Anastellin impacts on the processing of extracellular matrix fibronectin and stimulates release of cytokines from coronary artery smooth muscle cells.
Anastellin, a recombinant protein fragment from the first type III module of fibronectin, mimics a partially unfolded intermediate implicated in the assembly of fibronectin fibrils. Anastellin influences the structure of fibronectin and initiates in vitro fibrillation, yielding "superfibronectin", a polymer with enhanced cell-adhesive properties. This ability is absent in an anastellin double mutant, L37AY40A. Here we demonstrate that both wild-type and L37AY40A anastellin affect fibronectin processing within the extracellular matrix (ECM) of smooth muscle cells. Fibronectin fibrils are diminished in the ECM from cells treated with anastellin, but are partially rescued by supplementation with plasma fibronectin in cell media. Proteomic analyses reveal that anastellin also impacts on the processing of other ECM proteins, with increased collagen and decreased laminin detected in media from cells exposed to wild-type anastellin. Moreover, both anastellin forms stimulate release of inflammatory cytokines, including interleukin 6. At the molecular level, L37AY40A does not exhibit major perturbations of structural features relative to wild-type anastellin, though the mutant showed differences in heparin binding characteristics. These findings indicate that wild-type and L37AY40A anastellin share similar molecular features but elicit slightly different, but partially overlapping, responses in smooth muscle cells resulting in altered secretion of cytokines and proteins involved in ECM processing.


Exploring the Performance of Geometry-Based Markerless Registration in a Simulated Surgical Environment: A Comparative Study of Registration Algorithms in Medical Augmented Reality.
Augmented Reality (AR) has been utilized in multiple applications in the medical field, such as augmenting Computed Tomography (CT) images onto the patient's body during surgery. However, one of the challenges in its utilization is to register the pre-operative CT images to the patient's body accurately. The current registration process requires prior attachment of tracking markers, and their localization within the body and CT images. This process can be cumbersome, error-prone, and dependent on the surgeon's experience. Moreover, there are cases where medical instruments, drapes, or the body may occlude the markers. In light of these limitations, markerless registration algorithms have the potential to aid the registration process in the clinical setting. While those algorithms have been successfully used in other sectors, such as multimedia, they have not yet been thoroughly investigated in a clinical setting, especially in surgery, where there are more challenging cases with different positions of the patients in the image and the surgical environment. In this paper, we benchmarked and evaluated the performance of 6 state-of-the-art markerless registration algorithms from the multimedia sector by registering a CT image onto the whole-body phantom dataset acquired from a simulated surgical environment. We also analyzed the suitability of these algorithms for use in the surgical setting and discussed their potential for the advancement of AR-assisted surgery.Clinical Relevance-Our study provides insight into the potential of AR-assisted surgery and helps practitioners in choosing the most suitable registration algorithm for their needs to improve patient outcomes, reduce the risk of surgical errors and shorten the time of preoperative planning.


Convective Radio Frequency Thermal Therapy for Treatment of Benign Prostatic Hyperplasia: Single Office Experience with 255 Patients over 4 Years.
Convective radio frequency thermal therapy with the Rezūm® system is a relatively new treatment for benign prostatic hyperplasia with proven short-term durability. We report an update of previously published data from a single center showing durability through 4 years. A retrospective review of 255 patients who underwent the Rezūm procedure from a single surgeon was performed, including 25 patients from the Rezūm II study, from March 2014 to April 2018. Maximum urinary flow rate, I-PSS (International Prostate Symptom Score), I-PSS-QOL (quality of life), post-void residual, medication use and adverse events were monitored. Data were analyzed at baseline, and 3, 6, 12, 24, 36 and 48 months after treatment. Statistically significant improvement in maximum urinary flow rate (57.2%), I-PSS (54.7%) and I-PSS-QOL (59.2%) appear to be durable through 48 months, with improvement greater than 50% at most recent followup. We report a similarly low reoperation rate compared to the most recent data from the Rezūm II study (3.1% vs 4.4%), but with higher rates of urinary tract infection (18.8% vs 3.7%) and urinary retention (15.7% vs 3.7%). Overall satisfaction with the procedure experience (93.9%) and the outcome (90.9%) was high, with 97% of men interviewed recommending the procedure to a friend. In addition, 80% of men were able to stop all medication. Our experience provides the largest published cohort of patients undergoing this procedure and shows durable improvements in maximum urinary flow rate, I-PSS and I-PSS-QOL through 4 years. Patients outside of the inclusion criteria of Rezūm II appear to benefit from the procedure.


Orderly recruitment of thermoeffectors in resting humans.
The recruitment of thermoeffectors, including thermoregulatory behavior, relative to changes in body temperature has not been quantified in humans. We tested the hypothesis that changes in skin blood flow, behavior, and sweating or metabolic rate are initiated with increasing changes in mean skin temperature (Tskin) in resting humans. While wearing a water-perfused suit, 12 healthy young adults underwent heat (Heat) and cold stress (Cold) that induced gradual changes in Tskin. Subjects controlled the temperature of their dorsal neck to their perceived thermal comfort. Thus neck skin temperature provided an index of thermoregulatory behavior. Neck skin temperature (Tskin), core temperature (Tcore), metabolic rate, sweat rate, and nonglabrous skin blood flow were measured continually. Data were analyzed using segmental regression analysis, providing an index of thermoeffector activation relative to changes in Tskin. In Heat, increases in skin blood flow were observed with the smallest elevations in Tskin ( P < 0.01). Thermal behavior was initiated with an increase in Tskin of 2.4 ± 1.3°C (mean ± SD, P = 0.04), while sweating was observed with further elevations in Tskin (3.4 ± 0.5°C, P = 0.04), which coincided with increases in Tcore ( P = 0.98). In Cold, reductions in skin blood flow occurred with the smallest decrease in Tskin ( P < 0.01). Thermal behavior was initiated with a Tskin decrease of 1.5 ± 1.3°C, while metabolic rate ( P = 0.10) and Tcore ( P = 0.76) did not change throughout. These data indicate that autonomic and behavioral thermoeffectors are recruited in coordination with one another and likely in an orderly manner relative to the comparative physiological cost.


Senescent human diploid fibroblasts are able to support DNA synthesis and to express markers associated with proliferation.
The characteristic limited reproductive life-span of normal human fibroblasts in culture is due to a steadily decreasing fraction of cells able to proliferate in the standard rich growth media. We have observed that restricting the growth factor supply to old cells for variable lengths of time in culture increases the fraction of cells that can enter S-phase; although these cells do not go on to divide. Thus, it seems that there is a transient phase between the proliferating state and the irreversibly post-mitotic, senescent state. Perhaps a 'quiescent-G0' state, which can be maintained in the presence of growth factors, is a stage on the pathway to mortalization and senescence.


Analysis of spurious diffraction orders of computer-generated hologram in symmetric aspheric metrology.
Computer-generated hologram (CGH) has been widely used as a wavefront compensator in symmetric aspheric metrology. As a diffractive element, it generates different diffraction orders, but only the 1st-order diffraction is used to test aspheric surface. The light from spurious diffraction orders (SDO) will produce many high-frequency fringes in interferogram and reduce measurement accuracy. In this paper, we regard the CGH null system as an imaging system and develop an aberration model in Seidel formalism to analyze the SDO. This model has the advantage to address the difference between the SDO (k1, k2) and (k2, k1). We consider the effect of the pupil distortion so that our model can analyze the SDO with a large pupil distortion. We derive the condition to ensure the 2nd-order and 4th-order aberrations have the same sign and calculate the minimum defocused distance (power carrier frequency) of CGH. According to the marginal-ray heights (h1andh3) on the CGH in the first and second passes, we determine the condition that the SDO covers the whole CGH in the second pass. We analyze the SDO of 4 CGH designs and compare the results from our aberration model with these from real ray trace. These results validate that our aberration model is feasible whether the aspheric part is convex or concave and whether CGH is inside or outside the focus of the transmission sphere.


Electrocatalytic activity of silver nanoparticles modified glassy carbon electrode as amperometric sensor for hydrogen peroxide.
A simple chemical route has been applied for the preparation of quasi-spherical silver (Ag) nanoparticles (NPs) with average diameter of 265 and 8 nm. The as prepared products were characterized by powder X-ray diffraction (XRD), transmission electron microscopy (TEM) and UV-vis absorption spectroscopy. Ag NPs immobilized on glassy carbon (GC) electrode showed a superior electrocatalytic activity for the reduction of hydrogen peroxide (H2O2) in aqueous medium. The fabricated electrode was also applied for the amperometric detection of H2O2 and showed a favorable response at an applied potential of -0.5 V (vs. Ag/AgCl). The results demonstrate that the fabricated electrode has potential application for hydrogen peroxide sensor.


Single-step multimodal locoregional treatment for unresectable hepatocellular carcinoma: balloon-occluded percutaneous radiofrequency thermal ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE).
This study was undertaken to evaluate the feasibility, safety and efficacy of a new combined single-step therapy in patients with unresectable multinodular unilobar hepatocellular carcinoma (HCC), with at least one lesion >3 cm, with balloon-occluded radiofrequency ablation (BO-RFA) plus transcatheter arterial chemoembolization (TACE) of the main lesion and TACE of the other lesions. The second purpose of our study was to compare the initial effects in terms of tumour necrosis of this new combined therapy with those obtained in a matched population treated with TACE alone in a singlestep treatment in our centre in the previous year. This pilot study was approved by the institutional review board, and informed consent was obtained from all patients. Ten consecutive patients with multinodular (two to six nodules) unilobar unresectable HCC and with a main target lesion >3 cm (range, 3.5-6 cm) not suitable for curative therapy were enrolled in our single-centre multidisciplinary pilot study. The schedule consisted of percutaneous RFA (single 3-cm monopolar needle insertion) of the target lesion during occlusion of the hepatic artery supplying the tumour, followed by selective TACE, plus lobar TACE for other lesions (450-mg carboplatin and lipiodol plus temporary embolisation with SPONGOSTAN). Adverse events and intra- and periprocedural complications were clinically assessed. Early local efficacy was evaluated on 1-month follow-up multiphasic computed tomography (CT) on the basis of the Modified Response Evaluation Criteria in Solid Tumors (m-RECIST). A separate evaluation of target lesions in terms of enhancement, necrotic diameter and presence and distribution of lipiodol uptake was also performed. No major complications occurred. Overall technical success, defined as complete devascularisation of all nodules during the arterial phase, was achieved in seven of 10 patients, with three cases of partial response (persistence of small hypervascular nodules). When considering only target lesions, technical success was obtained in all patients, with a nonenhancing area corresponding in shape to the previously identified HCC (necrotic diameter, 3.5-5 cm) and with circumferential peripheral lipiodol uptake (safety margin) of at least 0.5 cm (0.5-1.3cm). TACE and BO-RFA, plus TACE in a singlestep approach seems to be a safe and effective combined therapy for treating advanced, unresectable HCC lesions, allowing a high rate of complete local response to be achieved in large lesions also.


Analyzing Social Media to Explore the Attitudes and Behaviors Following the Announcement of Successful COVID-19 Vaccine Trials: Infodemiology Study.
The rollout of COVID-19 vaccines has brought vaccine hesitancy to the forefront in managing this pandemic. COVID-19 vaccine hesitancy is fundamentally different from that of other vaccines due to the new technologies being used, rapid development, and widespread global distribution. Attitudes on vaccines are largely driven by online information, particularly information on social media. The first step toward influencing attitudes about immunization is understanding the current patterns of communication that characterize the immunization debate on social media platforms. We aimed to evaluate societal attitudes, communication trends, and barriers to COVID-19 vaccine uptake through social media content analysis to inform communication strategies promoting vaccine acceptance. Social network analysis (SNA) and unsupervised machine learning were used to characterize COVID-19 vaccine content on Twitter globally. Tweets published in English and French were collected through the Twitter application programming interface between November 19 and 26, 2020, just following the announcement of initial COVID-19 vaccine trials. SNA was used to identify social media clusters expressing mistrustful opinions on COVID-19 vaccination. Based on the SNA results, an unsupervised machine learning approach to natural language processing using a sentence-level algorithm transfer function to detect semantic textual similarity was performed in order to identify the main themes of vaccine hesitancy. The tweets (n=636,516) identified that the main themes driving the vaccine hesitancy conversation were concerns of safety, efficacy, and freedom, and mistrust in institutions (either the government or multinational corporations). A main theme was the safety and efficacy of mRNA technology and side effects. The conversation around efficacy was that vaccines were unlikely to completely rid the population of COVID-19, polymerase chain reaction testing is flawed, and there is no indication of long-term T-cell immunity for COVID-19. Nearly one-third (45,628/146,191, 31.2%) of the conversations on COVID-19 vaccine hesitancy clusters expressed concerns for freedom or mistrust of institutions (either the government or multinational corporations) and nearly a quarter (34,756/146,191, 23.8%) expressed criticism toward the government's handling of the pandemic. Social media content analysis combined with social network analysis provides insights into the themes of the vaccination conversation on Twitter. The themes of safety, efficacy, and trust in institutions will need to be considered, as targeted outreach programs and intervention strategies are deployed on Twitter to improve the uptake of COVID-19 vaccination.


Tb(HSO4)(SO4) - a green emitting hydrogensulfate sulfate with second harmonic generation response.
Recently, sulfates have attracted attention as materials for non-linear optical applications. This compound class is extended by Tb(HSO4)(SO4), which is solvothermally synthesised from Tb4O7 and sulfuric acid. The compound crystallises in the non-centrosymmetric space group P21 (Z = 2, a = 665.03(5) pm, b = 659.41(5) pm, c = 680.24(5) pm, and β = 104.640(2)°) and is homeotypic with Ni2In. The terbium ions adopt the indium sites and the sulfate and hydrogen sulfate anions are situated on the nickel sites. The compound shows green luminescence based on f-f-transitions and the positions of the f-d-excitation bands reveal a weak coordination behaviour of the sulfate anions. Tb(HSO4)(SO4) exhibits a second harmonic generation response comparable to KH2PO4 (KDP). Furthermore, the material is characterised by electrostatic calculations, infrared spectroscopy and thermal analysis.


FluB-RAM and FluB-RANS: Genome Rearrangement as Safe and Efficacious Live Attenuated Influenza B Virus Vaccines.
Influenza B virus (IBV) is considered a major respiratory pathogen responsible for seasonal respiratory disease in humans, particularly severe in children and the elderly. Seasonal influenza vaccination is considered the most efficient strategy to prevent and control IBV infections. Live attenuated influenza virus vaccines (LAIVs) are thought to induce both humoral and cellular immune responses by mimicking a natural infection, but their effectiveness has recently come into question. Thus, the opportunity exists to find alternative approaches to improve overall influenza vaccine effectiveness. Two alternative IBV backbones were developed with rearranged genomes, rearranged M (FluB-RAM) and a rearranged NS (FluB-RANS). Both rearranged viruses showed temperature sensitivity in vitro compared with the WT type B/Bris strain, were genetically stable over multiple passages in embryonated chicken eggs and were attenuated in vivo in mice. In a prime-boost regime in naïve mice, both rearranged viruses induced antibodies against HA with hemagglutination inhibition titers considered of protective value. In addition, antibodies against NA and NP were readily detected with potential protective value. Upon lethal IBV challenge, mice previously vaccinated with either FluB-RAM or FluB-RANS were completely protected against clinical disease and mortality. In conclusion, genome re-arrangement renders efficacious LAIV candidates to protect mice against IBV.


Uptake in the liver: the nature of the process.
The methodology developed to assess the permeability of capillaries has been extended and applied to the study of the uptake of materials by the intact liver. The sinusoidal membrane has been found to be freely permeable to dissolved substances, so that the Disse spaces are functionally a simple extension of the sinusoidal plasma space. With this free access, a concentration bolus of material dissolved in plasma is found to be propagated in a delayed fashion, to behave as if it were flowing within this larger space. Within the space an exclusion phenomenon is found: the collagen and ground substance within it reduce the proportion of the space accessible to larger molecules in a graded fashion. Beyond the Disse spaces the first biological barrier for substances characteristically taken up by the liver is the cell membrane of the hepatic parenchymal cells. The uptake of materials, in general, therefore has the characteristics of a membrane carrier transport process. The phenomena distinctively associated with this process include saturation kinetics, competitive inhibition, and isotope countertransport. Beyond the membrane those substances sequestered by biochemical transformations or biliary secretion are handled by processes that also show saturation effects. The multiple indicator dilution technique has been adapted to the study of the uptake of materials at the liver cell surface. The process has been modeled and outflow profiles have been shown to consist of a throughput component (which has not entered the cells) and a returning component (which has entered the cells and returned to the plasma space to emerge at the outflow). When the process at the cell membrane is concentrative, the throughput component is emphasized by the relatively larger delay caused in the returning component by virtue of the concentratively enlarged cellular volume. When the process is nonconcentrative, the returning component emerges earlier, so that throughput and returning components are not longer directly apparent and must be separated out by carrying out model analysis of the data with a digital computer. The uptake of tracer rubidium was found to be a typically concentrative process, and that of tracer glucose a nonconcentrative process. When substrate undergoes intracellular sequestration, a new set of phenomena emerge. The sequestration reduces the magnitude of the returning component in a tracer experiment and, with this, produces a steady state gradient in lobular concentration, a profile decreasing in magnitude from the portal area to the adjacent terminal hepatic venules. The diminution in returning components has been observed both for galactose and for the group of compounds characteristically secreted in bile in high concentration. The lobular gradient for galactose has been demonstrated autoradiographically. It is evident that a powerful new set of tools has emerged...


Sustained release of decorin to the surface of the eye enables scarless corneal regeneration.
Disorganization of the transparent collagenous matrix in the cornea, as a consequence of a variety of infections and inflammatory conditions, leads to corneal opacity and sight-loss. Such corneal opacities are a leading cause of blindness, according to the WHO. Public health programs target prevention of corneal scarring, but the only curative treatment of established scarring is through transplantation. Although attempts to minimize corneal scarring through aggressive control of infection and inflammation are made, there has been little progress in the development of anti-scarring therapies. This is owing to eye drop formulations using low viscosity or weak gelling materials having short retention times on the ocular surface. In this study, we report an innovative eye drop formulation that has the ability to provide sustained delivery of decorin, an anti-scarring agent. The novelty of this eye drop lies in the method of structuring during manufacture, which creates a material that can transition between solid and liquid states, allowing retention in a dynamic environment being slowly removed through blinking. In a murine model of Pseudomonas keratitis, applying the eye drop resulted in reductions of corneal opacity within 16 days. More remarkably, the addition of hrDecorin resulted in restoration of corneal epithelial integrity with minimal stromal opacity endorsed by reduced α-smooth muscle actin (αSMA), fibronectin, and laminin levels. We believe that this drug delivery system is an ideal non-invasive anti-fibrotic treatment for patients with microbial keratitis, potentially without recourse to surgery, saving the sight of many in the developing world, where corneal transplantation may not be available.


Proteomic analysis of salt-sensitive outer membrane proteins of Vibrio parahaemolyticus.
Vibrio parahaemolyticus, a universal marine pathogen with available genome sequences, could be used as a bacterial model to clarify the various physiological phenomena of its native and host environments. In the present study, proteomic methodologies were applied to investigate the expression pattern of outer membrane proteins (OMPs) of V. parahaemolyticus at different NaCl concentrations. OmpW, OmpV, elongation factor TU and polar flagellin were determined to be osmoregulation-sensitive OMPs, among which OmpW and OmpV were reported to vary with changed NaCl concentrations in the pattern of osmolarity regulation. Therefore, our results not only expand our knowledge on osmoregulation-related proteins, but also provide a valuable strategy for the screening of salt-sensitive proteins.


The development of the respiratory chain of Saccharomyces carlsbergensis during respiratory adaptation.
1. Subcellular fractionation of sphaeroplasts produced at different stages during the first 4h of respiratory adaptation of anaerobically grown glucose-de-repressed Saccharomyces carlsbergensis gave mitochondrial fractions that contained all the detectable c- and a-type cytochromes. 2. The rates of cytochrome formation were studied; individual cytochromes were produced at different rates so as to give respiratory chains having widely differing cytochrome ratios. A CO-reacting haemoprotein other than cytochrome a(3) also increased throughout 8h of respiratory adaptation. 3. Even after short periods of aeration, organisms contained mitochondria in which cytochrome-cytochrome interactions and the reaction of cytochrome a(3) with O(2) proceeded at rates almost as fast as in organelles from aerobically grown cells. 4. The technique of flow-flash photolysis enabled kinetic resolution of the reoxidation of cytochromes a(3) and a to be achieved and their individual contributions to extinction changes in the Soret region were assessed. The ratio cytochrome a(3)/cytochrome a increased over the early stages of adaptation.


Altered Cortical Ensembles in Mouse Models of Schizophrenia.
In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine (KET) administration and Df(16)A+/-, modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gamma-band abnormalities similar to patient studies. Two-photon calcium imaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles), which was not a simple consequence of altered single-neuron activity. This effect was present in ongoing and sensory-evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an "attractor" disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia.


Minimally Invasive Breast Biopsy After Neoadjuvant Systemic Treatment to Identify Breast Cancer Patients with Residual Disease for Extended Neoadjuvant Treatment: A New Concept.
Breast cancer patients with residual disease after neoadjuvant systemic treatment (NAST) have a worse prognosis compared with those achieving a pathologic complete response (pCR). Earlier identification of these patients might allow timely, extended neoadjuvant treatment strategies. We explored the feasibility of a vacuum-assisted biopsy (VAB) after NAST to identify patients with residual disease (ypT+ or ypN+) prior to surgery. We used data from a multicenter trial, collected at 21 study sites (NCT02948764). The trial included women with cT1-3, cN0/+ breast cancer undergoing routine post-neoadjuvant imaging (ultrasound, MRI, mammography) and VAB prior to surgery. We compared the findings of VAB and routine imaging with the histopathologic evaluation of the surgical specimen. Of 398 patients, 34 patients with missing ypN status and 127 patients with luminal tumors were excluded. Among the remaining 237 patients, tumor cells in the VAB indicated a surgical non-pCR in all patients (73/73, positive predictive value [PPV] 100%), whereas PPV of routine imaging after NAST was 56.0% (75/134). Sensitivity of the VAB was 72.3% (73/101), and 74.3% for sensitivity of imaging (75/101). Residual cancer found in a VAB specimen after NAST always corresponds to non-pCR. Residual cancer assumed on routine imaging after NAST corresponds to actual residual cancer in about half of patients. Response assessment by VAB is not safe for the exclusion of residual cancer. Response assessment by biopsies after NAST may allow studying the new concept of extended neoadjuvant treatment for patients with residual disease in future trials.


The transcriptional regulator NFIL3 controls IgE production.
Cytokines are essential modulators of the immune response that underlies the inflammatory component of atopic asthma and other allergic diseases, lnterleukin-4 is an important cytokine for the regulation of allergic immune responses. However, the molecular mechanisms that regulate the response of cells to IL-4 are still not completely defined. IL-4 plays an important role in B cell biology. It can regulate B cell differentiation. For example, IL-4 induces immunoglobulin heavy chain class switching to IgE by inducing germline immunoglobulin heavy chain transcription. It also induces expression of CD23 and MHC class II. Further understanding of the mechanisms by which IL-4 mediates these biologic responses may lead to novel mechanisms for therapeutic intervention and control of allergy. To define how different signaling pathways activated by IL-4 regulate gene transcription, we identified many differentially expressed genes by IL-4 stimulation by microarray analysis. NFIL3 (nuclear factor, interleukin 3 regulated) is the most strongly induced transcription factor by IL-4 stimulation in a STAT6-dependent manner. To analyze the role of NFIL3 in the immune system, we have generated NFIL3-deficient mice. NFIL3-deficient mice showed greatly impaired IgE production in response to antigen. NFIL3-deficient B cells fail to produce IgE in response to LPS plus IL-4. These defects may be due to the reduced production of immunoglobulin heavy chain germline epsilon transcripts in the absence of NFIL3. Moreover, NFIL3 KO mice sensitized and challenged with ovalbumin showed reduced airway hyper-responsiveness when compared to wild-type mice. Therefore, we hypothesize that NFIL3 is a critical regulator for IgE production and airway hyper-responsiveness.


Nickel-Substituted Rubredoxin as a Minimal Enzyme Model for Hydrogenase.
A simple, functional mimic of [NiFe] hydrogenases based on a nickel-substituted rubredoxin (NiRd) protein is reported. NiRd is capable of light-initiated and solution-phase hydrogen production and demonstrates high electrocatalytic activity using protein film voltammetry. The catalytic voltammograms are modeled using analytical expressions developed for hydrogenase enzymes, revealing maximum turnover frequencies of approximately 20-100 s(-1) at 4 °C with an overpotential of 540 mV. These rates are directly comparable to those observed for [NiFe] hydrogenases under similar conditions. Like the native enzymes, the proton reduction activity of NiRd is strongly inhibited by carbon monoxide. This engineered rubredoxin-based enzyme is chemically and thermally robust, easily accessible, and highly tunable. These results have implications for understanding the enzymatic mechanisms of native hydrogenases, and, using NiRd as a scaffold, it will be possible to optimize this catalyst for application in sustainable fuel generation.


Comb-like Pseudopeptides Enable Very Rapid and Efficient Intracellular Trehalose Delivery for Enhanced Cryopreservation of Erythrocytes.
Cell cryopreservation plays a key role in the development of reproducible and cost-effective cell-based therapies. Trehalose accumulated in freezing- and desiccation-tolerant organisms in nature has been sought as an attractive nontoxic cryoprotectant. Herein, we report a coincubation method for very rapid and efficient delivery of membrane-impermeable trehalose into ovine erythrocytes through reversible membrane permeabilization using pH-responsive, comb-like pseudopeptides. The pseudopeptidic polymers containing relatively long alkyl side chains were synthesized to mimic membrane-anchoring fusogenic proteins. The intracellular trehalose delivery efficiency was optimized by manipulating the side chain length, degree of substitution, and concentration of the pseudopeptides with different hydrophobic alkyl side chains, the pH, temperature, and time of incubation, as well as the polymer-to-cell ratio and the concentration of extracellular trehalose. Treatment of erythrocytes with the comb-like pseudopeptides for only 15 min yielded an intracellular trehalose concentration of 177.9 ± 8.6 mM, which resulted in 90.3 ± 0.7% survival after freeze-thaw. The very rapid and efficient delivery was found to be attributed to the reversible, pronounced membrane curvature change as a result of strong membrane insertion of the comb-like pseudopeptides. The pseudopeptides can enable efficient intracellular delivery of not only trehalose for improved cell cryopreservation but also other membrane-impermeable cargos.


[Mechanical study of potential ceramic implant materials for minimal invasive anterior lumbar interbody fusion].
While autologous bone grafts are highly suitable for use in spinal arthrodesis, their use is also associated with problems (traumatization, complications). Ceramic bone substitute materials provide an attractive alternative for lumbar interbody spinal fusion. The aim of the present study was to investigate the mechanical properties of various types of ceramic using a specific fusion method. Ten specimens each of 7 different types of ceramic were tested using a hydraulic testing machine with two different sample holders: polyurethane foam (mechanical properties similar to cancellous bone) and aluminium. The parameters axial compression and axial torque were investigated. With the polyurethane foam holders, none of the ceramic implants failed under compression, while under axial rotation, two types of ceramic failed. With the aluminium holders, 3 ceramics showed no failure up to 25 kN under compression, while under torsion all the ceramics failed. One type of ceramic showed specific fracture properties with a higher load-bearing capacity after failure in comparison with all the other types studied.


Reduced Systolic Function and Not Genetic Variants Determine Outcome in Pediatric and Adult Left Ventricular Noncompaction Cardiomyopathy.
Background: Left ventricular noncompaction cardiomyopathy (LVNC CMP) is a genetic cardiomyopathy. Genotype-phenotype correlation and clinical outcome of genetic variants in pediatric and adult LVNC CMP patients are still unclear. Methods: The retrospective multicenter study was conducted in unrelated index patients with LVNC CMP, diagnosed between the years 1987 and 2017, and all available family members. All index patients underwent next-generation sequencing for genetic variants in 174 target genes using the Illumina TruSight Cardio Sequencing Panel. Major adverse cardiac events (MACE) included mechanical circulatory support, heart transplantation, survivor of cardiac death, and/or all-cause death as combined endpoint. Results: Study population included 149 LVNC CMP patients with a median age of 27.8 (9.2-44.8) years at diagnosis; 58% of them were symptomatic, 18% suffered from non-sustained and sustained arrhythmias, and 17% had an implantable cardioverter defibrillator (ICD) implanted. 55/137 patients (40%) were ≤ 18 years at diagnosis. A total of 134 variants were identified in 87/113 (77%) index patients. 93 variants were classified as variant of unknown significance (VUS), 24 as likely pathogenic and 15 as pathogenic. The genetic yield of (likely) pathogenic variants was 35/113 (31%) index patients. Variants occurred most frequently in MYH7 (n=19), TTN (n = 10) and MYBPC3 (n = 8). Altogether, sarcomere gene variants constituted 42.5% (n = 57) of all variants. The presence or absence of (likely) pathogenic variants or variants in specific genes did not allow risk stratification for MACE. Reduced left ventricular (LV) systolic function and increased left ventricular end-diastolic diameter (LVEDD) were risk factors for event-free survival in the Kaplan-Meier analysis. Through multivariate analysis we identified reduced LV systolic function as the main risk factor for MACE. Patients with reduced LV systolic function were at a 4.6-fold higher risk for MACE. Conclusions: Genetic variants did not predict the risk of developing a MACE, neither in the pediatric nor in the adult cohort. Multivariate analysis emphasized reduced LV systolic function as the main independent factor that is elevating the risk for MACE. Genetic screening is useful for cascade screening to identify family members at risk for developing LVNC CMP.


Transcriptome Analysis Reveals Key Genes Involved in Weevil Resistance in the Hexaploid Sweetpotato.
Because weevils are the most damaging pests of sweetpotato, the development of cultivars resistant to weevil species is considered the most important aspect in sweetpotato breeding. However, the genes and the underlying molecular mechanisms related to weevil resistance are yet to be elucidated. In this study, we performed an RNA sequencing-based transcriptome analysis using the resistant Kyushu No. 166 (K166) and susceptible Tamayutaka cultivars. The weevil resistance test showed a significant difference between the two cultivars at 30 days after the inoculation, specifically in the weevil growth stage and the suppressed weevil pupation that was only observed in K166. Differential expression and gene ontology analyses revealed that the genes upregulated after inoculation in K166 were related to phosphorylation, metabolic, and cellular processes. Because the weevil resistance was considered to be related to the suppression of larval pupation, we investigated the juvenile hormone (JH)-related genes involved in the inhibition of insect metamorphosis. We found that the expression of some terpenoid-related genes, which are classified as plant-derived JHs, was significantly increased in K166. This is the first study involving a comprehensive gene expression analysis that provides new insights about the genes and mechanisms associated with weevil resistance in sweetpotato.


Quantitative analysis of lymphocyte differentiation and proliferation in vitro using carboxyfluorescein diacetate succinimidyl ester.
Mature T and B lymphocytes respond to receptor-delivered signals received during and following activation. These signals regulate the rates of cell death, growth, differentiation and migration that ultimately establish the behaviour patterns collectively referred to as immune regulation. We have been pursuing the philosophy that in vitro systems of lymphocyte stimulation, when analysed quantitatively, help reveal the logical attributes of lymphocyte behaviour. The development of carboxyfluorescein diacetate succinimidyl ester (CFSE) to track division has enabled the variable of division number to be incorporated into these quantitative analyses. Our studies with CFSE have established a fundamental link between differentiation and division number. Isotype switching, expression of T cell cytokines, surface receptor alterations and changes to intracellular signalling components all display independent patterns of change with division number. The stochastic aspects of these changes and the ability of external signals to independently regulate them argue for a probabilistic modelling framework for describing and understanding immune regulation.


Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 1: thyroid-stimulating hormone.
Laboratory testing of serum thyroid-stimulating hormone (TSH) is an essential tool for the diagnosis and management of various thyroid disorders whose collective prevalence lies between 4% and 8%. However, between-assay discrepancies in TSH results limit the application of clinical practice guidelines. We performed a method comparison study with 40 sera to assess the result comparability and performance attributes of 16 immunoassays. Thirteen of 16 assays gave mean results within 10% of the overall mean. The difference between the most extreme means was 39%. Assay-specific biases could be eliminated by recalibration to the overall mean. After recalibration of singlicate results, all assays showed results within the biological total error goal (22.8%), except for 1 result in each of 4 assays. For a sample with a TSH concentration of 0.016 mIU/L, 6 assays either did not report results or demonstrated CVs >20%. Within-run and total imprecision ranged from 1.5% to 5.5% and 2.5% to 7.7%, respectively. Most assays were able to match the internal QC targets within 5%. Within-run drifts and shifts were observed. Harmonization of TSH measurements would be particularly beneficial for 3 of the 16 examined assays. These data demonstrate that harmonization may be accomplished by establishing calibration traceability to the overall mean values for a panel of patient samples. However, the full impact of the approach must be further explored with a wider range of samples. Although a majority of assays showed excellent quality of performance, some would benefit from improved within-run stability.


Long-term outcomes with Boston type 1 keratoprosthesis in ocular burns.
To evaluate the long-term outcomes of Boston type I keratoprosthesis (B-Kpro) in the management of patients with ocular burn injuries. This prospective study included all patients with ocular burns who underwent B-Kpro implantation at a tertiary eye care center between February 2008 and November 2015. Twelve patients (12 eyes) were enrolled. The procedures performed for managing ocular injury were identified, and information on ocular history, surgical procedures performed, and postoperative outcomes was collected. The main outcome measures were visual acuity, prosthesis retention, postoperative complications, and required surgical procedures. Twelve eyes from 12 patients met the inclusion criteria for B-Kpro implantation, including nine eyes with alkali burns and three eyes with thermal burns. A total of 13 B-Kpro devices were implanted in the 12 eyes. The mean follow-up period was 60.8 months (range, 13-91 months). Preoperative best-corrected visual acuity ranged from counting fingers to light perception. Postoperative best-corrected visual acuity was better than 20/200 in 83.3%, 66.6%, and 57.1% of patients at 12, 48, and 60 months, respectively. The initial keratoprosthesis was retained in 10 (83.3%) eyes and was successfully replaced in one eye. The major cause of worsening of initial visual acuity was advanced glaucoma (four of 12 eyes). The anatomical and functional results support the use of B-Kpro for managing bilateral limbal stem cell deficiency secondary to ocular burns. However, glaucoma should be carefully evaluated, as it is a continuous threat that may result in irreversible visual loss in this population.


Opuntia ficus-indica ingestion stimulates peripheral disposal of oral glucose before and after exercise in healthy men.
The purpose of this study was to investigate the effect of Opuntia ficus-indica (OFI) cladode and fruit-skin extract on blood glucose and plasma insulin increments due to high-dose carbohydrate ingestion, before and after exercise. Healthy, physically active men (n = 6; 21.0 ± 1.6 years, 78.1 ± 6.0 kg) participated in a double-blind placebo-controlled crossover study involving 2 experimental sessions. In each session, the subjects successively underwent an oral glucose tolerance test at rest (OGTT(R)), a 30-min cycling bout at ~75% VO(2max), and another OGTT after exercise (OGTT(EX)). They received capsules containing either 1,000 mg OFI or placebo (PL) 30 min before and immediately after the OGTT(R). Blood samples were collected before (t₀) and at 30-min intervals after ingestion of 75 g glucose for determination of blood glucose and serum insulin. In OGTT(EX) an additional 75-g oral glucose bolus was administered at t₆₀. In OGTT(R), OFI administration reduced the area under the glucose curve (AUC(GLUC)) by 26%, mainly due to lower blood glucose levels at t₃₀ and t₆₀ (p < .05). Furthermore, a higher serum insulin concentration was noted after OFI intake at baseline and at t₃₀ (p < .05). In OGTT(EX), blood glucose at t₆₀ was ~10% lower in OFI than in PL, which resulted in a decreased AUC(GLUC) (-37%, p < .05). However, insulin values and AUC(INS) were not different between OFI and PL. In conclusion, the current study shows that OFI extract can increase plasma insulin and thereby facilitate the clearance of an oral glucose load from the circulation at rest and after endurance exercise in healthy men.


Thrombin generation and platelet activation in cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy - A prospective cohort study.
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal peroperative chemotherapy (HIPEC), indicated for patients with peritoneal metastases from digestive or gynecological malignancies alike, demonstrates a considerable impact on hemostatic metabolism, both on platelet and on coagulation level. The potential hemostatic interference in CRS and HIPEC is phase dependent. The hypothesis of this prospective cohort study is that the procedure exposed an increased thrombotic risk, resulting in a faster and increased thrombin generation and hyper platelet function. This study explores the combined use of ROTEM (rotational thromboelastometry), PACT (platelet activation test) and CAT (thrombin generation test) assays during CRS and HIPEC with a follow-up of 7 days postoperative in 27 patients with confirmed histological diagnosis of peritoneal disease. Platelet reactivity (relative to before incision values) to CRP (collagen-related peptide) (p value 0.02) and TRAP (thrombin receptor activator peptide) (p value 0.048) seems to be slightly reduced during CRS and HIPEC with regard to αIIbβ3 activation, while P-selectin expression is not affected. During surgery, CAT demonstrates that, the LT (lagtime) (p value 0.0003) and TTP (time-to-thrombin peak) values (p value 0.002) decrease while and the TP (thrombin peak) (p value 0.004) and ETP (endogenous thrombin potential) (p value 0.02) increase. Subsequently, after surgery, the LT and TTP increase and ETP and TP decrease in time. ROTEM EXTEM (extrinsic) MCF (maximum clot firmness) (p value 0.005), INTEM (intrinsic) MCF (p value 0.003) and FIBTEM (fibrinogen) MCF (p value <0.001) decreased during CRS. At day 7 INTEM and FIBTEM MCF values (p values of 0.004 and <0.001) were significantly higher than before surgery. No considerable changes in platelet count and hemoglobin concentration and absence of leukopenia are noticed. This approach detects changes in coagulation much earlier than noticed by standard coagulation tests.


An AIS-based high-resolution ship emission inventory and its uncertainty in Pearl River Delta region, China.
Ship emissions contribute significantly to air pollution and impose health risks to residents along the coastal area. By using the refined data from the Automatic Identification System (AIS), this study developed a highly resolved ship emission inventory for the Pearl River Delta (PRD) region, China, home to three of ten busiest ports in the world. The region-wide SO2, NOX, CO, PM10, PM2.5, and VOC emissions in 2013 were estimated to be 61,484, 103,717, 10,599, 7155, 6605, and 4195t, respectively. Ocean going vessels were the largest contributors of the total emissions, followed by coastal vessels and river vessels. In terms of ship type, container ship was the leading contributor, followed by conventional cargo ship, dry bulk carrier, fishing ship, and oil tanker. These five ship types accounted for >90% of total emissions. The spatial distributions of emissions revealed that the key emission hot spots all concentrated within the newly proposed emission control area (ECA) and ship emissions within ECA covered >80% of total ship emissions in the PRD, highlighting the importance of ECA in emissions reduction in the PRD. The uncertainties of emission estimates of pollutants were quantified, with lower bounds of -24.5% to -21.2% and upper bounds of 28.6% to 33.3% at 95% confidence intervals. The lower uncertainties in this study highlighted the powerfulness of AIS data in improving ship emission estimates. The AIS-based bottom-up methodology can be used for developing and upgrading ship emission inventory and formulating effective control measures on ship emissions in other port regions wherever possible.


Variations in sexual fitness among natural strains of the opportunistic human fungal pathogen Aspergillus fumigatus.
Aspergillus fumigatus is a ubiquitous ascomycete fungus, naturally inhabiting the soil and compost piles. Its conidia readily disperse into the atmosphere and cause opportunistic infections known as aspergillosis. With the emerging resistance to many antifungal drugs, our understanding of A. fumigatus epidemiology has become increasingly important for developing effective control and treatment strategies. As a pathogen capable of both sexual and asexual reproduction, mutations causing drug resistance and increased virulence could be spread rapidly in A. fumigatus populations. However, relatively little is known about the distributions of sexual reproductive fitness among natural strains of A. fumigatus. Here we investigated the formation of sexual reproductive structure (i.e. cleistothecia) and sexual spore viability among 60 natural strains of A. fumigatus. These strains were from six geographically distant countries (India, China, Canada, Cameroon, Saudi Arabia, and New Zealand), with 10 strains (including five MAT1-1 strains and five MAT1-2 strains) from each country. These strains were crossed in all combinations with strains of the opposite mating type. In addition, all 60 strains were crossed with either AFB62-1 (MAT1-1) or AFIR928 (MAT1-2), two reference supermater strains. Of the 900 crosses among the 60 natural strains, 136 crosses (15.1%) produced cleistothecia. Our analyses revealed that strains from China had the highest average ability to form cleistothecia, followed by those from New Zealand, Saudi Arabia, India, Canada, and Cameroon. Among the crosses that produced cleistothecia, about 40% produced viable ascospores, with the rate of ascospore germination varied significantly among crosses. Interestingly, neither the ability to form cleistothecia nor ascospore germination rate showed any distinct relationships with either geographic or genetic distance between parental strains. Our results suggest that genetic exchange among geographically and genetically divergent strains of A. fumigatus are possible. However, the rates of genetic exchange likely vary among strains and populations in nature.


Couples and chronic obstructive airway diseases: the role of gender in coping and depression.
Social support, stress, health locus of control, active and avoidance coping, and depression were studied with 107 married couples in which one partner had a chronic obstructive airway disease (mean age = 62 years old). Differences between couples were evident when gender of the patient was assessed. Female patient couples that were older appeared more at risk than male patient couples for distress. In the analyses of spouse depression, gender moderated the relation of coping, social support, and health locus of control with depression. For patients, coping and social support were directly related to depression rather than moderated by gender. Implications for prevention and future research are discussed.


Enhancement of chemical sensing capability in a photonic crystal fiber with a hollow high index ring defect at the center.
A new type of index-guided photonic crystal fiber is proposed to enhance chemical sensing capability by introducing a hollow high index ring defect that consists of the central air hole surrounded by a high index GeO2 doped SiO2 glass ring. Optical properties of the fundamental guided mode were numerically analyzed using the full-vector finite element method varying the design parameters of both the defects in the center and the hexagonal air-silica lattice in the cladding. Enhanced evanescent wave interaction in the holey region and lower confinement loss by an order of magnitude were achieved simultaneously, which shows a high potential in hyper sensitive fiber-optic chemical sensing applications.


Presurgical evaluation of epilepsy patients.
Epilepsy surgery has been established as an effective treatment in pharmacoresistant focal epilepsies. Most candidates for epilepsy surgery are patients with partial epilepsy syndromes refractory to medical treatment. The curative surgery procedure is resection of the epileptogenic zone; therefore, precise detection of the site responsible for seizure generation is necessary. Modern structural and functional imaging techniques have made presurgical evaluation less invasive and available for a higher number of patients. Video electroencephalography (EEG) monitoring, high-resolution structural and functional imaging techniques are used widely for presurgical evaluation. When noninvasive evaluation is not sufficient for the detection of the epileptogenic zone, invasive EEG monitoring and intracarotid amobarbital test are used. A classical example of a surgically curable epilepsy syndrome is mesial temporal lobe epilepsy with about 70-80% of patients becoming free of seizures after surgery. Results in extratemporal epilepsies are also satisfactory. Despite worldwide expansion during the recent decade, epilepsy surgery remains underutilized. Better understanding of advances in presurgical evaluation should reduce fears of epilepsy surgery and help to select patients who could achieve complete seizure control or significant amelioration after surgery.


Q fever in the Basque Country: 1981-1984.
One hundred thirty cases of Q fever were seen in the Basque region of Spain between 1981 and 1984. Approximately 40% of these were related to epidemic outbreaks, and the remainder were isolated cases. The large majority of cases occurred in young men and women between 20 and 40 years of age. A seasonal peak coincided with lambing time in the region. Treatment had favorable outcome in each case, and no chronic disease was seen.


Detergent extraction from rat synaptosomal plasma membranes reveals difference in mu and delta opioid receptor binding.
Rat synaptosomal plasma membranes were extracted with a detergent (CHAPS, a zwitterionic derivative of cholic acid). mu and delta opioid receptor binding and adenylate cyclase activities were tested in the intact membranes and in the supernatants from detergent treated membranes. The 6000 X g/8 min. supernatant contained mu receptor binding equal to 33% of the mu receptor binding measured in the untreated membranes. When the detergent treated membranes were sedimented at (50,000 X g/10 min.), 23% of the mu receptor binding was recovered in the supernatant. After a 100,000 X g/30 min. centrifugation the supernatant contained 10% of the mu receptor binding when compared to untreated membranes. Of the delta receptor binding found in intact membranes, 10% or less was recovered in the 3 supernatants described above. Furthermore, the mu and delta receptor binding were distributed differently among particles in the supernatants. This indicates differences in the chemical properties of the mu and delta opioid receptors. Adenylate cyclase assays showed that the G/F site of this enzyme complex was inactivated in the supernatants from detergent treated membranes parallel to the delta receptor binding decrease. However, the catalytic part of adenylate cyclase was present in the supernatants and seemed resistant to the detergent.


Effect of reduction in renal artery pressure on atrial natriuretic peptide-induced natriuresis.
Studies were undertaken in anesthetized male Sprague-Dawley rats to investigate the effects of lowering renal arterial pressure within the autoregulatory range (to 85-95 mmHg) on the renal response to atriopeptin II (AP II) and atrial extract (AE). The natriuresis and diuresis produced by bolus injections of AP II at three dose levels (250-1,000 ng) was abolished or substantially reduced at lowered arterial pressure (85 mmHg). When renal artery pressure was lowered at the same time as an AE infusion was begun it completely blocked the natriuresis and diuresis. When pressure was reduced after 45 min of AE infusion the natriuresis was blunted, but not fully abolished. The effect of prior reduction in renal arterial pressure on the response to AP II (100 ng/min) and furosemide was compared; the AP II natriuresis was prevented when arterial pressure was lowered to 90 mmHg, but the natriuretic effect of furosemide was only slightly diminished. There was no significant rise in glomerular filtration rate (GFR) with AP II and no correlation between GFR changes and the Na excretory response. Reducing renal arterial pressure prior to, at the same time as, or 45 min after beginning an infusion of atrial natriuretic peptide substantially blunts or completely abolishes the natriuresis. Reductions in renal arterial pressure may block the natriuretic and diuretic effects of these compounds by interfering with their hemodynamic actions or by causing sufficient enhancement of salt reabsorption to limit delivery to terminal nephron segments.


Conservation therapy for T1-3 carcinoma of the breast. The role of radiation therapy.
Breast conservation therapy may be offered as an alternative to mastectomy for appropriately selected patients with T1 through T3 breast carcinoma. Patients management requires a well coordinated team approach involving the patient, radiation oncologist, surgeon, medical oncologist, diagnostic radiologist and pathologist. The cosmetic result is good to excellent in most cases if careful attention is paid to surgery and radiation techniques. Lesions less than 5 cm in diameter are most appropriate. After completion of breast conservation therapy it is very important to follow patients closely. Thus both physical examination and mammography are important.


Effects of the inhibitors of IMP dehydrogenase, tiazofurin and mycophenolic acid, on glycoprotein metabolism.
The effects of the inhibitors of IMP dehydrogenase, tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide) and mycophenolic acid, on the synthesis of cellular glycoproteins were evaluated in Sarcoma 180 cells. Both tiazofurin and mycophenolic acid decreased the rate of incorporation of [2-3H]mannose and [2-3H]fucose into acid-precipitable glycoproteins within 4 hr of exposure; this inhibitory activity was concentration dependent and occurred in the absence of a significant effect on the incorporation of labeled glucosamine and leucine into acid-insoluble material. Interference with the utilization of [3H]mannose for the formation of glycoproteins was paralleled by an inhibition of [3H] mannose incorporation into their lipid-linked oligosaccharide precursors following treatment with cytotoxic concentrations of tiazofurin (100 microM) or mycophenolic acid (10 microM); these actions occurred within 3 hr of exposure to these agents, with maximal reductions being observed at 12 hr. Under these conditions, intracellular GTP levels were reduced by 80%, whereas ATP pools remained unaffected ant UTP levels were markedly increased. Guanosine (100 microM) prevented the cytotoxic actions of tiazofurin and mycophenolic acid and reversed the drug-induced decrease in GTP pools and in the incorporation of mannose and other metabolic precursors into acid-insoluble material. Inhibition of fucose and mannose incorporation into lipid-linked oligosaccharides and glycoproteins were preceded by decreases in the labeling of their respective guanosine nucleotide sugars and were followed sequentially by alterations in the plasma membrane as detected by both the binding and the rate of cell agglutination caused by the plant lectin, concanavalin A. The findings that tiazofurin and mycophenolic acid produce alterations in the utilization of [3H]mannose for the formation of glycoproteins and in membrane architecture are indicative of metabolic lesions induced by agents that selectively depress guanine nucleotide synthesis through inhibition of IMP dehydrogenase.


Trends in Ultrasound Use in Low and Middle Income Countries: A Systematic Review.
Evidence on recent trends regarding the impact and cost-benefits of ultrasound in resource-constrained settings is limited. This study presents a systematic review to determine recent trends in the utility and applicability of ultrasound use in low and middle income countries (LMIC). The review includes characterizing and evaluating trends in (1) the geographic and specialty specific use of ultrasound in LMICs, (2) the innovative applications and the accompanying research findings, and (3) the development of associated educational and training programs. The electronic databases Medline OVID, EMBASE, and Cochrane were searched from 2010 to 2018 for studies available in English, French, and Spanish. Commentaries, opinion articles, reviews and book chapters were excluded. Two categories were created, one for reported applications of ultrasound use in LMICs and another for novel ultrasound studies. A total of 6,276 articles were identified and screened, 4,563 studies were included for final review. 287 studies contained original or novel applications of ultrasound use in LMICs. Nearly 70% of studies involved ultrasound usage originating from Southeast Asia and sub-Saharan Africa, the latter being the region with the highest number of innovative ultrasound use. Educational studies, global collaborations, and funded studies were a substantial subset of overall ultrasound research. Our findings are limited by the lack of higher quality evidence and limited number of randomized clinical trials reported. Our systematic literature review of ultrasound use in LMICs demonstrates the growing utilization of this relatively low-cost, portable imaging technology in low resource settings.


The horse homolog of congenital aniridia conforms to codominant inheritance.
Anterior segment dysgenesis syndrome occurs frequently in Rocky Mountain horses and has two distinct ocular phenotypes: (1) large cysts originating from the temporal ciliary body or peripheral retina and (2) multiple anterior segment anomalies including ciliary cysts, iris hypoplasia, iridocorneal adhesions and opacification, nuclear cataract, and megalocornea. To determine if anterior segment dysgenesis syndrome is heritable in horses we performed ophthalmic examinations and collected pedigree information on horses (n = 516) in an extended Rocky Mountain horse pedigree. Logistic regressive segregation analysis of a subset of animals (n = 337) in which the ocular phenotypes of progeny and both parents were known indicated that the codominant inheritance model best fit the data. This model predicted cyst phenotype expression in heterozygous animals and multiple anterior segment anomalies in homozygous animals. Several cases of nonpenetrance of the cyst phenotype were detected in one lineage. The close resemblance between the inheritance and lesions observed in Small eye mice and rats, humans with congenital aniridia or anterior segment malformation, and horses with anterior segment dysgenesis syndrome supported the conclusion that anterior segment dysgenesis syndrome in the horse may be homologous to similar ophthalmic anomalies in other species.


IgE and T-cell responses to house dust mite allergen components.
Using the terminology for Dermatophagoides pteronyssinus, IgE responses to house dust mites have been shown to be mostly directed to the serodominant Der p 1, 2 and 23 allergen components with mid -tier responses to Der p 4, 5, 7 and 21 that are made by 30-50% of subjects with titers proportional to those of the serodominant specificities. This pattern can be seen to evolve in childhood and although responses to minor allergens appear to contribute little to the total IgE they are at least markers for a greater propensity to develop disease. While Der p 23 is a component that induces prevalent IgE responses, sometimes in the absence of responses to Der p 1and 2, not all studies have found high titers so further investigation is needed. From limited knowledge adult onset IgE responses might have a different pattern that is not so centered on Der p 1 and 2. Responses that induce under 3.5 IU/ml of IgE antibody are not usually associated with disease and should be examined for cross reactivity expected from IgE responses to other allergens and antigens of infectious agents. Scabies that has 40% endemicity in some regions and is spread by immigration can give rise to high-titer binding that can be recognized by component resolved diagnosis. Recent studies with synthetic peptides representing allergens and non-allergenic HDM proteins now offer new research avenues on HDM induced immune responses, including the ability to use peptides representing the serodominant allergens as defined reagents for long overdue reproducible T-cell investigations.


Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240).
On Aug 14, 2014, the US Food and Drug Administration approved the antiangiogenesis drug bevacizumab for women with advanced cervical cancer on the basis of improved overall survival (OS) after the second interim analysis (in 2012) of 271 deaths in the Gynecologic Oncology Group (GOG) 240 trial. In this study, we report the prespecified final analysis of the primary objectives, OS and adverse events. In this randomised, controlled, open-label, phase 3 trial, we recruited patients with metastatic, persistent, or recurrent cervical carcinoma from 81 centres in the USA, Canada, and Spain. Inclusion criteria included a GOG performance status score of 0 or 1; adequate renal, hepatic, and bone marrow function; adequately anticoagulated thromboembolism; a urine protein to creatinine ratio of less than 1; and measurable disease. Patients who had received chemotherapy for recurrence and those with non-healing wounds or active bleeding conditions were ineligible. We randomly allocated patients 1:1:1:1 (blocking used; block size of four) to intravenous chemotherapy of either cisplatin (50 mg/m2 on day 1 or 2) plus paclitaxel (135 mg/m2 or 175 mg/m2 on day 1) or topotecan (0·75 mg/m2 on days 1-3) plus paclitaxel (175 mg/m2 on day 1) with or without intravenous bevacizumab (15 mg/kg on day 1) in 21 day cycles until disease progression, unacceptable toxic effects, voluntary withdrawal by the patient, or complete response. We stratified randomisation by GOG performance status (0 vs 1), previous radiosensitising platinum-based chemotherapy, and disease status (recurrent or persistent vs metastatic). We gave treatment open label. Primary outcomes were OS (analysed in the intention-to-treat population) and adverse events (analysed in all patients who received treatment and submitted adverse event information), assessed at the second interim and final analysis by the masked Data and Safety Monitoring Board. The cutoff for final analysis was 450 patients with 346 deaths. This trial is registered with ClinicalTrials.gov, number NCT00803062. Between April 6, 2009, and Jan 3, 2012, we enrolled 452 patients (225 [50%] in the two chemotherapy-alone groups and 227 [50%] in the two chemotherapy plus bevacizumab groups). By March 7, 2014, 348 deaths had occurred, meeting the prespecified cutoff for final analysis. The chemotherapy plus bevacizumab groups continued to show significant improvement in OS compared with the chemotherapy-alone groups: 16·8 months in the chemotherapy plus bevacizumab groups versus 13·3 months in the chemotherapy-alone groups (hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·007). Final OS among patients not receiving previous pelvic radiotherapy was 24·5 months versus 16·8 months (0·64 [0·37-1·10]; p=0·11). Postprogression OS was not significantly different between the chemotherapy plus bevacizumab groups (8·4 months) and chemotherapy-alone groups (7·1 months; 0·83 [0·66-1·05]; p=0·06). Fistula (any grade) occurred in 32 (15%) of 220 patients in the chemotherapy plus bevacizumab groups (all previously irradiated) versus three (1%) of 220 in the chemotherapy-alone groups (all previously irradiated). Grade 3 fistula developed in 13 (6%) versus one (<1%). No fistulas resulted in surgical emergencies, sepsis, or death. The benefit conferred by incorporation of bevacizumab is sustained with extended follow-up as evidenced by the overall survival curves remaining separated. After progression while receiving bevacizumab, we did not observe a negative rebound effect (ie, shorter survival after bevacizumab is stopped than after chemotherapy alone is stopped). These findings represent proof-of-concept of the efficacy and tolerability of antiangiogenesis therapy in advanced cervical cancer. National Cancer Institute.


Paradigm shifts: new techniques to answer new questions.
The advent of a multiple-channels approach to spatial vision 20 years ago raised important questions that were difficult to approach empirically, given the technology and analytic tools of the time. These questions concerned the interaction or combination of different components of a stimulus--questions that have recently resurfaced in more complex form. Classical psychophysical methods for assessing whether two stimulus aspects are coded independently (e.g., masking, adaptation, and cue-summation) provide only limited information about the nature of whatever interactions are discovered. In both older work in detection and recent work in complex pattern discrimination, we have used a double-judgment paradigm in which the observer rates two aspects of a stimulus simultaneously. The paradigm provides a rich source of information about the codes underlying each psychophysical decision and which are unique in permitting us to psychophysically investigate effects resulting from neural noise in the system. Our analyses draw on theories of dimensional interaction in signal detection theory and in information theory, and on methods from several branches of statistics, including categorical data analysis and structural equation modeling. We review the theoretical, technological, methodological, and personal influences that led us to develop this approach.


[Malaria at the dawn of the millennium: lessons taken from the literature].
The entomological approach has dominated in the past the geographical--epidemiological study of malaria. Nowadays, new approaches are considering aspects such as representations, attitudes to adopt, change in the transmission process according to the ecosystems. The geographical approach here highlighted implies firstly the knowledge of the geo-epidemiology at the small areas love. This approach should also consider the entomological parameters, the environmental factors and the therapeutic behaviors in order to evaluate the efficiency of the action programmes.


Overall Splenectomy Rates Stable Despite Increasing Usage of Angiography in the Management of High-grade Blunt Splenic Injury.
The purpose of this study was to understand the contemporary trends of splenectomy in blunt splenic injury (BSI) and to determine if angiography and embolization (ANGIO) may be impacting the splenectomy rate. The approach to BSI has shifted to increasing use of nonoperative management, with a greater reliance on ANGIO. However, the impact ANGIO has on splenic salvage remains unclear with little contemporary data. The National Trauma Data Bank was used to identify patients 18 years and older with high-grade BSI (Abbreviated Injury Scale >II) treated at Level I or II trauma centers between 2008 and 2014. Primary outcomes included yearly rates of splenectomy, which was defined as early if performed within 6 hours of ED admission and delayed if greater than 6 hours, ANGIO, and mortality. Trends were studied over time with hierarchical regression models. There were 53,689 patients who had high-grade BSI over the study period. There was no significant difference in the adjusted rate of overall splenectomy over time (24.3% in 2008, 24.3% in 2014, P value = 0.20). The use of ANGIO rapidly increased from 5.3% in 2008 to 13.5% in 2014 (P value < 0.001). Mortality was similar overtime (8.7% in 2008, 9.0% in 2014, P value = 0.33). Over the last 7 years, the rate of angiography has been steadily rising while the overall rate of splenectomy has been stable. The lack of improved overall splenic salvage, despite increased ANGIO, calls into question the role of ANGIO in splenic salvage on high-grade BSI at a national level.


The ecology and genetics of fitness in Chlamydomonas. X. The relationship between genetic correlation and genetic distance.
A necessary condition for the maintenance of genetic variation in heterogeneous environments is that the relative fitnesses of a collection of genotypes vary as conditions of growth change. This can be detected by estimating the amount of gene-by-environment interaction (G x E) when a range of types are tested across a range of conditions. However it is the sign and magnitude of the genetic correlation, which is a component of G x E, that governs the ultimate fate of variation. Whether genetic variation will be preserved, then, depends on how the genetic correlation changes as a function of the ecological differences among environments and the genetic differences among genotypes. To evaluate this, we assayed the performance of 15 chlorophyte species of known genetic relation in 20 environments. We found that the quantity of G x E increased as both the environmental variance across environments and the genetic distance increased. Moreover the genetic correlation declined as the environmental variance between pairs of environments and the genetic distance between pairs of genotypes increased. These results suggest that divergent selection will be more likely to maintain genetic variation when environments are strongly contrasted and genotypes widely divergent.


The relationship between intracellular pH, the pH gradient and potassium transport in Escherichia coli.
The capacity of E. coli cells to regulate intracellular pH (pHi) during net potassium uptake has been investigated. The data show: (a) that cells sense their intracellular pH; (b) that the pH gradient (delta pH) exerts a feedback regulation on pHi; (c) that a mechanism of regulation of pHi exists which may be independent of Na+ [Zilberstein, Agmon, Schuldiner & Padan (1982) J. Biol. Chem. 257, 3687-3691]; and (d) that cells have a limited capacity to raise their intracellular pH in the absence of net K+ transport.


Multiple classifier system for remote sensing image classification: a review.
Over the last two decades, multiple classifier system (MCS) or classifier ensemble has shown great potential to improve the accuracy and reliability of remote sensing image classification. Although there are lots of literatures covering the MCS approaches, there is a lack of a comprehensive literature review which presents an overall architecture of the basic principles and trends behind the design of remote sensing classifier ensemble. Therefore, in order to give a reference point for MCS approaches, this paper attempts to explicitly review the remote sensing implementations of MCS and proposes some modified approaches. The effectiveness of existing and improved algorithms are analyzed and evaluated by multi-source remotely sensed images, including high spatial resolution image (QuickBird), hyperspectral image (OMISII) and multi-spectral image (Landsat ETM+). Experimental results demonstrate that MCS can effectively improve the accuracy and stability of remote sensing image classification, and diversity measures play an active role for the combination of multiple classifiers. Furthermore, this survey provides a roadmap to guide future research, algorithm enhancement and facilitate knowledge accumulation of MCS in remote sensing community.


Smoking and the risk of leukemia, lymphoma, and multiple myeloma (Sweden).
While several epidemiologic studies have indicated a link between smoking and the risk of developing hematolymphoproliferative cancers (chiefly leukemias, lymphomas, and multiple myelomas), in particular myeloid leukemia, the role of tobacco in the etiology of these neoplasms remains unclear. To evaluate the potential impact of tobacco use on development of leukemia, lymphoma, and multiple myeloma, we conducted a cohort study of 334,957 Swedish construction workers using prospectively collected exposure-information with complete long-term follow-up. A total of 1,322 incident neoplasms occurred during the study period, 1971-91. We found no significant association between smoking status, number of cigarettes smoked, or duration of smoking and the risk of developing leukemias, lymphomas, or multiple myeloma. There was a suggestion of a positive association between smoking and the risk of developing Hodgkin's disease, although the rate ratios were not significantly elevated, except for young current smokers. No positive dose-risk trends emerged. Our study provides no evidence that smoking bears any major relationship to the occurrence of leukemias, non-Hodgkin's lymphomas, or multiple myeloma.


Associations Between Physiological Correlates of Cochlear Synaptopathy and Tinnitus in a Veteran Population.
Animal models and human temporal bones indicate that noise exposure is a risk factor for cochlear synaptopathy, a possible etiology of tinnitus. Veterans are exposed to high levels of noise during military service. Therefore, synaptopathy may explain the high rates of noise-induced tinnitus among Veterans. Although synaptopathy cannot be directly evaluated in living humans, animal models indicate that several physiological measures are sensitive to synapse loss, including the auditory brainstem response (ABR), the middle ear muscle reflex (MEMR), and the envelope following response (EFR). The purpose of this study was to determine whether tinnitus is associated with reductions in physiological correlates of synaptopathy that parallel animal studies. Participants with normal audiograms were grouped according to Veteran status and tinnitus report (Veterans with tinnitus, Veterans without tinnitus, and non-Veteran controls). The effects of being a Veteran with tinnitus on ABR, MEMR, and EFR measurements were independently modeled using Bayesian regression analysis. Modeled point estimates of MEMR and EFR magnitude showed reductions for Veterans with tinnitus compared with non-Veterans, with the most evident reduction observed for the EFR. Two different approaches were used to provide context for the Veteran tinnitus effect on the EFR by comparing to age-related reductions in EFR magnitude and synapse numbers observed in previous studies. These analyses suggested that EFR magnitude/synapse counts were reduced in Veterans with tinnitus by roughly the same amount as over 20 years of aging. These findings suggest that cochlear synaptopathy may contribute to tinnitus perception in noise-exposed Veterans. https://doi.org/10.23641/asha.24347761.


Do multiple families alter estimates of risk for age-related cataract in a population-based study? The Beaver Dam Eye Study.
We sought to determine the effect of "genetic" load on the strengths of risk factors for age-related cataracts in the population-based Beaver Dam Eye Study. Of the 4,926 participants in the baseline examination in 1988 to 1990, 2,338 were members of 594 family groups. There were no important differences in the risks due to pack-years smoked, systolic and diastolic blood pressures, body mass index, current smoking, hypertension or hormone replacement therapy for either the whole population or subgroups created by omitting siblings or any family relation. There were some differences when the analyses were limited to only a randomly selected family member or a randomly selected sibling. These latter findings may relate to the older average age of those in sibships or in families compared to those not in families. We conclude that for the associations we explored, the relatively large number of families in our population had little effect on the strengths of the risk factors, and that limiting analyses to only those not in families may distort risk factor associations by altering the age structure in this population.


The zoonotic potential of avian influenza viruses isolated from wild waterfowl in Zambia.
Whilst remarkable progress in elucidating the mechanisms governing interspecies transmission and pathogenicity of highly pathogenic avian influenza viruses (AIVs) has been made, similar studies focusing on low-pathogenic AIVs isolated from the wild waterfowl reservoir are limited. We previously reported that two AIV strains (subtypes H6N2 and H3N8) isolated from wild waterfowl in Zambia harbored some amino acid residues preferentially associated with human influenza virus proteins (so-called human signatures) and replicated better in the lungs of infected mice and caused more morbidity than a strain lacking such residues. To further substantiate these observations, we infected chickens and mice intranasally with AIV strains of various subtypes (H3N6, H3N8, H4N6, H6N2, H9N1 and H11N9) isolated from wild waterfowl in Zambia. Although some strains induced seroconversion, all of the tested strains replicated poorly and were nonpathogenic for chickens. In contrast, most of the strains having human signatures replicated well in the lungs of mice, and one of these strains caused severe illness in mice and induced lung injury that was characterized by a severe accumulation of polymorphonuclear leukocytes. These results suggest that some strains tested in this study may have the potential to infect mammalian hosts directly without adaptation, which might possibly be associated with the possession of human signature residues. Close monitoring and evaluation of host-associated signatures may help to elucidate the prevalence and emergence of AIVs with potential for causing zoonotic infections.


[Interpretation of laboratory data during cryptic leishmaniasis in dog].
Leishmaniasis is a zoonosis caused by an intracellular parasite belonging to the genus Leishmania. In Europe, Africa, South America and China, visceral leishmaniasis is caused by L. infantum. The vectors of leishmaniasis are phlebotomine sandflies belonging to the genera Phlebotomus. According to the World Health Organization there are 2 million new cases each year and 1/10 of the world's population is at risk of infection. Leishmaniasis is considered a zoonosis and human are generally accidental hosts. The animal reservoir includes rodents, dog and other mammals. Several studies have indicate that half of the dogs with antileishmanial antibodies have no signs of disease although, animal with subclinical infections are potentially infectious to sand flies. The factors determining susceptibility or resistence to visceral leishmaniasis remain unclear, but the genetics of the host may play a major role. Clinical signs are: intermittent fever, hepatosplenomegaly, skin lesions and ulcers, alopecia, onychogryphosis, anemia, thrombocytopenia and hypergammaglobulinemia. In mice, the outcome of infection depends on the polarized activation of one of two subsets of CD4+ T cells, Th1 or Th2, the subdivision into Th1 and Th2 cells is based on the pattern of cytokines that they produce. Th1 cells produce gamma interferon (IFN-gamma) and interleukin -2 (IL-2), whereas Th2 cells produce IL-4, IL-5, and IL-10. An important difference between susceptible and resistant mice is that the resistant mice are able to switch to a Th1 profile and control the disease. An important factor in the "decision" to form a Th1 or Th2 phenotype is the early cytokine environment, and IL-12 is one of the cytokines that contributes significantly to the establishment of the Th1 phenotype. Canine leishmaniosis is endemic in the Mediterranean basin and, in most cases is caused by the parasite Leishmania infantum. The main clinical findings are skin lesions, local or generalized lymphoadenopathy, loss of body weight, glomerulopathy, ocular lesions, epistaxis and lameness. Non pruritic skin lesions are the usual manifestation and several forms have been described, such as exfoliative dermatitis and alopecia, and ulcerative, nodular and pustular dermatitis. Seroepidemiological studies of canine leishmaniasis have revealed a large number of asymptomatic seropositive animals. Moreover in areas where leishmaniasis is highly endemic, high proportion of apparently healthy animals show low levels of anti-Leishmania antibodies. Others have regressive forms of the desease, and their antibody levels will decrease in the following months or years; still others maintain low levels of antibodies without developing the desease for many years. However, the total number of infected animals is unknown. Canine leishmaniasis is a major zoonosic parasitic disease, enzootic in the Mediterranean area, caused by the intracellular protozoan Leishmania infantum. The dog is the main reservoir host of the parasite. However, most infected dogs do not present any clinical signs, and there is evidence that Leishmania infection prevalence rates in areas of endemicity are higher than those ascertained by serological studies. Visceral leishmaniasis is becoming a real problem of public health because it is an opportunistic infection in immunocompromised patients and in human immunodeficiency virus-positive subjects. The detection of the extent of the infection, particularly among asymptomatic dogs, is of great importance for the control of leishmaniasis. PCR has been applied successfully in recent years to detect Leishmania spp. even in the cases with any of the clinical manifestation of leishmaniasis. Very recently, real-time PCR for Leishmania has been applied to evaluate the parasitic load of dog tissues both at the time of the diagnosis and during follow-up of the therapy and to measure cytokine mRNA levels in different clinical samples of infected and uninfected dogs.


Differential Effects of Cannabis and Tobacco on Lung Function in Mid-Adult Life.
Rationale: Evidence suggests that the effects of smoking cannabis on lung function are different from tobacco. However, long-term follow-up data are scarce and mostly based on young adults. Objectives: To assess the effects of cannabis and tobacco on lung function in mid-adult life. Methods: Cannabis and tobacco use were reported at ages 18, 21, 26, 32, 38, and 45 years in a population-based cohort study of 1,037 participants. Spirometry, plethysmography, and carbon monoxide transfer factor were measured at age 45. Associations between lung function and cannabis use were adjusted for tobacco use. Measurements and Main Results: Data were available from 881 (88%) of 997 surviving participants. Cumulative cannabis use was associated with lower FEV1/FVC ratios, owing to a tendency toward higher FVCs. Cannabis use was also associated with higher TLC, FRC, residual volume, and Va along with lower midexpiratory flows, airway conductance, and transfer factor. Quitting regular cannabis use between assessments was not associated with changes in spirometry. Conclusions: Cannabis use is associated with higher lung volumes, suggesting hyperinflation. There is evidence of increased large-airway resistance and lower midexpiratory airflow, but impairment of FEV1/FVC ratio is because of higher FVC. This pattern of effects is different to those of tobacco. We provide the first evidence that lifetime cannabis use may be associated with impairment of gas transfer.


Acute inhibition of rat heart protein synthesis in vitro during beta-adrenergic stimulation or hypoxia.
In the anterogradely perfused rat heart with glucose as fuel, 1 microM isoproterenol (ISO) inhibited the insulin (INS) plus adenosine deaminase (AdoDA) stimulation of ventricular protein synthesis by 72%. ISO (1 microM) alone had no effect on ventricular protein synthesis but inhibited atrial protein synthesis by 20%. The concentration dependence of the ISO inhibition was similar to the stimulation of glucose uptake by ISO. Inhibition could not be overcome by increasing INS concentrations. The effects of ISO were diminished by propranolol and could be partially mimicked by forskolin (FSK) or 8-(4-chlorophenylthio-)adenosine 3',5'-cyclic monophosphate (CPT-cAMP). The stimulation of protein synthesis by noncarbohydrate fuels was antagonized by ISO. Hypoxia (PO2 = 50%) also antagonized the INS stimulation of ventricular protein synthesis but did not affect basal rates. ATP contents were decreased by ISO but not by a PO2 of 50%. Both manipulations increased lactate output. The inhibition of protein synthesis by ISO could possibly be explained by indirect effects of ISO on cardiac "energy status." Furthermore, inhibition may thus represent purely an in vitro phenomenon and may not occur in vivo. However, the possibility that there are more direct effects of ISO on the machinery of protein synthesis has not been excluded. The inhibition of protein synthesis by hypoxia cannot be explained by changes in energy status and may result from intracellular lactoacidosis.


L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity.
Repeated Ag exposure results in a shift in the time course of contact hypersensitivity (CH) from a typical delayed-type to an immediate-type response followed by a late phase reaction. Chronic CH responses are clinically relevant to human skin allergic diseases, such as atopic dermatitis, that are usually caused by repeated stimulation with environmental Ags. Chronic inflammatory responses result in part from infiltrating leukocytes. To determine the role of leukocyte adhesion molecules in chronic inflammation, chronic CH responses were assessed in mice lacking L-selectin, ICAM-1, or both adhesion molecules. Following repeated hapten sensitization for 24 days at 2-day intervals, wild-type littermates developed an immediate-type response at 30 min after elicitation, followed by a late phase reaction. By contrast, loss of ICAM-1, L-selectin, or both, eliminated the immediate-type response and inhibited the late phase reaction. Similar results were obtained when wild-type littermates repeatedly exposed to hapten for 22 days were treated with mAbs to L-selectin and/or ICAM-1 before the elicitation on day 24. The lack of an immediate-type response on day 24 paralleled a lack of mast cell accumulation after 30 min of elicitation and decreased serum IgE production. Repeated Ag exposure in wild-type littermates resulted in increased levels of serum L-selectin, a finding also observed in atopic dermatitis patients. The current study demonstrates that L-selectin and ICAM-1 cooperatively regulate the induction of the immediate-type response by mediating mast cell accumulation into inflammatory sites and suggests that L-selectin and ICAM-1 are potential therapeutic targets for regulating human allergic reactions.


X-ray Diffraction, Mössbauer Spectroscopy, Magnetic Susceptibility, and Specific Heat Investigations of Na4NpO5 and Na5NpO6.
The hexavalent and heptavalent sodium neptunate compounds Na4NpO5 and Na5NpO6 have been investigated using X-ray powder diffraction, Mössbauer spectroscopy, magnetic susceptibility, and specific heat measurements. Na4NpO5 has tetragonal symmetry in the space group I4/m, while Na5NpO6 adopts a monoclinic unit cell in the space group C2/m. Both structures have been refined for the first time using the Rietveld method. The valence states of neptunium in these two compounds, i.e., Np(VI) and Np(VII), respectively, have been confirmed by the isomer shift values of their Mössbauer spectra. The local structural properties obtained from the X-ray refinements have also been related to the quadrupole coupling constants and asymmetry parameters determined from the Mössbauer studies. The absence of magnetic ordering has been confirmed for Na4NpO5. However, specific heat measurements at low temperatures have suggested the existence of a Schottky-type anomaly at around 7 K in this Np(VI) phase.


Experimental study on the PAR-1 expression around hemotoma following intracerebral hemorrhage in rats.
In order to explore the PAR-1 mRNA and protein expression around hemotoma following intracerebral hemorrhage and the relation between the PAR-1 expression and thrombin, collagenase VII was stereotaxically injected into right caudate nucleus in rats. The PAR-1 mRNA expression was detected by RT-PCR method and the PAR-1 protein expression by immunohistochemical method respectively. It was found that the PAR-1 mRNA and protein expression around hemotoma was increased at 6 h after intracerebral hemorrhage (P<0.05), peaked at 2 days (P<0.01), and then declined. The change pattern of the PAR-1 mRNA and protein expression was similar to that of intracerebral hemorrhage after thrombin intracerebral injection. The PAR-1 mRNA and protein expression in hirudin group showed no significant difference with control group. These results indicated that the PAR-1 mRNA and protein expression were markedly increased after intracerebral hemorrhage, which may be closely related to thrombin. Upregulation of the PAR-1 expression may involve in neurotoxic injury induced by thrombin.


Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patient's values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0-3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75-325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age < or =75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75-325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S-629S. For patients with AF of > or =48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of > or = 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0-3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non-TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C).


[Results of X-ray follow-up in late silicosis].
The authors present clinical and X-ray data of 30 patients with "late silicosis" that occurred in 5-20 years after they had retired from dust-related occupation. Follow-up over 4-25 years demonstrated progression of nodular pneumosclerosis up to macronodular forms or silicotuberculoma formation. The diseases mostly developed gradually, usually was diagnosed by casual X-ray examination and was long considered as tuberculosis, sarcoidosis or other disseminated lesion.