Applications and potential uses of fish gill cell lines: examples with RTgill-W1.
Gills are unique structures involved in respiration and osmoregulation in piscinids as well as in many aquatic invertebrates. The availability of the trout-derived gill cell line, RTgill-W1, is beginning to make impacts in fish health and toxicology. These cells are available from the American Type Culture Collection as ATCC CRL 2523. The cells have an epithelioid morphology and form tight monolayer sheets that can be used for testing epithelial resistance. The cells can be grown in regular tissue culture surfaces or in transwell membranes in direct contact with water on their apical surfaces. The ability of RTgill-W1 to withstand hypo- and hyper-osmotic conditions and their optimal growth capacity at room temperature, make these cells ideal sentinel models for in vitro aquatic toxicology as well as model systems to study fish gill function and gill diseases. RTgill-W1 support growth of paramyxoviruses and orthomyxoviruses like salmon anemia virus. RTgill-W1 also support growth of Neoparamoeba pemaquidensis, the causative agent of amoebic gill disease. The cells have been used to understand mechanisms of toxicity, ranking the potencies of toxicants, and evaluating the toxicity of environmental samples. These cells are also valuable for high throughput toxicogenomic and toxicoproteomic studies which are easier to achieve with cell lines than with whole organisms. RTgill-W1 cell line could become a valuable complement to whole animal studies and in some cases as gill replacements in aquatic toxicology.


Sequence-dependent synergism and antagonism between paclitaxel and gemcitabine in breast cancer cells: the importance of scheduling.
The marked clinical anticancer activity of the paclitaxel (PTX) and gemcitabine (GEM) combination has suggested that the two drugs may interact more than additively. We have analyzed the in vitro growth and molecular interactions of the two chemotherapy drugs in a panel of human breast cancer cells. We evaluated cell viability in four breast cancer cell lines (i.e., MCF-7, MDA-MB-231, MDA-MB-468, and SKBR3) that were treated with PTX and GEM combined either simultaneously (PTX + GEM) or sequentially (PTX --> GEM; GEM --> PTX). PTX-GEM interactions at the cellular level were assessed mathematically employing both the isobologram analysis (Berenbaum) and the combination index (Chou-Talalay) method. PTX-GEM molecular interactions on the apoptotic markers PARP, Bcl-2 and Bax were analyzed by immunoblotting procedures. Apoptosis was detected using a DNA ladder assay. We observed significant synergistic growth inhibitory interactions when PTX was administered before GEM. Additive interactions were observed when both the simultaneous regimen and the GEM followed by PTX regimen were used. DNA ladder and Western blotting results in the PTX followed by GEM sequence revealed a significant increase in the apoptotic cell death of breast cancer cells related to the Bax/Bcl-2 apoptotic pathway. In summary, the occurrence of clinically relevant synergism between PTX and GEM suggests a sequence-dependent nature in human breast cancer cells. This synergistic interaction on the PTXright curved arrow GEM schedule appears to be related to an increase in the Bcl-2-related mitochondrial apoptotic pathway. The synergism that we have observed may explain the favorable clinical responses that have been achieved in clinical studies, in which patients are administered PTX first, and then GEM.


Systematic review of guidelines for internal validity in the design, conduct and analysis of preclinical biomedical experiments involving laboratory animals.
Over the last two decades, awareness of the negative repercussions of flaws in the planning, conduct and reporting of preclinical research involving experimental animals has been growing. Several initiatives have set out to increase transparency and internal validity of preclinical studies, mostly publishing expert consensus and experience. While many of the points raised in these various guidelines are identical or similar, they differ in detail and rigour. Most of them focus on reporting, only few of them cover the planning and conduct of studies. The aim of this systematic review is to identify existing experimental design, conduct, analysis and reporting guidelines relating to preclinical animal research. A systematic search in PubMed, Embase and Web of Science retrieved 13 863 unique results. After screening these on title and abstract, 613 papers entered the full-text assessment stage, from which 60 papers were retained. From these, we extracted unique 58 recommendations on the planning, conduct and reporting of preclinical animal studies. Sample size calculations, adequate statistical methods, concealed and randomised allocation of animals to treatment, blinded outcome assessment and recording of animal flow through the experiment were recommended in more than half of the publications. While we consider these recommendations to be valuable, there is a striking lack of experimental evidence on their importance and relative effect on experiments and effect sizes.


Three-dimensional image compression with integer wavelet transforms.
A three-dimensional (3-D) image-compression algorithm based on integer wavelet transforms and zerotree coding is presented. The embedded coding of zerotrees of wavelet coefficients (EZW) algorithm is extended to three dimensions, and context-based adaptive arithmetic coding is used to improve its performance. The resultant algorithm, 3-D CB-EZW, efficiently encodes 3-D image data by the exploitation of the dependencies in all dimensions, while enabling lossy and lossless decompression from the same bit stream. Compared with the best available two-dimensional lossless compression techniques, the 3-D CB-EZW algorithm produced averages of 22%, 25%, and 20% decreases in compressed file sizes for computed tomography, magnetic resonance, and Airborne Visible Infrared Imaging Spectrometer images, respectively. The progressive performance of the algorithm is also compared with other lossy progressive-coding algorithms.


Umingmakstrongylus pallikuukensis (Nematoda: Protostrongylidae) in gastropods: larval morphology, morphometrics, and development rates.
Morphological and morphometric aspects of larval development of Umingmakstrongylus pallikuukensis in Deroceras laeve and the effects of temperature on development rates in D. laeve and Deroceras reticulatum were investigated in the laboratory. Larval stages were best differentiated by separation of cuticular sheaths, tail structure, and viability following digestion. Growth in body and esophagus width was observed during the first-stage within the intermediate host, but the major increases in body length and width occurred immediately following the second molt. Larval development in D. laeve and D. reticulatum occurred more rapidly at warmer temperatures. The calculated threshold temperatures were 8.5 and 9.5 C in D. laeve and D. reticulatum, respectively, and 167 degree-days were required for development to third-stage larvae (L3) in both hosts. These thresholds are higher than those calculated from published data for the closely related Muellerius capillaris (4.2 C) but are similar to those for the more distantly related northern protostrongylid, Elaphostrongylus rangiferi (8.3-10.3 C). Conversely, degree-days required for development to infective L3 were more similar among the Muelleriinae than between this group and the Elaphostrongylinae. Developmental parameters for protostrongylid larvae may be influenced both by the environment and by features of the parasites and the intermediate hosts, including phylogeny.


Targeting Refractory Sarcomas and Malignant Peripheral Nerve Sheath Tumors in a Phase I/II Study of Sirolimus in Combination with Ganetespib (SARC023).
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas. Combining Hsp90 inhibitors to enhance endoplasmic reticulum stress with mTOR inhibition results in dramatic MPNST shrinkage in a genetically engineered MPNST mouse model. Ganetespib is an injectable potent small molecule inhibitor of Hsp90. Sirolimus is an oral mTOR inhibitor. We sought to determine the safety, tolerability, and recommended dose of ganetespib and sirolimus in patients with refractory sarcomas and assess clinical benefits in patients with unresectable/refractory MPNSTs. Patients and Methods. In this multi-institutional, open-label, phase 1/2 study of ganetespib and sirolimus, patients ≥16 years with histologically confirmed refractory sarcoma (phase 1) or MPNST (phase 2) were eligible. A conventional 3 + 3 dose escalation design was used for phase 1. Pharmacokinetic and pharmacodynamic measures were evaluated. Primary objectives of phase 2 were to determine the clinical benefit rate (CBR) of this combination in MPNSTs. Patient-reported outcomes assessed pain. Twenty patients were enrolled (10 per phase). Toxicities were manageable; most frequent non-DLTs were diarrhea, elevated liver transaminases, and fatigue. The recommended dose of ganetespib was 200 mg/m2 intravenously on days 1, 8, and 15 with sirolimus 4 mg orally once daily with day 1 loading dose of 12 mg. In phase 1, one patient with leiomyosarcoma achieved a sustained partial response. In phase 2, no responses were observed. The median number of cycles treated was 2 (1-4). Patients did not meet the criteria for clinical benefit as defined per protocol. Pain ratings decreased or were stable. Despite promising preclinical rationale and tolerability of the combination therapy, no responses were observed, and the study did not meet parameters for further evaluation in MPNSTs. This trial was registered with (NCT02008877).


Grip strength and hand dominance: challenging the 10% rule.
The purpose of this study was to test the utility of the 10% rule in hand rehabilitation. The 10% rule states that the dominant hand possesses a 10% greater grip strength than the nondominant hand. This rule has been used for many years to assist therapists in setting strength goals for patients with injured hands. The sample for this study consisted of 310 male and female students, faculty, and staff from a small, private liberal arts college located in Pennsylvania. Grip strength was measured with a factory-calibrated Jamar dynamometer. Results showed an overall 10.74% grip strength difference between dominant and nondominant hands. This finding verified the 10% rule. However, when the data were separated into left-handed and right-handed subjects, a 12.72% difference for right-handed subjects and a -0.08% difference for left-handed subjects was found. In conclusion, this study showed that the 10% rule is valid for right-handed persons only; for left-handed persons, grip strength should be considered equivalent in both hands.


Structure and Properties of Some Layered U2O5 Phases: A Density Functional Theory Study.
U2O5 is the boundary composition between the fluorite and the layered structures of the UO2→3 system and the least studied oxide in the group. δ-U2O5 is the only layered structure proposed so far experimentally, although evidence of fluorite-based phases has also been reported. Our DFT work explores possible structures of U2O5 stoichiometry by starting from existing M2O5 structures (where M is an actinide or transition metal) and replacing the M ions with uranium ions. For all structures, we predicted structural and electronic properties including bulk moduli and band gaps. The majority of structures were found to be less stable than δ-U2O5. U2O5 in the R-Nb2O5 structure was found to be a competitive structure in terms of stability, whereas U2O5 in the Np2O5 structure was found to be the most stable overall. Indeed, by including the vibrational contribution to the free energy using the frequencies obtained from the optimized unit cells we predict that Np2O5 structured U2O5 is the most thermodynamically stable under ambient conditions. δ-U2O5 only becomes more stable at high temperatures and/or pressures. This suggests that a low-temperature synthesis route should be tested and so potentially opens a new avenue of research for pentavalent uranium oxides.


Manufacture of Fior di Latte cheese by incorporation of probiotic lactobacilli.
This work aimed to select heat-resistant probiotic lactobacilli to be added to Fior di Latte (high-moisture cow milk Mozzarella) cheese. First, 18 probiotic strains belonging to Lactobacillus casei, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus rhamnosus, and Lactobacillus reuteri were screened. Resistance to heating (65 or 55°C for 10 min) varied markedly between strains. Adaptation at 42°C for 10 min increased the heat resistance at 55°C for 10 min of all probiotic lactobacilli. Heat-adapted L. delbrueckii ssp. bulgaricus SP5 (decimal reduction time at 55°C of 227.4 min) and L. paracasei BGP1 (decimal reduction time at 55°C of 40.8 min) showed the highest survival under heat conditions that mimicked the stretching of the curd and were used for the manufacture of Fior di Latte cheese. Two technology options were chosen: chemical (addition of lactic acid to milk) or biological (Streptococcus thermophilus as starter culture) acidification with or without addition of probiotics. As determined by random amplified polymorphic DNA-PCR and 16S rRNA gene analyses, the cell density of L. delbrueckii ssp. bulgaricus SP5 and L. paracasei BGP1 in chemically or biologically acidified Fior di Latte cheese was approximately 8.0 log(10)cfu/g. Microbiological, compositional, biochemical, and sensory analyses (panel test by 30 untrained judges) showed that the use of L. delbrueckii ssp. bulgaricus SP5 and L. paracasei BGP1 enhanced flavor formation and shelf-life of Fior di Latte cheeses.


Thermal quantification of region myocardial perfusion and heat generation.
A technique for experimental determination of regional myocardial blood flow and heat generation has been developed, based on a heat-clearance method. This method allows repetitive and frequent measurements of regional blood flow without necessity for biopsy or microspheres. Testing was performed on a pedicle preparation, an intact segment of left ventricular myocardium dependent on a single diagonal coronary artery and situated in situ in the left ventricular free wall. Total blood flow to the pedicle was measured by an electromagnetic flow probe. A specially designed 3-thermistor microprobe was positioned in the pedicle to continuously sense temperature changes in the subepicardium, midmyocardium, and subendocardium. The theory underlying this method is based on a heat balance that includes local myocardial heating, conduction, and convection. Comparison of the predicted time- and position-dependent temperature with that measured experimentally allows extraction of the local myocardial blood flow and heating rates. This method allows resolution of differential flows in subendocardial, midmyocardial, and subepicardial myocardium and provides quantification of dynamic flow changes in each layer in response to various stimuli such as ischemia or pressor agents, without in itself causing damage to the myocardial microvasculature. Our data show total flow, based on summation of thermally calculated regional flows, to have correlation coefficients of 0.88 with both the flowmeter and microsphere results. Resting flow values for Nembutal-anaesthetized, open-chest dogs of 0.66 ml/(g . min) compare favorably with values obtained by microsphere studies. Infusion of norepinephrine increased total flow and all layer flows, but the increase in subendocardial flow with norepinephrine was less than the increase of the other layers, perhaps accounting for the vulnerability of this region during catecholamine stress. Local myocardial heating rates in subepicardial, midendocardial, and subendocardial layers are shown to follow the same dependence on local myocardial blood flow in response to anoxic stress or norepinephrine-induced vasodilation. Specifically, local heating rate increases to a factor of 10 at flow below resting level.


Fast Track THR: One Hospital's Experience with a 2-Day Length of Stay Protocol for Total Hip Replacement.
Current trends in total joint replacement have focused on shorter hospital stays. This study aimed to determine if a pathway for total hip replacement (THR) with the goal of a 2-day discharge (fast track) is safe and effective compared to our traditional pathway (control). One hundred forty-nine patients undergoing unilateral, uncomplicated, THR were enrolled in an accelerated postoperative pathway and 134 were enrolled in the traditional pathway. Patients were followed prospectively and outcomes included hospital length of stay, intra- and postoperative complications, readmissions, reoperations. A statistical model was created to determine factors predictive of a 2-day discharge. At 1 year, there were no differences in complications, readmissions, or reoperations. The average length of stay decreased from 4.1 to 2.6 days (p < 0.0001). In the fast track group, 58% of patients were discharged home within 2 days. Barriers to a 2-day discharge were postoperative pain, nausea, and dizziness. The only preoperative factor that was predictive of a 2-day discharge was hypertension. In a select group of patients, a protocol that allows for a 2-day discharge following THR is safe and effective.


Mutants of the Drosophila ncd microtubule motor protein cause centrosomal and spindle pole defects in mitosis.
Nonclaret disjunctional (ncd) is a kinesin-related microtubule motor protein required for meiotic and early mitotic chromosome distribution in Drosophila. ncd translocates on microtubules with the opposite polarity to kinesin, toward microtubule minus ends, and is associated with spindles in chromosome/spindle preparations. Here we report a new mutant of ncd caused by partial deletion of the predicted coiled-coil central stalk. The mutant protein exhibits a velocity of translocation and ability to generate torque in motility assays comparable to near full-length ncd, but only partially rescues a null mutant for chromosome mis-segregation. Antibody staining experiments show that the partial loss-of-function and null mutants cause centrosomal and spindle pole defects, including centrosome splitting and loss of centrosomes from spindle poles, and localize ncd to centrosomes as well as spindles of wild-type embryos. Association of ncd with spindles and centrosomes is microtubule- and cell cycle-dependent: inhibition of microtubule assembly with colchicine abolishes ncd staining and centrosomal staining is observed in prometaphase, metaphase and anaphase, but diminishes in late anaphase/telophase. The cell cycle dependence of centrosomal staining and the defects of mutants provide clear evidence for activity of the ncd motor protein near or at the spindle poles in mitosis. The ncd motor may interact with centrosomal microtubules and spindle fibers to attach centrosomes to spindle poles, and mediate poleward translocation (flux) of kinetochore fibers, a process that may underlie poleward movement of chromosomes in mitosis. Together with previous work, our findings indicate that ncd is important in maintaining spindle poles in mitosis as well as in meiosis.


Relationship between systematic feedback to faculty and ratings of clinical teaching.
To examine whether frequent written feedback to faculty would improve their teaching in clinical settings. Forty-four pediatrics faculty at the Medical College of Wisconsin participated in 1987 and 1988 in a prospective randomized trial of feedback about clinical teaching. During a six-month baseline period all the faculty were rated on ten teaching traits by residents and students using a seven-point Likert scale; evaluation summaries were placed in the teaching folders of the faculty. During a 12-month treatment period, 21 faculty were randomly selected to be given directed feedback every two months in the form of mailed computer-generated summaries that contained the most recent and cumulative mean ratings for the individual faculty member and the department, as well as written comments. Mean ratings were compared within the feedback and control groups and between the two groups by using two-tailed paired t-tests and Student's t-tests, respectively. The faculty receiving feedback showed significantly increased ratings over time for the traits of knowledge (p = .025), demonstrates skill(s) (p = .001), provides feedback to trainee (p = .006), and sets reasonable expectations (p = .03). The faculty receiving feedback had an average increase in ratings across all ten traits that was significantly greater than the average increase of their control-group peers (p < .05). Those in the feedback group who had received mean ratings for overall teaching effectiveness that were below the department mean at baseline showed the greatest improvement by the end of the treatment period (p < .05). The provision of written feedback improved the ratings of teaching effectiveness, especially among the faculty who had been rated below average.


Ageusia as a side effect of clopidogrel treatment.
Clopidogrel is prescribed in cardiac and extracardiac vascular diseases. It is generally well tolerated; however, few cases of taste disorders have been reported. We present a case of clopidogrel-induced ageusia notified in Sfax pharmacovigilance center on March 13, 2009. A 46-year-old patient developed ageusia with decreased appetite five weeks after starting clopidogrel. Other etiologies including ear nose throat (ENT) examination were ruled out. Five months after reduction of clopidogrel dose, ageusia partially decreased. Clopidogrel was strongly suspected as a causal drug. According to the French imputation method, score of imputability was considered as plausible (C2S2) I2. Physiopathology of this side effect is not yet understood. However, it seems to be a reversible and dose-related event. Although it is not life-threatening, loss of taste can have significant effect on the quality of life of patients.


The advantages of the surface Laplacian in brain-computer interface research.
Brain-computer interface (BCI) systems frequently use signal processing methods, such as spatial filtering, to enhance performance. The surface Laplacian can reduce spatial noise and aid in identification of sources. In BCI research, these two functions of the surface Laplacian correspond to prediction accuracy and signal orthogonality. In the present study, an off-line analysis of data from a sensorimotor rhythm-based BCI task dissociated these functions of the surface Laplacian by comparing nearest-neighbor and next-nearest neighbor Laplacian algorithms. The nearest-neighbor Laplacian produced signals that were more orthogonal while the next-nearest Laplacian produced signals that resulted in better accuracy. Both prediction and signal identification are important for BCI research. Better prediction of user's intent produces increased speed and accuracy of communication and control. Signal identification is important for ruling out the possibility of control by artifacts. Identifying the nature of the control signal is relevant both to understanding exactly what is being studied and in terms of usability for individuals with limited motor control.


The impact of MEG source reconstruction method on source-space connectivity estimation: A comparison between minimum-norm solution and beamforming.
Despite numerous important contributions, the investigation of brain connectivity with magnetoencephalography (MEG) still faces multiple challenges. One critical aspect of source-level connectivity, largely overlooked in the literature, is the putative effect of the choice of the inverse method on the subsequent cortico-cortical coupling analysis. We set out to investigate the impact of three inverse methods on source coherence detection using simulated MEG data. To this end, thousands of randomly located pairs of sources were created. Several parameters were manipulated, including inter- and intra-source correlation strength, source size and spatial configuration. The simulated pairs of sources were then used to generate sensor-level MEG measurements at varying signal-to-noise ratios (SNR). Next, the source level power and coherence maps were calculated using three methods (a) L2-Minimum-Norm Estimate (MNE), (b) Linearly Constrained Minimum Variance (LCMV) beamforming, and (c) Dynamic Imaging of Coherent Sources (DICS) beamforming. The performances of the methods were evaluated using Receiver Operating Characteristic (ROC) curves. The results indicate that beamformers perform better than MNE for coherence reconstructions if the interacting cortical sources consist of point-like sources. On the other hand, MNE provides better connectivity estimation than beamformers, if the interacting sources are simulated as extended cortical patches, where each patch consists of dipoles with identical time series (high intra-patch coherence). However, the performance of the beamformers for interacting patches improves substantially if each patch of active cortex is simulated with only partly coherent time series (partial intra-patch coherence). These results demonstrate that the choice of the inverse method impacts the results of MEG source-space coherence analysis, and that the optimal choice of the inverse solution depends on the spatial and synchronization profile of the interacting cortical sources. The insights revealed here can guide method selection and help improve data interpretation regarding MEG connectivity estimation.


Concurrent Validity of Depth-Sensing Cameras for Noncontact ACL Injury Screening During Side-Cut Maneuvers in Adolescent Athletes: A Preliminary Study.
Anterior cruciate ligament (ACL) injury is one of the most common knee injuries among adolescent athletes. Majority of the ACL injuries occur due to pivoting, sudden deceleration, and direction change without contact with any player. Preventive interventions can reduce risks of the ACL injury, thus developing a clinician friendly biomechanical assessment tool to identify athletes with such risk factors is crucial. In this study, the authors investigated the concurrent validity of a commercially available depth sensor, Microsoft Kinect, as a cost-effective alternative to the gold-standard 3-dimensional motion analysis systems in noncontact ACL screening for adolescent athletes during side-cut maneuvers. Study participants performed 45° side-cut maneuvers while collecting data from both systems concurrently. The sagittal and frontal plane kinematics were analyzed during the full stance phase and the first 20% of the stance (early deceleration). Absolute agreement (range: ICC = .767-.989) and consistency (range: ICC = .799-.992) were excellent for all measures except early deceleration frontal plane hip angle, which displayed good absolute agreement (ICC = .643) and consistency (ICC = .625). Findings showed that the Kinect has the potential to be an effective clinical assessment tool for sagittal and frontal plane trunk, hip, and knee kinematics during the side-cut maneuvers.


Acute optogenetic silencing of orexin/hypocretin neurons induces slow-wave sleep in mice.
Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. To help determine how these neurons promote wakefulness, we generated transgenic mice in which orexin neurons expressed halorhodopsin (orexin/Halo mice), an orange light-activated neuronal silencer. Slice patch-clamp recordings of orexin neurons that expressed halorhodopsin demonstrated that orange light photic illumination immediately hyperpolarized membrane potential and inhibited orexin neuron discharge in proportion to illumination intensity. Acute silencing of orexin neurons in vivo during the day (the inactive period) induced synchronization of the electroencephalogram and a reduction in amplitude of the electromyogram that is characteristic of slow-wave sleep (SWS). In contrast, orexin neuron photoinhibition was ineffective during the night (active period). Acute photoinhibition of orexin neurons during the day in orexin/Halo mice also reduced discharge of neurons in an orexin terminal field, the dorsal raphe (DR) nucleus. However, serotonergic DR neurons exhibited normal discharge rates in mice lacking orexin neurons. Thus, although usually highly dependent on orexin neuronal activity, serotonergic DR neuronal activity can be regulated appropriately in the chronic absence of orexin input. Together, these results demonstrate that acute inhibition of orexin neurons results in time-of-day-dependent induction of SWS and in reduced firing rate of neurons in an efferent projection site thought to be involved in arousal state regulation. The results presented here advance our understanding of the role of orexin neurons in the regulation of sleep/wakefulness and may be relevant to the mechanisms that underlie symptom progression in narcolepsy.


Significance of radiographic splenic vessel involvement in the pancreatic ductal adenocarcinoma of the body and tail of the gland.
Unlike pancreatic head tumors, little is known about the biological significance of radiographic vessel involvement with pancreatic body/tail adenocarcinoma. We hypothesized radiographic splenic vessel involvement may be an adverse prognostic factor. All distal pancreatectomies performed for resectable pancreatic adenocarcinoma between 2000 and 2016 were reviewed and clinicopatholgic data were collected, retrospectively. Preoperative computed tomography imaging was re-reviewed and splenic vessel involvement was graded as none, abutment, encasement, or occlusion. Among a total of 71 patients, splenic artery or vein encasement/occlusion was present in 41% (29 of 71) of patients, each. There were no significant differences in tumor size or grade, margin positivity, and perineural or lymphovascular invasion. However, splenic artery encasement/occlusion (P = 0.001) and splenic vein encasement/occlusion (P = 0.038) both correlated with lymph node positivity. Splenic artery encasement was associated with a reduced median overall survival (20 vs 30 months, P = 0.033). Multivariate analysis also showed that splenic artery encasement was an independent risk factor of worse survival (hazard ratio, 2.246; 95% confidence interval, 1.118-4.513; P = 0.023). Patients with cancer of the body or tail of the pancreas presenting with radiographic encasement of the splenic artery, but not the splenic vein, have a poorer prognosis and perhaps should be considered for neoadjuvant therapy before an attempt at curative resection.


Multicomponent-assembled nanodiamond hybrids for targeted and imaging guided triple-negative breast cancer therapy via a ternary collaborative strategy.
Uniting combinational strategies has been confirmed to be a robust choice for high-performance cancer treatment due to their abilities to overcome tumor heterogeneity and complexity. However, the development of a simple, effective, and multifunctional theranostics nanoplatform still remains a challenge. In this study, we integrated multicomponent hyaluronic acid (HA), protamine (PS), nanodiamonds (NDs), curcumin (Cur), and IR780 into a single nanoplatform (denoted as HPNDIC) based on the combination of hydrophobic and electrostatic noncovalent interactions for dual-modal fluorescence/photoacoustic imaging guided ternary collaborative Cur/photothermal/photodynamic combination therapy of triple-negative breast cancer (TNBC). A two-step coordination assembly strategy was utilized to realize this purpose. In the first step, PS was utilized to modify the NDs clusters to form positively charged PS@NDs (PND) and the simultaneous encapsulation of the natural small-molecule drug Cur and the photosensitive small-molecule IR780 (PNDIC). Second, HA was adsorbed onto the outer surface of the PNDIC through charge complexation for endowing a tumor-targeting ability (HPNDIC). The resulting HPNDIC had a uniform size, high drug-loading ability, and excellent colloidal stability. It was found that under the near-infrared irradiation condition, IR780 could be triggered to exhibit both PTT/PDT dual-pattern therapy effects, leading to an enhanced therapy efficiency of Cur both in vitro and in vivo with good biocompatibility. Due to the intrinsic imaging property of IR780, the biodistribution and accumulation behavior of HPNDIC in vivo could be monitored by dual-modal fluorescence/photoacoustic imaging. Taken together, our current work demonstrated the assembly of a NDs-based multicomponent theranostic platform for dual-modal fluorescence/photoacoustic imaging guided triple-collaborative Cur/photothermal/photodynamic against TNBC.


Self-phase modulation of incoherent light revisited.
The effects of self-phase modulation on a Gaussian incoherent field propagating in a dispersionless nonlinear Kerr medium are calculated without assuming the mean-field-theory approximation. Deviations between the exact and approximate solutions for the correlation time compression ratio as a function of the pulse power and fiber length are computed.


Distribution of pathogenicity islands in Salmonella spp.
We investigated the phylogenetic distribution of the SPI-1 and SPI-2 pathogenicity islands in Salmonella spp. SPI-1 was present in representatives of all eight subspecific groups, but no SPI-2-hybridizing sequences were detected in group V (S. bongori). Our data suggest that SPI-2 was acquired by S. enterica after its split from S. bongori.


Clostridium difficile in faeces from healthy dogs and dogs with diarrhea.
This study was conducted to evaluate the faecal occurrence and characterization of Clostridium difficile in clinically healthy dogs (N = 50) and in dogs with diarrhea (N = 20) in the Stockholm-Uppsala region of Sweden. Clostridium difficile was isolated from 2/50 healthy dogs and from 2/20 diarrheic dogs. Isolates from healthy dogs were negative for toxin A and B and for the tcdA and tcdB genes. Both isolates from diarrheic dogs were positive for toxin B and for the tcdA and tcdB genes. The C. difficile isolates from healthy dogs had PCR ribotype 009 (SE-type 6) and 010 (SE-type 3) whereas both isolates from dogs with diarrhoea had the toxigenic ribotype 014 (SE-type 21). One of the isolates from healthy dogs was initially resistant to metronidazole. This study revealed presence of toxigenic C. difficile in faecal samples of diarrheic dogs and low number of non- toxigenic isolates in healthy dogs from Uppsala-Stockholm region in Sweden. However, more comprehensive studies are warranted to investigate the role of C. difficile in gastrointestinal disease in dogs.


Recognition of emotion from vocal cues.
In two studies investigating the recognition of emotion from vocal cues, each of four emotions (joy, sadness, anger, and fear) was posed by an actress speaking the same, semantically neutral sentence. Judgments of emotion expressed in these segments were compared with similar judgments of voice-synthesized (Moog synthesizer) samples (study 1) or with three different alterations of the full-speech mode (study 2). Correct identification of the posed emotion was high in the full-speech samples. Voice-synthesized samples seemed to capture some cues promoting emotion recognition, but correct identification did not approach that of other segments. Recognition of emotion decreased, but not as dramatically as expected in each of the three alterations of the original samples.


Interventions to enhance work participation of workers with a chronic disease: a systematic review of reviews.
The aim of this systematic review was to provide an overview of the available effective interventions that enhance work participation of people with a chronic disease, irrespective of their diagnosis. A search was conducted in PubMed, EMBASE, PsycINFO, CINAHL and the Cochrane Library, searching for systematic reviews published between 2004 and February 2015. Systematic reviews were eligible for inclusion if they described an intervention aimed at enhancing work participation and included participants of working age (18-65 years) with a chronic disease. Reviews had to include populations having different chronic diseases. The quality of the included reviews was evaluated using the quality instrument AMSTAR. Results of reviews of medium and high quality were described in this review. The search resulted in 9 reviews, 5 of which were of medium quality. No high quality reviews were retrieved. 1 review reported inconclusive evidence for policy-based return to work initiatives. The 4 other reviews described interventions focused on changes at work, such as changes in work organisation, working conditions and work environment. Of these 4 reviews, 3 reported beneficial effects of the intervention on work participation. Interventions examined in populations having different chronic diseases were mainly focused on changes at work. The majority of the included interventions were reported to be effective in enhancing work participation of people with a chronic disease, indicating that interventions directed at work could be considered for a generic approach in order to enhance work participation in various chronic diseases.


Quality of radiosurgery for single brain metastases with respect to treatment technology: a matched-pair analysis.
A comparison of treatment parameters and quality of clinical outcome in patients with single brain metastases treated with two different technologies for radiosurgery (Gamma Knife and CyberKnife). Treatment parameters were statistically analyzed. Clinical outcome was assessed by matched-pair analysis based on the treatment device, differences in dose prescription, and the date of the treatment. Patients were matched according to their tumor size, age, gender, primary cancer, and Radiation Therapy Oncology Group score. Survival post-radiosurgery, local and distant tumor control, and complications were analyzed. Predictive factors were investigated. 423 single brain metastases were treated with Gamma Knife and 73 with CyberKnife. Tumor volumes were similar. The parameters minimum tumor dose, maximum tumor dose, prescription isodose volume, conformality index, homogeneity index, volume of tissue receiving a dose of 10 Gy or more were significantly larger in Gamma Knife group. Sixty-three patients were good matches. These showed the same pattern in parameters. Concerning the outcome analysis, only overall survival differed significantly between groups, twice as long with CyberKnife (P < 0.03). According to pooled data, dose was predictive of local failure, whole brain radiation therapy and chemotherapy were predictive of toxicity, the Radiation Therapy Oncology Group score was predictive of survival after radiosurgery, and date of treatment was predictive of overall survival. No factor predicted new brain metastases, including whole brain radiation therapy. The most important result of this study was the finding that the obvious differences in treatment-related parameters between Gamma Knife and CyberKnife had no impact on the quality of the clinical outcome after radiosurgery. Survival time increased chronologically, presumably due to an intensified anti-cancer therapy in the more recent era of the CyberKnife treatments.


The mediating effect of chronic pain on the relationship between obesity and physical function and disability in older adults.
To determine the extent to which bodily pain mediates the effect of obesity on disability and physical function. Cross-sectional analysis. Population-based sample of residents in the greater Boston area. Community-dwelling adults aged 70 and older (N=736). Body mass index (BMI), obtained from measured height and weight, was categorized as normal weight (19.0-24.9 kg/m2), overweight (25.0-29.9 kg/m2), or obese (≥30.0 kg/m2). Main outcome measures were the Physical Component Summary of the Medical Outcomes Study 12-item Short-Form Survey (PCS), activity of daily living (ADL) disability, and Short Physical Performance Battery (SPPB) score. Chronic pain was assessed according to the number of weight-bearing joint sites that had pain (hips, knees, feet and pain all over). Older obese adults had greater ADL disability and lower SPPB and PCS scores than their nonobese counterparts, although in sex-stratified adjusted analyses, obesity was adversely associated with outcomes only in women. Obesity was associated with greater number of pain sites; and more pain sites were associated with greater odds of disability. Mediation analysis suggests that pain is a significant mediator (22-44%) of the adverse effect of obesity on disability and physical function in women. Bodily pain may be an important treatable mediator of the adverse effect of obesity on disability and physical function in women.


Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy and Imaging.
In the past decades, new methods for tumor staging, restaging, treatment response monitoring, and recurrence detection of a variety of cancers have emerged in conjunction with the state-of-the-art positron emission tomography with 18F-fluorodeoxyglucose ([18F]-FDG PET). 13C magnetic resonance spectroscopic imaging (13CMRSI) is a minimally invasive imaging method that enables the monitoring of metabolism in vivo and in real time. As with any other method based on 13C nuclear magnetic resonance (NMR), it faces the challenge of low thermal polarization and a subsequent low signal-to-noise ratio due to the relatively low gyromagnetic ratio of 13C and its low natural abundance in biological samples. By overcoming these limitations, dynamic nuclear polarization (DNP) with subsequent sample dissolution has recently enabled commonly used NMR and magnetic resonance imaging (MRI) systems to measure, study, and image key metabolic pathways in various biological systems. A particularly interesting and promising molecule used in 13CMRSI is [1-13C]pyruvate, which, in the last ten years, has been widely used for in vitro, preclinical, and, more recently, clinical studies to investigate the cellular energy metabolism in cancer and other diseases. In this article, we outline the technique of dissolution DNP using a 3.35 T preclinical DNP hyperpolarizer and demonstrate its usage in in vitro studies. A similar protocol for hyperpolarization may be applied for the most part in in vivo studies as well. To do so, we used lactate dehydrogenase (LDH) and catalyzed the metabolic reaction of [1-13C]pyruvate to [1-13C]lactate in a prostate carcinoma cell line, PC3, in vitro using 13CMRSI.


Doses from radon and its decay products to children.
This paper considers doses from radon and decay products when inhaled or ingested by one year old infants and by ten year old children. Doses from decay products deposited on skin are also discussed. For inhalation and ingestion, the general pattern of doses to organs is broadly similar to that in adults. Much the largest doses are received by the organ of intake (respiratory tract and stomach respectively). Otherwise, tissues with higher fat content tend to receive somewhat higher doses from radon gas than other tissues. Dose coefficients (dose per unit intake factors) for children are generally larger than those for adults. However, total annual doses are more similar across the age groups because of smaller intakes of air and water by children. Radon decay products deposited on skin may be able to induce skin cancer. However, the location of the sensitive cells is not known with certainty and they may lie too deep to receive significant dose. If they are irradiated, it is likely that doses to children would be larger than for adults. The radiological significance of doses to children is discussed.


Efficacy of kava extract for treating anxiety: systematic review and meta-analysis.
Synthetic anxiolytic drugs are effective for treating anxiety, but they are burdened with adverse effects. Constraints on resources and time often render therapies such as psychologic interventions impracticable. Thus, an effective oral medication with few adverse effects would be a welcome addition to the therapeutic repertoire. This systematic review and meta-analysis was aimed at assessing the evidence for or against the efficacy of kava extract as a symptomatic treatment for anxiety. Systematic literature searches were performed in the computerized databases MEDLINE, EMBASE, BIOSIS, AMED, CISCOM, and the Cochrane Library (all from their respective inception to June 1998). The search terms used were kava, kawa, kavain, Piper methysticum, and Rauschpfeffer (German term for Piper methysticum). Experts on the subject were contacted to provide further information. There were no restrictions regarding the language of publication. Double-blind, randomized, placebo-controlled trials of oral kava extract for the treatment of anxiety were included. All publications were blinded before assessment by a person not involved in the study. Data were extracted in a standardized, predefined fashion independently by the two reviewers. The methodologic quality of all trials was assessed. Superiority of kava extract over placebo was suggested by all seven reviewed trials. The meta-analysis of three trials suggests a significant difference in the reduction of the total score on the Hamilton Rating Scale for Anxiety in favor of kava extract (weighted mean difference, 9.69; 95% confidence interval, 3.54-15.83). These data imply that kava extract is superior to placebo as a symptomatic treatment for anxiety. Therefore, kava extract is an herbal treatment option for anxiety that is worthy of consideration.


The nature of the silicaphilic fluorescence of PDMPO.
PDMPO (2-(4-pyridyl)-5-((4-(2-dimethylaminoethylaminocarbamoyl)methoxy)phenyl)oxazole), has unique silica specific fluorescence and is used in biology to understand biosilicification. This 'silicaphilic' fluorescence is not well understood nor is the response to local environmental variables like solvent and pH. We investigated PDMPO in a range of environments: using UV-vis and fluorescence spectroscopy supported by computational data, (SPARC, molecular dynamics simulations, density functional theory calculations), dynamic light scattering and zeta potential measurements to understand the PDMPO-silica interaction. From absorption data, PDMPO exhibited a pKa of 4.20 for PDMPOH2(2+) to PDMPOH(+). Fluorescence emission measurements revealed large shifts in excited state pKa* values with different behaviour when bound to silica (pKa* of 10.4). PDMPO bound to silica particles is located in the Stern layer with the dye exhibiting pH dependent depolarising motion. In aqueous solution, PDMPO showed strong chromaticity with correlation between the maximum emission wavelength for PDMPOH(+)* and dielectric constant (4.8-80). Additional chromatic effects were attributed to changes in solvent accessible surface area. Chromatic effects were also observed for silica bound dye which allow its use as a direct probe of bulk pH over a range far in excess of what is possible for the dye alone (3-5.2). The unique combination of chromaticity and excited state dynamics allows PDMPO to monitor pH from 3 to 13 while also reporting on surface environment opening a new frontier in the quantitative understanding of (bio)silicification.


Increased RhoA/Rho-kinase signaling mediates spontaneous tone in aorta from angiotensin II-induced hypertensive rats.
Spontaneous tone in large arteries may contribute to the pathogenesis of hypertension. Reactive oxygen species and Ca2+ influx have been shown to stimulate the development of spontaneous tone in isolated aortic rings in several models of hypertensive rats. The aim of this study was to investigate the role of the RhoA/Rho-kinase signaling pathway in the development of spontaneous tone in angiotensin II-induced hypertension and to explore the underlying mechanisms of RhoA/Rho-kinase activation. Our results showed that spontaneous tone was greatly enhanced in endothelium-denuded aortic rings from angiotensin II-induced hypertensive rats compared with their normotensive counterparts (73+/-5 versus 7+/-3% of phenylephrine-induced maximal contraction, respectively). The Rho-kinase inhibitor (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide (Y-27632) (0.1-10 microM) concentration dependently inhibited spontaneous tone in aortic rings from angiotensin II-treated rats. NADPH oxidase inhibitors diphenylene iodonium and apocynin also significantly reduced spontaneous tone. Chronic angiotensin II treatment markedly increased RhoA protein expression (57%) but had no effect on Rho guanine nucleotide exchange factor mRNA or Rho-kinase protein expression levels. In endothelium-denuded rings from normotensive rats, angiotensin II (100 nM) increased RhoA membrane translocation and phosphorylation of the myosin light chain phosphatase target subunit, which were both blocked by the NADPH oxidase inhibitor diphenylene iodonium (10 microM). In conclusion, these data suggest that chronic treatment with angiotensin II leads to up-regulation of the RhoA/Rho-kinase pathway, contributing to spontaneous tone development in rat aorta. Increased NADPH oxidase-dependent reactive oxygen species may be one of the mechanisms mediating the RhoA/Rho-kinase activation.


Curcumin-loaded magnetic nanoparticles for breast cancer therapeutics and imaging applications.
The next generation magnetic nanoparticles (MNPs) with theranostic applications have attracted significant attention and will greatly improve nanomedicine in cancer therapeutics. Such novel MNP formulations must have ultra-low particle size, high inherent magnetic properties, effective imaging, drug targeting, and drug delivery properties. To achieve these characteristic properties, a curcumin-loaded MNP (MNP-CUR) formulation was developed. MNPs were prepared by chemical precipitation method and loaded with curcumin (CUR) using diffusion method. The physicochemical properties of MNP-CUR were characterized using dynamic light scattering, transmission electron microscopy, and spectroscopy. The internalization of MNP-CUR was achieved after 6 hours incubation with MDA-MB-231 breast cancer cells. The anticancer potential was evaluated by a tetrazolium-based dye and colony formation assays. Further, to prove MNP-CUR results in superior therapeutic effects over CUR, the mitochondrial membrane potential integrity and reactive oxygen species generation were determined. Magnetic resonance imaging capability and magnetic targeting property were also evaluated. MNP-CUR exhibited individual particle grain size of ~9 nm and hydrodynamic average aggregative particle size of ~123 nm. Internalized MNP-CUR showed a preferential uptake in MDA-MB-231 cells in a concentration-dependent manner and demonstrated accumulation throughout the cell, which indicates that particles are not attached on the cell surface but internalized through endocytosis. MNP-CUR displayed strong anticancer properties compared to free CUR. MNP-CUR also amplified loss of potential integrity and generation of reactive oxygen species upon treatment compared to free CUR. Furthermore, MNP-CUR exhibited superior magnetic resonance imaging characteristics and significantly increased the targeting capability of CUR. MNP-CUR exhibits potent anticancer activity along with imaging and magnetic targeting capabilities. This approach can be extended to preclinical and clinical use and may have importance in cancer treatment and cancer imaging in the future. Further, if these nanoparticles can functionalize with antibody/ligands, they will serve as novel platforms for multiple biomedical applications.


Risk factor analysis of 170 single-institutional contegra implantations in pulmonary position.
The aim of this study is to evaluate risk factors affecting survival of Contegra grafts used in the pulmonary position. One hundred seventy Contegra implanted (2001 to 2007) in the pulmonary position for replacement after a prior repair (90), Ross procedure (29), tetralogy of Fallot and variants (22), truncus arteriosus (13), Rastelli procedure (8), and miscellaneous (8) were reviewed. Median age was 107 (0.1 to 894) months. Follow-up was 96% complete with a median duration of 65 (7 to 98) months. There were 7 early and 6 late deaths (none Contegra related) with a survival of 92%±2% at 98 months. Thirty-four Contegra were replaced at a median duration of 43 (7 to 82) months. Eight of 28 balloon-dilated Contegra remain palliated at 49 (23 to 73) months. Multivariate analysis showed Contegra less than 16 mm (p<0.001; HR [hazard ratio] 0.07), high pulmonary pressure (p<0.001; HR 4), and prior operation era (p=0.006; HR 0.3) as independent risk factors for Contegra replacement. The freedom from replacement for Contegra less than 16 mm and 16 mm or greater were 48%±8% and 98%±2%; for presence and absence of high pulmonary pressure were 52%±11% and 88%±3% and for era 1 and 2 were 77%±5% and 88%±4% at 60 months, respectively. Twenty-three of 123 surviving Contegra have a mean Doppler gradient greater than 20 mm Hg. Contegra less than 16 mm, smaller age group, obstructive arborization, and era 1 were significantly associated with higher gradients. While 18 (15%) surviving Contegra have moderate or more regurgitation, 88 (72%) have no significant gradient or regurgitation. Contegra grafts integrate well into the body. Larger Contegra show predictable function with a survival approaching homografts over medium term. Better case selection as one ascends the learning curve tends to improve survival. With easy availability and predictable quality, Contegra grafts continue to be a promising complement to homografts.


Effects of triiodothyronine and vasopressin on cardiac function and myocardial blood flow after brain death.
Previous studies have documented decreases in serum-free triiodothyronine (T3) after brain death and improved hemodynamics with its replacement, suggesting its controversial, but promising, clinical utility for managing potential organ donors. Vasopressin is also commonly used clinically as a pressor agent after brain death. A load-independent analysis of cardiac function and an assessment of myocardial blood flow (MBF) with these agents have not been reported, however. Eighteen pigs were instrumented with left ventricular epicardial dimension transducers and a left ventricular micromanometer. MBF was assessed by standard microsphere techniques. Baseline left ventricular pressure-dimension data were collected, and brain death was induced by ligating the innominate and left subclavian arteries. Left ventricular function data were collected every 30 minutes after brain death to 6 hours or until the animal died. Microsphere injections were performed before brain death and hourly thereafter to 4 hours. At 90 minutes after brain death, animals were assigned to a vasopressin (2 units/hr, intravenously, n = 6), T3 (0.05 microgram/kg/hr, intravenously, n = 6), or control (n = 6) treatment group. Preload recruitable stroke work (PRSW), a load-independent index of left ventricular function, was derived from the pressure-dimension data. MBF was calculated by conventional methods. At 4 hours after brain death, PRSW and MBF decreased significantly in the control, vasopressin, and T3 groups relative to the baseline, pre-brain dead state (PRSW: -36% +/- 12%, -48 +/- 7%, -52% +/- 5%; MBF: -27% +/- 15%, -38% +/- 5%, -78% +/- 2%, respectively). Neither vasopressin nor T3, however, showed any advantage over the control group in terms of preserving left ventricular function or prolonging survival. Furthermore, these data show a marked decrease in MBF in the T3 group (p < 0.01 versus control and vasopressin groups) without a significant change in cardiac function. Analysis of endocardial to epicardial flow ratios disclosed no significant differences between groups at any time. In summary, animals treated with T3 had a greater decline in MBF than the control group at 4 hours, without any benefit to cardiac function. Further studies examining the mechanism responsible for the deterioration of MBF and cardiac dysfunction will be necessary to optimally manage the brain dead patient before organ harvest, especially regarding the precise role of T3.


Development of an enzyme immunoassay for detection of antibodies against Coccidioides in dogs and other mammalian species.
Coccidioides is a soil-dwelling fungus that causes coccidioidomycosis, a disease also known as Valley fever, which affects humans and a variety of animal species. Recent findings of Coccidioides in new, unexpected areas of the United States have demonstrated the need for a better understanding of its geographic distribution. Large serological studies on animals could provide important information on the geographic distribution of this pathogen. To facilitate such studies, we used protein A/G, a recombinant protein that binds IgG antibodies from a variety of mammalian species, to develop an enzyme immunoassay (EIA) that detects IgG antibodies against Coccidioides in a highly sensitive and high-throughput manner. We showed the potential of this assay to be adapted to multiple animal species by testing a collection of serum and/or plasma samples from dogs, mice, and humans with or without confirmed coccidioidomycosis. We then evaluated the performance of the assay in dogs, using sera from dogs residing in a highly endemic area, and found seropositivity rates significantly higher than those in dogs of non-endemic areas. We further evaluated the specificity of the assay in dogs infected with other fungal pathogens known to cross-react with Coccidioides. Finally, we used the assay to perform a cross-sectional serosurvey investigating dogs from Washington, a state in which infection with Coccidioides has recently been documented. In summary, we have developed a Coccidioides EIA for the detection of antibodies in canines that is more sensitive and has higher throughput than currently available methods, and by testing this assay in mice and humans, we have shown a proof of principle of its adaptability for other animal species.


Inflammatory signalings involved in airway and pulmonary diseases.
In respiratory diseases, there is an increased expression of multiple inflammatory proteins in the respiratory tract, including cytokines, chemokines, and adhesion molecules. Chemokines have been shown to regulate inflammation and immune cell differentiation. Moreover, many of the known inflammatory target proteins, such as matrix metalloproteinase-9 (MMP-9), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), cyclooxygenase-2 (COX-2), and cytosolic phospholipase A2 (cPLA2), are associated with airway and lung inflammation in response to various stimuli. Injuriously environmental stimuli can access the lung through either the airways or the pulmonary and systemic circulations. The time course and intensity of responses by resident and circulating cells may be regulated by various inflammatory signalings, including Src family kinases (SFKs), protein kinase C (PKC), growth factor tyrosine kinase receptors, nicotinamide adenine dinucleotide phosphate (NADPH)/reactive oxygen species (ROS), PI3K/Akt, MAPKs, nuclear factor-kappa B (NF-κB), activator protein-1 (AP-1), and other signaling molecules. These signaling molecules regulate both key inflammatory signaling transduction pathways and target proteins involved in airway and lung inflammation. Here, we discuss the mechanisms involved in the expression of inflammatory target proteins associated with the respiratory diseases. Knowledge of the mechanisms of inflammation regulation could lead to the pharmacological manipulation of anti-inflammatory drugs in the respiratory diseases.


Quadrant detector calibration for vortex beams.
This Letter reports an experimental and theoretical study of the response of a quadrant detector (QD) to an incident vortex beam, specifically a Laguerre-Gaussian (LG) beam. We have found that the LG beam response depends on the vorticity index ℓ. We compare LG beams with hard-ringed beams and find that at higher ℓ values, the QD response to LG beams can be approximated by its response to hard-ringed beams. Our findings are important in view of the increasing interest in optical vortex beams.


In vivo photoacoustic micro-imaging of microvascular changes for Achilles tendon injury on a mouse model.
Since neovascularization has been reported that it is associated with tendinopathy, assessments of vascularity are important for both diagnosis and treatment estimation. Photoacoustic imaging, taking the advantages of good ultrasonic resolution and high optical absorption contrast, has been shown a promising tool for vascular imaging. In this study, we explore the feasibility of photoacoustic micro-imaging in noninvasive monitoring of microvascular changes in Achilles tendon injuries on a mouse model in vivo. During collagenase-induced tendinitis, a 25-MHz photoacoustic microscope was used to image microvascular changes in Achilles tendons of mice longitudinally up to 23 days. In addition, complementary tissue structural information was revealed by collateral 25-MHz ultrasound microscopy. Morphological changes and proliferation of new blood vessels in Achilles tendons were observed during and after the acute inflammation. Observed microvascular changes during tendinitis were similar to the findings in the literatures. This study demonstrates that photoacoustic imaging can potentially be a complementary tool for high sensitive diagnosis and assessment of treatment performance in tendinopathy.


The endo-beta-1,4-xylanase xyn11A is required for virulence in Botrytis cinerea.
Phytopathogenic fungi can degrade xylan, an abundant hemicellulose in plant cell walls, by the coordinate action of a group of extracellular enzymes. Among these, endo-beta-1,4-xylanases carry out the initial breakdown by cleaving internal bonds in the polymer backbone. We have isolated and characterized a gene, xyn11A, coding for an endo-beta-1,4-xylanase belonging to family 11 of glycosyl hydrolases. xyn11A was shown to be induced by xylan and repressed by glucose and to be expressed in planta. The disruption of xyn11A caused only a moderate decrease, about 30%, in the level of extracellular endo-beta-1-4-xylanase activity and in the growth rate, with beechwood xylan as the only carbon source. However, deletion of the gene had a more pronounced effect on virulence, delaying the appearance of secondary lesions and reducing the average lesion size by more than 70%. Reintroducing the wild-type gene into the mutant strains reversed this phenotype back to wild type.


ADHD prevalence and association with hoarding behaviors in childhood-onset OCD.
It has been suggested that attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD), both neurodevelopmental disorders with onset in childhood, are highly comorbid, but previous studies examining ADHD and OCD comorbidity have been quite variable, partly because of inconsistency in excluding individuals with tic disorders. Similarly, ADHD has been postulated to be associated with hoarding although this potential relationship is largely methodologically unexplored. This study aimed to examine the prevalence of ADHD among individuals with childhood-onset OCD but without comorbid tic disorders, as well as to examine the relationship between clinically significant hoarding behaviors (hoarding) and ADHD. ADHD prevalence rates and the relationship between ADHD and hoarding were examined in 155 OCD-affected individuals (114 probands and 41 relatives, age range 4-82 years) recruited for genetic studies and compared to pooled prevalence rates derived from previously published studies. In total, 11.8% met criteria for definite ADHD, whereas an additional 8.6% had probable or definite ADHD (total=20.4%). In total, 41.9% of participants with ADHD also had hoarding compared to 29.2% of participants without ADHD. Hoarding was the only demographic or clinical variable independently associated with ADHD (odds ratio=9.54, P<0.0001). ADHD rates were elevated in this sample of individuals with childhood-onset OCD compared to the general population rate of ADHD, and there was a strong association between ADHD and clinically significant hoarding behavior. This association is consistent with recent studies suggesting that individuals with hoarding may exhibit substantial executive functioning impairments and/or abnormalities, including attentional problems.


HIV disclosure to partners and family among women enrolled in prevention of mother to child transmission of HIV program: implications for infant feeding in poor resourced communities in South Africa.
The introduction of routine HIV counselling and testing (HCT) has increased the number of pregnant women being tested and receiving prevention of mother to child transmission of HIV (PMTCT) interventions in South Africa. While many women may enroll in PMTCT, there are barriers that hinder the success of PMTCT programmes. The success of the PMTCT is dependent on the optimal utilization of PMTCT interventions which require the support of the woman's partner, and other members of her family. We conducted focus groups interviews with 25 HIV-positive post-natal women enrolled in PMTCT, in the City of Tshwane, South Africa. The study explored HIV-positive status disclosure to partners and significant family members and assessed the effect of nondisclosure on exclusive infant feeding. Most women disclosed to partners while few disclosed to significant family members. Most women initiated mixed feeding practices as early as one month and reported that they were pressurized by the family to mix feed. Mixed feeding was common among women who had not disclosed their HIV-positive status to families, and women who had limited understanding of mother to child transmission of HIV. Women who disclosed to partners and family were supported to adhere to the feeding option of choice. Health providers have a critical role to play in developing interventions to support HIV pregnant women to disclose in order to avoid mixed feeding. Improving the quality of information provided to HIV-positive pregnant women during counselling will also reduce mixed feeding.


Neuroimaging Findings on Amodal Completion: A Review.
Amodal completion is the phenomenon of perceiving completed objects even though physically they are partially occluded. In this review, we provide an extensive overview of the results obtained from a variety of neuroimaging studies on the neural correlates of amodal completion. We discuss whether low-level and high-level cortical areas are implicated in amodal completion; provide an overview of how amodal completion unfolds over time while dissociating feedforward, recurrent, and feedback processes; and discuss how amodal completion is represented at the neuronal level. The involvement of low-level visual areas such as V1 and V2 is not yet clear, while several high-level structures such as the lateral occipital complex and fusiform face area seem invariant to occlusion of objects and faces, respectively, and several motor areas seem to code for object permanence. The variety of results on the timing of amodal completion hints to a mixture of feedforward, recurrent, and feedback processes. We discuss whether the invisible parts of the occluded object are represented as if they were visible, contrary to a high-level representation. While plenty of questions on amodal completion remain, this review presents an overview of the neuroimaging findings reported to date, summarizes several insights from computational models, and connects research of other perceptual completion processes such as modal completion. In all, it is suggested that amodal completion is the solution to deal with various types of incomplete retinal information, and highly depends on stimulus complexity and saliency, and therefore also give rise to a variety of observed neural patterns.


Propionibacterium acnes: from commensal to opportunistic biofilm-associated implant pathogen.
Propionibacterium acnes is known primarily as a skin commensal. However, it can present as an opportunistic pathogen via bacterial seeding to cause invasive infections such as implant-associated infections. These infections have gained more attention due to improved diagnostic procedures, such as sonication of explanted foreign materials and prolonged cultivation time of up to 14 days for periprosthetic biopsy specimens, and improved molecular methods, such as broad-range 16S rRNA gene PCR. Implant-associated infections caused by P. acnes are most often described for shoulder prosthetic joint infections as well as cerebrovascular shunt infections, fibrosis of breast implants, and infections of cardiovascular devices. P. acnes causes disease through a number of virulence factors, such as biofilm formation. P. acnes is highly susceptible to a wide range of antibiotics, including beta-lactams, quinolones, clindamycin, and rifampin, although resistance to clindamycin is increasing. Treatment requires a combination of surgery and a prolonged antibiotic treatment regimen to successfully eliminate the remaining bacteria. Most authors suggest a course of 3 to 6 months of antibiotic treatment, including 2 to 6 weeks of intravenous treatment with a beta-lactam. While recently reported data showed a good efficacy of rifampin against P. acnes biofilms, prospective, randomized, controlled studies are needed to confirm evidence for combination treatment with rifampin, as has been performed for staphylococcal implant-associated infections.


Sporadic enteric reactive arthritis and undifferentiated spondyloarthropathy: evidence for involvement of Salmonella typhimurium.
To define the candidate bacterial trigger and cytokine profile of synovial fluid mononuclear cells (SFMC) in patients with sporadic enteric reactive arthritis (ReA) and undifferentiated spondyloarthropathy (uSpA). The study group comprised 10 patients with ReA and 23 with uSpA who fulfilled European Spondylarthropathy Study Group criteria. Ten patients with rheumatoid arthritis (RA) served as disease controls. IgG, IgA, and IgM antibodies to Shigella flexneri, Salmonella typhimurium, and Yersinia enterocolitica were measured in sera and SF by ELISA. Peripheral blood mononuclear cell (PBMC) and SFMC proliferation assays were done in the presence or absence of crude bacterial lysates. Bacterial antigens and DNA in synovial cells were detected by indirect immunofluorescence and polymerase chain reaction, respectively. Interferon-g (IFN-g), interleukin 10 (IL-10), and IL-4 were measured in 18 h SFMC culture supernatants in presence of bacterial lysate. Antibodies to S. typhimurium were significantly elevated in the sera of 8 of 25 patients compared to controls (0/22; p < 0.05). The ratio of SF:serum anti-salmonella IgA was significantly higher in patients compared to controls (p < 0.0002). The ratio of SF:serum IgA antibodies to S. typhimurium was higher than that for S. flexneri (p < 0.007) and Y. enterocolitica (p < 0.05). Out of 25 patients, 8, 2, and none had elevated antigen-specific SFMC proliferation response to S. typhimurium, S. flexneri, and Y. enterocolitica, respectively, whereas no control had elevated response. Salmonella antigens were detected in the synovial cells of 4 out of 14 patients. There was significantly higher IFN-g production from SFMC of patients who had increased proliferative response to Salmonella (LTT+) in the presence of Salmonella antigens compared to antigen control. The mean +/- SD of the ratio of IFN-g:IL-10 in the LTT+ patients was significantly lower compared to controls. Conclusion. S. typhimurium is probably one of the triggers for enteric ReA and uSpA in our cohort of patients, and the immune response is characterized by increased production of both IL-10 and IFN-g.


Review of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: an evidence-based approach to diagnosis and management by clinicians.
This review was written from the viewpoint of the treating clinician to educate health care professionals and the public about Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). It includes: the clinical definition of ME/CFS with emphasis on how to diagnose ME/CFS; the etiology, pathophysiology, management approach, long-term prognosis and economic cost of ME/CFS. After reading this review, you will be better able to diagnose and treat your patients with ME/CFS using the tools and information provided. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, chronic medical condition characterized by symptom clusters that include: pathological fatigue and malaise that is worse after exertion, cognitive dysfunction, immune dysfunction, unrefreshing sleep, pain, autonomic dysfunction, neuroendocrine and immune symptoms. ME/CFS is common, often severely disabling and costly. The Institute of Medicine (IOM) reviewed the ME/CFS literature and estimates that between 836,000 and 2.5 million Americans have ME/CFS at a cost of between 17 and 24 billion dollars annually in the US. The IOM suggested a new name for ME/CFS and called it Systemic Exertion Intolerance Disease (SEID). SEID's diagnostic criteria are less specific and do not exclude psychiatric disorders in the criteria. The 2010 Canadian Community Health Survey discovered that 29% of patients with ME/CFS had unmet health care needs and 20% had food insecurity--lack of access to sufficient healthy foods. ME/CFS can be severely disabling and cause patients to be bedridden. Yet most patients (80%) struggle to get a diagnosis because doctors have not been taught how to diagnose or treat ME/CFS in medical schools or in their post-graduate educational training. Consequently, the patients with ME/CFS suffer. They are not diagnosed with ME/CFS and are not treated accordingly. Instead of compassionate care from their doctors, they are often ridiculed by the very people from whom they seek help. The precise etiology of ME/CFS remains unknown, but recent advances and research discoveries are beginning to shed light on the enigma of this disease including the following contributors: infectious, genetic, immune, cognitive including sleep, metabolic and biochemical abnormalities. Management of patients with ME/CFS is supportive symptomatic treatment with a patient centered care approach that begins with the symptoms that are most troublesome for the patient. Pacing of activities with strategic rest periods is, in our opinion, the most important coping strategy patients can learn to better manage their illness and stop their post-exertional fatigue and malaise. Pacing allows patients to regain the ability to plan activities and begin to make slow incremental improvements in functionality.


Simultaneous regeneration of two 160 Gbit/s WDM channels in a single highly nonlinear fiber.
We experimentally demonstrate simultaneous all-optical regeneration of two 160-Gbit/s wavelength-division multiplexed (WDM) channels in a single highly nonlinear fiber (HNLF). The multi-channel regeneration performance is confirmed by bit-error rate (BER) measurements. The receiver powers at a BER of 10(-9) are improved by about 4.9 dB and 2.1 dB for the two channels, respectively. The BER performance is not degraded by the presence of a second channel. Mitigation of the inter-channel nonlinearities is achieved through bidirectional propagation.


Linear noise approximation for oscillations in a stochastic inhibitory network with delay.
Understanding neural variability is currently one of the biggest challenges in neuroscience. Using theory and computational modeling, we study the behavior of a globally coupled inhibitory neural network, in which each neuron follows a purely stochastic two-state spiking process. We investigate the role of both this intrinsic randomness and the conduction delay on the emergence of fast (e.g., gamma) oscillations. Toward that end, we expand the recently proposed linear noise approximation (LNA) technique to this non-Markovian "delay" case. The analysis first leads to a nonlinear delay-differential equation (DDE) with multiplicative noise for the mean activity. The LNA then yields two coupled DDEs, one of which is driven by additive Gaussian white noise. These equations on their own provide an excellent approximation to the full network dynamics, which are much longer to integrate. They further allow us to compute a theoretical expression for the power spectrum of the population activity. Our analytical result is in good agreement with the power spectrum obtained via numerical simulations of the full network dynamics, for the large range of parameters where both the intrinsic stochasticity and the conduction delay are necessary for the occurrence of oscillations. The intrinsic noise arises from the probabilistic description of each neuron, yet it is expressed at the system activity level, and it can only be controlled by the system size. In fact, its effect on the fluctuations in system activity disappears in the infinite network size limit, but the characteristics of the oscillatory activity depend on all model parameters including the system size. Using the Hilbert transform, we further show that the intrinsic noise causes sporadic strong fluctuations in the phase of the gamma rhythm.


Chronic health conditions in adult survivors of childhood cancer.
Only a few small studies have assessed the long-term morbidity that follows the treatment of childhood cancer. We determined the incidence and severity of chronic health conditions in adult survivors. The Childhood Cancer Survivor Study is a retrospective cohort study that tracks the health status of adults who received a diagnosis of childhood cancer between 1970 and 1986 and compares the results with those of siblings. We calculated the frequencies of chronic conditions in 10,397 survivors and 3034 siblings. A severity score (grades 1 through 4, ranging from mild to life-threatening or disabling) was assigned to each condition. Cox proportional-hazards models were used to estimate hazard ratios, reported as relative risks and 95% confidence intervals (CIs), for a chronic condition. Survivors and siblings had mean ages of 26.6 years (range, 18.0 to 48.0) and 29.2 years (range, 18.0 to 56.0), respectively, at the time of the study. Among 10,397 survivors, 62.3% had at least one chronic condition; 27.5% had a severe or life-threatening condition (grade 3 or 4). The adjusted relative risk of a chronic condition in a survivor, as compared with siblings, was 3.3 (95% CI, 3.0 to 3.5); for a severe or life-threatening condition, the risk was 8.2 (95% CI, 6.9 to 9.7). Among survivors, the cumulative incidence of a chronic health condition reached 73.4% (95% CI, 69.0 to 77.9) 30 years after the cancer diagnosis, with a cumulative incidence of 42.4% (95% CI, 33.7 to 51.2) for severe, disabling, or life-threatening conditions or death due to a chronic condition. Survivors of childhood cancer have a high rate of illness owing to chronic health conditions.


Transcriptomic and phenotypic analysis of murine embryonic stem cell derived BMP2+ lineage cells: an insight into mesodermal patterning.
Bone morphogenetic protein (BMP)2 is a late mesodermal marker expressed during vertebrate development and plays a crucial role in early embryonic development. The nature of the BMP2-expressing cells during the early stages of embryonic development, their transcriptome and cell phenotypes developed from these cells have not yet been characterized. We generated a transgenic BMP2 embryonic stem (ES) cell lineage expressing both puromycin acetyltransferase and enhanced green fluorescent protein (EGFP) driven by the BMP2 promoter. Puromycin resistant and EGFP positive BMP2+ cells with a purity of over 93% were isolated. Complete transcriptome analysis of BMP2+ cells in comparison to the undifferentiated ES cells and the control population from seven-day-old embryoid bodies (EBs; intersection of genes differentially expressed between undifferentiated ES cells and BMP2+ EBs as well as differentially expressed between seven-day-old control EBs and BMP2+ EBs by t-test, p < 0.01, fold change >2) by microarray analysis led to identification of 479 specifically upregulated and 193 downregulated transcripts. Transcription factors, apoptosis promoting factors and other signaling molecules involved in early embryonic development are mainly upregulated in BMP2+ cells. Long-term differentiation of the BMP2+ cells resulted in neural crest stem cells (NCSCs), smooth muscle cells, epithelial-like cells, neuronal-like cells, osteoblasts and monocytes. Interestingly, development of cardiomyocytes from the BMP2+ cells requires secondary EB formation. This is the first study to identify the complete transcriptome of BMP2+ cells and cell phenotypes from a mesodermal origin, thus offering an insight into the role of BMP2+ cells during embryonic developmental processes in vivo.


Bi-frequency symmetry difference electrical impedance tomography-a novel technique for perturbation detection in static scenes.
A novel method for the imaging of static scenes using electrical impedance tomography (EIT) is reported with implementation and validation using numerical and phantom models. The technique is applicable to regions featuring symmetry in the normal case, asymmetry in the presence of a perturbation, and where there is a known, frequency-dependent change in the electrical conductivity of the materials in the region. The stroke diagnostic problem is used as a motivating sample application. The head is largely symmetrical across the sagittal plane. A haemorrhagic or ischaemic lesion located away from the sagittal plane will alter this natural symmetry, resulting in a symmetrical imbalance that can be detected using EIT. Specifically, application of EIT stimulation and measurement protocols at two distinct frequencies detects deviations in symmetry if an asymmetrically positioned lesion is present, with subsequent identification and localisation of the perturbation based on known frequency-dependent conductivity changes. Anatomically accurate computational models are used to demonstrate the feasibility of the proposed technique using different types, sizes, and locations of lesions with frequency-dependent (or independent) conductivity. Further, a realistic experimental head phantom is used to validate the technique using frequency-dependent perturbations emulating the key numerical simulations. Lesion presence, type, and location are detectable using this novel technique. Results are presented in the form of images and corresponding robust quantitative metrics. Better detection is achieved for larger lesions, those further from the sagittal plane, and when measurements have a higher signal-to-noise ratio. Bi-frequency symmetry difference EIT is an exciting new modality of EIT with the ability to detect deviations in the symmetry of a region that occur due to the presence of a lesion. Notably, this modality does not require a time change in the region and thus may be used in static scenarios such as stroke detection.


Hippocampal Contribution to Ordinal Psychological Time in the Human Brain.
The chronology of events in time-space is naturally available to the senses, and the spatial and temporal dimensions of events entangle in episodic memory when navigating the real world. The mapping of time-space during navigation in both animals and humans implicates the hippocampal formation. Yet, one arguably unique human trait is the capacity to imagine mental chronologies that have not been experienced but may involve real events-the foundation of causal reasoning. Herein, we asked whether the hippocampal formation is involved in mental navigation in time (and space), which requires internal manipulations of events in time and space from an egocentric perspective. To address this question, we reanalyzed a magnetoencephalography data set collected while participants self-projected in time or in space and ordered historical events as occurring before/after or west/east of the mental self [Gauthier, B., Pestke, K., & van Wassenhove, V. Building the arrow of time… Over time: A sequence of brain activity mapping imagined events in time and space. Cerebral Cortex, 29, 4398-4414, 2019]. Because of the limitations of source reconstruction algorithms in the previous study, the implication of hippocampus proper could not be explored. Here, we used a source reconstruction method accounting explicitly for the hippocampal volume to characterize the involvement of deep structures belonging to the hippocampal formation (bilateral hippocampi [hippocampi proper], entorhinal cortices, and parahippocampal cortex). We found selective involvement of the medial temporal lobes (MTLs) with a notable lateralization of the main effects: Whereas temporal ordinality engaged mostly the left MTL, spatial ordinality engaged mostly the right MTL. We discuss the possibility of a top-down control of activity in the human hippocampal formation during mental time (and space) travels.


Transcription-induced DNA double strand breaks: both oncogenic force and potential therapeutic target?
An emerging model of transcriptional activation suggests that induction of transcriptional programs, for instance by stimulating prostate or breast cells with androgens or estrogens, respectively, involves the formation of DNA damage, including DNA double strand breaks (DSB), recruitment of DSB repair proteins, and movement of newly activated genes to transcription hubs. The DSB can be mediated by the class II topoisomerase TOP2B, which is recruited with the androgen receptor and estrogen receptor to regulatory sites on target genes and is apparently required for efficient transcriptional activation of these genes. These DSBs are recognized by the DNA repair machinery triggering the recruitment of repair proteins such as poly(ADP-ribose) polymerase 1 (PARP1), ATM, and DNA-dependent protein kinase (DNA-PK). If illegitimately repaired, such DSBs can seed the formation of genomic rearrangements like the TMPRSS2-ERG fusion oncogene in prostate cancer. Here, we hypothesize that these transcription-induced, TOP2B-mediated DSBs can also be exploited therapeutically and propose that, in hormone-dependent tumors like breast and prostate cancers, a hormone-cycling therapy, in combination with topoisomerase II poisons or inhibitors of the DNA repair components PARP1 and DNA-PK, could overwhelm cancer cells with transcription-associated DSBs. Such strategies may find particular utility in cancers, like prostate cancer, which show low proliferation rates, in which other chemotherapeutic strategies that target rapidly proliferating cells have had limited success.


The Trigger Tool as a Method to Measure Harmful Medication Errors in Children.
The aim of this study was to improve medication safety for children; it is important to quantify the occurrence of preventable medication errors (MEs). A trigger tool may be an effective and time-saving strategy, but its measurement performance is unclear. Therefore, we aimed to estimate the performance of a pediatric medication-focused trigger tool in detecting harmful MEs. First, we established a multifaceted method as a reference comparison. Second, we compared the pediatric medication-focused trigger tool with the multifaceted method in a new cohort of patients. All patients admitted in February and March 2013 were screened using the trigger tool and the multifaceted method to obtain full verification. Data collection was performed in separate teams to guarantee blinding of the test results. Review of the clinical records and the voluntary incident reports was most effective in detecting harmful MEs, so this approach was chosen as a reference comparison. In the second part of the study, 369 patients were included. The multifaceted method identified 33 harmful MEs. In contrast, the trigger tool did not identify any harm. When the 2 symptoms pain and nausea/vomiting were added to the trigger tool, 19 harmful MEs were identified. This extended trigger tool resulted in a sensitivity of 21.2 and a positive predictive value of 36.8. The original pediatric medication-focused trigger tool yielded only false-positive scores and left unsafe situations undiscovered. We conclude that a multifaceted method remains the preferred method to detect harmful MEs. The additional value of the trigger tool stays unclear.


Humans and mice express similar olfactory preferences.
In humans, the pleasantness of odors is a major contributor to social relationships and food intake. Smells evoke attraction and repulsion responses, reflecting the hedonic value of the odorant. While olfactory preferences are known to be strongly modulated by experience and learning, it has been recently suggested that, in humans, the pleasantness of odors may be partly explained by the physicochemical properties of the odorant molecules themselves. If odor hedonic value is indeed predetermined by odorant structure, then it could be hypothesized that other species will show similar odor preferences to humans. Combining behavioral and psychophysical approaches, we here show that odorants rated as pleasant by humans were also those which, behaviorally, mice investigated longer and human subjects sniffed longer, thereby revealing for the first time a component of olfactory hedonic perception conserved across species. Consistent with this, we further show that odor pleasantness rating in humans and investigation time in mice were both correlated with the physicochemical properties of the molecules, suggesting that olfactory preferences are indeed partly engraved in the physicochemical structure of the odorant. That odor preferences are shared between mammal species and are guided by physicochemical features of odorant stimuli strengthens the view that odor preference is partially predetermined. These findings open up new perspectives for the study of the neural mechanisms of hedonic perception.


Sensitive and specific immunodetection of human glandular kallikrein 2 in serum.
Human glandular kallikrein 2 (hK2) is expressed in the prostate and is present in serum from men with prostate cancer. Specific detection in serum is difficult mainly because of low concentrations and immunological cross-reactivity with prostate-specific antigen (PSA). Our objectives were to design an assay with improved analytical detection and functional sensitivity and nonsignificant cross-reactivity with PSA, and to characterize different immunoreactive forms of hK2. In the assay, critical PSA epitopes were blocked with four monoclonal antibodies (MAbs) specific for PSA. Subsequently, hK2 was captured using a MAb against hK2 (5% cross-reactivity with PSA), and after washing, hK2 was detected by a europium-labeled MAb with identical affinity for hK2 and PSA. The analytical detection limit was <10 ng/L, and functional sensitivity was 30 ng/L. Cross-reaction with PSA was <0.01%. Between-assay imprecision was 3.1% for 1600 ng/L hK2 and 4. 8% for 160 ng/L hK2; corresponding values for within-assay precision were 1.9% and 4.5%, respectively. Complexes of hK2-alpha(1)-antichymotrypsin (ACT) were detected in vitro with -6% bias compared with the free form of hK2. Gel filtration of patient samples showed that hK2 correlated in size mainly with free hK2; only 4-19% corresponded to hK2 possibly complexed with ACT or protein C inhibitor. Our assay had extremely low cross-reactivity with PSA, provided a very low detection limit, and allowed close to equimolar detection of the free and complexed forms of hK2. Moreover, we found that free hK2 is the predominant immunoreactive form of hK2 in serum.


Hypertension and Risk of Post-Operative Cognitive Dysfunction (POCD): A Systematic Review and Meta-Analysis.
Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery. Hypertension is well-established as a risk factor for age-related cognitive impairment, but it is unclear whether or not it also increases the risk of POCD. To evaluate the role of hypertension in POCD risk in a systematic review and meta-analysis. PubMed, Ovid SP and the Cochrane Database of Systematic Reviews were searched for longitudinal studies of adults undergoing surgery with reporting of hypertension, blood pressure and/or anti-hypertensive treatment associations with POCD as relative risks or odds ratios. Fixed-effects meta-analyses were performed using Review Manager (version 5.3). Twenty-four studies on 4317 patients (mean age 63 years) were included. None of the studies had set out to assess hypertension as a risk factor for POCD. Hypertension was used as a categorical predictor throughout and only 2 studies adjusted for potential confounders. Across all 24 studies, hypertension was not significantly associated with POCD risk (RR 1.01; 95% CI 0.93, 1.09; p=0.82), though among 8 studies with >75% males, we found hypertension associations with a 27% increased risk of POCD (RR 1.27, 95% CI 1.07, 1.49; p=0.005). Our findings do not support the hypothesis that hypertension is a risk factor for POCD. However, since none of the studies included in our analysis were hypothesis-driven and most did not adjust for potential confounders, further systematic investigations are needed to evaluate the role of hypertension in the epidemiology of POCD.