Chemotherapy-induced ovarian failure: manifestations and management.
Thanks to improvements in treatment regimens, more and more patients are now surviving cancer. However, cancer survivors are faced with the serious long-term effects of the different modalities of cancer treatments. One of these adverse effects is chemotherapy-induced irreversible damage to the ovarian tissues, which leads to premature ovarian failure and its resulting consequences such as hot flashes, osteoporosis, sexual dysfunction and the risk of infertility. Chemotherapy-induced ovarian failure (or chemotherapy-induced premature menopause) affects the quality of life of female cancer survivors. Although there is no clear definition of chemotherapy-induced ovarian failure, irreversible amenorrhoea lasting for several months (>12 months) following chemotherapy and a follicle stimulating hormone level of > or = 30 MIU/mL in the presence of a negative pregnancy test seems to be an appropriate characterisation. Different chemotherapy agents, alkylating cytotoxics in particular, have the potential to cause progressive and irreversible damage to the ovaries. The result of this damage is a state of premature ovarian failure, with progressive declining of estrogen levels, decreasing bone mass and an increased risk of fractures. Historically, hormonal replacement therapy (HRT) has been used to treat menopausal problems in the general population, but concerns about the potential of estrogen to increase the risk of breast cancer in women at high-risk or increase the risk of recurrence in cancer survivors, have forced physicians to utilise alternative treatments. This review discusses some of the newer therapies that are now available to provide appropriate symptom control, avoid complications such as fractures and possibly prevent infertility by making the ovarian epithelium less susceptible to cytotoxic agents.


Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures.
The genus Flavivirus contains many mosquito-borne human pathogens of global epidemiological importance such as dengue virus, West Nile virus, and Zika virus, which has recently emerged at epidemic levels. Infections with these viruses result in divergent clinical outcomes ranging from asymptomatic to fatal. Myriad factors influence infection severity including exposure, immune status and pathogen/host genetics. Furthermore, pre-existing infection may skew immune pathways or divert immune resources. We profiled immune cells from dengue virus-infected individuals by multiparameter mass cytometry (CyTOF) to define functional status. Elevations in IFNβ were noted in acute patients across the majority of cell types and were statistically elevated in 31 of 36 cell subsets. We quantified response to in vitro (re)infection with dengue or Zika viruses and detected a striking pattern of upregulation of responses to Zika infection by innate cell types which was not noted in response to dengue virus. Significance was discovered by statistical analysis as well as a neural network-based clustering approach which identified unusual cell subsets overlooked by conventional manual gating. Of public health importance, patient cells showed significant enrichment of innate cell responses to Zika virus indicating an intact and robust anti-Zika response despite the concurrent dengue infection.


Microvascular Doppler ultrasound-assisted neuroendoscopic surgery.
To achieve endoscopic procedures more safely and less invasively, an operative strategy with ultrasound-assisted neuroendoscopic surgery is described. The improvement in the endoscope unit is that endoscopic viewing can be stopped on the display, anytime we choose and simultaneously visualize the ongoing view on the same display. The ultrasound unit, using a miniature Doppler probe, is to able to detect even invisible vessels in real-time, easily and non-invasively. The information from both units can be switched intraoperatively, whenever required.


Flexible DMRG-Based Framework for Anharmonic Vibrational Calculations.
We present a novel formulation of the vibrational density matrix renormalization group (vDMRG) algorithm tailored to strongly anharmonic molecules described by general, high-dimensional model representations of potential energy surfaces. For this purpose, we extend the vDMRG framework to support vibrational Hamiltonians expressed in the so-called n-mode second-quantization formalism. The resulting n-mode vDMRG method offers full flexibility with respect to both the functional form of the PES and the choice of the single-particle basis set. We leverage this framework to apply, for the first time, vDMRG based on an anharmonic modal basis set optimized with the vibrational self-consistent field algorithm on an on-the-fly constructed PES. We also extend the n-mode vDMRG framework to include excited-state-targeting algorithms in order to efficiently calculate anharmonic transition frequencies. We demonstrate the capabilities of our novel n-mode vDMRG framework for methyloxirane, a challenging molecule with 24 coupled vibrational modes.


Association of intra-operative metaphyseal fractures with prosthesis size during hemiarthroplasty of the hip.
To study the possible causes of intra-operative metaphyseal fractures in elderly patients undergoing hemiarthroplasty for displaced intracapsular femoral neck fracture. 36 men and 228 women aged 61 to 89 years with 273 displaced femoral neck fractures underwent hemiarthroplasty using a hydroxyapatite ceramic-coated Furlong bipolar prosthesis. Anteroposterior and lateral radiographs were taken immediately after surgery to evaluate the presence and type of any intra-operative fractures (classified according to the Vancouver system) and their effect on stem stability or osseointegration. Pain and clinical outcomes were evaluated using a visual analogue scale and the Harris Hip Score. Regarding the 273 surgeries for displaced femoral neck fracture, 28 (10%) were associated with intra-operative metaphyseal fracture (21 Vancouver type AL and 7 type AG). There was a correlation between intra-operative metaphyseal fractures and stem size. A size-9 stem was used in 64 surgeries without any fracture. A size-10 stem was used in 129 surgeries in which 11 (9%) sustained fractures, and a size-12 stem was used in 80 surgeries in which 17 (21%) sustained fractures. Postoperatively, 25 cases developed hip-related problems (thigh pain=14 and periprosthetic fractures=8) after 3 to 18 months. No patient whose metaphyseal fracture was fixed had hip problems. In elderly women with compromised bone quality, extra care is needed to achieve better fitting so as to avoid iatrogenic metaphyseal fractures. Under-sizing or cementing of the prosthesis is recommended when encountering difficulties.


Characterization of a wild strain of Alicyclobacillus acidoterrestris: heat resistance and implications for tomato juice.
This article reports the characterization of a wild strain of Alicyclobacillus acidoterrestris and describes the implications of the heat resistance of this microorganism in tomato juice. The strain (labeled as A. acidoterrestrisγ4) showed pH and temperature ranges for growth typical of the species (3.0 to 6.0 for the pH and 35 to 60 °C for the temperature); heat resistance in tomato juice was as follows: D(T) values of 40.65, 9.47, and 1.5 min (at 85, 90, and 95 °C, respectively) and z-value of 7 °C. A treatment at 70 °C for 15 min was found to be optimal for spore activation, whereas Malt Extract Agar, acidified to pH 4.5, showed good results for spore recovery. Concerning the implications of heat resistance of A. acidoterrestris on tomato juice, high temperatures required for spore inactivation determined a general decrease of the antioxidant activity (increase of the redox potential and reduction of the chain-breaking activity), but not the formation of brown compounds (namely, hydroxymethylfurfural), thus suggesting an effect on the secondary antioxidants (carotenoids and ascorbic acid) rather than on lycopene. Alicyclobacillus acidoterrestris is an emerging spore-forming microorganism, capable of causing spoilage in tomato juice. Due to their high thermal resistance, spores could be used as targets for the optimization of heat processing; this article reports on the assessment of thermal resistance of a wild strain of A. acidoterrestris, then focusing on the effect of the thermal treatment necessary to inactivate spores on the quality of tomato juice.


Understanding early organogenesis using a simplified in situ hybridization protocol in Xenopus.
Organogenesis is the study of how organs are specified and then acquire their specific shape and functions during development. The Xenopuslaevis embryo is very useful for studying organogenesis because their large size makes them very suitable for identifying organs at the earliest steps in organogenesis. At this time, the primary method used for identifying a specific organ or primordium is whole mount in situ hybridization with labeled antisense RNA probes specific to a gene that is expressed in the organ of interest. In addition, it is relatively easy to manipulate genes or signaling pathways in Xenopus and in situ hybridization allows one to then assay for changes in the presence or morphology of a target organ. Whole mount in situ hybridization is a multi-day protocol with many steps involved. Here we provide a simplified protocol with reduced numbers of steps and reagents used that works well for routine assays. In situ hybridization robots have greatly facilitated the process and we detail how and when we utilize that technology in the process. Once an in situ hybridization is complete, capturing the best image of the result can be frustrating. We provide advice on how to optimize imaging of in situ hybridization results. Although the protocol describes assessing organogenesis in Xenopus laevis, the same basic protocol can almost certainly be adapted to Xenopus tropicalis and other model systems.


Sequence analysis of the complete S genomic segment of a newly identified hantavirus isolated from the white-footed mouse (Peromyscus leucopus): phylogenetic relationship with other sigmodontine rodent-borne hantaviruses.
Four Corners (FC) or Sin Nombre virus, a hantavirus harbored by the deer mouse (Peromyscus maniculatus), is the principal etiologic agent of hantavirus pulmonary syndrome (HPS). Recently, a hantavirus, designated New York (NY) virus, isolated from a white-footed mouse (Peromyscus leucopus) captured on Shelter Island, New York, was molecularly linked to a fatal case of HPS occurring in the northeastern United States. To clarify the genetic and phylogenetic relationship between NY and FC viruses and other sigmodontine rodent-borne hantaviruses, we amplified and sequenced the entire S genomic segment of NY virus. The S segment of NY virus was 2078 nucleotides long, with an open reading frame of 1284 nucleotides in the virus complementary strand, capable of encoding a protein of 428 amino acids, and with a 752-nucleotide long 3'-noncoding region, comprised of numerous imperfect repeats. Pairwise analysis indicated that NY virus was more similar to FC virus than to other sigmodontine rodent-borne hantaviruses, differing from strains of FC virus by 16.6-17.8% and 7.0-8.2% at the nucleotide and amino acid levels, respectively. As determined by the maximum parsimony and neighbor-joining methods, NY virus formed a separate lineage from FC virus and was phylogenetically distinct from hantaviruses harbored by other sigmodontine rodents. Whether or not NY and FC viruses represent distinct viral species is unclear. Further analyses of hantaviruses harbored by white-footed mice are needed to clarify the genetic diversity and evolution of Peromyscus-borne hantaviruses.


Heterogeneity of hepatocellular carcinoma contributes to cancer progression.
Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.


E5 proteins of human papillomavirus types 11 and 16 transactivate the c-fos promoter through the NF1 binding element.
Human papillomavirus type 11 (HPV-11) and HPV-16 contain an E5 gene that can induce c-fos gene expression in mouse fibroblasts. This study investigated the human c-fos promoter characteristics by mapping the c-fos promoter sequence with several deletion and point mutants that confer responsiveness to E5 of HPV-11 or HPV-16. The mutant studies show that NF1 binding sequences within the c-fos promoter were crucial for the induction of the c-fos gene by E5, and the gel shift assay study suggested that E5 of both HPV-11 and HPV-16 is associated, perhaps indirectly, with this NF1 element in the transactivation of the human c-fos promoter. Using an inducible system, we demonstrate that increased induction of the HPV-11 E5 gene in cells led to increased transactivation of the NF1 element. In addition, the transactivating activity of a series of HPV-11 E5 mutants on the NF1 element had a strong correlation with their respective transforming activities.


Identification of the Human Skeletal Stem Cell.
Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis. VIDEO ABSTRACT.


Quantitation of Cell Membrane Permeability of Cyclic Peptides by Single-Cell Cytoplasm Mass Spectrometry.
Cyclic peptides (CPs) have attracted attention as next-generation drugs because they possess both cell-permeable potential as small molecules and specific affinity similar to antibodies. As intracellular molecules are important targets of CPs, quantitation of the intracellular retention and transmembrane permeability of CPs is necessary for drug development. However, permeated CPs within cells cannot be directly assessed by conventional permeability assays using methods such as artificial membranes and cell monolayers. Here, we propose a new approach using single-cell cytoplasm mass spectrometry (SCC-MS). After cells were incubated with CPs, the cytoplasm was directly collected from a single cell using a microneedle followed by nanoelectrospray ionization mass spectrometry detection of the CPs. The height of the CP peak was plotted against time and fitted with a simple function, y = a(1 - e-bx), to calculate the apparent permeability coefficient (Papp) for both the influx and efflux directions. MCF-7 cells were selected as model cancer cells and cultured with cyclosporin A (CsA) and its demethylated analogs (dmCsA-1, -2, and -3) as model CPs. Papp values (10-6 cm/s) obtained from cells incubated with 50 μM CPs ranged from 0.017 to 0.121 for influx and 0.20 to 1.48 for efflux. The higher efflux ratio was possibly caused by efflux transporters such as P-glycoprotein, a well-known receptor of CsA. The equilibrated intracellular concentration of CPs was estimated to be as low as 4.1-6.8 μM, which showed good consistency with the high efflux ratio. SCC-MS is promising as a reliable permeability assay for next-generation CP-based pharmaceuticals.


Hematopoietic potential of IL-2-cultured peripheral blood stem cells from breast cancer patients.
Patients receiving autologous transplants for various malignancies generally experience an increased incidence of relapse compared with patients receiving unmanipulated allogeneic transplants. We initiated a protocol for IL-2 activation of peripheral blood stem cells (PBSC) for induction of in vitro and in vivo autologous graft-versus-tumor (GVT) activity in patients with breast cancer. In this study we analyzed the effects of 24 h of IL-2 incubation on the hematopoietic potential of PBSC from these patients. Cells collected by leukapheresis were first cryopreserved and stored in liquid nitrogen, then thawed rapidly and incubated with IL-2 in a serum-free system for 24 h, with samples analyzed before and after incubation. Although there was a significant drop in mononuclear cells (MNC) (from 4.5 to 3.7 x 10(8)/kg) and CD34+ cells (from 12.3 to 7.5 x 10(6)/kg) after 24 h in culture, there was no significant change in colony-forming units (CFU) (from 12.5 to 11.5 x 10(5)/kg). Time to engraftment (neutrophils: < 0.5 x 10(9)/l; platelets: > 20 x 10(9)/l) was comparable to a cohort of similar patients receiving non-cultured PBSC transplants. These results indicate that mobilized frozen/thawed PBSC which have been cultured in IL-2 for 24 h retain adequate potential for hematopoietic reconsistution in this group of patients.


Pesticide multiresidue determination in rice paddy water by gas chromatography coupled with triple quadrupole mass spectrometry.
Pollution of water sources by pesticides is a result of intensive use of these compounds, and the establishment of analytical methods for monitoring programs is very important. This paper presents a method for the determination of multiclass pesticide residues in rice paddy water based on SPE and GC/MS/MS. The validation results were satisfactory. All compounds showed adequate linearity (r2 >or= 0.99), and analysis by GC/MS/MS with a triple quadrupole mass spectrometer gave high selectivity and sensitivity. With the proposed SPE step an LOD of 0.06 microg/L was achieved. Recoveries from blank samples spiked at 0.2, 04, and 0.8 microg/L were between 70 and 120% with RSD <20% for most analyzed compounds, despite their different chemical nature, indicating good accuracy and precision. The proposed method is efficient for pesticide residue determination, including some metabolites, and gave good performance when applied to real samples.


Breaking sedentary behaviour has the potential to increase/ maintain function in frail older adults.
This pilot study aimed to evaluate the effect of a sedentary behaviour (SB) reduction intervention (Stomp Out (Prolonged) Sitting (SOS)) in frail older adults. Participants (>65years) were recruited from sheltered housing complexes and randomized into 2 groups. On weeks 2, 6 and 10 both groups had face-to-face 40min motivational sessions, including feedback on physical function and SB. One group had the addition of real-time tactile feedback on sitting. Total sedentary time and patterns of SB were recorded by activPAL, along with validated measures of function: Timed Up and Go (TUG), Sit-to-Stand (STS) and balance tests. Outcomes were analyzed by intention-to-treat mixed model analysis. Twenty-three participants started the SOS intervention. Health issues led to high attrition in this frail population. TUG (4 seconds faster) and STS (>2 rises more in 30 seconds) scores improved significantly in both groups. There were no significant changes in SB parameters. Motivational interviewing alongside functional test feedback, visual and real-time feedback on SB improved physical function over the study. This pilot study suggests that sit-to-stand transitions to break prolonged sitting time may help reduce frailty and functional decline in people who are often unable to engage in more intense exercise interventions.


Unveiling Circular RNA-Mediated Regulatory Mechanisms in Necroptosis in Premature Ovarian Failure.
Necroptosis is a programmed necrotic cell death, in which dying cells rupture and release intracellular components that trigger a proinflammatory response. The current study aimed at probing the circular RNA (circRNA)-mediated regulatory mechanisms in necroptosis in premature ovarian failure (POF). CircRNA sequencing analysis was conducted in ovarian tissues of control and POF rats and transcriptome microarrays were acquired from the GSE33423 dataset. Differential expression analysis of circRNAs and mRNAs was executed between the POF and control data. Both a necroptosis-based circRNA-microRNA (miRNA)-mRNA network and a protein-protein interaction (PPI) network were established. Then, the functional annotation and immunological traits were analyzed. Totally, 1266 upregulated and 1283 downregulated circRNAs as well as 1101 upregulated and 1168 downregulated mRNAs were determined in the POF rats versus the controls. The differentially expressed mRNAs predominantly correlated with necroptosis. The circRNA-miRNA-mRNA networks of downregulated necroptosis genes (comprising rno_circRNA_004995-rno-miR-148b-5p-H2afy2, rno_circRNA_016998-rno-miR-29a-5p-Hmgb1, and rno_circRNA_017593-rno-miR-29a-5p-Hmgb1) and upregulated necroptosis genes (comprising rno_circRNA_015900-rno-miR-935-Stat1, rno_circRNA_007946-rno-miR-328a-3p-Stat5a, rno_circRNA_007947-rno-miR-328a-3p-Stat5a, rno_circRNA_005064-rno-miR-18a-5p-Stat1, rno_circRNA_005064-rno-miR-18a-5p-Stat5a, rno_circRNA_005115-rno-miR-22-3p-Stat1, rno_circRNA_009028-rno-miR-342-5p-Stat1, rno_circRNA_011240-rno-miR-1224-Stat5a, rno_circRNA_016078-rno-miR-711-Stat5a) were built. POF-specific necroptosis genes (STAT1, STAT5A, PLA2G4A, HMG1L1, HMGB1, AGER, EGFR, HDAC7, IFNA1, IL10RB, IL27RA, PYGL, SOCS1, TRADD, CXCL10, DDX5, EZH2, FADS2, FER, H2AFY2, HIST1H2AF, IFI44L, IL27, IRGM, MX1, NFKB2, PAFAH2, PEMT, PGM2L1, PGR, PHKA2, and PLB1) were selected since they displayed notable associations with most immune cells, immune checkpoints, chemokines, human leukocyte antigen (HLA) molecules, and immune receptors. Altogether, we proposed the presence of widespread regulatory mechanisms of circRNAs in necroptosis and demonstrated that altered circRNA biogenesis might contribute to POF by affecting necroptosis.


Mechanical testing of fixation techniques for scaffold-based tissue-engineered grafts.
Full-thickness defects in articular cartilage can be functionally restored by autologous chondrocyte implantation (ACI). In past years, numerous types of scaffolds for tissue-engineered cartilage implants have been developed and thoroughly characterized. However, the fixation stability of the implants has been rarely investigated despite its well-known importance for successful therapy. In this study, we have mechanically tested the fixation stability of four commonly used biomaterials for ACI attached by four different fixation techniques (unfixed, fibrin glue, chondral suture, and transosseous suture) in situ. Scaffolds based on polyglycolic acid (PGA) and polyglycolic acid and poly-L-lactic acid (PGLA), collagen membranes, and a gel-like matrix material were fixed within rectangular full-thickness cartilage defects of 10 x 15 mm(2) and loaded in tension until failure. Fibrin glue fixation of PGLA-scaffolds withstood a load of 2.18 6 +/- 0.47 N, chondral sutured PGA-scaffolds of 26.29 6 +/- 1.55 N, and transosseous fixed PGA-scaffolds of 38.18 6 +/- 9.53 N. The PGA-scaffold could be loaded highest until failure for all fixation techniques compared to the PGLA-scaffold and collagen membrane. Our findings serve as basis for selecting the most suitable fixation technique for scaffold-based tissue-engineered grafts according to the expected in vivo loads.


A damage model for nonlinear tensile behavior of cortical bone.
To describe the time-dependent nonlinear tensile behavior observed in experimental studies of cortical bone, a damage model was developed using two internal state variables (ISV's). One ISV is a damage parameter that represents the loss of stiffness. A rule for the evolution of this ISV was defined based on previously observed creep behavior. The second ISV represents the inelastic strain due to viscosity and internal friction. The model was tested by simulating experiments in tensile and bending loading. Using average values from previous creep studies for parameters in the damage evolution rule, the model tended to underestimate the maximum nonlinear strains and to overestimate the nonlinear strain accumulated after load reversal in the tensile test simulations. Varying the parameters for the individual tests produced excellent fits to the experimental data. Similarly, the model simulations of the bending tests could produce excellent fits to the experimental data. The results demonstrate that the 2-ISV model combining damage (stiffness loss) with slip and viscous behavior could capture the nonlinear tensile behavior of cortical bone in axial and bending loading.


An explanatory model of factors related to well baby visits by age three years for Medicaid-enrolled infants: a retrospective cohort study.
Well baby visits (WBVs) are a cornerstone of early childhood health, but few studies have examined the correlates of WBVs for socioeconomically vulnerable infants. The study objective was to identify factors related to the number of WBVs received by Medicaid-enrolled infants in the first three years of life and to present a preliminary explanatory model. We analyzed Iowa Medicaid claims files and birth certificate data for infants born in calendar year 2000 (N = 6,085). The outcome measure was the number of well baby visits (WBVs) received by Medicaid-enrolled infants between age 1 and 41 months (range: 0 to 10). An ecological health model and existing literature were used to evaluate 12 observed factors as potential WBV correlates. We ran multiple variable linear regression models with robust standard errors (α = 0.05). There were a number of infant, maternal, and health system factors associated with the number of WBVs received by Medicaid-enrolled infants. Infants whose mothers had a greater number of prenatal healthcare visits (ß = 0.24 to 0.28; P = .001) or were married (ß = 0.20; P = .002) received more WBVs. Having a chronic health condition (ß = 0.51; P < .0001) and enrollment in a case management program (ß = 0.48; P < .0001) were also positively associated with WBVs. Eligibility for Medicaid through the Supplemental Security Income Program (ß = -0.70; P = .001), increased maternal age (ß = -0.27 to -0.35; P = .004), higher levels of maternal education (ß = -0.18; P = .005), maternal smoking (ß = -0.13; P = .018), and enrollment in a health maintenance organization plan (ß = -1.15; P < .0001) were negatively associated with WBVs. There was a significant interaction between enrollment in a health maintenance organization plan and enrollment in a Medicaid case management program (P = .015). Maternal race, maternal alcohol use during pregnancy, and rurality were not significantly related to the number of WBVs. Multiple infant, maternal, and health system variables were related to the number of WBVs received by Medicaid-enrolled infants. Additional research is needed to develop strategies to optimize access to WBVs for Medicaid-enrolled infants at risk for poor use of preventive medical care services.


Non-nutritional stress acclimation of mycorrhizal woody plants exposed to drought.
Mycorrhizal enhancement of drought resistance of two woody plant species, loblolly pine (Pinus taeda L.) and rose (Rosa hybrida L. cv. Ferdy), occurred independently of phosphorus nutrition. Mycorrhizae tended to alter root morphology and carbon allocation patterns of shoots and roots. Increased drought resistance of mycorrhizal plants was in part attributed to drought-induced colonization by mycorrhizae and the ability of the mycorrhizal plants to maintain high transpiration rates as a result of greater lateral root formation and lower shoot mass (in ectomycorrhizal loblolly pine), and a higher root/shoot ratio and leaf abscission (in endomycorrhizal roses). Neither the endo- nor ectomycorrhizal symbionts affected osmotic adjustment of droughted plants.


Internal degrees of freedom and transport of benzene on graphite.
In this paper, the chaotic internal degrees of freedom of a benzene molecule adsorbed on a graphite substrate, their interplay with thermal noise, and their effects on the diffusion and drift are investigated analytically by making use of the presence of two different time scales as well as by molecular-dynamics simulations. The effects of thermal noise are investigated, and it is found that noise does not significantly alter the dynamics of the internal degrees of freedom yet does affect the friction and diffusion of the center of mass. Qualitative and quantitative theoretical predictions for the friction and diffusion of the molecule on the substrate are made and are compared to molecular-dynamics simulations. Contributions to the friction and diffusion from the finite heat bath as well as the slow dynamics of the center of mass are formally identified. It is shown that the torsion in benzene, which dominates the nonlinear coupling, significantly affects the friction of the molecule on the surface. The results compare favorably with recent results from He-neutron spin echo experiments on this system. Based on the analytical and numerical results, some suggestions are made for experimental conditions under which the effects of internal degrees of freedom might be observable.


Impact of Immunoscore on the Management of Stage II Colon Cancer Patients: A Physician Survey.
Adjuvant chemotherapy use in stage II colon cancer is controversial. Current prognostic risk factors do not take the tumor immune microenvironment into account. Consideration of the Immunoscore, which measures the host immune response at the tumor site, may assist clinicians in reducing adjuvant chemotherapy use in patients who are unlikely to benefit from it. This study sought to determine the potential clinical utility of the Immunoscore, via its effect on medical oncologists' recommendations for management of patients with stage II colon cancer. De-identified vignettes of 10 patients with stage II colon cancer were presented to 25 practicing medical oncologists. Each participant completed surveys indicating recommendations for adjuvant chemotherapy and surveillance strategies. An educational session was subsequently conducted, and the same patient profiles were re-presented but included immunoscore results. Participants were again asked to provide their recommendations. A participant was counted as influenced if their responses were altered after immunoscore test results were provided. All but one participant (96%) altered a management recommendation for ≥1 case. For individual cases, a mean of 55% (range, 40-80%) of participants altered their recommendations for adjuvant chemotherapy and/or surveillance. For the immunoscore-high cases (low-risk of recurrence), recommendations for adjuvant chemotherapy use decreased from 60% to 31%. These results indicate a willingness by oncologists to integrate immunoscore information into clinical practice recommendations. Incorporation of immunoscore data resulted in the reduction of nonvalue care in the simulated population. Confirmation in prospective studies is planned.


An Inexpensive, Portable Shield to Improve Healthcare Worker Safety During Intubation Procedures.
Healthcare workers (HCW) are exposed to risk of infection during intubation procedures, in particular, in the prehospital setting. Here, we demonstrate a novel shield that can be used during intubation to block aerosols and droplets from reaching the HCW. The device is mounted on the patient's head and provides a barrier between patient and HCW. It incorporates a self-sealing port through which an endotracheal tube can be inserted. The port "floats" in the plane of the shield to facilitate maneuvering of the endotracheal tube. The shield is fabricated from transparent materials to enable the HCW to visualize the procedure. Using two complementary imaging methods, background oriented Schlieren imaging and laser sheet droplet imaging, we show that the device prevents detectable transmission of gas flow and droplets through the shield both before and after endotracheal tube insertion.Clinical Relevance- This device has the potential to protect HCWs from infections during intubation procedures, especially in the prehospital setting.


Role of Renin-Angiotensin system and oxidative stress on vascular inflammation in insulin resistence model.
(1) This study aims to demonstrate the causal involvement of renin angiotensin system (RAS) and oxidative stress (OS) on vascular inflammation in an experimental model of metabolic syndrome (MS) achieved by fructose administration to spontaneously hypertensive rats (FFHR) during 12 weeks. (2) Chronic treatment with candesartan (C) (10 mg/kg per day for the last 6 weeks) or 4OH-Tempol (T) (10(-3) mmol/L in drinking water for the last 6 weeks) reversed the increment in metabolic variables and systolic blood pressure. In addition, chronic C treatment reverted cardiovascular remodeling but not T. (3) Furthermore, chronic treatment with C was able to completely reverse the expression of NF-κB and VCAM-1, but T only reduced the expression. C reduced the expression of proatherogenic cytokines as CINC2, CINC3, VEGF, Leptin, TNF-alpha, and MCP-1 and also significantly reduced MIP-3, beta-NGF, and INF-gamma in vascular tissue in this experimental model. T was not able to substantially modify the expression of these cytokines. (4) The data suggest the involvement of RAS in the expression of inflammatory proteins at different vascular levels, allowing the creation of a microenvironment suitable for the creation, perpetuation, growth, and destabilization of vascular injury.


Tobacco mitochondrial small heat shock protein NtHSP24.6 adopts a dimeric configuration and has a broad range of substrates.
There is a broad range of different small heat shock proteins (sHSPs) that have diverse structural and functional characteristics. To better understand the functional role of mitochondrial sHSP, NtHSP24.6 was expressed in Escherichia coli with a hexahistidine tag and purified. The protein was analyzed by non-denaturing PAGE, chemical cross-linking and size exclusion chromatography and the H6NtHSP24.6 protein was found to form a dimer in solution. The in vitro functional analysis of H6NtHSP24.6 using firefly luciferase and citrate synthase demonstrated that this protein displays typical molecular chaperone activity. When cell lysates of E. coli were heated after the addition of H6NtHSP24.6, a broad range of proteins from 10 to 160 kD in size remained in the soluble state. These results suggest that NtHSP24.6 forms a dimer and can function as a molecular chaperone to protect a diverse range of proteins from thermal aggregation.


Ampakines Attenuate Staurosporine-induced Cell Death in Primary Cortical Neurons: Implications in the 'Chemo-Brain' Phenomenon.
Mounting evidence suggests that trophic cell signaling can be mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation. It has been demonstrated that exogenous application of brain-derived neurotrophic factor (BDNF) is highly neuroprotective in vitro against neurotoxic insults such as standard chemotherapies. Because positive allosteric modulation of AMPARs with ampakines can increase both BDNF mRNA and protein in vitro and in vivo, we examined whether application of the ampakines CX614 and CX729 promoted neuroprotection against staurosporine-induced cell death in rat primary cortical neurons using propidium iodide to stain for dead cells. A transient 2-h pretreatment with CX614 or CX729 performed 24 h prior to staurosporine produced significant, time-dependent neuroprotection that was resistant to the AMPAR antagonists NBQX or GYKI 52466, suggesting that this effect may be independent of ion flow. Furthermore, the pretreatment time requirements of CX729 matched the time course for increased BDNF expression previously reported to occur in hippocampal slices, suggesting that increased neurotrophin expression might be associated with the neuroprotective effects conferred by ampakines. Our data demonstrate that ampakines may be able to perturb neuronal toxicity and peripheral neuropathy of front-line chemotherapies.


Plan U: Universal access to scientific and medical research via funder preprint mandates.
Preprint servers such as arXiv and bioRxiv represent a highly successful and relatively low cost mechanism for providing free access to research findings. By decoupling the dissemination of manuscripts from the much slower process of evaluation and certification by journals, preprints also significantly accelerate the pace of research itself by allowing other researchers to begin building on new results immediately. If all funding agencies were to mandate posting of preprints by grantees-an approach we term Plan U (for "universal")-free access to the world's scientific output for everyone would be achieved with minimal effort. Moreover, the existence of all articles as preprints would create a fertile environment for experimentation with new peer review and research evaluation initiatives, which would benefit from a reduced barrier to entry because hosting and archiving costs were already covered.


Paracentesis as an aid to the diagnosis of intestinal gangrene: experience in 50 infants and children.
We performed paracentesis or peritoneal lavage on 50 seriously ill infants and children in whom the diagnosis of intestinal gangrene or perforation was suspected. Thirty-four infants had necrotizing enterocolitis and 16 had other conditions. In infants with suspected intestinal gangrene, the presence of brown peritoneal fluid and/or bacteria on Gram's stain was indicative of intestinal gangrene. In infants with pneumoperitoneum, the presence of cloudy fluid with leukocytosis was indicative of gastrointestinal perforation. Using these two criteria, the accuracy of paracentesis in predicting the need for operation was 90%. When combined with clinical judgment, the accuracy rose to 97.5%. The rate of negative findings from abdominal explorations was 5%. Analysis of the peritoneal fluid may improve the timing and accuracy of the operative decision.


Efficacy of a Web App for Cognitive Training (MeMo) Regarding Cognitive and Behavioral Performance in People With Neurocognitive Disorders: Randomized Controlled Trial.
Cognitive and behavioral symptoms are the clinical hallmarks of neurocognitive disorders. Cognitive training may be offered to reduce the risks of cognitive decline and dementia and to reduce behavioral symptoms, such as apathy. Information and communication technology approaches, including serious games, can be useful in improving the playful aspect of computerized cognitive training and providing motivating solutions in elderly patients. The objective of this study was to assess the effectiveness of employing the MeMo (Memory Motivation) Web app with regard to cognitive and behavioral symptoms in patients with neurocognitive disorders. MeMo is a Web app that can be used on any Web browser (computer or tablet). The training activities proposed in MeMo are divided into the following two parts: memory and mental flexibility/attention. The study included 46 individuals (mean age 79.4 years) with a diagnosis of neurocognitive disorders at the Institut Claude Pompidou Memory Center in Nice. This randomized controlled study compared the evolution of cognition and behavior between patients not using MeMo (control group) and patients using MeMo (MeMo group) for 12 weeks (four sessions per week). Patients underwent memory and attention tests, as well as an apathy assessment at baseline, week 12 (end of the training period), and week 24 (12 weeks after the end of the training sessions). In addition, to assess the impact of high and low game uses, the MeMo group was divided into patients who used MeMo according to the instructions (about once every 2 days; active MeMo group) and those who used it less (nonactive MeMo group). When comparing cognitive and behavioral scores among baseline, week 12, and week 24, mixed model analysis for each cognitive and behavioral score indicated no significant interaction between testing time and group. On comparing the active MeMo group (n=9) and nonactive MeMo group (n=13), there were significant differences in two attention tests (Trial Making Test A [P=.045] and correct Digit Symbol Substitution Test items [P=.045]) and in the Apathy Inventory (AI) (P=.02). Mixed analysis (time: baseline, week 12, and week 24 × number of active days) indicated only one significant interaction for the AI score (P=.01), with a significant increase in apathy in the nonactive MeMo group. This study indicates that the cognitive and behavioral efficacies of MeMo, a Web-based training app, can be observed only with regular use of the app. Improvements were observed in attention and motivation. ClinicalTrials.gov NCT04142801; https://clinicaltrials.gov/ct2/show/NCT04142801.


A Propensity Scoring Approach to Characterizing the Effects of Maternal Smoking During Pregnancy on Offspring's Initial Responses to Cigarettes and Alcohol.
When examining the effects of prenatal exposure to maternal smoking during pregnancy (MSDP) on later offspring substance use, it is critical to consider familial environments confounded with MSDP. The purpose of this study was to examine the effect of MSDP on offspring's initial reactions to cigarettes and alcohol, which are indicators of future substance-use related problems. We tested these effects using two propensity score approaches (1) by controlling for confounding using the MSDP propensity score and (2) examining effects of MSDP across the MSDP risk distribution by grouping individuals into quantiles based on their MSDP propensity score. This study used data from 829 unrelated mothers with a reported lifetime history of smoking to determine the propensity for smoking only during their first trimester (MSDP-E) or throughout their entire pregnancy (MSDP-T). Propensity score analyses focused on the offspring (N = 1616 female twins) of a large subset of these mothers. We examined the effects of levels of MSDP-E/T on offspring initial reactions to their first experiences with alcohol and cigarettes, across the distribution of liability for MSDP-E/T. MSDP-E/T emerged as significant predictors of offspring reactions to alcohol and cigarettes, but the effects were confounded by the familial liability for MSDP. Further, the unique MSDP effects that emerged were not uniform across the MSDP familial risk distribution. Our findings underscore the importance of properly accounting for correlated familial risk factors when examining the effects of MSDP on substance related outcomes.


Is there opponent-orientation coding in the second-order channels of pattern vision?
Is there opponency between orientation-selective processes in pattern perception, analogous to opponency between color mechanisms? Here we concentrate on possible opponency in second-order channels. We compare several possible second-order structures: SIGN-opponent-only channels in which there is no opponency between orientations (also called complex channels or filter-rectify-filter mechanisms); three structures we group under the name ORIENTATION-opponent; and finally BOTH-opponent channels which combine features of both SIGN-opponent-only and ORIENTATION-opponent channels but lead to predictions that are distinct from either of theirs. We measured observers' ability to segregate textures composed of checkerboard and striped arrangements of vertical and horizontal Gabor grating patches. The observers' performance was compared to model predictions from the alternative opponent structures. The experimental results are consistent with SIGN-opponent-only channels. The results rule out the ORIENTATION-opponent and BOTH-opponent structures. Further, when the models were expanded to include a contrast gain-control (inhibition among channels in a normalization network) the SIGN-opponent-only model was also able to explain a contrast-dependent effect we found, thus providing another piece of evidence that such normalization is an important process in human texture perception.


Species-specificity of estradiol regulated growth factors in breast cancer.
Recent evidence indicates that autocrine/paracrine mechanisms may mediate the mitogenic effect of estradiol (E2) both in human and experimental breast cancer. However, the species-specificity of E2-regulated growth factors with regard to their biologic action has not been evaluated. To test this issue, we examined, in the soft agar clonogenic assay, the colony-stimulating activity in human breast cancers of conditioned media obtained from rat mammary carcinomas exposed to E2 (rat E2-CM). Of 22 primary human breast cancers plated in soft agar in the absence of serum, 18 (82%) successfully grew with a mean colony number of 62.4 +/- 9.8 (S.E.M.) (range 14-193). Rat E2-CM significantly stimulated colony formation in 10/18 (56%) human breast cancers to 155 +/- 11% (S.E.M.) of control. E2 administration (10(-9) M) in these tumors had a virtually identical overall effect (154 +/- 13% of control colony number). In the remaining eight tumors (44%), neither rat E2-CM nor E2 had, in general, a significant colony-stimulating effect. The growth-promoting action of rat E2-CM and E2 was not influenced by the hormone receptor status of the tumor. These results suggest that E2-regulated growth factors may not be species-specific, at least with regard to their colony-stimulating effects in soft agar.


Mental rotation in a California sea lion (Zalophus californianus).
Mental rotation is a widely accepted concept that suggests an analogue mode of visual information-processing in certain visuospatial tasks. Typically, these tasks demand the discrimination between the image and mirror-image of rotated figures, for which human subjects need an increasing reaction time depending on the angular disparity between the rotated figures. In pigeons, tests of this kind yielded a time-independent rotational invariance, suggested as being the result of a non-analogue information-processing that has evolved in response to the horizontal plane that birds perceive from above while flying. Given that marine mammals use the water surface as the horizontal plane for orientation while diving, the ability of a California sea lion to mentally rotate two-dimensional shapes was tested. Using a successive two-alternative matching-to-sample procedure, the animal had to decide between the image and mirror-image of a previously shown sample. Both stimuli were rotated by a multiple of 30 degrees with respect to the sample. The animal's reaction time was measured by a computer-controlled touch-screen device, rewarding the animal for pressing its snout against the stimulus matching the sample. A linear regression analysis of the animal's mean reaction time against the angular rotation of the stimulus yielded a significant correlation coefficient. Thus, the present data can be explained by the mental rotation model, predicting an image-like representation of visual stimuli in this species. The present results therefore correspond well with those found for human subjects, but are inconsistent with the data reported for pigeons.


Phase I study of suramin combined with doxorubicin in the treatment of androgen-independent prostate cancer.
In this study, we determined the maximum tolerated plasma concentration of suramin (within the predetermined study target range) when combined with doxorubicin in the treatment of androgen-independent prostate cancer. Twenty-four patients received suramin dosages based on proportional adjustment of the steady-state plasma suramin concentration to achieve the targeted plasma concentrations of 50-100, 101-150, 151-200, or 201-250 microg/ml. Doxorubicin (20 mg/m2) was administered i.v. over 24 h at weekly intervals. Suramin was given i.v. over 2 h twice weekly. Patients received treatment until dose-limiting toxicity or disease progression. Side effects similar to those reported for suramin and doxorubicin administered as individual agents were observed. Dose-limiting motor neuropathy developed in three patients (13%). Twelve of 24 evaluable patients (50%; 95% confidence interval, 28-71%) and 6 of 10 evaluable patients (60%; 95% confidence interval, 26-88%) had a >50% decrease of prostate-specific antigen and measurable lesions, respectively. The maximum tolerated plasma level of suramin when combined with doxorubicin was 151-200 microg/ml. Future studies on suramin combined with doxorubicin or other agents could be performed using a fixed dosing scheme with a targeted suramin steady-state plasma concentration of 200 microg/ml.


Why we must leave our organs to others.
Organ procurement presents several ethical concerns (from what constitutes acceptable criteria for death to issues involved in specifically designating to whom an organ can be given), but none is more central than the concern for what are appropriate means for acquiring organs. The following discussion attempts a different perspective on the issue of organ procurement by arguing that, rather than appealing to our charitable consciences or our pocketbooks, relinquishing our organs after death in this day and age is, in fact, obligatory for most people. Each of us is pressed by the growing demand for our organs should we die "rightly," and that desperate need has risen to such a level that not to release our organs for transplantation would constitute a serious moral wrong.


Smoking prevalence in addiction treatment: a review.
This review explores whether smoking prevalence in addiction treatment samples exceeds that shown in epidemiological data for persons with alcohol or other drug use disorders and whether smoking may have decreased over time in the addiction treatment population as it has done in the general population. English language papers published between 1987 and 2009 were searched electronically. Forty papers reporting smoking prevalence for addiction treatment samples in the United States were identified, and key predictor variables were abstracted. Random logistic models were used to assess relationships between each individual predictor (year, treatment modality, primary drug treated, government status, and public/private funding status) and smoking prevalence. The lowest smoking prevalence aggregated for studies reported in any single year was 65%, well above epidemiological estimates reported among those with alcohol use and drug use disorders. The odds of smoking were higher in methadone maintenance programs (odds ratio [OR] = 2.25, CI = 1.08, 4.68) as compared with outpatient programs. No other variables in the model were significant. Reanalysis omitting recent studies that may represent outliers or confounding with type of treatment showed a small but significant decrease in smoking over time (OR = 0.9891, CI = 0.9888, 0.9893). The very high smoking rates reported in addiction treatment samples warrant significant, organized, and systemic response from addiction treatment systems, from agencies that fund and regulate those systems, and from agencies concerned with tobacco control.


From science to action and from action to science: the Nunavik Trichinellosis Prevention Program.
During the 1980s, walrus-meat consumption caused infections with the parasite Trichinella nativa in Nunavik inhabitants. In response to these events, stakeholders set up the community-based Nunavik Trichinellosis Prevention Program (NTPP). The objectives of the present communication are to review the NTPP, describe how science and action were interwoven in its development and identify its assets and limitations. Study design. Descriptive study. The NTPP relies on a pooled digestion assay of tongue samples taken from each harvested walrus. The public health recommendations depend on the results of the analyses: infected walrus meat should be destroyed; parasite-free meat may be eaten raw or cooked. All communities involved in the walrus hunt participate in the NTPP and a high percentage of harvested walruses are included in the NTPP. Infected animals account for 2.9% of the walruses tested (20/694) since 1992. The NTPP permitted the early management of a trichinellosis event in 1997. Since then, it prevented the new occurrence of outbreaks related to walruses hunted by Nunavimmiut. The absence of recent major outbreaks of trichinellosis in Nunavik may reasonably be attributed to the NTPP. The success of the program stands on many facilitating factors such as the nature of the disease and its source, the existence of an efficient analytic method, the strong involvement of the different partners including direct resource users, as well as the comprehensive bidirectional science-to-action approach that has been followed.


Physical activity in relation to overweight and obesity in children and adolescents.
Fitness and physical activity levels of children and adolescents are commonly addressed but data on scientific investigations are both equivocal and methodologically diverse. The intensity and type of physical activity that benefit health and development during childhood are not known. Measurement of activity in children is problematic since there is no valid method of assessing activity levels that is feasible for use in large field studies. Most studies using self-report methods, heart rate studies using low heart rate threshold and doubly labelled water studies indicate relatively high levels of activity in children. The three national surveys on large representative samples reported that 60% to 70% of all children were involved in sufficient physical activity according to various definitions. Heart rate studies demonstrate that children generally perform short bouts of moderate to vigorous activities and seldom participate in long-sustained vigorous activities. They also proved that children perform large volumes of activity in the lower heart rate zones. It is generally accepted that boys are more active than girls and physical activity declines by age (peak around 13 to 14 years of age). The difference between the physical activity of European and North American children or between children living in different European countries is difficult to judge due to the diversity of methodology and definitions. There is a need to identify more clearly the quantity and type of activity which improves the health and promotes the normal development of children and to improve the methods assessing physical activity.


A small-area ecologic study of myocardial infarction, neighborhood deprivation, and sex: a Bayesian modeling approach.
Socioeconomic inequalities in the risk of coronary heart disease (CHD) are well documented for men and women. CHD incidence is greater for men but its association with socioeconomic status is usually found to be stronger among women. We explored the sex-specific association between neighborhood deprivation level and the risk of myocardial infarction (MI) at a small-area scale. We studied 1193 myocardial infarction events in people aged 35-74 years in the Strasbourg metropolitan area, France (2000-2003). We used a deprivation index to assess the neighborhood deprivation level. To take into account spatial dependence and the variability of MI rates due to the small number of events, we used a hierarchical Bayesian modeling approach. We fitted hierarchical Bayesian models to estimate sex-specific relative and absolute MI risks across deprivation categories. We tested departure from additive joint effects of deprivation and sex. The risk of MI increased with the deprivation level for both sexes, but was higher for men for all deprivation classes. Relative rates increased along the deprivation scale more steadily for women and followed a different pattern: linear for men and nonlinear for women. Our data provide evidence of effect modification, with departure from an additive joint effect of deprivation and sex. We document sex differences in the socioeconomic gradient of MI risk in Strasbourg. Women appear more susceptible at levels of extreme deprivation; this result is not a chance finding, given the large difference in event rates between men and women.


Implantable diagnostic monitors in the early assessment of syncope and collapse.
The implantable diagnostic monitor, or loop recorder (ILR) is a subcutaneous monitor capable of continuous ECG monitoring up to 3 years. It is an elegant investigative tool for the assessment of patients with recurrent, unexplained syncope in whom an arrhythmic cause needs to be excluded, and is now increasingly utilised very early in the diagnostic work-up of these patients, in line with current guidelines. This review examines the evidence underpinning these recommendations as well as the relevant clinical trials evaluating the use of the ILR in syncope. Continued research will be needed to validate its role as a first line investigation in a sub-select of syncopal patients, especially with the addition of remote monitoring capabilities.


[DDT and related pesticides in maternal milk and other tissues of healthy women at term pregnancy].
Ten healthy patients with term pregnancy resolved by abdominal via. During the surgical procedure samples of umbilical chord serum and maternal adipose tissue, were taken. In all the samples, together with the maternal milk collected the day 10 of puerperium, the concentrations of the following organochlorine pesticides, were measured up: (PCC); beta-BHC; gamma-BHC; heptachloride; aldrin; dieldrin, DDE, DDD, DDT and methoxychloride. The identification and quantification of pesticides was done by the comparison with standards certified by NIST (National Institute of Standard Technology). The general characteristics of the participants were: primigestas of 24.1 years aged, married and of a low socioeconomical level. As to the neonates, of 39 weeks of gestational age, female sex; 3,311 g of corporal weight and size of 51.1 cm. In all the analyzed samples at least one of the organochlorine pesticides was present. The results of correlation analysis between DDT concentration, present in the maternal serum with those identified in the adipose tissue and serum from the umbilical chord were highly significant: a = 0.97 and 0.87, respectively. In the maternal milk the highest concentrations of total DDT, were found, average of 2053 ng/g lipidic base, which is 2.8 times more of daily accepted intake. Likewise, DDT concentration in maternal serum kept exponential relation, growing with age (a = 0.99).


Life cycle assessment of CO2 capture and utilization: a tutorial review.
Capturing CO2 and using it as an alternative carbon feedstock for chemicals, fuels and materials has the potential to reduce both CO2 emissions and fossil resource depletion. To assess the actual environmental benefits of CO2 capture and utilization (CCU), life cycle assessment (LCA) is considered as suitable metric. To enhance the use of LCA of CCU, this tutorial review gives a jargon-free introduction of LCA of CCU directed at LCA novices. Nine particularly important aspects for conducting an LCA of CCU are identified and illustrated with CCU examples. These aspects, phrased as action items, can serve LCA novices as a checklist through all steps in LCA of CCU: from defining the LCA purpose and the system boundaries, over data collection and environmental impact computation, to interpretation and sensitivity analysis of the results. Finally, in the context of CCU, an outlook is given on recent developments in LCA that aim to cover all pillars of sustainability (people, planet, and profit).


Posttraumatic stress disorder and identification in disaster workers.
Disaster workers who work with deceased victims are at increased risk of posttraumatic stress disorder (PTSD). Identification with the deceased has been proposed as one of the mechanisms in this stress-illness relationship. To examine this hypothesis, this study investigated three types of identification with the dead in a group of disaster workers: identification with the deceased as oneself, identification with the deceased as a friend, and identification with the deceased as a family member. Fifty-four volunteer disaster workers who worked with the dead following an explosion on the USS Iowa naval ship were assessed 1, 4, and 13 months after the disaster. PTSD symptoms (measured with the DSMPTSD-IV scale), intrusive and avoidant disaster-related symptoms (measured with the Impact of Event Scale), somatization and general distress (measured with the SCL-90-R), and health care utilization were assessed. Disaster workers who reported identification with the deceased as a friend were more likely than those who did not to have PTSD, more intrusive and avoidant symptoms, and greater levels of other posttraumatic symptoms including somatization. Disaster workers who reported identification with the deceased as a family member had greater intrusive symptoms 1 month after the disaster than those who did not. There were no differences between those who did and did not identify with the deceased as self. Health care utilization was not associated with identification. Identification with the deceased is a risk factor for PTSD and posttraumatic symptoms in disaster workers exposed to the dead. Identification with the dead as a friend is specifically associated with higher risk for these workers.


Complications of intrauterine intervention for treatment of fetal obstructive uropathy.
The intrauterine surgical placement of vesicoamniotic shunts in the treatment of fetal obstructive uropathy associated with prune-belly syndrome to avoid such complications as renal damage and oligohydramnios remains controversial. We present a case of an infant born with prune-belly syndrome at 33 weeks and 5 days of estimated gestational age to a mother of two by vaginal delivery after a pregnancy complicated by fetal obstructive uropathy with attempted intrauterine intervention. After sonographic and laboratory diagnostic and prognostic evaluations, an intrauterine procedure was performed in which a vesicoamniotic shunt was placed under ultrasound guidance. Complications included dislodgment of the initial shunt, with a failed subsequent attempt at placement, oligohydramnios, preterm labor and delivery, and traumatic gastroschisis through the surgical abdominal wall defect. His hospital stay was further complicated by chronic renal insufficiency, prematurity, respiratory distress, bowel malrotation, an episode of gram-negative sepsis with Enterobacter cloacae, signs of liver failure, an exploratory laparotomy for severe enterocolitis, and orchiopexy for bilateral undescended testes. At present, it is unclear whether vesicoamniotic shunt placement can provide any significant improvement in the morbidity or mortality for patients with prune-belly syndrome. A large, prospective, randomized trial is needed to determine its efficacy.


Effects of sympathectomy on heart size and function in aortic-constricted rats.
Effects of chemical sympathectomy with 6-hydroxydopamine on left ventricular mass, norepinephrine content, and performance in aortic-constricted and sham-constricted rats were examined. Sympathectomy did not affect mean arterial pressure but it led to lower final body weights in aortic-constricted rats. Of the hypertensive aortic-constricted rats, those that had also been sympathectomized showed greater increases in left ventricular weight-to-body weight, right ventricular weight-to-body weight, and lung weight-to-body weight ratios. Left ventricular norepinephrine content was depressed by either sympathectomy or aortic constriction and was severely depleted by their combination. Sympathectomy had no effect on maximal cardiac output or left ventricular stroke work during rapid saline infusion. In aortic-constricted rats, however, it lowered heart rate during the infusion and increased left ventricular end-diastolic pressure at peak stroke work. This evidence suggests that elimination of the adrenergic nervous system's chronotropic influence promotes greater left ventricular filling, and the resultant increase in preload may importantly contribute to the stimulation of cardiac hypertrophy.


Isolation and characterization of novel marine-derived actinomycete taxa rich in bioactive metabolites.
A unique selective enrichment procedure has resulted in the isolation and identification of two new genera of marine-derived actinobacteria. Approximately 90% of the microorganisms cultured by using the presented method were from the prospective new genera, a result indicative of its high selectivity. In this study, 102 actinomycetes were isolated from subtidal marine sediments collected from the Bismarck Sea and the Solomon Sea off the coast of Papua New Guinea. A combination of physiological parameters, chemotaxonomic characteristics, distinguishing 16S rRNA gene sequences, and phylogenetic analysis based on 16S rRNA genes provided strong evidence for the two new genera (represented by strains of the PNG1 clade and strain UMM518) within the family Micromonosporaceae. Biological activity testing of fermentation products from the new marine-derived actinomycetes revealed that several had activities against multidrug-resistant gram-positive pathogens, malignant cells, and vaccinia virus replication.


Long-term synaptic plasticity in deep layer-originated associational projections to superficial layers of rat entorhinal cortex.
Superficial layers of the entorhinal cortex (EC) relay the majority of cortical input projections to the hippocampus, whereas deep layers of the EC mediate a large portion of hippocampal output projections back to other cortical areas, suggesting a functional segregation between superficial and deep layers of the EC as input and output structures of the hippocampus, respectively. However, deep layers of the EC send associational projections to superficial layers, suggesting a potential interaction between neocortical input and hippocampus-processed output in superficial layers. This possibility was investigated by examining whether deep to superficial EC projections support long-term synaptic plasticity, and whether they interact with other pathways in superficial layers in rat medial EC slice preparations. Synaptic responses of the deep-to-superficial layer projections were verified based on field potential profiles, paired-pulse facilitation, physical separation between superficial and deep layers, and pharmacological manipulation. Long-term potentiation (LTP) was reliably induced in the deep-to-superficial layer projections by burst stimulations that emulated theta or sharp wave electroencephalogram (EEG),and it was blocked by an N-methyl-d-aspartate receptor antagonist (D-2-amino-5-phosphonopentanoic acid) and a calcium channel blocker (nifedipine). Prolonged low frequency stimulation induced long-term depression. A weak stimulation of deep layers, which induced a small degree of LTP by itself, generated a much larger degree of LTP when paired with a strong stimulation of superficial layers, indicating that the deep-to-superficial layer projections cooperate with other pathways in the superficial EC to enhance synaptic weights. Our results suggest that neocortical input and hippocampal output information are integrated in superficial layers of the EC.


Association of vagal tone with serum insulin, glucose, and diabetes mellitus--The ARIC Study.
Reduced vagal activity assessed by heart rate variability (HRV) has been observed in studies of diabetics, but this association has not been reported at the population level. To investigate the association of HRV with diabetes mellitus, as well as fasting serum insulin, and glucose, we examined a stratified random sample of 1933 individuals (154 diabetics and 1779 non-diabetics), aged 45-65 years from the Atherosclerosis Risk in Communities (ARIC) study cohort. Two-minute, resting, supine beat-to-beat heart rate records were collected. Power spectral density estimation was used to derive HRV high frequency power (HF, 0.15-0.35 Hz) as the conventional marker of vagal function. Age, race, and gender-adjusted geometric means of HF were 0.78 and 1.27 (beat/min)(2) for diabetics and non-diabetics respectively (P for mean difference <0.01), reflecting a reduced vagal activity in diabetics. In individuals not diagnosed as diabetics, a graded, inverse association was observed between fasting serum insulin and HF (P for trend <0.01): the age, race, and gender-adjusted geometric mean values of HF in the lowest and highest quartiles of serum insulin were 1.34 and 1.14 (beat/minute)(2), respectively. A similar association was observed between glucose and HF in a univariate model, but not in the adjusted model. This first population-based study on this subject confirmed that diabetics have significantly lower vagal activity than non-diabetics. In individuals not diagnosed as diabetics, serum insulin, and, to a lesser degree, serum glucose were inversely associated with vagal function, suggesting a role in the pathogenesis of diabetic neuropathy.


Penetrating Ocular Trauma with Retained Intraocular Foreign Body: Management, Follow-up and Medico-legal Evaluation.
Ocular trauma is the leading cause of acquired monocular blindness, accounting for 1.97-6% of such cases. Particularly, penetrating ocular injuries are among the most common eye injuries with this kind of outcome. Early diagnosis and prompt management are crucial to avoid complications, and the especially dreaded enucleation. In this article, the authors describe the clinical management, and evaluate the visual and anatomical results obtained in a case of ocular injury with retained intraocular foreign body (IOFB) in a 20-year old female patient. The course of treatment involved a combination of penetrating keratoplasty with a temporary keratoprosthesis, phacoemulsification with intraocular lens implantation and pars plana vitrectomy. At three years from the initial injury, the patient was able to count fingers at 30 centimetres and anatomical restitutio ad integrum of the globe had been achieved.


Synthesis of Bis(silylene) Iron Chlorides and Their Catalytic Activity for Dinitrogen Silylation.
In this study, three tetracoordinated bis(silylene) iron(II) chlorides, namely, [SiCHRSi]FeCl2 (1) (R = H), (2) (R = CH3), and (3) (R = Ph), were synthesized through the reactions of the three different bis(silylene) ligands [LSiCHRSiL] (L = PhC(NtBu)2, L1 (R = H), L2 (R = CH3), L3 (R = Ph)) with FeCl2·(THF)1.5 in THF. The bis(silylene) Fe complexes 1-3 could be used as effective catalysts for dinitrogen silylation, with complex 3 demonstrating the highest turnover number (TON) of 746 equiv among the three complexes. The catalytic mechanism was explored, revealing the involvement of the pentacoordinated bis(dinitrogen) iron(0) complexes [SiCHRSi]Fe(N2)2(THF), (4)-(6), as the active catalysts in the dinitrogen silylation reaction. Additionally, the cyclic silylene compound 10 was obtained from the reaction of L1 with KC8. Single-crystal X-ray diffraction analyses confirmed the molecular structures of complexes 1-3 and 10 in the solid state.


Functional polypeptides can be synthesized from human mitochondrial transcripts lacking termination codons.
The human mitochondrial genome (mtDNA) is a small, circular DNA duplex found in multi-copy in the mitochondrial matrix. It is almost fully transcribed from both strands to produce large polycistronic RNA units that are processed and matured. The 13 mtDNA-encoded polypeptides are translated from mt-mRNAs that have been matured by polyadenylation of their free 3'-termini. A patient with clinical features consistent with an mtDNA disorder was recently shown to carry a microdeletion, resulting in the loss of the termination codon for MTATP6 and in its juxtaposition with MTCO3. Cell lines from this patient exhibited low steady-state levels of RNA14, the bi-cistronic transcript encoding subunits 6 and 8 of the F(o)F(1)-ATP synthase, complex V, consistent with a decreased stability. Recent reports of 'non-stop' mRNA decay systems in the cytosol have failed to determine the fate of gene products derived from transcripts lacking termination codons, although enhanced decay clearly required the 'non-stop' transcripts to be translated. We wished to determine whether functional translation products could still be expressed from non-stop transcripts in the human mitochondrion. Although a minor defect in complex V assembly was noted in the patient-derived cell lines, the steady-state level of ATPase 6 was similar to controls, consistent with the pattern of de novo mitochondrial protein synthesis. Moreover, no significant difference in ATP synthase activity could be detected. We conclude that, in the absence of a functional termination codon, although mitochondrial transcripts are more rapidly degraded, they are also translated to generate stable polypeptides that are successfully integrated into functional enzyme complexes.


Evidence that avian tumour virus-immune chicken sera recognize only viral structural antigens on the surface of avian tumour virus-infected cells.
The specificity of the humoral response of chickens to avian tumour viruses (ATV) was investigated by reacting ATV-immune sera with Triton X-100 extracts of uninfected, infected and transformed chicken embryo fibroblasts. Analysis of these immune reactions by polyacrylamide gel electrophoresis revealed that avian leukosis virus-challenged and Rous sarcoma virus-challenged chickens recognized only two major cell surface antigens of 100000 and 29000 mol. wt. which were present on transformed and non-transformed virus-producing cells. No labelled antigens were precipitated from uninfected cells or transformed cells producing the envelope-defective mutant RSV(-). The antigens were shown to be related to the major envelope glycoproteins of the virus and to contain group-specific determinants common to ATV subgroups B and C. No group-specific determinants common to ATV subgroups A and B or subgroups A and C were detected. Chickens were found to have a strong antibody response to the 100000 and 29000 mol. wt. proteins prior to and during tumour rejection, even in the absence of neutralizing antibody to the challenge virus. No tumour-specific surface antigen distinct from the virion structural antigens was detected by any of the immune chicken sera on any of the transformed cells tested.


Amelioration of oxidative stress in the joint tissue may be the basis for the antiarthritic activity of Terminalia arjuna bark extract.
In this study we have evaluated the antioxidant and antiarthritic activity of Terminalia arjuna bark extract (TABE) in collagen-induced arthritis (CIA) in rats. Arthritis was induced in rats by intradermal injection of the collagen-complete Freund's adjuvant emulsion. Right hind paw thickness was measured as a primary marker for severity of arthritis. Biochemical parameters such as tissue levels of superoxide dismutase (SOD), catalase, reduced glutathione (GSH), nitrites and thiobarbituric acid reactive substances (TBARS) were measured to determine the effect of treatment on antioxidant defenses. Articular elastase (ELA) level in the arthritic tissue was measured as a marker for neutrophil infiltration. Terminalia arjuna bark extract administration significantly inhibited the increase in paw thickness induced by immunization with collagen as compared to CIA-control animals. Further, it attenuated the fall in tissue SOD and GSH levels and mitigated the increase in tissue nitrites and TBARS levels as compared to CIA-control animals. Tissue ELA levels, which were significantly increased in the CIA-control animals as compared to normal animals were also significantly reduced by TABE administration. Results of our study demonstrate the antioxidant and antiarthritic activity of TABE in CIA in rats. We believe that TABE could find clinical application in the management of rheumatoid arthritis and associated disorders.


The prognostic significance of APC gene mutation and miR-21 expression in advanced-stage colorectal cancer.
Colorectal cancer (CRC) is the second commonest cause of cancer death in Taiwan. Although numerous genes have been associated with tumorigenesis in colorectal cancer, only a few have been validated and used as biomarkers for predicting clinical outcome. The aim of this study was to analyse the association of APC gene mutation and miR-21 expression with clinical outcome in CRC patients. In total, 195 colorectal cancer patients were enrolled in a single medical centre between 2003 and 2007. APC gene mutation and expression of APC and miR-21 were analysed by direct DNA sequencing and real-time reverse transcription polymerase chain reaction. The primary outcome included 5-year overall survival and univariate (Kaplan-Meier) and multivariate (Cox regression) analyses of prognostic factors. The results showed that 66 (33.8%) of 195 tumour tissues contained an APC mutation. The predominant APC gene variations were deletion mutations (50.0%). APC gene expression was low in CRC and negatively correlated with miR-21 expression and gene mutation. In advanced-stage cancer, patients with APC mutation/high miR-21 had poorer overall survival rates than those with APC mutation/low miR-21, APC wild-type/high miR-21 and APC wild-type/low miR-21. In Taiwan, downregulation of the APC gene in CRC correlated with gene mutation and miR-21 upregulation. APC mutation and miR-21 expression could be used to predict the clinical outcome of CRC, especially in patients with advanced disease.


Eosinophilic Esophagitis for the General Pediatrician.
This article reviews pediatric eosinophilic esophagitis (EoE), a clinicopathologic disorder with symptoms related to esophageal dysfunction and characterized by eosinophil-predominant inflammation present on esophageal biopsy. As part of this review, we outline the pathophysiology, clinical features, diagnostic criteria, approved treatment options, and emerging therapies of EoE. Although previously considered a rare condition, EoE has emerged primarily in Western countries, with an estimated incidence of 4 per 100,000 persons. Understanding disease manifestation, diagnosis, and treatment options are critical for primary care physicians and specialists alike as EoE presentation varies by patient age. Several treatment options are approved for first-line management and can be used interchangeably based on symptoms and patient preference. Additionally, the collaboration of gastroenterologists, allergist-immunologists, and nutritionists is recommended for a multidisciplinary approach to long-term EoE management. [Pediatr Ann. 2021;50(8):e325-e329.].


Fiscal autonomy of subnational governments and equity in healthcare resource allocation: Evidence from China.
Promoting equity in healthcare resource allocation (EHRA) has become a critical political agenda of governments at all levels since the ambitious Universal Health Coverage was launched in China in 2009, while the role of an important institutional variable-fiscal autonomy of subnational governments-is often overlooked. The present study was designed to determine the effect of FASG on EHRA and its potential mechanism of action and heterogeneity characteristics to provide empirical support for the research field expansion and relative policies making of EHRA. From the start, we utilized the Theil index and the entropy method to calculate the EHRA index of 22 provinces (2011-2020) based on the medical resource data of 287 prefecture-level cities. Furthermore, we used the two-way fixed effects model (FE) to identify and analyze the impact of FASG on EHRA and then used three robustness test strategies and two-stage least squares (2SLS) regression to verify the reliability of the conclusions and deal with potential endogeneity problems, respectively. At last, we extend the baseline regression model and obtain the two-way FE threshold model for conducting heterogeneity analysis, which makes us verify whether the baseline model has nonlinear characteristics. The static value and the trend of interannual changes in the EHRA values in different provinces are both very different. The regression results of the two-way FE model show that FASG has a significant positive impact on EHRA, and the corresponding estimated coefficient is - 0.0849 (P < 0.01). Moreover, this promotion effect can be reflected through two channels: enhancing the intensity of government health expenditure (IGHE) and optimizing the allocation of human resources for health (AHRH). At last, under the different economic and demographic constraints, the impact of FASG on EHRA has nonlinear characteristics, i.e., after crossing a specific threshold of per capita DGP (PGDP) and population density (PD), the promotion effect is reduced until it is not statistically significant, while after crossing a particular threshold of dependency ratio (DR), the promotion effect is further strengthened and still statistically significant. FASG plays an essential role in promoting EHRA, which shows that subnational governments need to attach great importance to the construction of fiscal capability in the allocation of health care resources, effectively improve the equity of medical and health fiscal expenditures, and promote the sustainable improvement of the level of EHRA.


A call for standardized reporting of early-onset colorectal peritoneal metastases.
The incidence of colorectal cancer (CRC) in patients under 50 years of age, i.e., early-onset CRC, has increased in the past two decades. Colorectal peritoneal metastases (CPM) will develop in 10-30% of CRC patients. CPM traditionally had a dismal prognosis, but surgery and novel systemic treatments appear to increase survival. Determining potential age-associated risk and prognostic factors is optimized when analyses use standardized age groupings. We performed a review of early-onset CPM studies and compared variables used, e.g., age stratification and definitions of synchronous and metachronous CPM. We included studies published in PubMed up to November 2022 if results were stratified by age. Of 114 screened publications in English, only 10 retrospective studies met inclusion criteria. Incidence of CPM was higher in younger CRC patients (e.g. 23% vs. 2% for <25 vs. ≥25 years, P < 0.0001; and 57% vs. 39% vs. 4% for <20 vs. 20-25 vs. >25 years, P < 0.001); two studies reported higher proportion of younger African American CPM patients (e.g. 16% vs. 6% for <50 vs. ≥50 years). Studies used seven different age-stratification methods, presenting comparison challenges. Studies showed a higher proportion of CPM in younger patients, but directly comparing results was not possible due to inconsistent reporting. To better address this issue, CRC and CPM studies stratified by standard age groups (e.g. <50 vs. ≥50) are needed.


Estrogens, BRCA1, and breast cancer.
Findings obtained in in vitro assays and animal studies indicate that estrogens might influence the activity of the tumor suppressor gene BRCA1, and BRCA1 in turn may suppress the activity of the estrogen receptor. This review will discuss the possibility that interactions between estrogens and BRCA1 partly explain why elevated circulating estrogen levels appear to increase breast cancer risk among postmenopausal women but not among young women. A hypothesis is proposed that estrogens have a dual role in affecting breast cancer risk. In young women whose breasts have not yet accumulated critical mutations required for cancer initiation and promotion, activation of BRCA1 by estrogens helps to maintain genetic stability and induce differentiation, and therefore estrogens do not increase breast cancer risk. Breasts of older women, in contrast, are likely to contain transformed cells whose growth is stimulated by estrogens. Although BRCA1 is also probably activated by estrogens in older women, its function may have been impaired, for example, due to increased methylation associated with aging. Estrogen exposure in women who carry germ-line mutations in BRCA1 may always increase breast cancer risk because estrogens would be able to cause DNA damage and increase genetic instability without being opposed by BRCA1-induced repair activity. This might lead to an increase in the number of overall mutations, including those that initiate breast cancer. In addition to increasing genetic instability, reduced BRCA1 activity may also be linked to changes in the mammary gland morphology that predispose individuals to breast cancer. For example, a persistent presence of lobules type 1, which are the least differentiated lobular structures in the human breast, is seen in the BRCA1 mutation carriers. The aim of this review is to discuss the role of premenopausal estrogens in breast cancer and to initiate more research that would lead to novel means of reducing breast cancer risk, particularly among BRCA1 mutation carriers.


[Intravenous isoproterenol administration for diagnosing ischemic heart disease in women: a comparison with the data from bicycle ergometry and selective coronary angiography].
The significance of the test with intravenous injection of isoproterenol in the diagnosis of coronary heart disease (CHD) was evaluated in comparison with the clinical, bicycle ergometry and selective coronarography data obtained in 65 women. Twenty-four patients presented with stenosing coronary atherosclerosis and 41 patients had normal coronary arteries. On the use of the electrocardiographic signs of myocardial ischemia the sensitivity of the isoproterenol test in the diagnosis of hemodynamically appreciable coronary atherosclerosis was 74%, the specificity 78%. The sensitivity and specificity of bicycle ergometry were 66 and 90%, respectively.


YB-1 regulates Sox2 to coordinately sustain stemness and tumorigenic properties in a phenotypically distinct subset of breast cancer cells.
Sox2, a transcription factor and an embryonic stem cell marker, has been implicated in the pathogenesis of breast cancer (BC). YB-1 is another transcription factor that has been shown to promote stemness in BC cells. Western blotting, quantitative PCR, and siRNAs were used to query the regulatory relationships between YB-1, Sox2, and their downstream targets. Chromatin immunoprecipitation was used to detect YB-1 interactions at the Sox2 promoter. Mammosphere and soft agar assays were used to assess the phenotypic consequences of YB-1 knockdown. Here, we report that YB-1 regulates Sox2. YB-1 was found to bind to the SOX2 promoter and down-regulate its expression in MCF7 and ZR751. The regulatory interaction between YB-1 and Sox2 was drastically different between the two phenotypically distinct cell subsets, purified based on their differential response to a Sox2 reporter. They are referred to as the reporter unresponsive (RU) cells and the reporter responsive (RR) cells. Upon siRNA knockdown of YB-1, RU cells showed an increase in Sox2 expression but no change in Sox2 reporter activity; in contrast, RR cells exhibited increased expression and reporter activity of Sox2. Correlating with these findings, YB-1 knockdown induced a differential response in the expression of genes known to be regulated by both Sox2 and YB-1 (e.g. CCND1 and ITGA6). For instance, in response to YB-1 knockdown, CCND1 and ITGA6 expression were decreased or unchanged in RU cells but paradoxically increased in RR cells. Compared to RU cells, RR cells were significantly more resistant to the suppression of mammosphere formation due to YB-1 knockdown. Importantly, mammospheres derived from parental MCF7 cells treated with YB-1 siRNA knockdown exhibited higher expression levels of SOX2 and its downstream targets. To conclude, in a subset of BC cells, namely RR cells, YB-1 regulates Sox2 to coordinately maintain stemness and tumorigenic properties.


Optimizing peptide matrices for identifying T-cell antigens.
Mapping T-cell epitopes for a pathogen or vaccine requires a complex method for screening hundreds to thousands of peptides with a limited amount of donor sample. We describe an optimized deconvolution process by which peptides are pooled in a matrix format to minimize the number of tests required to identify peptide epitopes. Four peptide pool matrices were constructed to deconvolute the HIV-specific T-cell response in three HIV-infected individuals. ELISpot assays were used to map peptide antigens. Many HIV peptides were mapped in all three individuals. However, there were several challenges and limitations associated with the deconvolution process. Peptides that induced low-frequency responses or were masked by peptide competition within a given pool were not identified, because they did not meet the threshold criteria for a positive response. Also, amino acid sequence variation limited the ability of this method to map autologous HIV peptides. Alternative analysis strategies and revisions to the original matrix optimizations are presented that address ways to increase peptide identification. This optimized deconvolution method allows for efficient mapping of T-cell peptide epitopes. It is rapid, powerful, efficient, and unrestricted by HLA type.


Pre-attentive processing of spectrally complex sounds with asynchronous onsets: an event-related potential study with human subjects.
Neuronal mechanisms involved in the processing of complex sounds with asynchronous onsets were studied in reading subjects. The sound onset asynchrony (SOA) between the leading partial and the remaining complex tone was varied between 0 and 360 ms. Infrequently occurring deviant sounds (in which one out of 10 harmonics was different in pitch relative to the frequently occurring standard sound) elicited the mismatch negativity (MMN), a change-specific cortical event-related potential (ERP) component. This indicates that the pitch of standard stimuli had been pre-attentively coded by sensory-memory traces. Moreover, when the complex-tone onset fell within temporal integration window initiated by the leading-partial onset, the deviants elicited the N2b component. This indexes that involuntary attention switch towards the sound change occurred. In summary, the present results support the existence of pre-perceptual integration mechanism of 100-200 ms duration and emphasize its importance in switching attention towards the stimulus change.


A Coiled Carbon Nanotube Yarn-Integrated Surface Electromyography System To Monitor Isotonic and Isometric Movements.
A surface electromyogram (sEMG) electrode collects electrical currents generated by neuromuscular activity by a noninvasive technique on the skin. It is particularly attractive for wearable systems for various human activities and health care monitoring. However, it remains challenging to discriminate EMG signals from isotonic (concentric/eccentric) and isometric movements. By applying nanotechnology, we provide a coiled carbon nanotube (CNT) yarn-integrated sEMG device to overcome sEMG-based motion recognition. When the arm was contracted at different angles, the sEMG-derived root mean square amplitude signals were constant regardless of the angle of the moving arm. However, the coiled CNT yarn-derived open circuit voltage (OCV) signals proportionally increased when the arm's angle increased, and presented negative and positive values depending on the moving direction of the arm. Moreover, isometric contraction is characterized by the onset of EMG signals without an OCV signal, and isotonic contraction is determined by both EMG signals and OCV signals. Taken together, the integration of EMG and coiled CNT yarn electrodes provides complementary information, including the strength, direction, and degree of muscle movement. Therefore, we suggest that our system has high potential as a wearable system to monitor human motions in industrial and human system applications.


Does ought imply can?
Most philosophers believe that a person can have an obligation only insofar as she is able to fulfil it, a principle generally referred to as "Ought Implies Can". Arguably, this principle reflects something basic about the ordinary concept of obligation. However, in a paper published recently in this journal, Wesley Buckwalter and John Turri presented evidence for the conclusion that ordinary people in fact reject that principle. With a series of studies, they claimed to have demonstrated that, in people's judgements, obligations persist irrespective of whether those who hold them have the ability to fulfil them. We argue in this paper that due to some problems in their design, Buckwalter & Turri's conclusions may not be warranted. We present the results of a series of studies demonstrating the problems with their design and showing that, with an improved design, people judge that obligation depends on ability after all.


Diagnosis and management of atypical hypoadrenocorticism in a variable flying fox (Pteropus hypomelanus).
A 19-yr-old intact female variable flying fox (Pteropus hypomelanus) presented with lethargy, behavior changes, and substantial weight loss. Initial clinical pathology revealed hypoglycemia and reduced ionized serum calcium, and imaging, including computed tomography, did not lead to a diagnosis. An adrenocorticotropic hormone (ACTH) stimulation test revealed baseline and post-ACTH cortisol concentrations that were lower than reported normal baseline cortisol concentrations in this species. Treatment with prednisolone resolved the clinical signs and laboratory abnormalities. Repeated attempts to decrease the prednisolone dose caused recurrence of clinical signs and weight loss. Based on diagnostic test results and response to therapy, a diagnosis of atypical hypoadrenocorticism was made.


Immunofluorescent detection of bovine papillomavirus E4 antigen in the cytoplasm of cells permissive in vitro for viral DNA amplification.
The E4 gene of several human papillomavirus types is expressed in association with vegetative viral DNA synthesis in differentiated epidermal cells. To develop reagents to study expression of the bovine papillomavirus type 1 (BPV-1) E4 gene in warts and in virus-transformed cell lines, rabbit polyclonal antiserum was raised to the BPV-1 E4 antigen produced as a fusion polypeptide in Escherichia coli. By immunoblotting analysis of productively infected bovine fibropapilloma tissue, E4-related proteins of 16K, 21K, 30K and 42K were detected. In some but not all C127 cell lines transformed by BPV-1 or by a replication-competent BPV-1 deletion mutant, cytoplasmic E4 antigen with a predominantly perinuclear localization was detected by immunofluorescence analysis in a subpopulation of cells in stationary-phase cultures. The E4-expressing cells were identified by their grossly enlarged size to represent the same cell subpopulation shown earlier to support BPV-1 DNA amplification. The observation of synthesis of the E4 protein in association with viral DNA amplification in this system provides further evidence that there is a switch in viral early region gene expression in a subpopulation of division-arrested cells, which may accurately reflect events occurring during the vegetative phase of BPV-1 replication in terminally differentiated cells in vivo.


Reexamination of tetradecenyl acetates in oak leaf roller sex pheromone and in plants.
The chemistry of the oak leaf roller sex pheromone is shown by means of microozonolysis and computerized gas chromatography-mass spectrometry to be dominated by an approximate 70 to 30 ratio of E- and Z-11-tetradecenyl acetates. Tetradecenyl acetates are undetectable in highly purified oak leaf, apple leaf, and corn extracts analyzed by gas chromatography-mass spectrometry. These results reflect negatively on previous reports and on the hypothesis that plant components might govern insect chemical communication systems.


Commodity risk assessment of Fagus sylvatica plants from the UK.
The European Commission requested the EFSA Panel on Plant Health to prepare and deliver risk assessments for commodities listed in Commission Implementing Regulation (EU) 2018/2019 as 'High risk plants, plant products and other objects'. This Scientific Opinion covers plant health risks posed by plants of Fagus sylvatica imported from the United Kingdom (UK) as: (a) 1- to 7-year-old bare root plants for planting, (b) < 1- to 15-year-old plants in pots and (c) bundles of 1- to 2-year-old whips and seedlings, taking into account the available scientific information, including the technical information provided by the UK. All pests associated with the commodity were evaluated against specific criteria for their relevance for this opinion. Two EU quarantine pests, Phytophthora ramorum (non-EU isolates) and Thaumetopoea processionea, and two pests not regulated in the EU, Meloidogyne mali and Phytophthora kernoviae, fulfilled all relevant criteria and were selected for further evaluation. For the selected pests, the risk mitigation measures implemented in the technical dossier from the UK were evaluated taking into account the possible limiting factors. For these pests an expert judgement is given on the likelihood of pest freedom taking into consideration the risk mitigation measures acting on the pest, including uncertainties associated with the assessment. In the assessment of risk, the age of the plants was considered, reasoning that older trees are more likely to be infested mainly due to longer exposure time and larger size. The degree of pest freedom varies among the pests evaluated, with M. mali being the pest most frequently expected on the imported plants. The expert knowledge elicitation (EKE) indicated with 95% certainty that between 9,793 and 10,000 plants in pots up to 15 years old per 10,000 will be free from M. mali.