The secretion of cytokines by peripheral blood mononuclear cells of patients with periodontitis and healthy controls when exposed to H2S.
Background: Hydrogen sulfide(H2S) is a bacterial metabolite produced as a result of bacterial growth in subgingival pockets, suggested to partake in the pathogenesis of periodontitis. H2S has previously been shown to induce the secretion of the pro-inflammatory cytokines IL-1β and IL-18 via the NLRP3 inflammasome in monocytes. Objective: To investigate the non-NLRP3 inflammasome-dependent immunological response of human peripheral blood mononuclear cells (PBMCs) of periodontitis patients and healthy controls exposed to H2S in vitro. Methods: PBMCs of periodontitis patients(N = 31) and healthy controls(N = 32) were exposed to 1 mM sodium hydrosulfide (NaHS) at 37°C for 24 h and the secretion of cytokines was compared to resting cells. TNF-α, IFN-γ, IL-6, IL-8, IL-12p40, IL-12p70, IL-17, MCP-1, and IL-1Ra secretions were measured with Bio-Plex Pro™ Human Cytokine Assay. Results: H2S triggered the secretion of the pro-inflammatory IFN-γ, IL-6, IL-17, TNF-α, IL-12p40, and IL-12p70, while the reverse was seen for IL-1Ra. In addition, a higher basal secretion of IFN-γ, IL-6, IL-12p70, IL-17 and MCP-1 was seen from PBMCs of periodontitis patients compared to healthy controls. Conclusion: The bacterial metabolite H2S triggers the secretion of pro-inflammatory cytokines from PBMCs and may thus have a prominent role in the host-bacteria interplay in periodontitis.


Environmental change, phenotypic plasticity, and genetic compensation.
When a species encounters novel environmental conditions, some phenotypic characters may develop differently than in the ancestral environment. Most environmental perturbations of development are likely to reduce fitness, and thus selection would usually be expected to favor genetic changes that restore the ancestral phenotype. I propose the term "genetic compensation" to refer to this form of adaptive evolution. Genetic compensation is a subset of genetic accommodation and the reverse of genetic assimilation. When genetic compensation has occurred along a spatial environmental gradient, the mean trait values of populations in different environments may be more similar in the field than when representatives of the same populations are raised in a common environment (i.e., countergradient variation). If compensation is complete, genetic divergence between populations may be cryptic, that is, not detectable in the field. Here I apply the concept of genetic compensation to three examples involving carotenoid-based sexual coloration and then use these and other examples to discuss the concept in a broader context. I show that genetic compensation may lead to a cryptic form of reproductive isolation between populations evolving in different environments, may explain some puzzling cases in which heritable traits exposed to strong directional selection fail to show the expected evolutionary response, and may complicate efforts to monitor populations for signs of environmental deterioration.


From Fragile to Resilient Insulation: Synthesis and Characterization of Aramid-Honeycomb Reinforced Silica Aerogel Composite Materials.
The production of a new composite material embedding aramid honeycomb materials into nano-porous silica aerogels is studied. Our aim is to improve the poor mechanical strength of silica aerogels by aramid honeycombs without losing the amazing properties of the aerogels like little density and low thermal conductivity. The composite materials were prepared using two formulations of silica aerogels in combination with aramid honeycomb materials of different cell sizes. The silica aerogels are prepared using silicon alkoxides methyltrimethoxysilane and tetraethylorthosilicate as precursors in a two-step acid⁻base sol⁻gel process. Shortly in advance of the gelation point, the aramid honeycombs were fluted by the sol, gelation occurred and, after the aging process, the gel bodies were supercritically dried. The properties of the received composite materials are satisfying. Even the thermal conductivities and the densities are a bit higher than for pure aerogels. Most importantly, the mechanical strength is improved by a factor of 2.3 compared to aramid honeycomb materials and by a factor of 10 compared to the two silica aerogels themselves. The composite materials have a good prospective to be used as an impressive insulation material.


[Genic and non-genic regulation of low frequence pulsed electromagnetic fields on osteoblasts differentiation].
Objective: To study the genic and non-genic regulation of 50 Hz 0.6 mT pulsed electromagnenic fields (PEMF) on rat calvarial osteoblasts (ROB) differentiation. Methods: ROBs were achieved by enzyme digestion, and treated with 50 Hz 0.6 mT PEMFs for 1.5 hours after subculture. The alkaline phosphatase (ALP) activity, mRNA transcription of ALP, Runx2 and OSX and protein expression of Runx2 and OSX were detected at 0, 3, 6, 9 and 12 hours after PEMF treatment. Results: The ALP activity at 3 hours after treatment was significantly higher than that in the control(P<0.01), while the mRNA transcription of ALP began to increase at 6 hours after treatment. The mRNA transcription of Runx2 increased immediately after treatment and regressed at 6 hours, then increased again. The protein expression of it corresponded but with a little lag. The mRNA transcription of OSX also raised instantly after treatment, then returned to the level of control at 6 hours, and lower than control at 12 hours significantly. The protein expression of it also corresponded but with a bit delay. Conclusions: There are genic regulation for the protein expression of Runx2 and OSX, and non-genic regulation for the ALP activity on the process of 50 Hz 0.6 mT PEMFs prompts ROBs differentiation.


Agreement of intraocular lens power calculation between 2 SS-OCT-based biometers.
To assess agreement of measurements by 2 swept-source optical coherence tomography biometers and to evaluate the prediction error (PE) in intraocular lens power calculation with 7 formulas. Tertiary public eye hospital. Consecutive observational. Axial length (AL), keratometry (K), anterior chamber depth (ACD), lens thickness (LT), and corneal diameter (CD) were measured with the IOLMaster 700 (Biometer A) and Anterion (Biometer B). Agreement was quantified by the limits of agreement and concordance correlation coefficient (CCC). The PE, the median absolute error, and the mean absolute error of the Barrett Universal II, EVO 2.0, Haigis, Hoffer Q, Holladay 1, Kane, and SRK/T formulas were investigated after constant optimization. In 78 eyes from 78 patients, excellent agreement was obtained for AL (CCC >0.99), very good agreement for K, ACD, and LT (CCC >0.95), and strong agreement for CD (CCC >0.72). An additive offset of 0.07 mm was measured for ACD and LT whose mean values were higher with Biometer B (P < .001). No statistically significant difference was found between the PEs and their absolute values when comparing the results of each formula between the 2 biometers. Agreement of biometric measurements by the 2 biometers was high, although Biometer B provided higher mean values of ACD and LT by 0.07 mm. In cataract patients with normal eye length, measurements by the 2 biometers did not lead to different refractive outcomes with the 7 formulas investigated.


Probability of Soluble Tissue Factor Release Lead to the Elevation of D-dimer as a Biomarker for Traumatic Brain Injury.
d-dimer is a potential biomarker for the detection of traumatic brain injury (TBI). However, the mechanisms that trigger elevation of d-dimer in TBI remain unclear. The purpose of this study was to evaluate the reliability of d-dimer in blood as a biomarker for TBI and to determine the mechanisms involved in regulating its blood levels. Nine patients with moderate to severe isolated TBI (Glasgow Coma Scale [GCS] score 7-13) were admitted to our hospital from May 2013 to June 2014. Blood samples were collected from systemic arteries on arrival and at 1, 3, 5, and 7 days after injury. Blood levels of neuron specific enolase (NSE), d-dimer, and soluble tissue factor (sTF) were measured. NSE (33.4 ng/ml: normal <12.0 ng/ml) and d-dimer (56.1 μg/ml: normal <1.0 μg/ml) were elevated at admission and declined on day 1 after injury. At admission, there were significant correlations of d-dimer levels with NSE (R = 0.727, P = 0.026) and sTF (R = 0.803, P = 0.009) levels. The blood level of d-dimer accurately reflects the degree of brain tissue damage indicated by NSE levels. Our data suggest that release of sTF induced by brain tissue damage may activate the coagulation cascade, leading to elevation of d-dimer.


The water uptake of poly(tetrahydrofurfuryl methacrylate).
Poly(tetrahydrofurfuryl methacrylate) possesses some unique characteristics with respect to its biocompatibility and behaviour in water. The water uptake is high (>70%) and very slow (over 3 yr), but the material remains rigid throughout the process. The mechanism behind the uptake is in two stages; an initial Fickian stage, then as the matrix approaches saturation (about 3 wt%) a second clustering mechanism takes over. The rate of uptake of the second stage of the uptake is controlled by creep (or stress relaxation), and the chemical potential driving the uptake from clustering of the furfuryl rings of the polymer. If clustering or the creep is prevented (by appropriate co-polymerisation) the polymer behaves in an ideal, Fickian manner.


Police involvement and influence in involuntary civil commitment.
Although observers agree that the police play an important role in involuntary civil commitment of mentally ill individuals, there are scant empirical data to document the importance of the police in swaying the commitment decision. The authors studied 3,570 randomly selected case records of individuals referred to two county offices of civil commitment in Washington State to determine the types of referrals police become involved in , the extent to which referral sources request police assistance, and the percentage of referrals resulting in commitment with and without police involvement. The authors conclude that police most often are asked to assist in cases involving violent behavior, but that under almost all circumstances police involvement is the primary factor in determining whether referral will result in commitment.


Accuracy of investigations for asymptomatic colorectal liver metastases.
The aim of this study was to prospectively assess the accuracy of the most promising imaging and tumor marker tests in liver metastasis diagnosis on follow-up of asymptomatic colorectal cancer patients during a median of 57 months after primary tumor resection. One hundred patients, who were considered free of liver metastases after primary colorectal cancer resection and conventional follow-up, were screened for liver metastases by computerized tomography, magnetic resonance and ultrasound scans, ultrasound Doppler and isotope assessment of changes in hepatic arterial and portal venous flow, and serum estimation of carcinoembryonic antigen. Patients were followed up during a median of 41 months to identify those who developed liver metastases. The most sensitive technique was computerized tomography (sensitivity 0.67, specificity 0.91). Computerized tomography and magnetic resonance but not ultrasound were 100 percent accurate in differentiating liver metastases from other hepatic lesions. Techniques based on changes in hepatic arterial and portal venous flow had lower diagnostic accuracies (Doppler perfusion index, sensitivity 0.58, specificity 0.57; hepatic perfusion index, sensitivity 0.50, specificity 0.55), whereas ultrasound scanning identified only 43 percent (sensitivity 0.43, specificity 0.96) and serum carcinoembryonic antigen 33 percent (sensitivity 0.33, specificity 0.81) of patients with asymptomatic liver metastasis. Sensitivity could be improved by using tests in combination but this reduced specificity. Computerized tomography was the most sensitive test for asymptomatic colorectal liver metastases, but only 67 percent of affected patients were identified.


Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells.
Peroxisome proliferator-activated receptor delta (PPARdelta) is a nuclear transcription factor that is recently implicated in tumorigenesis besides lipid metabolism. This study describes the cross-talk between the PPARdelta and prostaglandin (PG) signaling pathways that coordinately regulate human hepatocellular carcinoma (HCC) cell growth. Activation of PPARdelta by its pharmacologic ligand, GW501516, enhanced the growth of three human HCC cell lines (HuH7, HepG2, and Hep3B), whereas inhibition of PPARdelta by small interfering RNA prevented growth. PPARdelta activation up-regulates the expression of cyclooxygenase (COX)-2, a rate-limiting enzyme for PG synthesis, and tumor growth. PPARdelta activation or PGE(2) treatment also induced the phosphorylation of cytosolic phospholipase A(2)alpha (cPLA(2)alpha), a key enzyme that releases arachidonic acid substrate for PG production via COX. Activation of cPLA(2)alpha by the calcium ionophore A23187 enhanced PPARdelta binding to PPARdelta response element (DRE) and increased PPARdelta reporter activity, which was blocked by the selective cPLA(2)alpha inhibitors. Consistent with this, addition of arachidonic acid to isolated nuclear extracts enhanced the binding of PPARdelta to DRE in vitro, suggesting a direct role of arachidonic acid for PPARdelta activation in the nucleus. Thus, PPARdelta induces COX-2 expression and the COX-2-derived PGE(2) further activates PPARdelta via cPLA(2)alpha. Such an interaction forms a novel feed-forward growth-promoting signaling that may play a role in hepatocarcinogenesis.


Photon Harvesting in Sunscreen-Based Functional Nanoparticles.
The ultraviolet light component in the solar spectrum is known to cause several harmful effects, such as allergy, skin ageing, and skin cancer. Thus, current research attention has been paid to the design and fundamental understanding of sunscreen-based materials. One of the most abundantly used sunscreen molecules is Avobenzone (AB), which exhibits two tautomers. Here, we highlight the preparation of spherically shaped nanoparticles from the sunscreen molecule AB as well as from sunscreen-molecule-encapsulated polymer nanoparticles in aqueous media and study their fundamental photophysical properties by steady-state and time-resolved spectroscopy. Steady-state studies confirm that the AB molecule is in the keto and enol forms in tetrahydrofuran, whereas the enol form is stable in the case of both AB nanoparticles and AB-encapsulated poly(methyl methacrylate) (PMMA) nanoparticles. Thus, the keto-enol transformation of AB molecules is restricted to a nanoenvironment. An enhancement of photostability in both the nanoparticle and PMMA-encapsulated forms under UV light irradiation is observed. The efficient excited energy transfer (60 %) from AB to porphyrin molecules opens up further prospects in potential applications as light-harvesting systems.


Phenolic compounds isolated from fermented blueberry juice decrease hepatocellular glucose output and enhance muscle glucose uptake in cultured murine and human cells.
We recently reported that blueberry juice fermented (FJ) with Serratia vaccinii bacterium has antidiabetic activities both in vivo and in vitro. The purpose of this project was to elucidate the effect of FJ on glucose homeostasis in liver and skeletal muscle cells and to identify active fractions/compounds responsible for this effect. FJ was fractionated using standard chromatography procedures. Hepatic (H4IIE, HepG2) and skeletal muscle cells (C2C12) were treated with maximum non-toxic concentrations of FJ, fractions and isolated compounds thereof. Glucose-6-phosphatase (G6Pase) activity was measured using glucose oxidase method. To measure glucose uptake and glycogen synthase (GS) activity, radioactive assays were used. Fractionation of FJ yielded seven fractions. FJ and its phenolic fractions F2, F3-1 and F3-2 respectively inhibited G-6Pase by 31, 45, 51 and 26%; activated GS by 2.3-, 2.3-, 2.2- and 2-fold; and stimulated glucose uptake by 19, 25, 18 and 15%, as compared to DMSO vehicle control. Subfractionation of the active fractions yielded 4 compounds (catechol, chlorogenic, gallic and protocatechuic acid). Catechol, yielding the greatest bioactivity in G6Pase and glucose uptake assays, decreased G6Pase activity by 54%, increased GS by 2-fold and stimulated glucose uptake by 44% at 45.5 μM. This study identifies novel potential antidiabetic compounds that can help standardize FJ.


Challenges in the implementation of an electronic surveillance system in a resource-limited setting: Alerta, in Peru.
Infectious disease surveillance is a primary public health function in resource-limited settings. In 2003, an electronic disease surveillance system (Alerta) was established in the Peruvian Navy with support from the U.S. Naval Medical Research Center Detachment (NMRCD). Many challenges arose during the implementation process, and a variety of solutions were applied. The purpose of this paper is to identify and discuss these issues. This is a retrospective description of the Alerta implementation. After a thoughtful evaluation according to the Centers for Disease Control and Prevention (CDC) guidelines, the main challenges to implementation were identified and solutions were devised in the context of a resource-limited setting, Peru. After four years of operation, we have identified a number of challenges in implementing and operating this electronic disease surveillance system. These can be divided into the following categories: (1) issues with personnel and stakeholders; (2) issues with resources in a developing setting; (3) issues with processes involved in the collection of data and operation of the system; and (4) issues with organization at the central hub. Some of the challenges are unique to resource-limited settings, but many are applicable for any surveillance system. For each of these challenges, we developed feasible solutions that are discussed. There are many challenges to overcome when implementing an electronic disease surveillance system, not only related to technology issues. A comprehensive approach is required for success, including: technical support, personnel management, effective training, and cultural sensitivity in order to assure the effective deployment of an electronic disease surveillance system.


Complete Cranial Iliac Osteotomy to Approach the Lumbosacral Foramen.
An approach using a complete cranial iliac osteotomy (CCIO) to access the lumbosacral (LS) foramen in dogs from lateral was developed using cadavers and applied in a clinical patient with degenerative lumbosacral stenosis (DLSS). The foraminal enlargement in the cadavers and the patient was documented on postoperative CT scans. The preoperative CT scan of the patient showed moderate cranial telescoping of the sacral roof and a moderate central disk protrusion, leading to moderate to severe compression of the cauda equina. In addition, there was lateral spondylosis with consequential stenosis of the right LS foramen. The right L7 nerve had lost its fat attenuation and appeared thickened. After a routine L7S1 dorsal laminectomy with a partial discectomy, a CCIO was performed, providing good access to the LS foramen and the adhesions around the proximal L7 nerve caudoventral to the foramen. The osteotomy was stabilized with a locking plate and a cerclage wire. The dog recovered well from the procedures and after 36 h, the dog walked normally and was discharged from the hospital. Eight and 16 weeks later, the signs of the DLSS had markedly improved. From these data, it can be concluded that the CCIO is a useful approach to the LS foramen and intervertebral disk in selected patients with DLSS, giving good access to the structures around the LS foramen.


MR-guided intravascular catheter manipulation: feasibility of both active and passive tracking in experimental study and initial clinical applications.
To evaluate clinically the feasibility and usefulness of MR-guided intravascular procedures with either active or passive tracking. With an active MR tacking system and a 0.2 Tesla open MR imager, real-time and biplane displays of positions of a receive-only coil at the tip of catheters were obtained. For passive tracking, 4 Fr catheters with suitable susceptibility for passive tracking were used. Passive tracking with a 1.5 Tesla MR imager could be performed with parameters of TR 15-50 msec, TE 2.2-2.7 msec, and FA 30 degrees. The temperature of each tracking catheter was monitored in vitro. Clinical trials were performed on six patients (three each). The catheter was introduced to the superior mesenteric artery (SMA) under MR guidance by active or passive tracking to perform MR imaging during arterial portography. The temperature increased minimally. In humans, the SMA and celiac artery could be easily introduced on active tracking. MR-guided manipulation of catheters by active or passive tracking in the model and in dogs' vessels was very successful. Introduction of the catheter into the SMA was successful in two cases of active tracking and in all cases of passive tracking. The MR-guided intravascular manipulation of catheters by active or passive tracking may be a clinically feasible method.


Amyloid-β Impairs Vesicular Secretion in Neuronal and Astrocyte Peptidergic Transmission.
Regulated secretion of neuropeptides and neurotrophic factors critically modulates function and plasticity of synapses and circuitries. It is believed that rising amyloid-β (Aβ) concentrations, synaptic dysfunction and network disorganization underlie early phases of Alzheimer's disease (AD). Here, we analyze the impact of soluble Aβ1-42 assemblies on peptidergic secretion in cortical neurons and astrocytes. We show that neurons and astrocytes differentially produce and release carboxypeptidase E (CPE) and secretogranin III (SgIII), two dense-core vesicle (DCV) markers belonging to the regulated secretory pathway. Importantly, Aβ1-42, but not scrambled Aβ1-42, dramatically impairs basal and Ca2+-regulated secretions of endogenously produced CPE and SgIII in cultured neurons and astrocytes. Additionally, KCl-evoked secretion of the DCV cargo brain-derived neurotrophic factor (BDNF) is lowered by Aβ1-42 administration, whereas glutamate release from synaptic vesicle (SVs) remains unchanged. In agreement with cell culture results, Aβ1-42 effects on CPE and SgIII secretion are faithfully recapitulated in acute adult brain slices. These results demonstrate that neuronal and astrocyte secretion of DCV cargos is impaired by Aβ in vitro and in situ. Furthermore, Aβ-induced dysregulated peptidergic transmission could have an important role in the pathogenesis of AD and DCV cargos are possible candidates as cerebrospinal fluid (CSF) biomarkers.


Bayesian network analysis of multi-compartmentalized immune responses in a murine model of sepsis and direct lung injury.
Inflammatory disease processes involve complex and interrelated systems of mediators. Determining the causal relationships among these mediators becomes more complicated when two, concurrent inflammatory conditions occur. In those cases, the outcome may also be dependent upon the timing, severity and compartmentalization of the insults. Unfortunately, standard methods of experimentation and analysis of data sets may investigate a single scenario without uncovering many potential associations among mediators. However, Bayesian network analysis is able to model linear, nonlinear, combinatorial, and stochastic relationships among variables to explore complex inflammatory disease systems. In these studies, we modeled the development of acute lung injury from an indirect insult (sepsis induced by cecal ligation and puncture) complicated by a direct lung insult (aspiration). To replicate multiple clinical situations, the aspiration injury was delivered at different severities and at different time intervals relative to the septic insult. For each scenario, we measured numerous inflammatory cell types and cytokines in samples from the local compartments (peritoneal and bronchoalveolar lavage fluids) and the systemic compartment (plasma). We then analyzed these data by Bayesian networks and standard methods. Standard data analysis demonstrated that the lung injury was actually reduced when two insults were involved as compared to one lung injury alone. Bayesian network analysis determined that both the severity of lung insult and presence of sepsis influenced neutrophil recruitment and the amount of injury to the lung. However, the levels of chemoattractant cytokines responsible for neutrophil recruitment were more strongly linked to the timing and severity of the lung insult compared to the presence of sepsis. This suggests that something other than sepsis-driven exacerbation of chemokine levels was influencing the lung injury, contrary to previous theories. To our knowledge, these studies are the first to use Bayesian networks together with experimental studies to examine the pathogenesis of sepsis-associated lung injury. Compared to standard statistical analysis and inference, these analyses elucidated more intricate relationships among the mediators, immune cells and insult-related variables (timing, compartmentalization and severity) that cause lung injury. Bayesian networks are an effective tool for evaluating complex models of inflammation.


Coupled-mode solutions in generalized ocean environments.
This paper presents the application of the differential equation approach to solving the second-order coupled-mode equations in inhomogeneous ocean environments. The model incorporates sound velocity profile points to construct depth-dependent, piecewise linear, ocean and bottom environments along a range grid. Modal solutions are evaluated in terms of Airy functions. The formalism to evaluate analytically the mode-coupling coefficients is presented. Comparisons to conventional expressions of the coefficients are made. The integro-differential form of the coupled equations is solved using an approach developed in nuclear theory that incorporates the Lanczos method [Knobles, J. Acoust. Soc. Am. 96, 1741-1747 (1994)]. Demonstration of the practicality of this approach is made by applying the results in actual calculations with realistic ocean environments. The formalism to evaluate analytically the mode-coupling coefficients is presented. Several benchmark examples were examined in order to validate the model and are discussed, including propagation over a hill, benchmark wedge problems, and a range-varying sound speed profile benchmark. The importance of this model is also demonstrated by the physical insight gained in having a coupled-mode approach to solving range-dependent problems.


Specific precipitating antibody to human urinary erythropoietin.
In the present experiments, human urinary erythropoietin was purified from the urine of a patient suffering from pure red cell aplasia, using ethanol precipitation, gel filtration on the Sephadex G-100 column and electrofocusing. The anti-human urinary erythropoietin was prepared by injecting the isolated erythropoietin with Freund's complete adjuvant into rabbits intracutaneously. The specificity of the anti-human urinary erythropoietin was ascertained by a double diffusion technique and immunoelectrophoresis, observing a single precipitation line at the alpha2-globulin region against human serum or human urinary erythropoietin (Standard B). This precipitating anti-human urinary erythropoietin inhibited completely the effects of erythropoietin (Standard B) on the heme synthesis of bone marrow cells in vitro. The precipitating antigen with the specific anti-human urinary erythropoietin, that is, erythropoietic stimulating factor of the fraction 2, had the ability to enhance heme synthesis in bone marrow cells in vitro. The specific anti-human urinary erythropoietin makes it possible to determine the serum erythropoietin levels in various diseases by means of quantitative immunoelectrophoresis.


The role of REM sleep theta activity in emotional memory.
While non-REM (NREM) sleep has been strongly implicated in the reactivation and consolidation of memory traces, the role of rapid-eye movement (REM) sleep remains unclear. A growing body of research on humans and animals provide behavioral evidence for a role of REM sleep in the strengthening and modulation of emotional memories. Theta activity-which describes low frequency oscillations in the local field potential within the hippocampus, amygdala and neocortex-is a prominent feature of both wake and REM sleep in humans and rodents. Theta coherence between the hippocampus and amygdala drives large-scale pontine-geniculo-occipital (PGO) waves, the density of which predicts increases in plasticity-related gene expression. This could potentially facilitate the processing of emotional memory traces within the hippocampus during REM sleep. Further, the timing of hippocampal activity in relation to theta phase is vital in determining subsequent potentiation of neuronal activity. This could allow the emotionally modulated strengthening of novel and gradual weakening of consolidated hippocampal memory traces during REM sleep. Hippocampal theta activity is also correlated with REM sleep levels of achetylcholine - which is thought to reduce hippocampal inputs in the neocortex. The additional low levels of noradrenaline during REM sleep, which facilitate feedback within the neocortex, could allow the integration of novel memory traces previously consolidated during NREM sleep. We therefore propose that REM sleep mediates the prioritized processing of emotional memories within the hippocampus, the integration of previously consolidated memory traces within the neocortex, as well as the disengagement of consolidated neocortical memory traces from the hippocampus.


The diagnosis and management of a vertebral artery loop causing cervical radiculopathy.
Cervical radiculopathies are rarely caused by vertebral artery loop formation, which is estimated to be present in less than 3% of patients. It is uncertain what causes the loop formation: some propose an association with spondylotic changes or trauma, whilst others suggest hypertension and atherosclerosis may be responsible. CASE REPORT 1: A 35-year-old male patient presented with signs and symptoms of cervical radiculopathy that was not improved with anterior cervical discectomy and fusion surgery performed 2 years beforehand. Vertebral artery loop was discovered at the level C5/6 on the MRI. Vertebral artery transposition surgery via a lateral approach was performed at the level of the left C5/6 for symptoms of left C6 radiculopathy. Deroofing of the transverse process was performed with post-surgical complete improvement in weakness and pain. CASE REPORT 2: A 48-year-old female patient presented with a 10-year history of left shoulder pain with occasional radiation into her middle three fingers accompanied by intermittent paraesthesia and weakness. Numerous shoulder surgeries, Botox injections and suprascapular nerve blocks had not provided any significant benefit. A vertebral artery loop was identified at the level of C3/4 and C4/5 on the left with cervical MRI. Transposition surgery of these two levels provided some post-surgical improvement in pain. Vertebral artery loop formations are a rare but potential cause for cervical radiculopathy. In two cases, the loop formations were not radiographically reported on MRI, thus clinicians should be aware of this as a differential diagnosis in the management of cervical radiculopathy. The presented surgical approach may be useful in managing future cases of vertebral artery loop formation causing cervical radiculopathy resistant to conservative measures.


Validation of personal exposure models for sulfate and aerosol strong acidity.
Personal exposure models for sulfates (SO4 =) and aerosol strong acidity (H+) were previously developed using concentration and activity pattern data collected from a personal monitoring study conducted in Uniontown, Pennsylvania, during the summer of 1990. Models were constructed based on time-weighted micro-environmental exposures. For SO4 =, the "best-fit" model included a correction factor, while for H+, it included both a correction factor and a neutralization term. In this paper, we present the validation of these models using data collected in a personal monitoring study conducted in State College, Pennsylvania, during the summer of 1991. Indoor and outdoor concentration and activity pattern data collected in this study were used as inputs for the "best-fit" models for SO4 = and H+. Predicted personal exposures subsequently were compared to the measured personal exposures from State College to determine their accuracy and precision. Predicted personal exposures for both SO4 = and H+ were in excellent agreement with measured personal exposures from State College. The models explained 91 and 62 percent of the variability in personal SO4 = and H+ exposures, respectively, and were able to estimate personal exposures substantially better than outdoor concentrations alone. Validation results suggest that the models' correction and neutralization factors are not site specific and support the models' future application as a technique to assess the personal acid aerosol exposures of children living in similar rural and semi-rural communities.


Morphophenotype of medulloblastoma in children and adults. The size of nuclei.
Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.


Plasmon hybridization in spherical nanoparticles.
We show that the plasmon resonances in single metallic nanoshells and multiple concentric metallic shell particles can be understood in terms of interaction between the bare plasmon modes of the individual surfaces of the metallic shells. The interaction of these elementary plasmons results in hybridized plasmons whose energy can be tuned over a wide range of optical and infrared wavelengths. The approach can easily be generalized to more complex systems, such as dimers and small nanoparticle aggregates.


Biodegradation of 2-chloro-4-nitrophenol via a hydroxyquinol pathway by a Gram-negative bacterium, Cupriavidus sp. strain CNP-8.
Cupriavidus sp. strain CNP-8 isolated from a pesticide-contaminated soil was able to utilize 2-chloro-4-nitrophenol (2C4NP) as a sole source of carbon, nitrogen and energy, together with the release of nitrite and chloride ions. It could degrade 2C4NP at temperatures from 20 to 40 °C and at pH values from 5 to 10, and degrade 2C4NP as high as 1.6 mM. Kinetics assay showed that biodegradation of 2C4NP followed Haldane substrate inhibition model, with the maximum specific growth rate (μmax) of 0.148/h, half saturation constant (Ks) of 0.022 mM and substrate inhibition constant (Ki) of 0.72 mM. Strain CNP-8 was proposed to degrade 2C4NP with hydroxyquinol (1,2,4-benzenetriol, BT) as the ring-cleavage substrate. The 2C4NP catabolic pathway in strain CNP-8 is significant from those reported in other Gram-negative 2C4NP utilizers. Enzymatic assay indicated that the monooxygenase initiating 2C4NP catabolism had different substrates specificity compared with previously reported 2C4NP monooxygenations. Capillary assays showed that strain CNP-8 exhibited metabolism-dependent chemotactic response toward 2C4NP at the optimum concentration of 0.5 mM with a maximum chemotaxis index of 37.5. Furthermore, microcosm studies demonstrated that strain CNP-8, especially the pre-induced cells, could remove 2C4NP rapidly from the 2C4NP-contaminated soil. Considering its adaptability to pH and temperature fluctuations and great degradation efficiency against 2C4NP, strain CNP-8 could be a promising candidate for the bioremediation of 2C4NP-contaminated sites.


Using a Poisson approximation to predict the isotopic distribution of sulphur-containing peptides in a peptide-centric proteomic approach.
Breen et al. (Electrophoresis 2000; 21: 2243) proposed a method for finding monoisotopic peptide peaks in mass spectra based on an approximation of the distribution of different isotopic variants of a peptide by a Poisson distribution. They developed the method using all protein sequences from the SWISS-PROT database. We investigate the suitability of this method to predict the isotopic distribution in an environment which enriches for peptides carrying sulphur. More specifically, we focus on mass spectra obtained by a COmbined FRActional DIagonal Chromatography (COFRADIC) approach, developed by Gevaert et al. (Nature Biotechnology 2003; 21: 566), targeting a specific subset of peptides, in this case the N-terminal peptides. One can therefore ask whether the original results of Breen et al. apply to spectra generated by the particular COFRADIC method. We investigate whether the proposed approximation holds for N-terminal peptides. We also evaluate whether ignoring sulphur atoms while developing the approximation, as proposed by Breen et al., does not increase the risk of missing monoisotopic peaks corresponding to sulphur-containing peptides. Finally, we check the sensitivity of the quality of the approximation to optimization criteria used in the development process. The results are not simply restricted to a COFRADIC setting but are also applicable more generally, for any method which enriches for sulphur-containing peptides.


Orexin contributes to eupnea within a critical period of postnatal development.
Orexin neurons are active in wakefulness and mostly silent in sleep. In adult rats and humans, orexin facilitates the hypercapnic ventilatory response but has little effect on resting ventilation. The influence of orexin on breathing in the early postnatal period, and across states of vigilance, have not been investigated. This is relevant as the orexin system may be impaired in Sudden Infant Death Syndrome (SIDS) cases. We addressed three hypotheses: 1) orexin provides a drive to breathe in infancy; 2) the effect of orexin depends on stage of postnatal development; and 3) orexin has a greater influence on breathing in wakefulness compared with sleep. Whole body plethysmography was used to monitor breathing of infant rats at three ages: postnatal days (P) 7-8, 12-14, and 17-19. Respiratory variables were analyzed in wakefulness (W), quiet sleep (QS), and active sleep (AS), following suvorexant (5 mg/kg ip), a dual orexin receptor antagonist, or vehicle (DMSO). Effects of suvorexant on ventilatory responses to graded hypercapnia ([Formula: see text] = 0.02, 0.04, 0.06), hypoxia ([Formula: see text] = 0.10), and hyperoxia ([Formula: see text] = 1.0) at P12-14 were also tested. At P12-14, but not at other ages, suvorexant significantly reduced respiratory frequency in all states, reduced the ventilatory equivalent in QW and QS, and increased [Formula: see text] to ∼5 mmHg. Suvorexant had no effect on ventilatory responses to graded hypercapnia or hypoxia. Hyperoxia eliminated the effects of suvorexant on respiratory frequency at P12-14. Our data suggest that orexin preserves eupneic frequency and ventilation in rats, specifically at ∼2 wk of age, perhaps by facilitating tonic peripheral chemoreflex activity.


When Viruses Cross Developmental Pathways.
Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.


[Specific IgE against inhaled allergens in dystreptic children with food allergy].
Immunoglobulin E specific for the selected inhalator allergens have been determined in 42 children with food allergy and failure to thrive, using tests and equipment 3M (Bio Whittaker). Co-existence of food allergy with hypersensitivity to inhaled allergens have been confirmed in 41 children (41%). An equivalent expression grade of IgE antibodies against food and inhaled antigens has usually been noted. Specific IgE produced in response to house dust and mixed feathers have been seen most frequently, and the first have been found in 37% of the tested children in the concentration exceeding 1.0 Ul/ml (2nd, 3rd and 4th class). The obtained results confirmed that specific IgE antibodies against inhaled allergens are being present in children who fail to grow and suffer from the food allergy. These findings should advocate further investigations in specific IgE antibodies to other groups of allergens.


Public Health Profile of Road Traffic Accidents in Kosovo 2010-2015.
To determine the characteristics of the Socio-medical profile of road traffic accidents in Kosovo, between 2010 and 2015 year. Retrospective study. A descriptive method based on the database of road traffic accidents from the National Police of Kosovo. In Kosovo for the period 2010-2015, on average, the yearly number of road traffic accidents is 18437 with mortality rate 7.4 per 100000 and lethality of 1.5%. The highest number of fatal cases are drivers and above 19 years old with more than 80%. Among injured significantly highest percentage is among passengers for all years and above 19 years old. Road traffic accident with a vehicle occurs most frequently, with approximately over 70%, mostly on dry road 72.9% and clear weather 71.1%. The driver is the contributing factors of road traffic accidents on average 99.3% whereas climatic conditions only 0.5%, with over 50% of crashes occurring in urban road 56.2%, mostly during Monday 16.0% and in the afternoon rush hours between 14.00-18.00 with 31.0%. There is a slight decrease in the mortality rate of 0.1‰ and lethality rate of 0.1% each year, whereas there is an increase of 21.5‰ for traumatism rate for each year.


Immunogenicity of Haemophilus influenzae type b polysaccharide-tetanus toxoid conjugate vaccine in infants.
To compare the safety and immunogenicity of three investigational lots of Haemophilus influenzae type b polysaccharide-tetanus toxoid (PRP-T) conjugate vaccine in infants. A multicenter, randomized immunogenicity trial. Infants were vaccinated at 2, 4, and 6 months of age with one of three lots of PRP-T. A control group received H influenzae type b oligomers conjugated to CRM197 (HbOC). Serum was obtained before each injection and 1 month after the third dose, and assayed blindly for antibody in one laboratory. Four hundred eighty-four infants from private pediatric practices located in five geographic areas. There were no significant differences in the number of adverse events reported for infants receiving PRP-T or HbOC, and the rates did not exceed those observed previously in infants given diphtheria-tetanus-pertussis vaccine alone. Total serum anti-PRP antibody responses were analyzed in 336 infants who met strict inclusion criteria. After one, two, or three doses, the respective antibody responses to each of the three lots of PRP-T and to HbOC vaccine were similar. The only exception was one lot of PRP-T, which after one or two injections elicited significantly higher geometric mean antibody responses than the other two lots or the HbOC vaccine. After a third injection, there were no significant lot differences. Combining the data from the different lots, there were no significant differences in the geometric mean antibody concentration after three doses of PRP-T or HbOC (8.3 vs 7.7 micrograms/mL), and 95% and 91%, respectively, of infants had greater than 1.0 microgram/mL of antibody. There were no significant differences in the magnitudes of the respective IgG1-, IgG2-, and IgM-specific antibody concentrations between infants given PRP-T or HbOC. The three investigational lots of PRP-T tested were safe and were as immunogenic as or more so than the licensed HbOC conjugate vaccine.


Temporal genetic change in the last remaining population of woolly mammoth.
During the Late Pleistocene, the woolly mammoth (Mammuthus primigenius) experienced a series of local extinctions generally attributed to human predation or environmental change. Some small and isolated populations did however survive far into the Holocene. Here, we investigated the genetic consequences of the isolation of the last remaining mammoth population on Wrangel Island. We analysed 741 bp of the mitochondrial DNA and found a loss of genetic variation in relation to the isolation event, probably caused by a demographic bottleneck or a founder event. However, in spite of ca 5000 years of isolation, we did not detect any further loss of genetic variation. Together with the relatively high number of mitochondrial haplotypes on Wrangel Island near the final disappearance, this suggests a sudden extinction of a rather stable population.


[Problems and Perspectives of Echocardiographic Evaluation of the Left Ventricular Diastolic Function].
This literature review is devoted to noninvasive evaluation of the left ventricular (LV) diastolic function by echocardiography with special stress on existing problems of detection of LV dysfunction by Doppler echocardiography of transmitral blood flow. Basing on existent algorithms one often cannot clearly judge whether LV dysfunction is present even when such methods are used as assessment of blood flow in pulmonary veins, transmitral blood flow during the Valsalva maneuver, etc. The review also contains discussion and analysis of newly suggested Doppler echocardiography based algorithms of detection of LV diastolic dysfunction and estimation of its severity (two-dimensional deformation of left atrial walls, three-dimensional echocardiography and three-dimensional deformation of the left ventricle).


Total Particle Number Emissions from Modern Diesel, Natural Gas, and Hybrid Heavy-Duty Vehicles During On-Road Operation.
Particle emissions from heavy-duty vehicles (HDVs) have significant environmental and public health impacts. This study measured total particle number emission factors (PNEFs) from six newly certified HDVs powered by diesel and compressed natural gas totaling over 6800 miles of on-road operation in California. Distance-, fuel- and work-based PNEFs were calculated for each vehicle. Distance-based PNEFs of vehicles equipped with original equipment manufacturer (OEM) diesel particulate filters (DPFs) in this study have decreased by 355-3200 times compared to a previous retrofit DPF dynamometer study. Fuel-based PNEFs were consistent with previous studies measuring plume exhaust in the ambient air. Meanwhile, on-road PNEF shows route and technology dependence. For vehicles with OEM DPFs and Selective Catalytic Reduction Systems, PNEFs under highway driving (i.e., 3.34 × 1012 to 2.29 × 1013 particles/mile) were larger than those measured on urban and drayage routes (i.e., 5.06 × 1011 to 1.31 × 1013 particles/mile). This is likely because a significant amount of nucleation mode volatile particles were formed when the DPF outlet temperature reached a critical value, usually over 310 °C, which was commonly achieved when vehicle speed sustained over 45 mph. A model year 2013 diesel HDV produced approximately 10 times higher PNEFs during DPF active regeneration events than nonactive regeneration.


Effects of high-intensity interval training on cardiometabolic risk in overweight and obese African-American women: a pilot study.
Little is known about high-intensity interval training (HIIT) in African-American (AA) women. The purpose of this pilot study was to evaluate the effects of HIIT and steady-state (SS) exercise on cardiometabolic risk factors in young AA women. A 16-week exercise intervention was conducted 3x/week. Twenty-seven AA women were randomized to SS (n = 11; 32 continuous minutes of treadmill walking at 60-70% of maximum heart rate (HRmax)), or HIIT (n = 16; 32 min of treadmill HIIT alternating 3 min at 60-70% of HRmax with 1 min at 80-90% of HRmax). Two-way repeated measures ANOVA with intention-to-treat analysis was used to identify changes between groups. Significance was accepted at P ≤ 0.05. Of the 27 women who entered the study (age: 30.5 ± 6.8 years; BMI: 35.1 ± 5.1 kg/m2; 5274 ± 1646 baseline steps/day), 14 completed the intervention. HIIT significantly decreased waist circumference (107.0 ± 11.3 to 105.1 ± 11.9 cm) compared to SS, which showed no change. There was a significant time effect for steps where HIIT increased steps/day (5334 ± 1586 to 7604 ± 1817 steps/day), and SS had no change. There were no significant changes in either group for any other measurements. HIIT was more effective at reducing waist circumference and increasing daily steps/day than SS treadmill exercise over 16 weeks. Further research in a larger sample is indicated to evaluate the effects of each protocol on cardiometabolic risk factors.


Current anthelmintic treatment is not always effective at controlling strongylid infections in German alpaca herds.
Endoparasites are considered a major health problem of South American camelids as shown in a recent survey among German and Austrian camelid owners. Although prophylactic and therapeutic measures such as application of anthelmintics are commonly used, treatment efficacy is usually not assessed. Owners have expressed significant concerns regarding the effect of antiparasitic therapy, so this study aimed to evaluate the outcome of anthelmintic treatment in German alpaca herds with different drugs. Overall, 617 samples from 538 clinically healthy alpacas > 1 year-old from 27 farms (n = 11-157 animals/herd) were examined. The most common parasites detected by flotation were Eimeria spp. (75.1%) followed by strongylids (55.0%), Nematodirus spp. (19.3%), cestodes (3.1%) and Trichuris (2.7%). After initial coproscopical examination by flotation and strongylid egg quantification by the McMaster technique, positive animals excreting at least 150 eggs per gram of faeces were included in a faecal egg count reduction test (FECRT) using fenbendazole (n = 71 samples), moxidectin (n = 71) or monepantel (n = 66). Pre-treatment larval cultures (n = 23 positive pooled farm samples) revealed Haemonchus (87% of the farms), Cooperia (43.5%), Trichostrongylus (21.7%), Ostertagia (13.0%), Nematodirus and Oesophagostomum (4.3% each). Fenbendazole treatment reduced egg excretion by 45%, moxidectin by 91% and monepantel by 96%. On the farm level, 13/18 farms that used fenbendazole, 6/6 farms that used moxidectin and 2/5 farms that used monepantel had individual FECR values < 90% (fenbendazole) or < 95% (moxidectin, monepantel). Haemonchus and Cooperia were overrepresented on the farms with reduced treatment efficacy. Gastrointestinal strongylids are common in German alpacas and fenbendazole in particular was not sufficiently effective to reduce strongylid egg excretion. Although the FECRT could not unambiguously determine anthelmintic resistance in the present study, the finding that small ruminant strongylids, especially Haemonchus, are common in alpacas indicates that determination of effective anthelmintic doses, monitoring of efficacy and adapted (selective) treatment regimens must be implemented as part of sustainable deworming practices in this species in accordance with recommendations for ruminants.


Psychological factors affecting pediatric inflammatory bowel disease.
Psychological factors affecting pediatric inflammatory bowel disease, intervention and other therapeutic resources are reviewed. Children with inflammatory bowel disease are at risk for more difficulties in psychosocial functioning than healthy children, particularly depression, anxiety and social difficulties. Psychosocial difficulties are generally similar to those found in other pediatric chronic illnesses and are clinically significant in only a subset of those with inflammatory bowel disease. Conflicting results have been reported for the areas of family dysfunction and body image, and few studies have been published in the areas of stress/coping and eating disorders. One pilot study suggests psychotherapy is effective for depressed adolescents with inflammatory bowel disease. The scant existing research limits conclusions about which children are most at risk for experiencing problems. Future research should investigate a range of psychosocial outcomes and risk factors for developing problems. Prevention and intervention strategies aimed at improving psychosocial functioning in children with inflammatory bowel disease should be developed and evaluated.


Management of patients with facial paralysis in the dental office: A brief review of the literature and case report.
In the dental office, the dentist may have to examine patients with facial asymmetry and functional disorders caused by facial paralysis (FP). Following clinical examination, it is important for the dental practitioner to establish whether FP was caused by injury to the facial nerve, and to focus on the site of the lesion and potential risk factors. The risks of dental treatment in a patient with FP should also be assessed. Through dental or surgical procedures, the dentist may cause transient or permanent FP. Interdisciplinary collaboration is required for the confirmation of diagnosis and etiology, and for the complex treatment of FP. This article aims to examine the role of the dentist within the multidisciplinary medical team and to present two cases with transient FP following intraoral anesthesia in the dental office.


Special toxicology--physical dependence potential, antigenicity and mutagenicity--of mabuterol.
The physical dependence potency of dl-1- (4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-tert.-butyl-amino-ethanol hydrochloride (mabuterol) was tested in male rats dosed with 20, 100 and weekly increasing doses of 20, 40, 60, 80 and 100 mg/kg over 7 weeks. The results were compared with those after the same increasing dosages of morphine. 10 males were used per group. The effects of the antagonist levallorphan on drug dependency were also studied. No withdrawal signs were observed in any mabuterol-treated groups. No antigenic potency of mabuterol was found in a series of studies on guinea pigs and rats. In a series of mutagenicity studies (Ames-test, DNA repair test and micronucleus test) it could be demonstrated that mabuterol is not a mutagen.


Traumatized primary anterior teeth. Prognosis related to calcific reactions in the pulp cavity.
The frequency of a complicating pulp necrosis and the process of the physiologic root resorption were studied in traumatized primary teeth exhibiting partial or total pulp obliteration. The material comprised 88 incisors in 72 children aged 0.7--5.7 years (mean 2.9 years) at the time of injury. Trauma had resulted either in subluxation (25 teeth), or luxation (13 teeth), whereas the type of injury was unknown in 50 teeth. All cases were observed until eruption of the permanent incisors. Forty-four teeth initially displayed a reversible greyish color. The ultimate finding observed in all teeth was, however, varying degrees of yellow discoloration. Periapical pathologic findings indicative of pulp necrosis were observed in 9 teeth, from 1.6--4 years (mean 3 years) after the time of injury. Extraction was performed immediately, and none of the successional teeth showed developmental disturbances. The process of root resorption was classified as normal in all primary teeth. Subsequent eruption of the permanent successors occurred without any registered complications.


OUTSTANDING CHARACTERISTICS OF THROMBOKINASE ISOLATED FROM BOVINE PLASMA.
Thrombokinase has been isolated from bovine plasma by a procedure which begins with the highly purified product of a previously described method, chromatographs it on DEAE-cellulose, and then fractionates it by continuous flow electrophoresis, yielding 0.2 mg per liter of oxalated plasma. The electrophoretic fraction has shown a single boundary in the ultracentrifuge; and its esterase activity on toluenesulfonylarginine methyl ester has been about the same as that of thrombokinase previously isolated by repeated electrophoretic fractionations. Thrombokinase is a euglobulin with minimum solubility near pH 5.0. It is most stable within the pH range 7.5 to 9.5; but there is also a peak in the stability curve near pH 1.8. A few micrograms of thrombokinase per milliliter can activate prothrombin in the presence of EDTA. A few thousandths of a microgram causes rapid production of thrombin in the system: prothrombin, thrombokinase, calcium chloride, phosphatide, "accelerator." But, thrombokinase has less than 1/175 the proteolytic activity of crystallized trypsin.


Evaluation of in vitro inhibitory effects of some natural compounds on tyrosinase activity and molecular docking study: Antimelanogenesis potential.
Tyrosinase enzyme is a functional oxidase that is extensively divided in nature. It is the main enzyme in melanin synthesis and is also involved in designating the color of mammalian hair and skin. Additionally, it is accountable for the unfavorable enzymatic browning that happens in plant-derived foods, limiting the shelf-life of new-cut crops with the resultant economic harm. Recently, there has been a remarkable concern to study the inhibitory activity of the tyrosinase enzyme and some inhibitory molecules isolated from natural sources. For tyrosinase enzyme, afzelin, narcissoside, justiciresinol, thalassiolin B, carpachromene, neobavaisoflavone, and kojic acid (as standard) as natural phenols have IC50 values in the range of 2.37-7.90 µM. Theoretical methods, such as gaussian software program and molecular modeling, were used to compare the biological and chemical activity values of molecules. To compare the biochemical and chemical activity values of molecules, chemical activities with quantum chemical parameters, and biological activities against tyrosinase with the ID of 5M8L molecules were investigated.


Combining computed tomography and biologically effective dose in radiomics and deep learning improves prediction of tumor response to robotic lung stereotactic body radiation therapy.
The aim of this study is to improve the performance of machine learning (ML) models in predicting response of non-small cell lung cancer (NSCLC) to stereotactic body radiation therapy (SBRT) by integrating image features from pre-treatment computed tomography (CT) with features from the biologically effective dose (BED) distribution. Image features, consisting of crafted radiomic features or machine-learned features extracted using a convolutional neural network, were calculated from pre-treatment CT data and from dose distributions converted into BED for 80 NSCLC lesions over 76 patients treated with robotic guided SBRT. ML models using different combinations of features were trained to predict complete or partial response according to response criteria in solid tumors, including radiomics CT (RadCT ), radiomics CT and BED (RadCT,BED ), deep learning (DL) CT (DLCT ), and DL CT and BED (DLCT,BED ). Training of ML included feature selection by neighborhood component analysis followed by ensemble ML using robust boosting. A model was considered as acceptable when the sum of average sensitivity and specificity on test data in repeated cross validations was at least 1.5. Complete or partial response occurred in 58 out of 80 lesions. The best models to predict the tumor response were those using BED variables, achieving significantly better area under curve (AUC) and accuracy than those using only features from CT, including a RadCT,BED model using three radiomic features from BED, which scored an accuracy of 0.799 (95% confidence intervals (0.75-0.85)) and AUC of 0.773 (0.688-0.846), and a DLCT,BED model also using three variables with an accuracy of 0.798 (0.649-0.829) and AUC of 0.812 (0.755-0.867). According to our results, the inclusion of BED features improves the response prediction of ML models for lung cancer patients undergoing SBRT, regardless of the use of radiomic or DL features.


The platelet-derived growth factor controls c-myc expression through a JNK- and AP-1-dependent signaling pathway.
Pro-inflammatory cytokines, environmental stresses, as well as receptor tyrosine kinases regulate the activity of JNK. In turn, JNK phosphorylates Jun members of the AP-1 family of transcription factors, thereby controlling processes as different as cell growth, differentiation, and apoptosis. Still, very few targets of the JNK-Jun pathway have been identified. Here we show that JNK is required for the induction of c-myc expression by PDGF. Furthermore, we identify a phylogenetically conserved AP-1-responsive element in the promoter of the c-myc proto-oncogene that recruits in vivo the c-Jun and JunD AP-1 family members and controls the PDGF-dependent transactivation of the c-myc promoter. These findings suggest the existence of a novel biochemical route linking tyrosine kinase receptors, such as those for PDGF, and c-myc expression through JNK activation of AP-1 transcription factors. They also provide a novel potential mechanism by which both JNK and Jun proteins may exert either their proliferative or apoptotic potential by stimulating the expression of the c-myc proto-oncogene.


Endothelial cells and macrophages, partners in atherosclerotic plaque progression.
Heart disease and stroke, the main cardiovascular diseases (CVD), have become global epidemics in our days. High levels of cholesterol and other abnormal lipids are among the main risk factors of atherosclerosis, the number one killer in the world. However, recent advances in CVD treatment together with improvements in surgical techniques have increased the quality of life and reduced premature death rates and disabilities. Nevertheless, they still add a heavy burden to the rising global costs of health care. The medical priorities highlight not only the need for early recognition of the warning signs of a heart attack, but also the need for early biomarkers for prevention. Two active partners in the development and progression of atherosclerotic plaques are the macrophages and endothelial cells that influence each other and modify the microenvironment composition of the plaque leading to either rapid progression or regression of individual lesions in patients. In this review we address two specific aspects related to atherosclerosis: i) the way in which folic acid and folic acid conjugates may be helpful to identify activated macrophages and ii) the high potential of proteomic analysis to evidence and identify the multiple changes induced in activated vascular cells.


Improved local control of thoracic disease in small cell lung cancer with higher dose thoracic irradiation and cyclic chemotherapy.
Over the past decade, improvement in survival has developed for patients with small cell lung carcinoma (SCLC) due to treatment strategies that include: cyclic combination chemotherapy, thoracic irradiation, and prophylactic cranial irradiation. In this study, we assess the outcome of treatment with initial cyclic combination chemotherapy including: cyclophosphamide, VP 16-123 and methotrexate combined with radiotherapy (RT), 6000 cGY [corrected] to the thorax for patients with limited disease and 3000 cGy [corrected] for patients with extensive disease. Forty-six patients are evaluated: 26 patients with limited disease and 20 with extensive disease. In patients who received 6000 cGy [corrected], to thoracic lesions, in combination with chemotherapy, administered for 3 courses prior to and following RT, the rate of clinically detected failure in the thorax was 3.8%. Morbidity was considered acceptable, although the occurrence of encephalopathy in 6 of 19 cases who received cranial irradiation, 3000 cGy [corrected], and concomitant chemotherapy was a serious consequence. Control of the primary tumor achieved by the use of higher dose RT is shown to be superior to that observed at lower doses of RT. This suggests that for the small cohort of patients whose disease is truly limited at the time of diagnosis, therapeutic regimens, which include higher dose RT, could increase the number of long term survivors of SCLC.


Degradation of the sodium taurocholate cotransporting polypeptide (NTCP) by the ubiquitin-proteasome system.
The sodium taurocholate cotransporting polypeptide (Ntcp, Slc10a1) is the major uptake system for bile acids into liver cells. This study investigated the degradation of rat Ntcp and human NTCP by the ubiquitin-proteasome system (UPS). In stably transfected HepG2 cells, rat Ntcp was complex-glycosylated and localized at the plasma membrane. Inhibition of proteasomes by MG-132 or lactacystin led to the accumulation of intracellular Ntcp, a process dependent on de novo protein synthesis. Intracellular Ntcp was core-glycosylated, indicating an endoplasmic reticulum (ER) origin. Core-glycosylated Ntcp was found in cytosolic, detergent-insoluble deposits with characteristics of aggresomes: they co-localized with ubiquitin at the microtubule organization center and Ntcp from these deposits was polyubiquitinated. Transient transfections of Ntcp/NTCP induced intracellular deposits that co-localized with ubiquitin, even in the absence of proteasome inhibitors. Similarly, in livers of patients with progressive familial intrahepatic cholestasis, NTCP could be detected co-localized with ubiquitin in hepatocytes. We conclude that maturing Ntcp/NTCP is degraded by the ubiquitin-proteasome system at the level of ER-associated degradation (ERAD). An imbalance in the synthesis and degradation of NTCP at the level of the ER or alterations in the ERAD machinery might be the cause of intracellular NTCP deposits in transient transfections and in cholestatic livers.


[Gilbert syndrome].
Gilbert disease is a benign disorder of the bilirubin conjugation, which affects 7-10% of the average population. The symptoms are usually only mild jaundice and the slightly elevated unconjugated bilirubin level, other laboratory tests and the liver functions are usually normal. In most cases, mutation of the UDP glucuronyltransferase gene leads to impaired bilirubin conjugation. Besides the usual laboratory methods, genetic analyses of the UDP glucuronyltransferase gene can help in the diagnosis. In 80-100% of the patients the (TA)-insertion in the promoter-region of the gene is present in homozygous - (TA) 7 /(TA) 7 - form, and leads to the decrease of the amount of functionally active enzyme. The role of missense mutations localized in the coding region has not been clarified yet, but their co-occurrence with the (TA) 7 promoter-variant might mean an explanation to the elevated bilirubin level, jaundice, and the familiar aggregation of Gilbert disease.


Prognostic significance of X-ray cross-complementing group 1 T-77C polymorphism in resected non-small cell lung cancer.
A novel T-77C polymorphism in the promoter region of the DNA repair gene X-ray cross-complementing group 1 (XRCC1) may modulate its transcription to increase the risk of lung cancer. Here, we attempt to clarify: (i) whether the XRCC1 T-77C polymorphism was associated with lung cancer risk in Taiwanese and (ii) whether this polymorphism could act as a prognostic indicator to predict the clinical outcome of non-small-cell lung cancer (NSCLC) patients. A total of 294 primary lung cancer patients and 288 potential controls were recruited into our study. Clinical data were collected. The genotypes of XRCC1 T-77C were identified by polymerase chain reaction. Our case-control study showed that the XRCC1 T-77C polymorphism was not associated with the risk of lung cancer in Taiwanese patients. To verify the impact of the XRCC1 T-77C polymorphism on the clinical outcome of NSCLC, survival analysis showed that patients with TT had a lower survival rate than those with the TC + CC genotype (33.1% versus 48.8%, P = 0.031). The Cox regression analysis further indicated that patients with the TT genotype had a 1.84-fold risk compared with those with the TC + CC genotype (95% CI, 1.16-2.86, P = 0.008). Our results suggest that XRCC1 T-77C variants (TC + CC) may act as a favorable prognostic indicator of resected NSCLC.


Predictors of stroke complicating carotid artery stenting.
The evolving technique of carotid stenting is being evaluated as an alternative to endarterectomy. Identification of the factors that predispose a patient to neurological complications would facilitate further refinement of the technique and optimize patient selection. We analyzed the impact of various clinical, morphological, and procedural determinants on the development of procedural strokes in 231 patients who underwent elective (primary) stenting of 271 extracranial carotid arteries. The mean age of the patients was 68.7+/-10 years, 165 (71%) were males, and 139 (60%) had symptoms attributed to the lesion treated. This series represented a high-risk subset with 164 patients (71%) having significant coronary artery disease, 91 (39%) having bilateral disease, and 28 (12%) having contralateral carotid occlusion. Of the treated vessels, 59 (22%) had prior carotid endarterectomy, 66 (24%) had ulcerated plaques, and 87 (32%) had calcified lesions. Only 37 treated vessels (14%) would have been eligible for inclusion in the North American Symptomatic Carotid Endarterectomy Trial (NASCET). There were 17 (6.2%) minor and 2 (0.7%) major strokes during and within 30 days of the procedure. NASCET-eligible patients had a low (2.7%) risk of procedural strokes after carotid stenting. The results of multivariate analysis revealed advanced age (P=.006) and presence of long or multiple stenoses (P=.006) as independent predictors of procedural strokes. During this procedural developmental phase of carotid stenting, neurological complications were highly dependent on patient selection. Advanced age and long or multiple stenoses were independent predictors of procedural stroke.


Highly accelerated T1-weighted abdominal imaging using 2-dimensional controlled aliasing in parallel imaging results in higher acceleration: a comparison with generalized autocalibrating partially parallel acquisitions parallel imaging.
The purpose of this study was to evaluate the feasibility and technical quality of an abdominal 3-dimensional interpolated breath-hold (volumetric interpolated breath-hold examination [VIBE]) magnetic resonance examination using the new parallel acquisition technique, controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA). In this institutional review board-approved study, 15 volunteers underwent an abdominal magnetic resonance imaging examination including axial unenhanced 3-dimensional VIBE sequences with the conventional parallel acquisition technique, generalized autocalibrating partially parallel acquisitions parallel imaging (GRAPPA), with an acceleration factor (R) of 2, 3, 4, and 2 × 2 in comparison with a CAIPIRINHA-VIBE sequence with an acceleration factor of 2 × 2. Images were evaluated regarding the overall image quality, liver edge sharpness, and parallel imaging artifacts. Signal-to-noise ratio was evaluated using 2 different methods. In a second study population, 17 patients were examined with our new routine protocol for abdominal imaging that now comprises VIBE sequences with CAIPIRINHA with R = 2 × 2. In the volunteer population, the overall image quality of CAIPIRINHA with R = 2 × 2 was significantly higher compared with GRAPPA with R = 3, 4, and 2 × 2 (P < 0.05). There were significantly less parallel imaging artifacts with CAIPIRINHA with R = 2 × 2 (P < 0.05). Acquisition time varied between 21.1 (GRAPPA with R = 2, 320 matrix) and 6.9 seconds (CAIPIRINHA with R = 2 × 2, 256 matrix). Signal-to-noise ratio performance of CAIPIRINHA with R = 2 × 2 was superior to GRAPPA with R = 3, 4, and 2 × 2. In the patient population, VIBE sequences with CAIPIRINHA with R = 2 × 2 showed consistently good image quality, minimal motion artifacts, and minimal parallel imaging artifacts. The CAIPRINHA-VIBE with an acceleration factor of R = 2 × 2 is feasible in a clinical setting and is characterized by fast and robust imaging with an image quality comparable with a 2-fold acceleration with GRAPPA.


Studies on the allergenic significance and structure of rat serum albumin.
This study evaluated the capacity of rat serum albumin and of its proteolytic fragments to activate human basophils for IgE-mediated histamine release. The leukocytes from 8 out of 33 patients allergic to rats released histamine with rat serum albumin. Two proteolytic fragments of rat serum albumin, each constituting half of the molecule, were used to study the IgE-reactive antigenic sites. These fragments released histamine with the cells of some of the donors, thus demonstrating the presence of at least 2 antigenic determinants on each fragment for a total minimum of 4 sites on the intact rat serum albumin molecule. Most of the allergenic activity, however, was not recovered in the 2 fragments (total recovery mean = 6.4%, range between 0.1 and 31%). This loss could be due to cleavage of the rat albumin molecule in the middle of the third domain with loss of antigenic sites and/or due to minor conformational changes in the fragments as compared with the intact molecule. There was up to a 500-fold difference in the percent of activity recovered in the fragments when tested on cells from different patients. Therefore, there is no single immunodominant site on the molecule equally important for all patients. The cells of all 8 patients also reacted with mouse serum albumin but only 2 with bovine serum albumin. At least 1 determinant on mouse and rat serum albumin is cross-reactive with IgE.


The meaning of a healthcare community of practice.
This study intends to explore the meaning of community of practice within the context of healthcare. Based on Walker and Avant's conceptual analysis method, this study identifies the contextual definitions, critical attributes, antecedents, and consequences of the community of practice phenomena in health care. The findings in articles appearing in peer-reviewed healthcare journals within publication dates of 2007-2012 concur that a healthcare community of practice shares a common domain of interest in which healthcare workers collaborate to enhance the practice, promote professional expertise, and augment institutional knowledge. Antecedents necessary for and consequences that occur because of a healthcare community of practice are detailed within this article. This analysis informed the decision to use a healthcare community of practice framework for an interprofessional dedicated education unit.


Multidisciplinary management of fetal surgical anomalies: the impact on maternal anxiety.
To assess the impact on maternal anxiety of a multidisciplinary approach in prenatal management of fetal surgical anomalies. A case-control study was undertaken: Group A (cases) consisted of 16 couples receiving a prenatal multidisciplinary counselling, Group B (controls) was represented by 16 couples, who received diagnosis of the fetal anomaly and the relevant counselling by an obstetrician only. The fetuses were affected by the following gastrointestinal anomalies: gastroschisis, omphalocele, intestinal atresia. The Italian version of the Spielberger State-Trait Anxiety Inventory was utilized to assess maternal anxiety. In Group A maternal anxiety level was assessed after the first antenatal counselling and at birth, whereas in Group B only at birth. At birth, Group A presented STAI-S scores significantly lower than after the first antenatal consultation with the team (Mean +/- SD = 39.87 +/- 6.46 versus 68.93 +/- 5.81; p < 0.01). At the end of the first day spent with the baby in the Neonatal Surgery Unit, Group A presented STAI-S scores significantly lower than Group B (Mean +/- SD = 39.87 +/- 6.46 versus 70.62 +/- 4.12; p < 0.01). This study provides evidence of the positive impact on maternal anxiety of a multidisciplinary approach in prenatal management of fetal surgical anomalies.


Cardiovascular Disease Update: Pulmonary Hypertension.
Pulmonary hypertension (PH) is a spectrum disorder with multiple causes of the elevation of pressure in the lungs. It often is difficult to diagnose because it mimics many commonly reported symptoms (eg, dyspnea, exercise intolerance, chest pain). Diagnosis is made via right heart catheterization; however, transthoracic echocardiography may show evidence of elevated pulmonary pressure as the first clue to the diagnosis. Diagnostic tests to consider include a liver panel, complete blood count, and thyroid function test; electrocardiogram; chest x-ray; pulmonary function testing; and possibly lung imaging via computed tomography scan or ventilation-perfusion scan. PH is grouped into several broad categories: group 1 is pulmonary artery hypertension, group 2 is PH due to left heart disease, group 3 is PH due to lung disease, group 4 is chronic thromboembolic PH, and group 5 is PH due to unclear or multifactorial mechanisms. Therapy targets the underlying etiology and may include physical activity and pulmonary rehabilitation; drugs such as diuretics, vasodilators, and anticoagulants; oxygen therapy; and lung transplantation. Significant PH can result in increased mortality risk. Because of its complex and heterogeneous nature, PH is best managed by subspecialists with expertise in the condition.


Influence of handle shape and size to reduce the hand-arm vibration discomfort.
Non-automated tool handles transmit a large magnitude of vibration to operators' hands, causing discomfort and pain. Therefore, the need for a better handle design is a matter of prime concern to overcome musculoskeletal disorders such as hand-arm vibration syndrome. This study aimed to examine the influence of handle shapes in reducing the transmission of hand-arm vibration. Seven different handles were designed and fabricated using 3D printing technology at the SSN College of Engineering, with consideration for the anatomical shape of the hand. The frequency-weighted Root Mean Square (RMS) values of the vibration levels transmitted were recorded at the wrist of twelve subjects, unaffected by musculoskeletal disorders. Subjective ratings of vibration and comfort perception were measured using the Borg Scale of Perceived Exertion. The total vibration value (ahv) of each of the six novel prototype handles (B-G) was compared to that of the reference handle denoted handle-A. The vibration reductions for handles B to G respectively were 0.542 m/s2 (14.59%), 0.481 m/s2 (12.95%), 0.351 m/s2 (9.45%), 0.270 m/s2 (7.27%), 0.407 m/s2 (10.96%) and 0.192 m/s2 (5.17%). A significant level of vibration reduction was achieved by the prototype handles. Qualitative feedback from the study subjects suggests that they were not aware of the levels of vibration being transmitted to the hand with each handle.


Angiographic changes in iris and iridocorneal angle neovascularization after intravitreal bevacizumab injection.
To evaluate the effects of the intravitreal (IV) injection of bevacizumab on anterior segment neovascularization using anterior segment angiography. We observed 1 eye with iris and iridocorneal angle neovascularization and 3 with neovascular glaucoma from 4 patients with diabetic retinopathy in 3 eyes and central retinal vein occlusion in 1 eye. Two healthy eyes from 2 other patients served as control eyes. Three eyes, including 1 normal eye, were examined by iris angiography; the other eyes underwent iridocorneal angle angiography with fluorescein (FA) and indocyanine green (IA) using a Heidelberg Retina Angiograph 2. After angiography, 4 eyes with neovascularization were treated with IV bevacizumab (1.25 mg per 0.05 mL) and underwent angiography once more 4 to 6 days after treatment. Iris angiography with indocyanine green revealed many iris vessels, but not dye leaking, in both normal and glaucomatous eyes, and the angiography with fluorescein showed intensive vessel leakage in the iris as well as iridocorneal angle neovascularization, but not in normal eyes. Angle angiography revealed vessel structures with indocyanine green and intensive leakage with fluorescein in the iris and showed iridocorneal angle neovascularization and neovascular glaucoma, whereas no vessel structures appeared with IA or FA in the normal eye. After IV bevacizumab injection in eyes with neovascularization, the vascular structure did not change with IA, but dye leakage remarkably decreased with FA in the iris and angle. However, newly formed vessels in the iris and iridocorneal angle seemed to disappear on slitlamp examination. Intravitreal injection of bevacizumab effectively reduces vascular permeability, whereas newly formed vessels are still present in the iris and iridocorneal angle.


Early diagnosis of bacterial infection in patients with septicopyemia by laboratory analysis of PCT, CRP and IL-6.
The aim of the present study was to investigate the early diagnostic values of measuring procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (lL-6) levels in patients with bacterial infections and septicopyemia. Ninety-two patients with septicopyemia who were diagnosed and treated in the First Affiliated Hospital of Fujian Medical University between December 2012 and October 2013 were randomly selected. Based on results of hemoculture, the patients were divided into the Gram-negative bacterial infection group (n=47) and the Gram-positive bacterial infection group (n=45). Immune nephelometry was used for measuring serum CRP levels, electrochemiluminescence assay was used to measure serum PCT and IL-6. The levels of serum CRP, PCT, and IL-6 in the Gram-negative bacterial infection group were significantly higher than in the Gram-positive group. Analysis with Spearman's correlation coefficient showed that there were positive correlations between the levels of PCT and CRP, and between PCT and IL-6 (P<0.05). The diagnosis of Gram-negative bacterial infections was as follows: The area under the PCT curve was 0.974 (P<0.05) with sensitivity and specificity of 96.8 and 93.5%, respectively. The area under the CRP curve was 0.953 (P<0.05) with sensitivity and specificity of 94.2 and 91.7%, respectively. The area under the IL-6 curve was 0.925 (P<0.05) with sensitivity and specificity of 93.6 and 90.5%, respectively. The diagnosis of Gram-negative bacterial infections was as follows: The area under the PCT curve was 0.854 (P<0.05) with sensitivity and specificity of 92.7 and 91.8%, respectively. The area under the CRP curve was 0.832 (P<0.05) with sensitivity and specificity of 90.2 and 89.3%, respectively. The area under the IL-6 curve was 0.817 (P<0.05) with sensitivity and specificity of 89.4 and 81.5%, respectively. In conclusion, PCT, CRP, and lL-6 can act as early diagnostic markers for bacterial infections in patients with septicopyemia.


Theta oscillations locked to intended actions rhythmically modulate perception.
Ongoing brain oscillations are known to influence perception, and to be reset by exogenous stimulations. Voluntary action is also accompanied by prominent rhythmic activity, and recent behavioral evidence suggests that this might be coupled with perception. Here, we reveal the neurophysiological underpinnings of this sensorimotor coupling in humans. We link the trial-by-trial dynamics of EEG oscillatory activity during movement preparation to the corresponding dynamics in perception, for two unrelated visual and motor tasks. The phase of theta oscillations (~4 Hz) predicts perceptual performance, even >1 s before movement. Moreover, theta oscillations are phase-locked to the onset of the movement. Remarkably, the alignment of theta phase and its perceptual relevance unfold with similar non-monotonic profiles, suggesting their relatedness. The present work shows that perception and movement initiation are automatically synchronized since the early stages of motor planning through neuronal oscillatory activity in the theta range.


Accelerating consensus on coevolving networks: the effect of committed individuals.
Social networks are not static but, rather, constantly evolve in time. One of the elements thought to drive the evolution of social network structure is homophily-the need for individuals to connect with others who are similar to them. In this paper, we study how the spread of a new opinion, idea, or behavior on such a homophily-driven social network is affected by the changing network structure. In particular, using simulations, we study a variant of the Axelrod model on a network with a homophily-driven rewiring rule imposed. First, we find that the presence of rewiring within the network, in general, impedes the reaching of consensus in opinion, as the time to reach consensus diverges exponentially with network size N. We then investigate whether the introduction of committed individuals who are rigid in their opinion on a particular issue can speed up the convergence to consensus on that issue. We demonstrate that as committed agents are added, beyond a critical value of the committed fraction, the consensus time growth becomes logarithmic in network size N. Furthermore, we show that slight changes in the interaction rule can produce strikingly different results in the scaling behavior of consensus time, T(c). However, the benefit gained by introducing committed agents is qualitatively preserved across all the interaction rules we consider.


Simvastatin Induces Apoptosis and Suppresses Insulin-Like Growth Factor 1 Receptor in Bile Duct Cancer Cells.
Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.


Cognition mediates response to anthropogenic noise in wild Western Australian magpies (Gmynorhina tibicen dorsalis).
Anthropogenic noise is a pollutant of growing concern, with wide-ranging effects on taxa across ecosystems. Until recently, studies investigating the effects of anthropogenic noise on animals focused primarily on population-level consequences, rather than individual-level impacts. Individual variation in response to anthropogenic noise may result from extrinsic or intrinsic factors. One such intrinsic factor, cognitive performance, varies between individuals and is hypothesised to aid behavioural response to novel stressors. Here, we combine cognitive testing, behavioural focals and playback experiments to investigate how anthropogenic noise affects the behaviour and anti-predator response of Western Australian magpies (Gymnorhina tibicen dorsalis), and to determine whether this response is linked to cognitive performance. We found a significant population-level effect of anthropogenic noise on the foraging effort, foraging efficiency, vigilance, vocalisation rate and anti-predator response of magpies, with birds decreasing their foraging, vocalisation behaviours and anti-predator response, and increasing vigilance when loud anthropogenic noise was present. We also found that individuals varied in their response to playbacks depending on their cognitive performance, with individuals that performed better in an associative learning task maintaining their anti-predator response when an alarm call was played in anthropogenic noise. Our results add to the growing body of literature documenting the adverse effects of anthropogenic noise on wildlife and provide the first evidence for an association between individual cognitive performance and behavioural responses to anthropogenic noise.


Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses.
Recent studies have clarified that endogenous cannabinoids (endocannabinoids) are released from depolarized postsynaptic neurons in a Ca(2+)-dependent manner and act retrogradely on presynaptic cannabinoid receptors to suppress inhibitory or excitatory neurotransmitter release. This type of modulation has been found in the hippocampus and cerebellum and was called depolarization-induced suppression of inhibition (DSI) or excitation (DSE). In this study, we quantitatively examined the effects of postsynaptic depolarization and a cannabinoid agonist on excitatory and inhibitory synapses in rat hippocampal slices and cultures. We found that both DSE and DSI can be induced, but DSE was much less prominent than DSI. For the induction of DSE, the necessary duration of depolarization was longer than for DSI. The magnitude of DSE was much smaller than that of DSI. To explore the reasons for these differences, we tested the sensitivity of EPSCs and IPSCs to a cannabinoid agonist, WIN55,212-2, in hippocampal cultures. IPSCs were dichotomized into two distinct populations, one with a high sensitivity to WIN55,212-2 (50% block at 2 nm) and the other with no sensitivity. In contrast, EPSCs were homogeneous and exhibited a low sensitivity to WIN55,212-2 (50% block at 60 nm). We estimated that the 5 sec depolarization elevated the local endocannabinoid concentration to a level equivalent to several nanomoles of WIN55,212-2. Using CB1 knock-out mice, we verified that both DSI and DSE were mediated by the cannabinoid CB1 receptor. These results indicate that presynaptic cannabinoid sensitivity is a major factor that determines the extent of DSI and DSE.


A one-year follow-up of the cognitive and psycho-behavioural skills in artistic gymnastics.
A good set of cognitive and psycho-behavioural skills are beneficial for young athletes to overcome and benefit from developmental challenges. Unfortunately, there is still a dearth of knowledge on how both these cognitive (i.e., executive functions; EF) and psycho-behavioural (i.e., psychological characteristics of developing excellence; PCDE) skills develop in youth athletes. Especially for athletes in early specialisation sports such as artistic gymnastics, the early EF and PCDE development might be important to be able to cope with the pressure and challenges that comes with a transition to the next stage. In the current study, artistic gymnasts between 9 and 22 years old were tested twice with a 12-month interval to investigate the changes in EF and PCDE. Results showed that EF developed within the youngest stage, but plateaued at the later stages. Most PCDE did not seem to change over time within each stage. Furthermore, the transition to a new stage does not seem to coincide with an increased improvement of PCDE. However, with a case study approach in the oldest stages, still inter-individual differences in EF and PCDE scores over time were observed. This study shows that EF and PCDE develop over time, albeit in a non-linear way, and along a variety of developmental trajectories.


The Effects of Growth Hormone on Nerve Regeneration and Alloimmunity in Vascularized Composite Allotransplantation.
Poor outcomes in functional recovery following upper extremity transplantation are largely due to denervation-induced muscle atrophy that occurs during the prolonged period of nerve regeneration. Growth hormone (GH) has well-established trophic effects on neurons, myocytes, and Schwann cells and represents a promising therapeutic approach to address this challenge. This study sought to confirm the positive effects of GH treatment on nerve regeneration and functional recovery and to evaluate the effects of GH treatment on the immune response in the setting of vascularized composite allotransplantation. Rats underwent orthotopic forelimb transplantation across a full MHC-mismatch and received either porcine-derived growth hormone or no treatment (n=18 per group). Functional recovery was measured using electrically-stimulated grip strength testing. Animals were monitored for clinical and subclinical signs of rejection. Neuromuscular junction reinnervation and grip strength were improved in GH-treated animals (p=0.005; p=0.08). No statistically significant differences were seen in muscle atrophy, degree of myelination, axon diameter, and axon counts between groups. The rates of clinical and histological rejection did not significantly differ among groups. Our findings alleviate concern for increased risk of transplant rejection during GH therapy and therefore support the translation of growth hormone as a therapeutic method to promote improved functional recovery in upper extremity transplantation.


Redefining radiotherapy for early-stage breast cancer with single dose ablative treatment: a study protocol.
A shift towards less burdening and more patient friendly treatments for breast cancer is currently ongoing. In low-risk patients with early-stage disease, accelerated partial breast irradiation (APBI) is an alternative for whole breast irradiation following breast-conserving surgery. MRI-guided single dose ablative APBI has the potential to offer a minimally burdening, non-invasive treatment that could replace current breast-conserving therapy. The ABLATIVE study is a prospective, single arm, multicenter study evaluating preoperative, single dose, ablative radiation treatment in patients with early-stage breast cancer. Patients with core biopsy proven non-lobular invasive breast cancer, (estrogen receptor positive, Her2 negative, maximum tumor size 3.0 cm on diagnostic MRI) and a negative sentinel node biopsy are eligible. Radiotherapy (RT) planning will be performed using a contrast enhanced (CE) planning CT-scan, co-registered with a CE-MRI, both in supine RT position. A total of twenty-five consecutive patients will be treated with a single ablative RT dose of 20 Gy to the tumor and 15 Gy to the tumorbed. Follow-up MRIs are scheduled within 1 week, 2, 4 and 6 months after single-dose RT. Breast-conserving surgery is scheduled at six months following RT. Primary study endpoint is pathological complete response. Secondary study endpoints are the radiological response and toxicity. Furthermore, patients will fill out questionnaires on quality of life and functional status. Cosmetic outcome will be evaluated by the treating radiation oncologist, patient and 'Breast Cancer Conservation Treatment cosmetic results' software. Recurrence and survival rates will be assessed. The patients will be followed up to 10 years after diagnosis. If patients give additional informed consent, a biopsy and a part of the irradiated specimen will be stored at the local Biobank and used for future research on radiotherapy response associated genotyping. The ABLATIVE study evaluates MRI-guided single dose ablative RT in patients with early-stage breast cancer, aiming at a less burdening and non-invasive alternative for current breast-conserving treatment. ClinicalTrials.gov registration number NCT02316561 . The trial was registrated prospectively on October 10th 2014.