistochemical markers (LGALS4, CDH17). In vitro sensitivity to 3 chemotherapy drugs (5-fluorouracil, cisplatin, oxaliplatin) was also assessed. Unsupervised cell line analysis identified 2 major intrinsic genomic subtypes (G-INT and G-DIF) that had distinct patterns of gene expression. The intrinsic subtypes, but not subtypes based on Lauren's histopathologic classification, were prognostic of survival, based on univariate and multivariate analysis in multiple patient cohorts. The G-INT cell lines were significantly more sensitive to 5-fluorouracil and oxaliplatin, but more resistant to cisplatin, than the G-DIF cell lines. In patients, intrinsic subtypes were associated with survival time following adjuvant, 5-fluorouracil-based therapy. Intrinsic subtypes of GC, based on distinct patterns of expression, are associated with patient survival and response to chemotherapy. Classification of GC based on intrinsic subtypes might be used to determine prognosis and customize therapy.


Women's empowerment in agriculture and child nutritional status in rural Nepal.
To examine the association between women's empowerment in agriculture and nutritional status among children under 2 years of age in rural Nepal. Cross-sectional survey of 4080 households conducted in 2012. Data collected included: child and maternal anthropometric measurements; child age and sex; maternal age, education, occupation and empowerment in agriculture; and household size, number of children, religion, caste and agro-ecological zone. Associations between the Women's Empowerment in Agriculture Index (WEAI)'s Five Domains of Empowerment (5DE) sub-index and its ten component indicators and child length-for-age Z-scores (LAZ) and weight-for-length Z-scores (WLZ) were estimated, using ordinary least-squares regression models, with and without adjustments for key child, maternal and household level covariates. Two hundred and forty rural communities across sixteen districts of Nepal. Children under 24 months of age and their mothers (n 1787). The overall WEAI 5DE was positively associated with LAZ (β=0·20, P=0·04). Three component indicators were also positively associated with LAZ: satisfaction with leisure time (β=0·27, P<0·01), access to and decisions regarding credit (β=0·20, P=0·02) and autonomy in production (β=0·10, P=0·04). No indicator of women's empowerment in agriculture was associated with WLZ. Women's empowerment in agriculture, as measured by the WEAI 5DE and three of its ten component indicators, was significantly associated with LAZ, highlighting the potential role of women's empowerment in improving child nutrition in Nepal. Additional studies are needed to determine whether interventions to improve women's empowerment will improve child nutrition.


An Elephant in the Emergency Department: Symptom of Disparities in Cancer Care.
Reliance on emergency departments (EDs) by economically disadvantaged people for initial cancer diagnosis in place of primary care and early diagnosis and treatment is 1 obvious plausible explanation for cancer disparities. Claims data from a safety net hospital for the years 2009-2010 were merged with hospital tumor registry data to compare hospitalizations for ED-associated initial cancer diagnoses to non-ED associated initial diagnoses. The proportion of initial cancer diagnoses associated with hospital admissions through the ED was relatively high (32%) for all safety net hospital patients, but disproportionately higher for African Americans and residents of the impoverished urban core. Use of the ED for initial diagnosis was associated with a 75% higher risk of stage 4 versus stage 1 cancer diagnosis, and a 176% higher risk of dying during the 2-year study period. Findings from this study of ED use within a safety net hospital documented profound disparities in cancer care and outcomes with major implications for monitoring disparities, Affordable Care Act impact, and safety net hospital utilization. (Population Health Management 2016;19:95-101).


In vitro toxicity model: Upgrades to bridge the gap between preclinical and clinical research.
The Centers for Disease Control and Prevention (CDC) provides extensive data that indicate our need for drugs to maintain human population health. Despite the substantial availability of drugs on the market, many patients lack specific drugs. New drugs are required to tackle this issue. Moreover, we need more reliable models for testing drug toxicity, as too many drug approval failures occur with the current models. This article briefly describes various approaches of the currently used models for toxicity screening, to justify the selection of in vitro cell-based models. Cell-based toxicity models have the best potential to reliably predict drug toxicity in humans, as they are developed using the cells of the target organism. However, currently, a large gap exists between in vitro cell-based approach to toxicity testing and the clinical approach, which may be contributing to drug approval failures. We propose improvements to in vitro cell-based toxicity models, which is often an insight approach, to better match this approach with the clinical homeostatic approach. This should enable a more accurate comparison of data between the preclinical as well as clinical models and provide a more comprehensive understanding of human physiology and biological effects of drugs.


Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitis.
Our aim was to understand the mechanism of immunological changes associated with the use of an adsorptive-type extracorporeal device (Adacolumn) that has been developed for selective adsorption of granulocytes and monocytes/macrophages from peripheral blood of patients with active ulcerative colitis. The column is filled with carriers (G-1 beads) that have a diameter of 2 mm and are made of cellulose diacetate. In peripheral blood treated with the G-1 beads or peripheral blood from patients with active ulcerative colitis following granulocyte and monocyte adsorption apheresis, a significant suppression of proinflammatory cytokines (tissue necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8) production by leukocytes, neutrophil chemotaxis, down-regulation of leukocyte adhesion molecule (L-selectin) and neutrophil adhesion to interleukin-1beta-activated endothelial cells were observed. Furthermore, after granulocyte adsorption therapy, the number of CD10-negative premature granulocytes increased, indicating increased turnover of these cells in the circulation. Our observations suggest that selective granulocyte and monocyte adsorption is associated with modified peripheral blood leukocyte function favorable to patients with ulcerative colitis and possibly other autoimmune disorders which reflect leukocyte hyperactivity.


Risk factors for HIV seropositivity among people consulting for HIV antibody testing: a pilot surveillance study in Quebec.
The surveillance of AIDS (acquired immune deficiency syndrome) through case reporting only reflects the epidemiologic features of HIV (human immunodeficiency virus) transmission a few years earlier and not the prevalence of HIV seropositivity. HIV infection is not a notifiable condition in Quebec. We were asked by the ministère de la Santé et des Services sociaux du Québec to perform a pilot project for the surveillance of HIV seropositivity using a network of sentinel physicians. From May 15, 1988, to Sept. 30, 1989, physicians from four collaborating centres collected data on the serologic status, demographic characteristics and risk factors for 4209 patients who underwent HIV antibody testing. Of the 3899 subjects included in the study 7.9% were HIV positive. Through logistic regression analysis the following variables were found to be significantly associated with HIV seropositivity: presence of HIV-related symptoms (prevalence odds ratio [POR] 36.5), origin from an endemic area (POR 9.1), homosexuality or bisexuality (POR 8.4), intravenous drug use (POR 4.2), male sex (POR 2.8), previous HIV antibody testing (POR 2.5) and previous sexually transmitted disease (POR 1.8). Over the study period we found a large increase in HIV seroprevalence among intravenous drug users (4.2% in 1988 to 19.0% in 1989) (p = 0.02). This increase might reflect a recent change in the epidemiologic pattern of HIV transmission in Quebec. Surveillance of HIV seropositivity through a network of sentinel physicians may be a reasonable alternative to mandatory reporting.


Electromyography Activation Levels of the 3 Gluteus Medius Subdivisions During Manual Strength Testing.
Cross-sectional. Gluteus medius (GM) muscle dysfunction is associated with overuse injury. The GM is functionally composed of 3 separate subdivisions: anterior, middle, and posterior. Clinical assessment of the GM subdivisions is relevant to detect strength and activation deficits and guide specific rehabilitation programs. However, the optimal positions for assessing the strength and activation of these subdivisions are unknown. The first aim was to establish which strength-testing positions produce the highest surface electromyography (sEMG) activation levels of the individual GM subdivisions. The second aim was to evaluate differences in sEMG activation levels between the tested and contralateral (stabilizing) leg. Twenty healthy physically active male subjects participated in this study. Muscle activity using sEMG was recorded for the GM subdivisions in 8 different strength-testing positions and analyzed using repeated-measures analysis of variance. Significant differences between testing positions for all 3 GM subdivisions were found. There were significant differences between the tested and the contralateral anterior and middle GM subdivisions (P < .01). The posterior GM subdivision showed no significant difference (P = .154). Side-lying in neutral and side-lying with hip internal rotation are the 2 positions recommended to evaluate GM function and guide specific GM rehabilitation.


Generating superposition of up-to three photons for continuous variable quantum information processing.
We develop an experimental scheme based on a continuous-wave (cw) laser for generating arbitrary superpositions of photon number states. In this experiment, we successfully generate superposition states of zero to three photons, namely advanced versions of superpositions of two and three coherent states. They are fully compatible with developed quantum teleportation and measurement-based quantum operations with cw lasers. Due to achieved high detection efficiency, we observe, without any loss correction, multiple areas of negativity of Wigner function, which confirm strongly nonclassical nature of the generated states.


Assessing the impacts of local knowledge and technology on climate change vulnerability in remote communities.
The introduction of new technologies into small remote communities can alter how individuals acquire knowledge about their surrounding environment. This is especially true when technologies that satisfy basic needs, such as freshwater use, create a distance (i.e., diminishing exposure) between individuals and their environment. However, such distancing can potentially be countered by the transfer of local knowledge between community members and from one generation to the next. The objective of this study is to simulate by way of agent-based modeling the tensions between technology-induced distancing and local knowledge that are exerted on community vulnerability to climate change. A model is developed that simulates how a collection of individual perceptions about changes to climatic-related variables manifest into community perceptions, how perceptions are influenced by the movement away from traditional resource use, and how the transmission of knowledge mitigates the potentially adverse effects of technology-induced distancing. The model is implemented utilizing climate and social data for two remote communities located on the Seward Peninsula in western Alaska. The agent-based model simulates a set of scenarios that depict different ways in which these communities may potentially engage with their natural resources, utilize knowledge transfer, and develop perceptions of how the local climate is different from previous years. A loosely-coupled pan-arctic climate model simulates changes monthly changes to climatic variables. The discrepancy between the perceptions derived from the agent-based model and the projections simulated by the climate model represent community vulnerability. The results demonstrate how demographics, the communication of knowledge and the types of 'knowledge-providers' influence community perception about changes to their local climate.


Let your enemy do the work: within-host interactions between two fungal parasites of leaf-cutting ants.
Within-host competition is an important factor in host-parasite relationships, yet most studies consider interactions involving only single parasite species. We investigated the interaction between a virulent obligate entomopathogenic fungus, Metarhizium anisopliae var. anisopliae, and a normally avirulent, opportunistic fungal pathogen, Aspergillus flavus, in their leaf-cutting ant host, Acromyrmex echinatior. Surprisingly, the latter normally out-competed the former in mixed infections and had enhanced fitness relative to when infecting in isolation. The result is most probably due to Metarhizium inhibiting the host's immune defences, which would otherwise normally prevent infections by Aspergillus. With the host defences negated by the virulent parasite, the avirulent parasite was then able to out-compete its competitor. This result is strikingly similar to that seen in immunocompromised vertebrate hosts and indicates that avirulent parasites may play a more important role in host life histories than is generally realized.