Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes.
Bile acids have been reported to activate several different cell signaling cascades in rat hepatocytes. However, the mechanism(s) of activation of these pathways have not been determined. This study aims to determine which bile acids activate the Raf-1/MEK/ERK cascade and the mechanism of activation of this pathway. Taurodeoxycholic acid (TDCA) stimulated (+235%) the phosphorylation of p(74) Raf-1 in a time (5 to 20 minutes) and concentration-dependent (10 to 100 micromol/L) manner. Raf-1 and ERK activities were both significantly increased by most bile acids tested. Deoxycholic acid (DCA) was the best activator of ERK (3.6-fold). A dominant negative Ras (N17) construct expressed in primary hepatocytes prevented the activation of ERK by DCA. The epidermal growth factor receptor (EGFR)-specific inhibitor (AG1478) significantly inhibited (approximately 81%) the activation of ERK by DCA. DCA rapidly (30 to 60 seconds) increased phosphorylation of the EGFR (approximately 2-fold) and Shc (approximately 4-fold). A dominant negative mutant of the EGFR (CD533) blocked the ability of DCA to activate ERK. In conclusion, these results show that DCA activates the Raf-1/MEK/ERK signaling cascade in primary hepatocytes primarily via an EGFR/Ras-dependent mechanism.


Intensive care nurse managers' experiences during the first wave of the Covid-19 pandemic: Implications for future epidemiological crises.
Nurse managers play an important role in coordinating the multidisciplinary teamwork, which is specifically important in emergency and crises situations like the COVID-19 pandemic. The aim of this qualitative study is twofold: (1) to explore the experiences of the Intensive care units (ICU) nurse managers regarding their work during the first wave of the COVID-19 pandemic, and (2) to analyse what implications might be provided based on experiences of nurse managers for future possible epidemiological crises. In-depth phone interviews were conducted to explore the experiences of ward managers-nurses (n = 15) working in different hospitals across Poland. Interviews were taped and transcribed verbatim, and then qualitatively analysed. Three main categories were identified: (1) Challenge of working with the unknown, (2) Nurse managers' expectations, and (3) Methods of coping and received support. The COVID-19 pandemic strongly affected the work of ICU nurse managers and uncovered the malfunctioning of the healthcare system. It is important to improve the knowledge and competence of hospital management personnel through exercises and in-service training on how to handle emergencies in order to improve the management of healthcare facilities, increase the safety of patients and employees, and the quality of healthcare.


Perceptions of mothers on child well-being, changes in everyday life and social sustainability: lessons learned from a community-based health promotion programme in Anuradhapura District, Sri Lanka.
From 2012 to 2015, a health promotion intervention (under a project called HADP) aiming to improve children's well-being was implemented in Horowpathana, Sri Lanka. The donor organization reports positive results regarding children's well-being and behaviour changes, but mixed results regarding its sustainability. A need for a complementary evaluation was therefore identified. The current study intended to provide a complementary evaluation at four months after the programme closure and to assess the sustainability of the HP intervention from the perspective of mothers who participated in the HADP. Ethical approval for this study was obtained from the ethics review subcommittee of Faculty of Applied Sciences, RUSL. A descriptive qualitative study was carried out using in-depth, semi-structured interviews with a convenient sample of 15 mothers who previously participated in HADP. Data analysis was done using the content analysis method. Mothers attributed diverse perceptions in line with the theme of "health literacy". Two sub-themes emerged: transformation for betterment and sustainability. The sub-theme of transformation for betterment consists of three categories: individual-level transformation, family-level transformation and social/community-level transformation. Sub-theme sustainability consists of two categories: (1) drivers/adaptations for continuation and (2) determinants that hinder the continuation. The mothers' perspectives were strongly related to the definition of health literacy, which emphasizes people's ability to use health information to make "well-informed" decisions that incorporate a public health perspective. They also acknowledged the responsibility of social organizations to address health literacy. From a health promotion perspective, the findings of our study indicate that people and organizations can use their health literacy skills to improve the health and well-being of their community and its members. Further research is necessary to explore the factors that affect the sustainability of health promotion interventions in the long run.


Pulmonary metastasectomy for sarcoma: a systematic review of reported outcomes in the context of Thames Cancer Registry data.
Sarcoma has a predilection to metastasis to the lungs. Surgical excision of these metastases (pulmonary metastasectomy) when possible has become standard practice. We reviewed the published selection and outcome data. Systematic review of published reports that include survival rates or any other outcome data. Survival data were put in the context of those in a cancer registry. Specialist thoracic surgical centres reporting the selection and outcome for pulmonary metastasectomy in 18 follow-up studies published 1991-2010. Patients having one or more of 1357 pulmonary metastasectomy operations performed between 1980 and 2006. All patients had surgical pulmonary metastasectomy. A first operation was reported in 1196 patients. Of 1357 patients, 43% had subsequent metastasectomy, some having 10 or more thoracotomies. Three studies were confined to patients having repeated pulmonary metastasectomy. Survival data to various time points usually 5 years and sometimes 3 or 10 years. No symptomatic or quality of life data were reported. About 34% and 25% of patients were alive 5 years after a first metastasectomy operation for bone or soft tissues sarcoma respectively. Better survival was reported with fewer metastases and longer intervals between diagnosis and the appearance of metastases. In the Thames Cancer Registry for 1985-1994 and 1995-2004 5 year survival rates for all patients with metastatic sarcoma were 20% and 25% for bone, and for soft tissue sarcoma 13% and 15%. The 5 year survival rate among sarcoma patients who are selected to have pulmonary metastasectomy is higher than that observed among unselected registry data for patients with any metastatic disease at diagnosis. There is no evidence that survival difference is attributable to metastasectomy. No data were found on respiratory or any other symptomatic benefit. Given the certain harm associated with thoracotomy, often repeated, better evidence is required.


Efficient production of mice from embryonic stem cells injected into four- or eight-cell embryos by piezo micromanipulation.
The conventional method for producing embryonic stem (ES) cell-derived knockout or transgenic mice involves injection of ES cells into normal, diploid blastocysts followed by several rounds of breeding of resultant chimeras and thus is a time-consuming and inefficient procedure. F0 ES cell pups can also be derived directly from tetraploid embryo complementation, which requires fusion of two-cell embryos. Recently, F0 ES cell pups have been produced by injection of ES cells into eight-cell embryos using a laser-assisted micromanipulation system. We report a simple method for producing F0 ES cell germline-competent mice by piezo injection of ES cells into four- or eight-cell embryos. The efficiency of producing live, transgenic mice by this method is higher than that with the tetraploid blastocyst complementation method. This efficient and economical technique for directly producing F0 ES cell offspring can be applicable in many laboratories for creating genetically manipulated mice using ES cell technology and also for stringent testing of the developmental potency of new ES cell or other types of pluripotent stem cell lines.


Combined 1-Deoxynojirimycin and Ibuprofen Treatment Decreases Microglial Activation, Phagocytosis and Dopaminergic Degeneration in MPTP-Treated Mice.
Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson's disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions. Graphical Abstract MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a protoxicant that, after crossing the Blood Brain Barrier, is metabolized by astrocytic MAO-B to MPDP+, a pyridinium intermediate, which undergoes further two-electron oxidation to yield the toxic metabolite MPP+ (methyl-phenyltetrahydropyridinium) that is then selectively transported into nigral neurons via the mesencephalic dopamine transporter. In this study, we demonstrated that MPTP induced death of dopaminergic neurons, microgliosis, increase of gliapses, motor impairment and neuroinflammation in mice, which were inhibited by combined 1-deoxynojirimycin and ibuprofen treatment.


Effects of thermal stress on tumor antigenicity and recognition by immune effector cells.
The primary rationale for the application of clinical hyperthermia in the therapy of cancer is based on the direct cytotoxic effect of heat and the radio-chemosensitization of tumor cells. More recently, additional attention is given to the observation that heat and heat-shock proteins can activate the host's immune system. The expression of heat-shock genes and proteins provides an adaptive mechanism for stress tolerance, allowing cells to survive non-physiologic conditions. However, the same adaptive mechanism can ultimately favor malignant transformation by interfering with pathways that regulate cell growth and apoptosis. Cytoprotection and thermotolerance raised the concern that heat-treated tumor cells might also be resistant to attack by immune effector mechanisms. Many studies, including those from our group, address this concern and document that heat-exposure, although transiently modulating sensitivity to CTL, do not hinder CTL attack. Moreover, there are promising reports of heat-related upregulation of NK-activating ligands, rendering those tumors which have lost MHC class I molecules target for NK cell attack. Heat-induced cytoprotection, therefore, does not necessarily extend protection from cytotoxic immune mechanisms. When interpreting the effects of heat, it is important to keep in mind that thermal effects on cell physiology are strongly dependent on the thermal dose, which is a function of the magnitude of change in temperature and the duration of heat exposure. The thermal dose required to induce cell death in vitro strongly varies from cell type to cell type and depends on microenvironmental factors (Dewey 1994). Therefore, to dissect the immunological behaviour of a given tumor and its micro-environment at different thermal doses, it is essential to characterize the thermosensitivity of every single tumor type and assess the proportion of cells surviving a given heat treatment. In this review, we summarize the pleiotropic effects that heat exposure has on tumor cells. In particular, we focus on the effects of heat on the antigen presentation of tumor cells and their susceptibility to immune effector mechanisms. We emphasize that the response to thermal stress is not a one-time point event, but rather a time period starting with the heat exposure and extending over several days of recovery. In addition, the response of tumor cells and their susceptibility to immune effector cells is strongly dependent on the model system, on the magnitude and duration of the thermal stress and on the time of recovery after heat exposure. Consideration of these aspects might help to explain some of the conflicting results that are reported in the field of thermal stress response.


Role of cytosolic and calcium independent phospholipases A(2) in insulin secretion impairment of INS-1E cells infected by S. aureus.
Cytosolic PLA2 (cPLA2) and Ca(2+)-independent PLA2 (iPLA2) play a significant role in insulin β-cells secretion. Bacterial infections may be responsible of the onset of diabetes. The mechanism by which Staphylococcus aureus infection of INS-1 cells alters glucose-induced insulin secretion has been examined. After acute infection, insulin secretion and PLA2 activities significantly increased. Moreover, increased expressions of phospho-cPLA2, phospho-PKCα and phospho-ERK 1/2 were observed. Chronic infection causes a decrease in insulin release and a significant increase of iPLA2 and COX-2 protein expression. Moreover, insulin secretion in infected cells could be restored using specific siRNAs against iPLA2 isoform and specific COX-2 inhibitor.


Prophenoloxidase system activation in the crayfish Procambarus clarki.
The prophenoloxidase system (proPO) was studied in primary cultures of hemocytes of the crayfish Procambarus clarki. Both zymosan and lipopolysaccharide (LPS) separately induced rapid degranulation and lysis of semigranular hemocytes, with concurrent release of proPO. ProPO could be demonstrated in the hemocyte lysate supernatant (HLS) obtained by a freeze/thaw method, and was specifically activated by LPS and zymosan. Phenoloxidase activity was blocked by serine protease inhibitors, such as soybean trypsin inhibitor (STI), leupeptin, and phenylmethyl-sulphonylfluoride (PMSF), and substantially increased by cysteine protease inhibitors (N-methylmaleimide, N-ethylmaleimide, and iodoacetamide). This enhancement was observed only when the proPO system was activated. Incubation without activators or preincubation with STI prevented the induced enhancement. Electrophoretic analyses of HLS treated with zymosan or LPS showed that three bands at 41, 39, and 37 kDa were specifically modified when the system was activated. These results suggest that a serine protease is involved in the activation of the proPO system in P. clarki, and a mechanism susceptible to cysteine protease inhibitors could be related to its regulation.


Analysis of chromatin fibers in Hela cells with electron tomography.
The presence and folding pattern of chromatin in eukaryotic cells remain elusive and controversial. In this study, we prepared ultra-thin sections of Hela cells with three different fixation and sectioning methods, i.e., chemical fixation, high pressure freezing with freeze substitution, and cryo-ultramicrotomy with SEM-FIB (focused ion beam), and analyzed in vivo architecture of chromatin fibers in Hela nuclei with electron tomography technology. The results suggest that the chromatin fibers in eukaryotic Hela cells are likely organized in an architecture with a diameter of about 30 nm.


Abnormal quantitative pupillary light responses following COVID-19.
To characterize alterations in pupillary light reflex responses in subjects following coronavirus disease 2019 (COVID-19), especially those with long-COVID. Thirty-five subjects with previous COVID-19 and 30 healthy control participants were enrolled in this cross-sectional comparative study. An infrared dynamic pupillometry system (MonPack One; Metrovision, France) was used to quantify pupillary light responses. The National Institute for Health and Care Excellence (NICE) long-COVID questionnaire was used to identify persisting symptoms at least 4 weeks after acute COVID-19. The median time after the diagnosis of acute COVID-19 was 4.0 (2.0-5.0) months. There was an increase in the latency of pupil contraction (P = 0.001) and a reduction in the duration of pupil contraction (P = 0.039) in post-COVID-19 subjects compared to healthy controls. No significant differences were observed in the initial pupil diameter, amplitude and velocity of pupil contraction or latency, velocity and duration of pupil dilation. Long-COVID was present in 25/35 (71%) subjects and their duration of pupil contraction was reduced compared to subjects without long-COVID (P = 0.009). The NICE long-COVID questionnaire total score (ρ = - 0.507; P = 0.002) and neurological score (ρ = - 0.412; P = 0.014) correlated with the duration of pupil contraction and the total score correlated with the latency of dilation (ρ = - 0.352; P = 0.038). Dynamic pupillometry reveals significant alterations in contractile pupillary light responses, indicative of parasympathetic dysfunction after COVID-19.


Freeze or dehydrate: only two options for the survival of subzero temperatures in the arctic enchytraeid Fridericia ratzeli.
Hygrophilic soil animals, like enchytraeids, overwintering in frozen soil are unlikely to base their cold tolerance on supercooling of body fluids. It seems more likely that they will either freeze due to inoculative freezing, or dehydrate and adjust their body fluid melting point to ambient temperature as has been shown for earthworm cocoons and Collembola. In the present study we tested this hypothesis by exposing field-collected adult Fridericia ratzeli from Disko, West Greenland, to freezing temperatures under various moisture regimes. When cooled at -1 degrees C min(-1) under dry conditions F. ratzeli had a mean temperature of crystallisation ( T(c)) of -5.8 degrees C. However, when exposed to temperatures above standard T(c) for 22 h, at -4 degrees C, most individuals (90%, n= 30) remained unfrozen. Slow cooling from -1 degrees C to -6 degrees C in vials where the air was in equilibrium with the vapour pressure of ice resulted in freezing in about 65% of the individuals. These individuals maintained a normal body water content of 2.7-3.0 mg mg(-1) dry weight and had body fluid melting points of about -0.5 degrees C with little or no change due to freezing. About 35% of the individuals dehydrated drastically to below 1.1 mg mg(-1) dry weight at -6 degrees C, and consequently had lowered their body fluid melting point to ca. -6 degrees C at this time. Survival was high in both frozen and dehydrated animals at -6 degrees C, about 60%. Approximately 25% of the animals (both frozen and dehydrated individuals) had elevated glucose concentrations, but the mean glucose concentration was not increased to any great extent in any group due to cold exposure. The desiccating potential of ice was simulated using aqueous NaCl solutions at 0 degrees C. Water loss and survival in this experiment were in good agreement with results from freezing experiments. The influence of soil moisture on survival and tendency to dehydrate was also evaluated. However, soil moisture ranging between 0.74 g g(-1) and 1.15 g g(-1) dry soil did not result in any significant differences in survival or frequency of dehydrated animals even though the apparent wetness and structure of the soil was clearly different in these moisture contents.


Eye contact does not facilitate detection in children with autism.
Eye contact is crucial in achieving social communication. Deviant patterns of eye contact behavior are found in individuals with autism, who suffer from severe social and communicative deficits. This study used a visual oddball paradigm to investigate whether children with high functioning autism have difficulty in detecting mutual gaze under experimental conditions. The results revealed that children with autism were no better at detecting direct gaze than at detecting averted gaze, which is unlike normal children. This suggests that whereas typically developing children have the ability to detect direct gaze, children with autism do not. This might result in altered eye-contact behavior, which hampers subsequent development of social and communicative skills.


Free energy changes in ribonuclease A denaturation. Effect of urea, guanidine hydrochloride, and lithium salts.
The unfolding of ribonuclease A by urea, guanidine hydrochloride, lithium perchlorate, lithium chloride, and lithium bromide has been followed by circular dichroic and difference spectral measurements. All three abnormal tyrosyl residues are normalized in urea and guanidine hydrochloride (delta epsilon 287 = -2700), only two are normalized in lithium bromide and lithium perchlorate (delta epsilon 287 = -1700), and only one is exposed in lithium chloride solutions (delta epsilon 287 = -700). The Gibbs energies are 4.7 +/- 0.1 kcal mol-1 for urea- and guanidine hydrochloride-denaturation, 3.8 +/- 0.2 kcal mol-1 for lithium perchlorate-denaturation, and 12.7 +/- 0.2 kcal mol-1 for lithium chloride- and lithium bromide-denaturation of ribonuclease A. The latter results suggest that the mechanism of the unfolding process in urea and guanidine hydrochloride is quite different from that in lithium salts.


Accuracy of sagittal oblique view in preoperative indirect magnetic resonance arthrography for diagnosis of tears involving the upper third of the subscapularis tendon.
The purpose of this study was to investigate the accuracy of sagittal oblique view (SOV) magnetic resonance imaging grading for tears involving the upper third of the subscapularis tendons in correlation with arthroscopic findings. We also propose a schematic classification in the SOV for upper-third subscapularis tears. The study analyzed 364 patients with an average age of 56.0 years. All patients underwent indirect magnetic resonance arthrography (MRA) before surgery. A slightly different magnetic resonance grading was introduced with SOV by musculoskeletal radiologists (Y.C.Y. and J.Y.Y.) and an orthopedic shoulder surgeon (H.Y.R.) who had no information about the clinical data. Subscapularis tendon tear classifications were all prospectively analyzed. Magnetic resonance grading was compared with the arthroscopic findings. The sensitivity, specificity, and accuracy of subscapularis tendon tear detection were 0.72, 0.77, and 0.75, respectively, for the radiologists. For the orthopedic surgeon, the corresponding values were 0.73, 0.83, and 0.79, respectively. The κ coefficients for interobserver agreement comparing magnetic resonance grade of the musculoskeletal radiologists with the arthroscopic grading showed fair values (κ value, 0.301). Interobserver agreement between the magnetic resonance grade of the orthopedic surgeon and arthroscopic grades was fair (κ value, 0.377). Interobserver agreement between the musculoskeletal radiologists and the orthopedic surgeon was moderate (κ value, 0.591). The accuracy of SOV indirect MRA for detecting tears was 0.75 to 0.79. Although the correlation between magnetic resonance and arthroscopic grading was only fair, for most of the magnetic resonancegrading on SOV, the first facet view showed similar results compared with arthroscopy. The accuracy of determining whether subscapularis repair is indicated was 0.82 to 0.83 with SOV indirect MRA.


Quantitative diffusion-weighted magnetic resonance imaging in the evaluation of parotid gland masses: a study with histopathological correlation.
We evaluated the quantitative diffusion-weighted magnetic resonance imaging (DW-MRI) for parotid masses. Seventy-five patients with 81 focal parotid masses were included. Following DW-MRI, 73 masses underwent surgical biopsy/resection, 6 underwent ultrasonography-guided fine-needle aspiration, and 2 underwent both procedures. The mean apparent diffusion coefficient (ADC) of benign tumors (n=49, 1.72×10(-3) mm(2)/s) was higher than that of malignant tumors (n=32, 1.05×10(-3) mm(2)/s) (P<.001). ADC was 2.15×10(-3) mm(2)/s for pleomorphic adenomas, which was higher than that for other tumors (P<.001 for all). ADC cutoff was 1.315 for distinguishing between pleomorphic adenomas and others including malignant tumors. Therefore, DW-MRI may be useful for distinguishing between pleomorphic adenomas and other parotid masses.


Excess of L-alanine in amino acids synthesized in a plasma torch generated by a hypervelocity meteorite impact reproduced in the Laboratory.
We present a laboratory reproduction of hypervelocity impacts of a carbon containing meteorite on a mineral substance representative of planetary surfaces. The physical conditions of the resulting impact plasma torch provide favorable conditions for abiogenic synthesis of protein amino acids: We identified glycine and alanine, and in smaller quantities serine, in the produced material. Moreover, we observe breaking of alanine mirror symmetry with L excess, which coincides with the bioorganic world. Therefore the selection of L-amino acids for the formation of proteins for living matter could have been the result from plasma processes occurring during the impact meteorites on the surface. This indicates that the plasma torch from meteorite impacts could play an important role in the formation of biomolecular homochirality. Thus, meteorite impacts possibly were the initial stage of this process and promoted conditions for the emergence of a living matter.


Genes located in a chromosomal inversion are correlated with territorial song in white-throated sparrows.
The genome of the white-throated sparrow (Zonotrichia albicollis) contains an inversion polymorphism on chromosome 2 that is linked to predictable variation in a suite of phenotypic traits including plumage color, aggression and parental behavior. Differences in gene expression between the two color morphs, which represent the two common inversion genotypes (ZAL2/ZAL2 and ZAL2/ZAL2(m) ), may therefore advance our understanding of the molecular underpinnings of these phenotypes. To identify genes that are differentially expressed between the two morphs and correlated with behavior, we quantified gene expression and terrirorial aggression, including song, in a population of free-living white-throated sparrows. We analyzed gene expression in two brain regions, the medial amygdala (MeA) and hypothalamus. Both regions are part of a 'social behavior network', which is rich in steroid hormone receptors and previously linked with territorial behavior. Using weighted gene co-expression network analyses, we identified modules of genes that were correlated with both morph and singing behavior. The majority of these genes were located within the inversion, showing the profound effect of the inversion on the expression of genes captured by the rearrangement. These modules were enriched with genes related to retinoic acid signaling and basic cellular functioning. In the MeA, the most prominent pathways were those related to steroid hormone receptor activity. Within these pathways, the only gene encoding such a receptor was ESR1 (estrogen receptor 1), a gene previously shown to predict song rate in this species. The set of candidate genes we identified may mediate the effects of a chromosomal inversion on territorial behavior.


Sensitive determination of capsaicin in pepper samples using a voltammetric platform based on carbon nanotubes and ruthenium nanoparticles.
A voltammetric platform based on modifying glassy carbon electrodes (GCEs) with ruthenium nanoparticles decorated carbon nanotubes (CNTs) was applied for the determination of capsaicin in pepper samples. The nanoparticles of ruthenium (RuNPs) were obtained at carbon nanotubes modified GCE by cyclic voltammetry. The composite of RuNPs-CNTs was characterized by scanning electron microscopy (SEM) and energy dispersive X-ray (EDX). The proposed voltammetric platform, RuNPs/CNTs/GCE, highly improved the voltammetric process of capsaicin in comparison to the CNTs/GCE and bare GCE. A linear concentration range was obtained from 1.0×10-8 to 4.1×10-7M (R2=0.9987) with a detection limit of 2.5×10-9M. The voltammetric platform has successfully been applied for quantifying capsaicin in various pepper samples including Isot. The proposed voltammetric platform offers advantages such as high sensitivity, selectivity and precision.


High affinity binding of the heat-stable protein kinase inhibitor to the catalytic subunit of cAMP-dependent protein kinase is selectively abolished by mutation of Arg133.
The two classes of physiological inhibitors of the catalytic subunit of cAMP-dependent protein kinase are the regulatory subunits and the heat-stable protein kinase inhibitors (PKIs), and both share a common mechanism of inhibition. Each has a similar inhibitor site that resembles a peptide substrate, and this occupies the P-3 to P+1 portion of the peptide recognition site. However, in addition to this consensus site, each inhibitor requires a peripheral binding site to achieve high affinity binding. Arg134 and Arg133 lie on the surface of the catalytic subunit with Arg133 coming close to the amphipathic helix of PKI(5-24) (Knighton, D. R., Zheng, J., Ten Eyck, L. F., Xuong, N.-h., Taylor, S. S., and Sowadski, J. M. (1991) Science 253, 414-420). Replacement of Arg134 and Arg133 with Ala selectively abolishes the high affinity binding of PKI. Replacement of Arg133 alone is sufficient to give the same phenotype. In the presence of MgATP, the Kd,app, is increased from < 0.2 to 105 nM and, in the absence of ATP, the Kd is too large to be reliably measured. Based on the crystal structure, Arg133 hydrogen bonds to the P-7 backbone carbonyl of PKI(5-24). However, more importantly, it also contributes to the hydrophobicity of the P-11 binding site in the C.PKI(5-24) complex. We predict that it is the perturbation of this hydrophobic pocket that accounts for the effects of this mutation. In the absence of peptide, Arg133 may help to stabilize Glu230, a buried carboxylate that binds to the P-2 Arg in the crystal structure of C.PKI(5-24). Replacement of Arg133 and Arg134 with Ala has little effect on catalysis using a heptapeptide substrate and has no effect on the inhibition of the catalytic subunit by the regulatory subunit. The results thus demonstrate that these two inhibitor proteins that both bind to the catalytic subunit with a high affinity utilize different sites on the enzyme to achieve tight binding. The gamma isoform of the catalytic subunit is insensitive to inhibition by PKI and in this isoform Arg133 is replaced with Gln. We predict that this change accounts for the altered inhibitor properties of C gamma.


Beneficial effects of running and milk protein supplements on Sirtuins and risk factors of metabolic disorders in rats with low aerobic capacity.
Physical activity and dietary intake of dairy products are associated with improved metabolic health. Dairy products are rich with branched chain amino acids that are essential for energy production. To gain insight into the mechanisms underlying the benefit of the sub-chronic effects of running and intake of milk protein supplements, we studied Low Capacity Runner rats (LCR), a rodent exercise model with risk for metabolic disorders. We especially focused on the role of Sirtuins, energy level dependent proteins that affect many cellular metabolic processes. Forty-seven adult LCR female rats sedentary or running voluntarily in wheels were fed normal chow and given supplements of either whey or milk protein drink (PD)-supplemented water, or water only for 21 weeks. Physiological responses were measured in vivo. Blood lipids were determined from serum. Mitochondrial markers and Sirtuins (Sirt1-7) including downstream targets were measured in plantaris muscle by western blotting. For the first 10 weeks whey-drinking rats ran about 50% less compared to other groups; still, in all runners glucose tolerance improved and triglycerides decreased. Generally, running induced a ∼six-fold increase in running capacity and a ∼8% decrease in % body fat. Together with running, protein supplements increased the relative lean mass of the total body weight by ∼11%. In comparison with sedentary controls, running and whey increased HDL (21%) and whey, with or without running, lowered LDL (-34%). Running increased mitochondrial biogenesis and Sirtuins 3 and 4. When combined with exercise, both whey and milk protein drink induced about a 4-fold increase in Sirt3, compared to runners drinking water only, and about a 2-fold increase compared to the respective sedentary group. Protein supplements, with or without running, enhanced the phosphorylation level of the acetyl-coA-carboxylase, suggesting increased fat oxidation. Both supplemented diets increased Sirt5 and Sirt7 without an additional effect from exercise. Running diminished and PD supplement increased Sirt6. We demonstrate in rats new sub-chronic effects of milk proteins on metabolism that involve Sirtuins and their downstream targets in skeletal muscle. The results show that running and milk proteins act on reducing the risk factors of metabolic disorders and suggest that the underlying mechanisms may involve Sirtuins. Notably, we found that milk protein supplements have some favorable effects on metabolism even without running.


Inhibition of adjuvant-induced TAM receptors potentiates cancer vaccine immunogenicity and therapeutic efficacy.
Analyzing immunomodulatory elements operating during antitumor vaccination in prostate cancer patients and murine models we identified IL-10-producing DC as a subset with poorer immunogenicity and clinical efficacy. Inhibitory TAM receptors MER and AXL were upregulated on murine IL-10+ DC. Thus, we analyzed conditions inducing these molecules and the potential benefit of their blockade during vaccination. MER and AXL upregulation was more efficiently induced by a vaccine containing Imiquimod than by a poly(I:C)-containing vaccine. Interestingly, MER expression was found on monocyte-derived DC, and was dependent on IL-10. TAM blockade improved Imiquimod-induced DC activation in vitro and in vivo, resulting in increased vaccine-induced T-cell responses, which were further reinforced by concomitant IL-10 inhibition. In different tumor models, a triple therapy (including vaccination, TAM inhibition and IL-10 blockade) provided the strongest therapeutic effect, associated with enhanced T-cell immunity and enhanced CD8+ T cell tumor infiltration. Finally, MER levels in DC used for vaccination in cancer patients correlated with IL-10 expression, showing an inverse association with vaccine-induced clinical response. These results suggest that TAM receptors upregulated during vaccination may constitute an additional target in combinatorial therapeutic vaccination strategies.


Effect of Vestibular Schwannoma Size and Nerve of Origin on Posterior External Auditory Canal Sensation: A Prospective Observational Study.
Posterior external auditory canal (EAC) hypesthesia (Hitselberger's sign) has been previously described to occur in all vestibular schwannomas (1966) but has not been studied since. We hypothesized that sensory loss may be related to tumor size and sought to determine if this clinical sign could predict preoperative characteristics of vestibular schwannomas, intraoperative findings, and/or surgical outcomes. Prospective observational study. Tertiary referral center. Twenty-five consecutive patients who underwent surgery for vestibular schwannoma. Patients were tested for the presence of EAC hypesthesia or anesthesia. Preoperative, intraoperative, and postoperative findings were recorded, including facial nerve function, hearing function, tumor size, tumor nerve of origin, and extent of resection. Twelve patients (48%) demonstrated either posterior EAC hypesthesia (11 patients) or anesthesia (1 patient). Sensory loss was a significant predictor of size (tumor maximal diameter) (p = 0.004). Median tumor diameter was 1.7 cm in the cohort with intact sensation versus 2.9 cm in the cohort with sensory loss. Patients with sensory loss were also significantly more likely to be associated with a superior vestibular nerve origin tumor (p = 0.01). Preoperative sensory loss did not significantly predict postoperative facial outcome (p = 0.10). Neurological exam findings may be overlooked in the workup of brain tumors. Posterior EAC hypesthesia is a predictor of tumor size and superior vestibular nerve origin. These findings may have implications for patient selection, particularly with the middle cranial fossa approach. Furthermore, given this relationship with tumor size, this clinical biomarker should be studied as a potential predictor of tumor growth.


Stigma-Related Stress and Its Correlates Among Men with Pedophilic Sexual Interests.
Despite decades of research on the adverse consequences of stereotyping and discrimination for many stigmatized groups, little is known about how people with pedophilia perceive and react to stigma. In this article, we present a framework that outlines how stigma-related stress might negatively affect emotional and social areas of functioning, cognitive distortions, and the motivation to pursue therapy, all of which may contribute to an increased risk of sexual offending. We tested our hypotheses in an online survey among self-identified German-speaking people with pedophilia (N = 104) using a wide range of validated indicators of social and emotional functioning (Brief Symptom Inventory-53, UCLA Loneliness Scale, Emotion Subscale of the Coping Inventory for Stressful Situations, Fear of Negative Evaluation-5, Rosenberg Self-Esteem Scale). Specific risk factors such as self-efficacy, cognitive distortions, and the motivation to seek treatment were also assessed. In line with our hypotheses, fear of discovery generally predicted reduced social and emotional functioning. Contrary to our predictions, perceived social distance and fear of discovery were not linked to self-efficacy, cognitive distortions, or treatment motivation. Results were controlled for the effects of confounding variables (e.g., age, educational level, social desirability, relationship status). We critically evaluate the empirical contribution of this study to research on stigma and child sex offenses, including a discussion of the results in light of the potential indirect effects that public stigma may have on the overall risk for sexual offenses.


Infantile gastroenteritis caused by rotavirus: comparison of enzyme-linked immunosorbent assay and electron microscopy for rapid diagnosis.
ELISA and negative contrast EM have used for the detection of rotavirus in one hundred stools from children, less than two years old, hospitalized for acute gastro-enteritis during the winter 1977-78. Samples obtained from the same children some months after hospitalization were also tested. A good correlation was found between the results given by EM and ELISA, but the later technique turned out to be more sensitive (12% more positive using ELISA). A rotavirus infection could be demonstrated in 73% of the patients. In the stools of 3 children we found a second virus in association with the rotavirus, and in two cases a pathogenic bacterium. When a second serum specimen was available from children previously infected by rotavirus it was always possible to detect a significant increase in CF antibodies. Several months after hospitalization a 2nd survey indicated that the rotavirus was no longer present but calicivirus, echovirus, coxsackievirus and adenovirus could be detected in those asymptomatic children.


Changes in causes of death over time after treatment for invasive aspergillosis.
Assessment of response to invasive aspergillosis (IA) therapy has been challenging in treatment trials. The causes of death over 12 weeks were categorized prospectively by a blinded data review committee using a priori defined criteria in participants in a randomized comparative trial of voriconazole versus amphotericin B as first-line therapy of proven or probable IA. Death occurred in 98 of 277 patients during the 12-week course of study. Seventy-three of the 98 deaths (74%) occurred in the first 6 weeks; 25 deaths occurred during the second 6 weeks. Of the 73 deaths during the first 6 weeks, 50 (68%) were judged to be attributable to IA. Of the 25 deaths during the second 6 weeks, only 6 (24%) were judged to be attributable to IA. Fifty of the 56 deaths (89%) attributable to IA occurred during the first 6 weeks. These data suggest that most deaths due to IA occur during the first 6 weeks after the start of therapy and 6 weeks may be a better interval to judge the effectiveness of antifungal therapy because most deaths after 6 weeks are due to causes related to the underlying disease and its treatment rather than due to IA. Attributable mortality when assessed using a priori definitions and conducted in a blinded manner by a central data review committee can be useful in the assessment of IA therapy.


Properties of odour-binding glycoproteins from rat olfactory epithelium.
The specific membrane glycoproteins with high affinity for camphor and decanal were isolated from rat olfactory epithelium. Antibodies to these glycoproteins inhibited both the electroolfactogram and the binding of odorants. The enzyme immunoassay has shown these glycoproteins to be present in the olfactory epithelium of rat, mouse, guinea-pig and hamster but not in that of frog and carp. The molecular mass of the odour-binding glycoproteins from rat olfactory epithelium solubilized by Triton X-100 was approx. 140 kDa. They consisted of two subunits (88 and 55 kDa). The 88 kDa subunit was capable of binding odorants. The data obtained suggest that the glycoproteins isolated have some properties that make them plausible candidates for olfactory receptor molecules.


Dietary supplementation with docosahexaenoic acid rich fish oil increases circulating levels of testosterone in overweight and obese men.
Pre-clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs), in particular, docosahexaenoic acid (DHA) have been shown to affect testosterone synthesis in males. This study is a secondary analysis of a randomized controlled trial which determined the effect of a DHA-enriched fish oil supplement on insulin resistance. The aim of the current study was to determine whether testosterone levels change in response to a DHA-enriched fish oil intervention. Overweight and obese men and women without diabetes were recruited to the study. Participants were stratified by sex and randomly allocated to intervention (860 mg DHA + 120 g EPA/day; FO) or an isocaloric control (corn oil; CO) for 12 weeks. A fasted blood sample was collected pre- and post-intervention. Fatty acid composition of erythrocyte membranes was measured using gas chromatography. Total testosterone and metabolic parameters were measured by an accredited commercial pathology laboratory. Sixty-one participants (CO/FO: n = 29/32) were included in the current analysis (male: n = 22, 36.07%). DHA-enriched fish oil supplementation increased total testosterone levels in males after adjusting for baseline levels, age and BMI. There was no treatment effect in females. Changes in testosterone levels in males were positively associated with changes to omega-3 PUFAs EPA and DHA and inversely correlated with omega-6 PUFA, arachidonic acid and dihomo-gamma-linolenic acid content in erythrocyte membranes, and was associated with beneficial changes to fasting insulin and HOMA-IR across the course of the study. DHA-enriched fish oil supplementation increases testosterone levels in overweight and obese men. Further research is warranted to substantiate these findings with a larger sample size and a longer follow-up period.


Tracheal occlusion in the fetal rat: a new experimental model for the study of accelerated lung growth.
Prenatal tracheal occlusion accelerates fetal lung growth, but the mechanism of this phenomenon is unknown. Previous animal models have been limited by expense, lack of species-specific molecular probes, or the stage of lung development when studies could be performed. To provide a model that is more amenable to systematic analysis, we have developed an in vivo rat model of prenatal tracheal occlusion. Time-dated pregnant rats underwent laparotomy at 19 days' gestational age (term, 22 days). The fetal head and neck were exteriorized through a hysterotomy, and the trachea was ligated under a dissecting microscope. The fetus was returned to the amniotic cavity, and the uterine and maternal abdominal incisions were closed. The dam and the fetuses were killed at 21.5 days' gestational age, and the fetal lungs were assessed for lung growth and compared with nonoperated littermate controls. Thirty-two of 50 manipulated fetuses survived. Of the 32 survivors, successful tracheal ligation was confirmed in 20, and these 20 fetuses were compared with 33 littermate controls. Fetal body weight (4.81+/-0.26 g v 4.87+/-0.41 g) and heart weight (0.05+/-0.01 g v 0.05+/-0.01 g) were not significantly different between ligated fetuses and littermate controls, whereas the wet lung weight (0.30+/-0.06 g v 0.13+/-0.02 g, P<.01), lung-to-body-weight ratio (6.34+/-1.16% v 2.64+/-0.41%, P<.01), dry lung weight (17.4+/-2.45 mg v 12.1+/-1.87 mg, P<.01), total lung DNA (1210+/-371 microg v 828+/-208 microg, P<.01), and total lung protein (14.3+/-5.3 mg v 8.7+/-1.7 mg, P<.01) were increased significantly in the ligated fetuses. The enlarged lung demonstrated normal histology findings after inflation fixation. Prenatal tracheal occlusion during the canalicular stage of lung development accelerates lung growth in the rat. In comparison with other large animal models, this relatively inexpensive small animal model has the distinct advantages of a short gestation, a large number of fetuses per litter, the availability of a developmental model of congenital diaphragmatic hernia, and the availability of well-defined molecular probes to investigate the mechanism of tracheal occlusion-induced lung growth.


Demecology in the Cambrian: synchronized molting in arthropods from the Burgess Shale.
The Burgess Shale is well known for its preservation of a diverse soft-bodied biota dating from the Cambrian period (Series 3, Stage 5). While previous paleoecological studies have focused on particular species (autecology) or entire paleocommunities (synecology), studies on the ecology of populations (demecology) of Burgess Shale organisms have remained mainly anecdotal. Here, we present evidence for mass molting events in two unrelated arthropods from the Burgess Shale Walcott Quarry, Canadaspis perfecta and a megacheiran referred to as Alalcomenaeus sp. These findings suggest that the triggers for such supposed synchronized molting appeared early on during the Cambrian radiation, and synchronized molting in the Cambrian may have had similar functions in the past as it does today. In addition, the finding of numerous juvenile Alalcomenaeus sp. molts associated with the putative alga Dictyophycus suggests a possible nursery habitat. In this nursery habitat a population of this animal might have found a more protected environment in which to spend critical developmental phases, as do many modern species today.


IMPACT OF AN ECONOMIC CRISIS Evidence from Turkey.
This paper evaluates the impact of the 2001 economic crisis on the tourism industry in Turkey. The research findings reveal that neither the government nor private organizations had any plans for dealing with the crisis before or after the event. It had both negative and positive impacts although its benefits were often overlooked. The overall implication of the study is that national culture, the level of economic development of a country, the availability of financial resources, and the ability and knowledge of its government officials and managers of private firms have a direct impact on how such an event is responded to and managed.


The inhibition capacity of concanavalin A on monomeric and polymeric hemolytic antibodies.
The ability of concanavalin A (Con A) to inhibit the complement consumption by sheep erythrocytes coated with IgG, (IgG2-SpA1)2 complex and IgM anti-Forssman antibodies was studied. The (IgG2-SpA1)2 anti-Forssman antibody complex showed an increased hemolytic activity compared to uncomplexed IgG antibody. Con A in the presence of the (IgG2-SpA1)2 complex or the IgM antibody exhibited a high inhibitory capacity. An inhibitory capacity of Con A on IgG antibody hemolytic activity was also proved but at a Con A:IgG antibody concn ratio about 10 times higher than that for the Con A-IgM antibody system. A time dependence of Con A inhibitory capacity was determined, thus explaining the variable behaviour of the IgG antibody in the inhibition experiments. Radioactivity experiments demonstrated that only half of the Con A interacted with the (IgG2-SpA1)2 complex compared to the amount of Con A which interacted with IgG uncomplexed antibody.


Hydrochemical characteristics and quality assessment of deep groundwater from the coal-bearing aquifer of the Linhuan coal-mining district, Northern Anhui Province, China.
There is little information available about the hydrochemical characteristics of deep groundwater in the Linhuan coal-mining district, Northern Anhui Province, China. In this study, we report information about the physicochemical parameters, major ions, and heavy metals of 17 groundwater samples that were collected from the coal-bearing aquifer. The results show that the concentrations of total dissolved solids, electrical conductivity, and potassium and sodium (K(+) + Na(+)) in most of the groundwater samples exceeded the guidelines of the World Health Organization (WHO) and the Chinese National Standards for Drinking Water Quality (GB 5749-2006). The groundwater from the coal-bearing aquifer was dominated by the HCO3·Cl-K + Na and HCO3·SO4-K + Na types. Analysis with a Gibbs plot suggested that the major ion chemistry of the groundwater was primarily controlled by weathering of rocks and that the coal-bearing aquifer in the Linhuan coal-mining district was a relatively closed system. K(+) and Na(+) originated from halite and silicate weathering reactions, while Ca(2+) and Mg(2+) originated from the dissolution of calcite, dolomite, and gypsum or anhydrite. Ion exchange reactions also had an influence on the formation of major ions in groundwater. The concentrations of selected heavy metals decreased in the order Mn > Zn > Cr > Cu > Ni > Pb. In general, the heavy metal concentrations were low; however, the Cr, Mn, and Ni concentrations in some of the groundwater samples exceeded the standards outlined by the WHO, the GB 5749-2006, and the Chinese National Standards for Groundwater (GB/T 14848-93). Analysis by various indices (% Na, SAR, and EC), a USSL diagram, and a Wilcox diagram showed that both the salinity and alkalinity of the groundwater were high, such that the groundwater could not be used for irrigating agricultural land without treatment. These results will be significant for water resource exploiting and utilization in coal mine area.


High yield of same-session EUS-guided liver biopsy by 19-gauge FNA needle in patients undergoing EUS to exclude biliary obstruction.
EUS-guided liver biopsy by Trucut yields variable specimen adequacy at high cost, limiting its utility. A modified EUS-guided technique with reliable adequacy could be a viable alternative to standard techniques in cost-effective clinical settings. To describe our experience with EUS-guided liver biopsy by 19-gauge FNA, non-Trucut, needle in a cost-effective setting: patients with abnormal liver test results of unclear etiology referred for EUS to exclude biliary obstruction in whom an unrevealing EUS would have prompted a next-step liver biopsy by the referring physician. Prospective case series. Tertiary-care teaching hospital. Consecutive patients with abnormal liver tests referred for EUS. EUS-guided liver biopsy by 19-gauge FNA needle (non-Trucut). Diagnostic yield, specimen adequacy, and complications. An adequate specimen was defined as a length of 15 mm or longer and 6 or more complete portal tracts (CPTs). Between July 2008 and July 2011, 22 of 31 consecutive patients meeting inclusion criteria underwent unrevealing EUS with same-session EUS-guided liver biopsy by 19-gauge FNA needle. A median of 2 FNA passes (range 1-3) yielded a median specimen length of 36.9 mm (range 2-184.6 mm) with a median of 9 CPTs (range 1-73 CPTs). EUS-guided liver biopsies yielded a histologic diagnosis and adequate specimens in 20 of 22 patients (91%). Expanded experience led to improved specimen adequacy. There were no complications. Small study size. EUS-guided liver biopsy by using a 19-gauge FNA needle appears to be feasible and safe and provides excellent diagnostic yield and specimen adequacy.


Clinical application of a real-time polymerase chain reaction test for CYP2C19 genotyping based on genotype distribution in a healthy Korean population.
With the recent reports of additional alleles of the CYP2C19 gene with decreased or no function, the clinical utility of real-time polymerase chain reaction (PCR)-based testing that detects only a small number of variant targets needs to be evaluated. We retrospectively reviewed 7-year data for real-time PCR test records from a single hospital and analyzed CYP2C19 genotypes from publicly available whole-genome or whole-exome data from a healthy Korean population. Of the 2327 test results in this hospital, the *1 allele was most common (60.5%), followed by *2 (28.0%), *3 (10.1%), and *17 (1.4%). Among 5305 healthy Korean individuals, the frequencies of the *2, *3, and *17 alleles were 28.6%, 9.9%, and 1.0%, respectively, which were not statistically different from those of the hospital data (P = .4439, P = .6025, and P = .1142, respectively). Interestingly, the total frequency of additional nonfunctional alleles (*4, *6, *22, and *24) that could not be detected using real-time PCR was only 0.1%, with a total allele count of 8. Our study shows that the clinical utility of real-time PCR for CYP2C19 genotyping remains satisfactory. However, caution should be exercised because the test can miss patients with decreased CYP2C19 function.


Cardiac Delayed Rectifier Potassium Channels in Health and Disease.
Cardiac delayed rectifier potassium channels conduct outward potassium currents during the plateau phase of action potentials and play pivotal roles in cardiac repolarization. These include IKs, IKr and the atrial specific IKur channels. In this article, we will review their molecular identities and biophysical properties. Mutations in the genes encoding delayed rectifiers lead to loss- or gain-of-function phenotypes, disrupt normal cardiac repolarization and result in various cardiac rhythm disorders, including congenital Long QT Syndrome, Short QT Syndrome and familial atrial fibrillation. We will also discuss the prospect of using delayed rectifier channels as therapeutic targets to manage cardiac arrhythmia.


A "Welcoming" Introduction to a Canadian Northwest Coast Thematic Papers Issue.
In this commentary, I provide an introduction to and the context for the four articles in the thematic series published to celebrate the Editorial Board Meeting of the Anatomical Record in Vancouver, British Columbia, Canada in July of 2017. The articles describe various aspects of whale anatomy and the potential for a new generation of digital tags to provide information on functional anatomy of free swimming animals in the wild. The whales described are all native to the northwest coast of North America, as well as being found elsewhere, and the authors are related in some way to the University of British Columbia in Vancouver. Anat Rec, 300:1930-1934, 2017. © 2017 Wiley Periodicals, Inc.


Use of complementary DNA oligomers to probe trp leader transcript secondary structures involved in transcription pausing and termination.
DNA oligomers were synthesized that are perfectly complementary to different segments of the tryptophan (trp) operon leader transcript. These 15 nucleotide long oligomers were used as probes of the involvement of transcript secondary structures in two processes: transcription pausing at the pause site located near base pair 90 in the leader region, and transcription termination at the attenuator. The 15-mers were complementary to the four segments of the trp leader transcript which have been shown to form the alternative secondary structures that are believed to be responsible for pausing, termination, and antitermination. Oligomers complementary to RNA segments 1 and 3 relieved termination while the 15-mer complementary to RNA segment 1 relieved pausing. 15-mers complementary to segment 2 had no effect on pausing and the oligomer complementary to segment 4 had virtually no effect on termination.


Obsessive slowness presenting as catatonia in a patient with Borderline Intelligence.
Obsessive slowness is described to be a syndrome of extreme slowness in ways various tasks are performed. Its existence as an independent syndrome is challenged by authors, who regard it to be a part of obsessive compulsive disorder. We describe here a case of a 24-year-old male patient who presented with catatonic symptoms. Diagnostic difficulties and management issues are highlighted.


Modulation of lysophosphatidylserine-dependent histamine release.
Apomorphine (2-30 microM) inhibits lysophosphatidyl-serine-dependent histamine release in rat and mouse peritoneal mast cells. The drug-induced inhibition is influenced by the concentration of lysophosphatidylserine. Log concentration-response curves show a surmountable type of antagonism between the two compounds.


Pharmacokinetics and pharmacodynamics of ethanol, whiskey, and ethanol with n-propyl, n-butyl, and iso-amyl alcohols.
Plasma ethanol concentration, reaction time, and electroencephalogram (EEG) were recorded in 6 normal men after ingestion of ethanol along (Group 1), whiskey (Group 2), or a mixture of ethanol, n-propanol, n-butanol, and iso-amyl alcohol (Group 3). The peak plasma ethanol concentration and the total area under the plasma concentration:time curve of ethanol did not depend upon the type of drink given, but the half-life of the terminal exponential phase of ethanol elimination was longer in Group 3. In each study period reaction time increased, there was a relative increase in delta activity (2 to 3 Hz) and a fall in mean dominant frequency in EEG activity. The extent of increase in reaction time depended on the rate of increase in plasma ethanol concentration and correlated with the concentration of ethanol while the plasma concentration of ethanol was falling. Differences in the effects of ethanol between study periods were minimal.


Quantitative multilevel mapping of hepatic blood flow by xenon computed tomography using aorta.
A noninvasive and quantitative technique has been developed to measure human hepatic blood flow by xenon computed tomography (Xe-CT). Accurate data on time-dependent xenon concentrations in the arterial blood are indispensable for Xe-CT to ensure quantitativeness of measured blood flow. A method has been established by our group to use both aorta and end-tidal data to obtain arterial xenon information. Multilevel (3 levels) maps of arterial blood flow (Fa), portal blood flow (Fp), and partition coefficient (lambda) were created for patients with chronic hepatitis. A method to objectively evaluate Fa, Fp, and lambda values for the whole liver has also been developed by our group.


Individual and environmental determinants of Cuterebra bot fly parasitism in the eastern chipmunk (Tamias striatus).
Understanding the interactions between parasites, hosts, and their shared environment is central to ecology. Variation in infestation prevalence may be the result of varying environmental and population characteristics; however, variations in parasitism may also depend on individual characteristics that influence both the exposure and susceptibility to parasites. Using 12 years of data from a population of wild eastern chipmunks relying on pulsed food resources, we investigated the determinants of bot fly parasitism at both the population and individual level. We assessed the relationship between infestation prevalence and weather conditions, population size and food abundance. Then, we assessed the relationship between infestation intensity and chipmunk behavior, sex, age, body mass and food abundance. Precipitation, temperature and population size were positively related to infestation prevalence, while beech masts were negatively related to infestation prevalence, highlighting the importance of local environmental conditions on hosts and parasites. We also found that the influence of activity and exploration on infestation intensity varied according to sex in adults. More active and faster exploring males had more parasites compared to females, suggesting that reproductive behaviors may influence parasite exposure. For juveniles, infestation intensity was greater when juveniles emerged in the spring as opposed to fall, possibly because spring emergence is synchronized with the peak of bot fly eggs in the environment, low food availability and longer activity period. Our results suggest that the environmental, population and host characteristics that are advantageous for reproduction and resource acquisition may come at the cost of increasing parasitism.


Disparities in access to effective treatment for infertility in the United States: an Ethics Committee opinion.
In the United States, economic, racial, ethnic, geographic, and other disparities exist in access to fertility treatment and in treatment outcomes. This opinion examines the factors that contribute to these disparities and proposes actions to address them.


Toxicity of Carbon Dioxide to Freshwater Fishes: Implications for Aquatic Invasive Species Management.
Carbon dioxide (CO2 ) has been approved by the US Environmental Protection Agency as a new aquatic pesticide to control invasive Asian carps and other aquatic nuisance species in the United States. However, limited CO2 toxicity data could make it challenging for resource managers to characterize the potential risk to nontarget species during CO2 applications. The present study quantified the toxicity of CO2 to 2 native riverine fishes, bluegill (Lepomis macrochirus) and fathead minnow (Pimephales promelas), using 12-h continuous flow-through CO2 exposure at 5, 15, and 25 °C water temperatures. Resulting survival indicated that bluegill (median lethal concentration [LC50] range 91-140 mg/L CO2 ) were more sensitive to CO2 than fathead minnow (LC50 range 235-306 mg/L CO2 ) across all water temperatures. Bluegill were also more sensitive to CO2 at 5 °C (LC50 91 mg/L CO2 , 95% CI 85-96 mg/L CO2 ) than at 25 °C (LC50 140 mg/L CO2 , 95% CI 135-146 mg/L CO2 ). Fathead minnow showed an opposite response and were less sensitive at 5 °C (LC50 306 mg/L CO2 , 95% CI 286-327 mg/L CO2 ) relative to 25 °C (LC50 235 mg/L CO2 , 95% CI 224-246 mg/L CO2 ). Our results show that CO2 toxicity can differ by species and water temperature. Data from the present study may inform decisions related to the use of CO2 as a control tool. Environ Toxicol Chem 2020;39:2247-2255. Published 2020. This article is a U.S. government work and is in the public domain in the USA.


Associations among serum markers of inflammation, life stress and suicide risk in patients with major depressive disorder.
Patients with major depressive disorder (MDD) are at high risk for suicide. As the worst outcome of MDD and common self-concealment in patients with suicide risk, studies of biomarkers may provide useful tools for suicide prevention and treatment. This study recruited 168 patients with MDD from the Objective Diagnostic Markers and Personalized Intervention in MDD patients (ODMPIM), including 50 patients with suicide risk. Based on previous evidence and hypothesis, 23 targeted serum biomarkers involving immune-inflammation, neurotrophins, hypothalamic-pituitary-adrenal (HPA) axis and metabolism, were measured. We used path analysis and principal components analysis (PCA) to clarify the associations among serum biomarkers, childhood adversities, adulthood life events, severity of depression and suicide risk. We identified that patients with suicide risk had a higher level of inflammatory markers in serum than patients without suicide risk (P < 0.001), especially chemokine (C-X-C motif) ligand 1 (CXCL-1). After using the Bonferroni correction, there were no differences in biomarkers related to neurotrophins, HPA-axis and metabolism. In addition, a higher proportion of patients with suicide risk had adulthood adversity (assessed by Life Events Scale) (P = 0.003). Intriguingly, path analysis demonstrated that the association between adulthood adversity and suicide risk mainly depended on severity of depression and inflammatory index. This study highlights the possible role of inflammation involved in suicide risk of MDD patients. Inflammatory markers have the potential for early identification and then reducing suicidal behaviors or becoming novel treatment targets in suicide risk management.


The role of trained immunity in COVID-19: Lessons for the next pandemic.
Trained immunity is a long-term increase in responsiveness of innate immune cells, induced by certain infections and vaccines. During the last 3 years of the COVID-19 pandemic, vaccines that induce trained immunity, such as BCG, MMR, OPV, and others, have been investigated for their capacity to protect against COVID-19. Further, trained immunity-inducing vaccines have been shown to improve B and T cell responsiveness to both mRNA- and adenovirus-based anti-COVID-19 vaccines. Moreover, SARS-CoV-2 infection itself induces inappropriately strong programs of trained immunity in some individuals, which may contribute to the long-term inflammatory sequelae. In this review, we detail these and other aspects of the role of trained immunity in SARS-CoV-2 infection and COVID-19. We also examine the learnings from the trained immunity studies conducted in the context of this pandemic and discuss how they may help us in preparing for future infectious outbreaks.


Surgical management of pancreatic cancer.
The overall prognosis after resection for adenocarcinoma of the pancreas remains poor; however, considerable progress has been made in terms of preoperative patient selection and radiographic staging, refinements in the technical aspects of surgical care, and investigations into the role of multimodality care for patients with potentially curable, resected cancers. Improvements in endoscopic decompression of malignant biliary obstruction have decreased the need for palliative bypass operations and have focused current surgical issues on ways to improve clinical outcomes after potentially curative resections. Controversies such as whether or not to perform extended lymph node dissections and standard versus pylorus-preserving resections have been addressed by randomized, prospective clinical trials. Major venous resections secondary to local tumor extension are now performed without an increase in morbidity or mortality and with survival rates comparable to standard resections. The impact of surgical specialization and regionalization of referrals to tertiary care centers is evident in markedly improved perioperative mortality rates. Neoadjuvant therapy is an area of current clinical investigation. This article describes the current preoperative, intraoperative, and postoperative issues in the surgical management of pancreatic cancer.


Localization of the PsbH subunit in photosystem II from the Synechocystis 6803 using the His-tagged Ni-NTA Nanogold labeling.
The PsbH protein belongs to a group of small protein subunits of photosystem II (PSII) complex. This protein is predicted to have a single transmembrane helix and it is important for the assembly of the PSII complex as well as for the proper function at the acceptor side of PSII. To identify the location of the PsbH subunit, the PSII complex with His-tagged PsbH protein was isolated from the cyanobacterium Synechocystis sp. PCC 6803 and labeled by Ni(2+)-nitrilo triacetic acid Nanogold. Electron microscopy followed by single particle image analysis identified the location of the labeled His-tagged PsbH protein at the periphery of the dimeric PSII complex. These results indicate that the N terminus of the PsbH protein is located at the stromal surface of the PSII complex and close to the CP47 protein.


Hippo in Gastric Cancer: From Signalling to Therapy.
The Hippo pathway is one of the most important ones in mammals. Its key functions in cell proliferation, tissue growth, repair, and homeostasis make it the most crucial one to be controlled. Many means have been deployed for its regulation, since this pathway is not only composed of core regulatory components, but it also communicates with and regulates various other pathways, making this signalisation even more complex. Its role in cancer has been studied more and more over the past few years, and it presents YAP/TAZ as the major oncogenic actors. In this review, we relate how vital this pathway is for different organs, and how regulatory mechanisms have been bypassed to lead to cancerous states. Most studies present an upregulation status of YAP/TAZ, and urge the need to target them. A focus is made here on gastric carcinogenesis, its main dysregulations, and the major strategies adopted and tested to counteract Hippo pathway disbalance in this disease. Hippo pathway targeting can be achieved by various means, which are described in this review. Many studies have tested different potential molecules, which are detailed hereby. Though not all tested in gastric cancer, they could represent a real interest.


An RNA aptamer that specifically binds pancreatic adenocarcinoma up-regulated factor inhibits migration and growth of pancreatic cancer cells.
Previously, we reported that a novel secretory protein, pancreatic adenocarcinoma up-regulated factor (PAUF), which is highly expressed in pancreatic cancer and mediates the growth and metastasis of pancreatic cancer cells. In this study, we generated and characterized a 2'-fluoropyrimidine modified RNA aptamer (P12FR2) directed against human PAUF. P12FR2 binds specifically to human PAUF with an estimated apparent K(D) of 77nM. P12FR2 aptamer inhibits PAUF-induced migration of PANC-1, human pancreatic cancer cells, in a wound healing assay. Moreover, intraperitoneal injection of P12FR2 decreased tumor growth by about 60% in an in vivo xenograft model with CFPAC-1 pancreatic cancer cells, without causing a loss of weight in the treated mice. Taken together, we propose here that PAUF-specific RNA aptamer, P12FR2, has the potential to be effective in the therapy of human pancreatic cancer.


Maximizing the treatment of overactive bladder in the elderly.
Overactive bladder syndrome affects millions of elderly people in the United States and is equally prevalent in men and women. Its impact on quality of life can be devastating, especially to elderly patients with other medical comorbidities. In order to maximize care, health care providers must be able to make the correct diagnosis and have a working knowledge of available therapies. Data exist supporting the efficacy and safety of nonpharmacologic and pharmacologic therapies.


Supercritical water pretreatment method for analysis of strontium and uranium in soil (Andosols).
Hydrothermal pretreatment of soils (Andosols) from Ibaraki prefecture (Japan) was used to improve methods for monitoring radioactive Sr and U. Calcined samples were pretreated with subcritical or supercritical water (SCW) followed by extraction with 0.5 M HNO3 solutions. With SCW pretreatment, recoveries of Sr and U were 70% and 40%, respectively. Experimental recoveries obtained can be described by a linear relationship in water density. The proposed method is robust and can lower environmental burden of routine analytical protocols.


One-way humoral immune cross-reactivity between bovine spinal cord protein and bovine myelin basic protein.
Whether bovine myelin basic protein (BP) and bovine spinal cord protein (SCP) cross-react at the humoral immune level was assessed with a sensitive solid-phase enzyme immunoassay. We found that a hyperimmune anti-SCP serum reacted strongly with SCP and cross-reacted nearly as well with BP. A hyperimmune anti-BP serum reacted only with BP. Antigenic competition analysis revealed that SCP and BP both inhibited binding of the hyperimmune anti-SCP serum to solid-phase adsorbed SCP and BP, while only BP inhibited binding of the hyperimmune anti-BP serum to solid-phase adsorbed BP. Finally, BP cross-reactivity antibodies were present in early bleedings from rabbits immunized with SCP that had been passed through an anti-BP immunosorbent column. These results clearly show there is a one-way humoral immune cross-reactivity between SCP and BP which goes in the direction of SCP to BP.


Transcription and DNA supercoiling.
Transcription and supercoiling of the DNA template are interrelated. This review summarizes recent progress in the study of how template topology affects transcription, and how transcription affects template topology inside wild-type and DNA topoisomerase mutant cells. The interplay between DNA supercoiling and transcription raises interesting questions on the regulation of adjacent genes, the organization of intracellular DNA, and the coupling between transcription and other cellular processes involving DNA.


Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery.
The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P<0.001) and less so by rauwolscine, indicating functional α₁- and α₂-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P<0.01) but augmented noradrenaline responses (n=8, P<0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by L-NOArg (n=7, P<0.05 and P<0.01 respectively) and ODQ (n=7, both P<0.05); in denuded arteries, nNOS inhibition with N(ω)-propyl-L-arginine increased neurogenic contraction (n=7, P<0.05). Western blotting indicated the presence of neural and endothelial origin NO (n=6, P<0.001). Tetraethylammonium (n=9, P<0.001), iberiotoxin (n=7, P<0.001) and 4-aminopyridine (n=8, P<0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca²⁺-activated K⁺ (BK(Ca)) and voltage-dependent K⁺ (K(v)) channels in noradrenergic responses. Bosentan pretreatment (n=8, P<0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n=9, P<0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n=5, P=0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK(Ca) and K(v) channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass.


Renal Microcirculation and Function in a Pig Model of Hemorrhagic Shock Resuscitation with Norepinephrine.
Rationale: Norepinephrine (NE) is commonly used in combination with fluid during resuscitation of hemorrhagic shock, but its impact on kidney microcirculation, oxygenation, and function is still unknown in this setting. Objectives: During hemorrhagic shock resuscitation, does a combination of fluid and NE affect kidney oxygenation tension, kidney microcirculatory perfusion, and 48-hour kidney function, as compared with fluid alone? Methods: Hemorrhagic shock was induced in 24 pigs, and 8 pigs were included as a sham group. Resuscitation of hemorrhagic shock was performed, using a closed-loop device, either by fluid alone (0.9% NaCl; fluid group) or associated with the administration of NE at two doses (moderate dose: mean rate of 0.64 μg ⋅ kg-1 ⋅ min-1; high dose: mean rate of 1.57 μg ⋅ kg-1 ⋅ min-1) to obtain a target systolic arterial pressure of 80 to 90 mm Hg. Resuscitation was followed by transfusion of the withdrawn blood. Measurements and Main Results: The amount of fluid required to reach the target systolic arterial pressure was lower in the NE groups than in the fluid group, with subsequently less hemodilution. NE restored kidney microcirculation, oxygenation, and function in a manner comparable to that achieved with fluid resuscitation alone. There were no histologic differences between animals resuscitated with fluid and those resuscitated with NE. Conclusions: In pigs with hemorrhagic shock, resuscitation with a combination of NE and fluid restored kidney microcirculation and oxygenation, as well as renal function, in a manner comparable to fluid resuscitation alone and without differences between the two NE doses. NE administration led to a fluid volume-sparing effect with subsequently less hemodilution.


Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora.
The H(2)-receptor antagonist ranitidine has previously been shown to be a substrate for colonic bacterial metabolism. The objective of the present study was to assess the in vitro stability of the other H(2)-receptor antagonists, cimetidine, famotidine and nizatidine, to colonic bacteria. One hundred milligrams of each drug were introduced into individual batch culture fermenters (100 ml) consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments, equivalent drug quantities in buffer medium without the presence of faeces, were also run in parallel. Samples were removed at set time intervals over a 24 h period and were subsequently analysed by HPLC. A selection of the samples removed from the fermenters was also subjected to analysis by UV spectroscopy and mass spectrometry. Following an initial dissolution phase in the fermentation system, a marked decline in nizatidine concentration was noted over time with virtually no drug remaining after 12 h, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted for cimetidine or famotidine or for any of the drugs in the control buffer systems. The metabolic reaction pathway for nizatidine was complex, although UV and mass spectrometry analysis indicated that metabolism was initiated via cleavage of an N-oxide bond within the molecule. These results in combination with those obtained from a previous study indicate that of the four commercially available H(2)-receptor antagonists, nizatidine and ranitidine are susceptible to metabolism by colonic bacteria, which in turn has ramifications for drug delivery and absorption.


Generalization gradients following differential intradimensional autoshaping.
Three pigeons were trained on a differential, intradimensional autoshaped discrimination. A 45 degrees line tilt was always paired with food whereas a 15 degrees line tilt was never paired with food. All subjects learned the discrimination within 17 sessions. The pigeons were then given generalization tests in extinction over seven line tilts (0 degrees, 15 degrees, 30 degrees, 45 degrees, 60 degrees, 75 degrees and 90 degrees). The subjects yielded generalization gradients with maxima at 45 degrees and minima at 15 degrees. An area shift, but no peak shift, was found for each subject.


Survival and reproductive outcomes after fertility-sparing surgery performed for borderline epithelial ovarian tumor in Japanese adolescents and young adults: Results of a retrospective nationwide study.
Epithelial borderline ovarian tumor (BOT) frequently occurs in young women. Because progression-free survival, overall survival, and reproductive function are important outcomes, BOT is often treated by fertility-sparing surgery (FSS). We conducted a Japan-wide study to understand post-FSS prognosis in relation to clinical characteristics and types of FSS performed. We analyzed clinical and outcome data pertaining to 531 adolescent and young adult (AYA) patients (aged 15-39 years) who underwent FSS for BOT between 2009 and 2013. Median (range) age was 30 (15-39) years, and median observation time was 70 (2-120) months. The disease was of FIGO stage I in 492 (93%) patients. Histopathologically, tumors were of the mucinous (n = 372, 70%), serous (n = 120, 23%), seromucinous (n = 23, 4%), and other (n = 16, 3%) types. Five-year overall survival was 99.5% among patients with stage I and 100% among those with stage II-IV. Five-year progression-free survival was 96.7% and 69.3%, respectively. Multivariate analysis in cases of stage I showed a positive peritoneal cytology to be a significant risk factor for recurrence (HR, 5.199; p = 0.0188). The post-FSS pregnancy rate was relatively low for patients aged ≥30 years (OR, 0.868; 95% CI, 1.16-3.00; p = 0.0090). Post-FFS outcomes in terms of overall and progression-free survival are favorable, especially for AYA patients with stage I BOT. However, the relapse rate is high for patients with FIGO stage II-IV and for those with stage I but a positive peritoneal cytology. A long-term prospective observation is needed before reproductive outcomes can be fully established.


Regulation of microRNA expression by hepatocyte growth factor in human head and neck squamous cell carcinoma.
Hepatocyte growth factor (HGF) is a multifunctional molecule that acts as mitogen, motogen, and/or morphogen in a variety of cells. MET, a specific receptor tyrosine kinase for HGF, is upregulated in various tumors including squamous cell carcinoma of the human head and neck (HNSCC), but how HGF affects the expression of downstream functional genes has not yet been elucidated in detail. In the present study, we examined the expression of microRNA (miRNA), non-coding small RNA that regulate cell proliferation and functions by interfering with the translation of target mRNA, with or without HGF stimulation in HNSCC cell line HSC3. Among several miRNAs, in which the expression was altered after HGF stimulation, we focused on miR-200c and miR-27b, both of which were drastically downregulated after HGF stimulation. Expression of ZEB1, a target mRNA for miR-200c, was upregulated 3 and 6 h after HGF stimulation, and that of E-cadherin, a downstream molecule of ZEB1, was downregulated 12 h after HGF stimulation. Expression of ST14/matriptase, an enzyme for extracellular matrix (ECM) degradation and HGF activation and a target mRNA for miR-27b, was drastically upregulated in the protein level after HGF stimulation, although it was not statistically altered in the mRNA level. These results suggest that miR-200c and miR-27b downregulated by HGF might play an important role in epithelial-mesenchymal transition mediated by ZEB1/E-cadherin and ECM degradation and HGF autoactivation mediated by ST14/matriptase, respectively. Altered expression of miRNA directly regulated by HGF might contribute enhanced progressive and invasive characteristics of HNSCC by regulating the translation of HGF-induced functional molecules.


Influence of hydrocortisone on cytopathic effect of Newcastle disease virus and stability to freezing of vescicular stomatitis virus.
The presence of hydrocortisone in virus-infected cell cultures leads to enhancement of the syncytia forming ability of Newcastle disease virus and to production of vescicular stomatitis virus particles which loose their infectivity upon storage below 0 degrees C.


Health and Nutritional Beliefs and Practices among Rural Elderly Population: An Ethnographic Study in Western Spain.
Demographic transition is causing an increasingly aged society, which has a significant impact on public health strategies. Increases in the size of the elderly cohort create a wider stratification and pose specific challenges. Nutrition and diet are one key issue. This study aims to describe food-related practices, beliefs, and representations of non-institutionalized older adults in rural communities in Extremadura (Western Spain). The ethnographic-based fieldwork was conducted from January to July 2019. Empirical material was collected through different research relationships (semi-structured interviews and informal conversations) and direct observation in various locations in Extremadura-involving a variety of agents associated with different aspects of the nutritional process. Data analysis revealed four major themes: (1) Limitations on choice and quality of food available; (2) food preferences and cooking methods; (3) the role of nostalgia in the construction of taste preferences; and (4) perceptions of what "healthy" food is and how respondents relate to the advice provided by health professionals. Nutritional choices among the group studied presented significant differences from medical advice-which was seen as a series of "bans" that did not carry enough authority to alter the symbolic value attached to their traditions.


Imaging of room-temperature ferromagnetic nano-domains at the surface of a non-magnetic oxide.
Two-dimensional electron gases at oxide surfaces or interfaces show exotic ordered states of matter, like superconductivity, magnetism or spin-polarized states, and are a promising platform for alternative oxide-based electronics. Here we directly image a dense population of randomly distributed ferromagnetic domains of ∼40 nm typical sizes at room temperature at the oxygen-deficient surface of SrTiO3, a non-magnetic transparent insulator in the bulk. We use laser-based photoemission electron microscopy, an experimental technique that gives selective spin detection of the surface carriers, even in bulk insulators, with a high spatial resolution of 2.6 nm. We furthermore find that the Curie temperature in this system is as high as 900 K. These findings open perspectives for applications in nano-domain magnetism and spintronics using oxide-based devices, for instance through the nano-engineering of oxygen vacancies at surfaces or interfaces of transition-metal oxides.


Impact of HIV on admissions and deaths in a tuberculosis hospital--recommendations for admission and discharge criteria.
Mortality and HIV prevalence rose concordantly at Brooklyn Chest Hospital from 1998 to 2001. Death and unconfirmed tuberculosis (TB) (15% of adult admissions in a sample from 2000) were associated with HIV seropositivity. Excluding unconfirmed TB and shortening length of stay would increase the number of patients able to benefit from hospitalisation.


The α2 helix in the DNA ligase IV BRCT-1 domain is required for targeted degradation of ligase IV during adenovirus infection.
In adenovirus E4 mutant infections, viral DNAs form concatemers through a process that requires host Non-homologous End Joining (NHEJ) proteins including DNA Ligase IV (LigIV). Adenovirus proteins E4 34k and E1b 55k form the substrate-selection component of an E3 ubiquitin ligase and prevent concatenation by targeting LigIV for proteasomal degradation. The mechanisms and sites involved in targeting this and other E3 ligase substrates generally are poorly-understood. Through genetic analysis, we identified the α2 helix of one LigIV BRCT domain (BRCT-1) as essential for adenovirus-mediated degradation. Replacement of the BRCT domain of DNA ligase III (LigIII), which is resistant to degradation, with LigIV BRCT-1 does not promote degradation. A humanized mouse LigIV that possesses a BRCT-1 α2 helix identical to the human protein, like its parent, is also resistant to adenovirus-mediated degradation. Thus, both the BRCT-1 α2 helix and an element outside BRCT-1 are required for adenovirus-mediated degradation of LigIV.


The relationship between hypertensive disorders in pregnancy and placental maternal and fetal vascular circulation.
We examined the impact of chronic hypertension (HTN), gestational HTN, and preeclampsia on placental maternal and fetal vascular circulation. Of the 1047 women who gave birth and underwent a placental histopathologic examination between 2007 and 2013 at Wolfson Medical Center, 140 women were included in the present study: 34 women with preeclampsia, 25 women with chronic HTN, 28 women with gestational HTN, and 53 women without hypertensive disorder, matched by age, gravidity, parity, and mode of delivery.Placental lesions related to maternal vascular malperfusion (MVM) differed significantly across groups (P < .0001) and were highest in subjects with chronic HTN and preeclampsia (72% and 65%, respectively) and lowest in women without hypertensive disorder (26%). Placental fetal vascular malperfusion rate did not differ significantly between groups (P = .767). In the logistic regression analysis, chronic HTN emerged as a significant predictor of placental MVM and increased the risk of this outcome more than sixfold (odds ratio 6.614, 95% confidence interval 2.047-21.37, P = .002). Preeclampsia emerged as a significant predictor of MVM and more than tripled the risk of this outcome (odds ratio 3.468, 95% confidence interval 1.083-11.103, P = .036). Gestational HTN was not significantly associated with increased MVM rate. We demonstrated that chronic HTN and preeclampsia were associated with an increased rate of vascular placental maternal malperfusion and emerged as significant independent predictors of this outcome.


Heterotransplantation of mixed mesodermal tumor cells in nude mouse--histology of metastatic foci.
The mixed mesodermal tumor has an admixture of carcinoma and sarcoma. The HIRS-BM tumor cell line, derived from the mixed mesodermal tumor, was transplanted into the peritoneal cavity of BALB/c nude mice, and the metastatic foci were examined histologically and karyologically. The HIRS-BM cells produced mixed mesodermal tumors (admixture of adenocarcinoma and rhabdomyosarcoma) resembling the original tumor. The normal interstitial tissue was not present on the boundary of the sarcoma and carcinoma. These results support the combination theory as the cause of mixed mesodermal tumor.


Reaction-time differences between the left and right hemispheres for face and letter discrimination in children and adults.
Twenty boys at each age level 7, 10, and 13 years and 20 adult males were tested for choice manual reaction times to photographs of faces or letter pairs tachistoscopically presented 3 1/2 degree to the left or 3 1/2 degree to the right of a central fixation point, in the left visual field (LVF) or the right visual field (RVF) respectively. All subjects were right-handed. Subjects were tested monocularly. They used a different hand and a different eye in the first and second half of trials. Eye order and hand order were randomized across subjects. Seven- and 10-year-olds were intermittently rewarded with a poker chip following fast correct responses. Analysis of correct reaction time scores indicated an overall LVF superiority for the speed of response to faces, but no significant field differences for responses to letter pairs. The interaction of these field-stimulus effects with age was not significant, suggesting that the obtained field effects with faces and letter pairs were consistent across the range of ages tested. The results of comparisons of field differences within individual subjects suggested a "switchover" from a left-field advantage with letter pairs at age 7 to a right-field advantage at the adult level; this tendency, however, was not significant. None of these results was influenced by the use of different hands or eyes or to frequencies of commission of errors. The results suggested that a left-field advantage in speed of response to familiarized faces is found as early as 7 years of age and does not change appreciably thereafter. The finding of a significant left-field advantage for faces in the 7-year-old group represented an earlier age of left-field, right hemisphere lateralization for face stimuli than that previously obtained by other investigators. The failure to find over field differences with letter pairs was attributed to a possible tendency among subjects to process to letters visually (i.e., graphemically), a tendency which may have been more marked in the 7-year-old group due to the relative inexperience of children of this age with alphabetical material.


[Application of pedicled parumbilical axial skin flap in the repair of skin defect of upper extremity].
The parumblical axial skin flap contained leap the parumbilical perforating branch of the inferiorle expigastic artery in its pedicle. It was designed to treat the scaring wounds of the upper limb in 5 patients with success. In the five patients, the scar on the dorsal aspect of the hand in 2, over the elbow in 1, on the palmar aspect in 1 and wound over the elbow in 1. The size of the flap ranged form 23 cm x 10 cm to 16 cm x 7 cm. The pedicle of the flap was made a tube. The limb was immobilized by plasten of paris after operation. All of the flaps were survived. The pedicle was divided at the hird week postoperation. The vascular supply of the flap was constant. The operation was also easy. This flap was feasible for the repair of the scar or wound of the hand, wrist, forearm, and, especially the elbow.


Recognition of visual symptoms in stroke: a challenge to patients, bystanders, and Emergency Medical Services.
Identification of visual symptoms as a sign of acute stroke can be challenging for both first line healthcare professionals and lay persons. Failed recognition of visual symptoms by medical dispatchers at the Emergency Medical Dispatch Center (EMDC-112) or personnel at the Out-of-Hours Health Service (OOHS) may delay stroke revascularization. We aimed to identify correct system response to visual symptoms in emergency calls. Phone calls from patient or bystander to the EMDC-112 or OOHS, which included visual symptoms on patients later verified with stroke/Transient ischemic attack (TIA) diagnosis, were analyzed. Data were stratified according to hospitalization within and after 4.5 h from symptom onset. Descriptive and multiple logistic regression analysis were performed. Of 517 calls identified, 290 calls fulfilled inclusion criteria. Only 30% of the patients received correct visitation by the medical dispatchers and referral to the hospital by a high-priority ambulance. Correct visitation was associated with early contact (adjusted OR: 2.37, 95% CI: 1.11, 5.03), contact to the EMDC-112 (adjusted OR: 3.18, 95% CI: 1.80, 5.62), and when the medical dispatcher asked additional questions on typical stroke symptoms (adjusted OR: 6.36, 95% CI: 3.01, 13.43). No specific visual symptom was associated with stroke recognition and fast hospitalization. First line healthcare professionals had significant problems in identifying visual symptoms as a sign of acute stroke and eliciting correct response. This highlights an urgent need to improve knowledge of visual symptoms in acute stroke and emphasize correct response to stroke symptoms in general.


Intravenous dilazep reduces blood pressure and peripheral vascular resistance in humans.
Dilazep, a coronary vasodilating drug with adenosine-mediated activity, was tested (acute double-blind study versus placebo) for its antihypertensive activity in 12 patients who had mild to moderate hypertension. Dilazep (0.2 mg/kg body weight by IV infusion for ten minutes) significantly reduced systolic and diastolic blood pressure (random-zero sphygmomanometer) on average by 13.3 and 10.6 mm Hg respectively. The antihypertensive effect started rapidly, reached its maximum 20 minutes after administration, and lasted for 90 minutes. Heart rate significantly increased between 10 and 30 minutes. The antihypertensive effect of dilazep was associated with a relevant vasodilating effect as demonstrated by the changes in upper limb blood flow (strain-gauge plethysmography, +32%; P less than .001) and vascular resistance (-29%, P less than .001). The maximal reduction of vascular resistance was directly correlated to its baseline value. For these characteristics of action, at least in acute administration, dilazep would be useful agent for the treatment of high blood pressure in mild to moderately hypertensive patients.


1,3-Dipolar cycloaddition of alkynes to azides. Construction of operationally functional metal responsive fluorophores.
The copper catalyzed 1,3-dipolar cycloaddition of 4-butoxyphenylazide with 2-, 3- or 4-ethynylpyridine furnishes 1,4-diaryltriazoles, which display turn-on fluorescence upon addition of metal cations.