Cough and glottic-stop reflex sensitivity in health and disease.
Little is known about the normal ranges and repeatability of cough reflex sensitivity measurements, or the relationship of cough reflex sensitivity to other upper airway reflexes in subjects with chronic dry cough. We set out to define the normal range of cough reflex sensitivity and its repeatability in health and disease, and to assess its relationship to the glottic-stop reflex. Prospective, cross-sectional study. We measured capsaicin cough reflex sensitivity in 134 healthy subjects and 88 patients with respiratory disease, and assessed the repeatability over 2 weeks in a subgroup of individuals (healthy subjects, 15; chronic cough patients, 15). In another subgroup (healthy patients, 16; chronic cough patients, 14), we measured the sensitivity of the glottic-stop reflex (using inhaled ammonia). Capsaicin cough sensitivity varied widely in the population of healthy subjects, and there was considerable overlap of cough reflex sensitivity between healthy control subjects and patients with cough. The intraclass correlation coefficients for repeatability of cough sensitivity (concentration of capsaicin that causes two coughs, and concentration of capsaicin that causes five coughs) were 0.89 and 0.88, respectively. Patients with chronic cough had a significantly more sensitive glottic-stop reflex than healthy subjects (glottic-stop sensitivity threshold, 483 ppm vs 1,029 ppm, respectively; p = 0.01), and there was a significant positive correlation between glottic-stop and cough reflex sensitivity (r = 0.5; p < 0.01). We have shown a wide variation of cough reflex sensitivity in healthy subjects, although the measurement does have good 2-week repeatability. There was a reasonably close relationship between cough sensitivity and glottic-stop reflex sensitivity, indicating either that the cough reflex and the glottic-stop reflex share a common pathway or that subjects who have a chronic cough have a global abnormality of upper airway reflexes.


[Acupuncture at five Shu points for treatment of 126 cases of numbness of hands and feet induced by peripheral diabetic neuropathies].
To observe therapeutic effect of acupuncture on peripheral diabetic neuropathies in the African area. Five Shiu points on the four limbs were selected. Jing (well-point) was needled by pricking method for blood letting, and acupuncture was given at points Xing (spring-point), Shu (stream-point), Jing (river-point) and He (sea-point), and after arrival of qi, the needles were retained for 30 min, once every other day, for 2 therapeutic courses. Forty-five cases were markedly effective and 68 cases were effective, the total effective rate being 89.68%. Acupuncture has obvious therapeutic effect on diabetic neuropathies in the African area.


Numerical computation of the Green's function for two-dimensional finite-size photonic crystals of infinite length.
We develop a numerical algorithm that computes the Green's function of Maxwell equation for a 2D finite-size photonic crystal, composed of rods of arbitrary shape. The method is based on the boundary integral equation, and a Nyström discretization is used for the numerical solution. To provide an exact solution that validates our code we derive multipole expansions for circular cylinders using our integral equation approach. The numerical method performs very well on the test case. We then apply it to crystals of arbitrary shape and discuss the convergence.


Rigorous Neural Network Simulations: A Model Substantiation Methodology for Increasing the Correctness of Simulation Results in the Absence of Experimental Validation Data.
The reproduction and replication of scientific results is an indispensable aspect of good scientific practice, enabling previous studies to be built upon and increasing our level of confidence in them. However, reproducibility and replicability are not sufficient: an incorrect result will be accurately reproduced if the same incorrect methods are used. For the field of simulations of complex neural networks, the causes of incorrect results vary from insufficient model implementations and data analysis methods, deficiencies in workmanship (e.g., simulation planning, setup, and execution) to errors induced by hardware constraints (e.g., limitations in numerical precision). In order to build credibility, methods such as verification and validation have been developed, but they are not yet well-established in the field of neural network modeling and simulation, partly due to ambiguity concerning the terminology. In this manuscript, we propose a terminology for model verification and validation in the field of neural network modeling and simulation. We outline a rigorous workflow derived from model verification and validation methodologies for increasing model credibility when it is not possible to validate against experimental data. We compare a published minimal spiking network model capable of exhibiting the development of polychronous groups, to its reproduction on the SpiNNaker neuromorphic system, where we consider the dynamics of several selected network states. As a result, by following a formalized process, we show that numerical accuracy is critically important, and even small deviations in the dynamics of individual neurons are expressed in the dynamics at network level.


Hereditary breast and ovarian cancer (HBOC): clinical features and counseling for BRCA1 and BRCA2, Lynch syndrome, Cowden syndrome, and Li-Fraumeni syndrome.
This article provides an overview of the molecular changes associated with inherited gynecologic malignancies and the incorporation of this information in the counseling of individuals at increased risk for developing malignancies, as well as conventional and emerging approaches to the screening of the general population. Cancer genetic counseling and its role in women's health care is examined. The focus is hereditary breast and ovarian cancer; however, cancer predisposition caused by genes other than BRCA1 and BRCA2 is also considered. The aim is to provide a foundation for counseling based on fundamental knowledge of the genes and their clinical consequences. The reader is then guided through the mechanics of risk assessment for individual patients, concluding with the psychosocial implications of counseling.


Chronic Fos-related antigens: stable variants of deltaFosB induced in brain by chronic treatments.
Fos family transcription factors are believed to play an important role in the transcriptional responses of the brain to a variety of stimuli. Previous studies have described 35 and 37 kDa Fos-like proteins, termed chronic Fos-related antigens (FRAs), that are induced in brain in a region-specific manner in response to several chronic perturbations, including chronic electroconvulsive seizures, psychotropic drug treatments, and lesions. We show in this study that the chronic FRAs are isoforms of deltaFosB, a truncated splice variant of FosB that accumulate in brain after chronic treatments because of their stability. doffaFosB cDNA encodes the expression of 33, 35, and 37 kDa proteins that arise from a single AUG translation start site. The 35 and 37 kDa proteins correspond to the chronic FRAs that are induced in brain by chronic treatments, whereas the 33 kDa protein corresponds to a Fos-like protein that is induced in brain by acute treatments, findings based on migration on one- and two-dimensional Western blots with anti-FRA and anti-FosB antibodies. Using cells in which deltaFosB or FosB expression is under the control of a tetracycline-regulated gene expression system, we show that the 37 kDa deltaFosB protein exhibits a remarkably long half-life, the 35 kDa DeltaFosB protein exhibits an intermediate half-life, and the 33 kDa deltaFosB protein and all FosB-derived proteins exhibit relatively short half-lives. Moreover, we show that the 33 kDa deltaFosB protein is the first to appear after activation of deltaFosB expression. Finally, deltaFosB proteins are shown to possess DNA-binding activity and to exert potent transactivating effects in reporter gene assays. Together, these findings support a scheme wherein deltaFosB, expressed as a 33 kDa protein, is modified to form highly stable isoforms of 35 and 37 kDa. As a result, these stable isoforms gradually accumulate in the brain with repeated treatments to mediate forms of long-lasting neural and behavioral plasticity.


Association of Restless Legs Syndrome With Incident Parkinson's Disease.
The association between restless legs syndrome (RLS) and Parkinson's disease (PD) has been extensively studied with inconclusive results; therefore, we prospectively examined the associations of the presence of RLS with development of incident PD. From a nationally representative prospective cohort of almost 3.5 million US veterans (age: 60 ± 14 years, 93% male, median follow-up time of 7.8 years [interquartile range: 6.4-8.4 years]), we created a propensity-matched cohort of 100882 PD-free patients and examined the association between prevalent RLS and incident PD. This association was also assessed in the entire cohort. Associations were examined using Cox models. There were 68 incident PD events (0.13%, incidence rate 1.87 [1.48-2.37]/10000 patient-years) in the RLS-negative group, and 185 incident PD events (0.37%, incidence rate 4.72 [4.09-5.45]/10000 patient-years) in the RLS-positive group in the propensity-matched cohort. Prevalent RLS was associated with more than twofold higher risk of incident PD (hazard ratio [HR]: 2.57, 95% confidence interval [CI]: 1.95-3.39) compared to RLS-negative patients. Qualitatively similar results were found when we examined the entire 3.5 million cohort: Prevalent RLS was associated with more than twofold higher risk of incident PD (multivariable adjusted HR: 2.81, 95%CI: 2.41-3.27). RLS and PD share common risk factors. In this large cohort of US veterans, we found that prevalent RLS is associated with higher risk of incident PD during 8 years of follow-up, suggesting that RLS could be an early clinical feature of incident PD.


piRNA pathway gene expression in the malaria vector mosquito Anopheles stephensi.
The ability of transposons to mobilize to new places in a genome enables them to introgress rapidly into populations. The piRNA pathway has been characterized recently in the germ line of the fruit fly, Drosophila melanogaster, and is responsible for downregulating transposon mobility. Transposons have been used as tools in mosquitoes to genetically transform a number of species including Anopheles stephensi, a vector of human malaria. These mobile genetic elements also have been proposed as tools to drive antipathogen effector genes into wild mosquito populations to replace pathogen-susceptible insects with those engineered genetically to be resistant to or unable to transmit a pathogen. The piRNA pathway may affect the performance of such proposed genetic engineering strategies. In the present study, we identify and describe the An. stephensi orthologues of the major genes in the piRNA pathway, Ago3, Aubergine (Aub) and Piwi. Consistent with a role in protection from transposon movement, these three genes are expressed constitutively in the germ-line cells of ovaries and induced further after a blood meal.


Kaspar Hauser's recovery and autopsy: a perspective on neurological and sociological requirements for language development.
The feral children literature has frequently been cited for relevance to understanding historical antecedents of autism. Kaspar Hauser, who appeared in Nuremberg, Germany in 1828, is one of these children, raised under conditions of extreme deprivation. His case history and gradual acquisition of language after age 17 years are summarized. There is strong evidence that he was the prince of Baden, abducted from his cradle in 1812. Findings of postmortem examination, conducted after his assassination, are discussed. Hauser's postadolescent recovery of language contradicts the notion of a "critical period" for language development.


Effect of radiotherapy and chemotherapy on bone marrow activity: a 18F-FLT-PET study.
Radiotherapy (RT) and chemotherapy are important treatment modalities for a variety of malignant tumor types. During therapy for malignant diseases, often the limitation for further therapy is determined by the capability of the bone marrow to withstand radiochemotherapeutic effects. Evaluation of hematologic toxicity is commonly performed with peripheral blood counts, and occasionally, sampling of marrow through a bone marrow biopsy. Neither method provides a comprehensive assessment, as bone marrow biopsy is invasive, and both are subject to sampling variability. Fluorine-18-3'-fluoro-3'-deoxy-L-thymidine-PET (18F-FLT-PET) is a noninvasive method and related to the rate of DNA synthesis and visualizes the high cycling activity of hematopoietic cells in the bone marrow compartment. To prove the clinical consistency of marrow function and imaging, we investigated populations of patients typically seen in clinical practice, after radiation and chemotherapy. In this feasibility study, patients were evaluated (i) to prove the ability of visualization and quantification of the activity of the bone marrow compartment with 18F-FLT-PET and (ii) to examine the effect of RT and chemotherapy on bone marrow activity and the correlation with clinical findings. Bone marrow activity in the cervical region of 10 patients with laryngeal carcinoma who received a mean total dose of 68 Gy (range 30-41 fractions) was evaluated with 18F-FLT-PET, before and 1 month after RT. Whole body FLT images were assessed in nine patients with nonseminomatous testicular germ cell tumor, before and 6 months after the last chemotherapy, consisting of four courses of bleomycin, cisplatin, and etoposide. The maximum standardized uptake value (SUVmax) was used to quantify FLT uptake in bone marrow at the standard bone marrow regions. A significant decrease in 18F-FLT-PET uptake was observed in all the studied laryngeal carcinoma patients in the cervical region after RT of the adjacent bone marrow compartment. Tumor stage and additional field-of-view of RT were inversely related to the 18F-FLT uptake in bone marrow. The mean 18F-FLT SUVmax before RT was 3.0+/-1.34 and after RT was 1.94+/-0.60 (P=0.013). The mean 18F-FLT SUVmax of the spine (Th5-Th12) regions outside the field-of-view of RT were stable and reproducible and not significantly different (5.56+/-1.56 vs. 5.16+/-1.35, P=0.16). Chemotherapy did not result in a significant difference of whole body SUVmax value, with a mean SUVmax of 4.99+/-1.15 prechemotherapy, and a mean SUVmax of 5.28+/-1.0 postchemotherapy (P=0.21). Laboratory analysis of the hematologic parameters confirmed repopulation of the bone marrow. 18F-FLT uptake in the bone marrow decreases after RT, but not after chemotherapy. We conclude that 18F-FLT-PET is a potential noninvasive tool that can be used in the assessment of quantification of cellular division in the hematopoietic organ.


Plant species richness and productivity determine the diversity of soil fungal guilds in temperate coniferous forest and bog habitats.
Fungi have important roles as decomposers, mycorrhizal root symbionts and pathogens in forest ecosystems, but there is limited information about their diversity and composition at the landscape scale. This work aimed to disentangle the factors underlying fungal richness and composition along the landscape-scale moisture, organic matter and productivity gradients. Using high-throughput sequencing, we identified soil fungi from 54 low-productivity Pinus sylvestris-dominated plots across three study areas in Estonia and determined the main predictors of fungal richness based on edaphic, floristic and spatial variables. Fungal richness displayed unimodal relationship with organic matter and deduced soil moisture. Plant richness and productivity constituted the key predictors for taxonomic richness of functional guilds. Composition of fungi and the main ectomycorrhizal fungal lineages and hyphal exploration types was segregated by moisture availability and soil nitrogen. We conclude that plant productivity and diversity determine the richness and proportion of most functional groups of soil fungi in low-productive pine forests on a landscape scale. Adjacent stands of pine forest may differ greatly in the dominance of functional guilds that have marked effects on soil carbon and nitrogen cycling in these forest ecosystems.


The advantages of functional phenotyping in pre-field screening for drought-tolerant crops.
Increasing worldwide demand for food, feed and fuel presents a challenge in light of limited resources and climatic challenges. Breeding for stress tolerance and drought tolerance, in particular, is one the most challenging tasks facing breeders. The comparative screening of immense numbers of plant and gene candidates and their interactions with the environment represents a major bottleneck in this process. We suggest four key components to be considered in pre-field screens (phenotyping) for complex traits under drought conditions: (i) where, when and under which conditions to phenotype; (ii) which traits to phenotype; (iii) how to phenotype (which method); and (iv) how to translate collected data into knowledge that can be used to make practical decisions. We describe some common pitfalls, including inadequate phenotyping methods, incorrect terminology and the inappropriate use of non-relevant traits as markers for drought tolerance. We also suggest the use of more non-imaging, physiology-based, high-throughput phenotyping systems, which, used in combination with soil-plant-atmosphere continuum (SPAC) measurements and fitting models of plant responses to continuous and fluctuating environmental conditions, should be further investigated in order to serve as a phenotyping tool to better understand and characterise plant stress response. In the future, we assume that many of today's phenotyping challenges will be solved by technology and automation, leaving us with the main challenge of translating large amounts of accumulated data into meaningful knowledge and decision making tools.


The effect of micro-ECoG substrate footprint on the meningeal tissue response.
There is great interest in designing implantable neural electrode arrays that maximize function while minimizing tissue effects and damage. Although it has been shown that substrate geometry plays a key role in the tissue response to intracortically implanted, penetrating neural interfaces, there has been minimal investigation into the effect of substrate footprint on the tissue response to surface electrode arrays. This study investigates the effect of micro-electrocorticography (micro-ECoG) device geometry on the longitudinal tissue response. The meningeal tissue response to two micro-ECoG devices with differing geometries was evaluated. The first device had each electrode site and trace individually insulated, with open regions in between, while the second device had a solid substrate, in which all 16 electrode sites were embedded in a continuous insulating sheet. These devices were implanted bilaterally in rats, beneath cranial windows, through which the meningeal tissue response was monitored for one month after implantation. Electrode site impedance spectra were also monitored during the implantation period. It was observed that collagenous scar tissue formed around both types of devices. However, the distribution of the tissue growth was different between the two array designs. The mesh devices experienced thick tissue growth between the device and the cranial window, and minimal tissue growth between the device and the brain, while the solid device showed the opposite effect, with thick tissue forming between the brain and the electrode sites. These data suggest that an open architecture device would be more ideal for neural recording applications, in which a low impedance path from the brain to the electrode sites is critical for maximum recording quality.


Moderately differentiated esophageal squamous cell carcinoma has a poor prognosis after neoadjuvant chemoradiotherapy.
Neoadjuvant chemoradiotherapy (NCRT) plus surgery is the standard treatment for esophageal squamous cell carcinoma (ESCC); however, further analysis is needed to detail the histopathological characteristics of ESCC and their clinical significance after NCRT. This study aimed to present the pathological characteristics of ESCC and their association with prognosis after NCRT. All patients with ESCC who underwent NCRT followed by surgical resection at Sichuan Cancer Hospital (China) from January 2018 to December 2019 were included. Resection specimens of both the primary disease and lymph nodes were re-evaluated by an experienced pathologist. After NCRT, the pathological characteristics of the residual tumor were evaluated based on the Japanese residual tumor pattern, Mandard tumor regression grade (Mandard-TRG), local inflammatory infiltration classification, and lymph node status. Among the 103 patients with ESCC included in this study, the pathological complete response (pCR) rate was 34% (35/103). The pCR rate of patients with poorly differentiated tumors (31/72) was higher (43.1%) than that of patients with well or moderately differentiated tumors (P<0.05). The residual tumor rate was 66% (68/103). A positive correlation was noted between the Japanese residual tumor pattern and Mandard-TRG (Kendall's tau-b =0.857, P<0.001). Tumor infiltration depth, lymph node positivity, moderate differentiation, and tumor recurrence were associated with poor oncological outcomes (P<0.05). Patients with poorly differentiated tumors can obtain an excellent short-term response; however, they have extremely poor long-term survival. For patients with moderately differentiated tumors, both the short- and long-term outcomes are poor. Lymph node status after NCRT is a prognostic factor for ESCC treated with NCRT.


Hip arthroscopy in the United States: an update following coding changes in 2011.
The purpose of this study is to define the incidence of hip arthroscopy-related procedures in the United States prior to and following 2011 and to determine if the rise in incidence has coincided with an increase in the complexity and diversity of procedures performed. Patients who underwent hip arthroscopy were identified from a publicly available US database. A distinction was made between 'traditional' and 'extended' codes. CPT-29999 (unlisted arthroscopy) was considered extended and counted only if associated with a hip pathology diagnosis. Codes directed toward femoroacetabular impingement pathology were also considered extended codes and were analyzed separately based on increased technical skill. Unpaired student t-tests and z-score tests were performed. From 2007 to 2014, there were a total of 2581 hip arthroscopies performed in the database (1.06 cases per 10 000 patients). The number of hip arthroscopies increased 117% from 2007 to 2014 (P < 0.001) and 12.5% from 2011 to 2014 (P = 0.045). Hip arthroscopies using extended codes increased 475% from 2007 to 2014 (P < 0.001) compared to 24% for traditional codes (P < 0.001). Codes addressing femoroacetabular impingement (FAI) pathology increased 55.7% between 2011 to 2014 (P < 0.001). The ratio of labral repair to labral debridement in patients younger than 50 years exceeded >1.0 starting in 2011 (P < 0.001). The total number of hip arthroscopies in addition to the complexity and diversity of hip arthroscopy procedures performed in the United States continues to rise. FAI-based procedures and labral repairs are being performed more frequently in younger patients, likely reflecting both improved technical ability and current evidence-based research.


Moral disengagement and callous-unemotional traits: A longitudinal study of Italian adolescents with a disruptive behaviour disorder.
Callous-unemotional traits have been proposed as risk factors for a poorer prognosis in young people with disruptive behaviour disorders. Identification of factors that may cause or maintain elevated levels of such traits could help in developing targeted therapeutic interventions. Some previous studies have investigated the role of moral cognitive mechanisms, such as moral disengagement, but these previous studies focused primarily on normal or 'at-risk' samples. We aimed to evaluate associations and possible interactions between moral disengagement as a cognitive dimension and callous-unemotional traits as an affective dimension in adolescents with disruptive behaviour disorders. We recruited 55 adolescents with a disruptive behaviour disorder from a community care hospital in Pisa. They were evaluated at baseline and after one year with measures that included a moral disengagement scale, the Antisocial Process Screening Device, to assess callous traits, and the Youth Self-Report, to explore externalising behaviour problems. Structural equation modelling showed that higher initial moral disengagement scores were associated with later higher levels of callous-unemotional traits in adolescents and vice versa, even after, respectively, controlling for previous levels of callous traits and moral disengagement. As impairments in either cognitive or affective traits may predispose to problematic development of the other, our findings would suggest that screening at the earliest opportunity possible for both moral disengagement and callous-unemotional traits among children with disruptive behaviour disorders could help to map natural outcome pathways and thus tailor more accurate interventions for prevention of antisocial or criminal behaviour. Copyright © 2016 John Wiley & Sons, Ltd.


Optimization of monoclonal antibody delivery via the lymphatics: the dose dependence.
After interstitial injection in mice, antibody molecules enter local lymphatic vessels, flow with the lymph to regional lymph nodes, and bind to target antigens there. Compared with i.v. administration, delivery via the lymphatics provides a more efficient means for localizing antibody in lymph nodes. An IgG2a (36-7-5) directed against the murine class I major histocompatibility antigen H-2Kk has proved useful for studying the pharmacology of lymphatic delivery. The antibody specifically binds to most cells in Kk-positive strains of mice and to none in Kk-negative mice. At very low doses, most of the antibody remains at the injection site in Kk-positive animals. As the dose is progressively increased, most effective labeling occurs first in nodes proximal to the injection site and then in the next group of nodes along the lymphatic chain. At higher doses, antibody overflows the lymphatic system and enters the blood-stream via the thoracic duct and other lymphatic-venous connections. Once in the blood, antibody is rapidly cleared, apparently by binding to Kk-bearing cells. These findings indicate that the single-pass distribution of monoclonal antibodies in the lymphatics can be strongly dose dependent, a principle which may be of clinical significance in the improvement of immunolymphoscintigraphic imaging, especially with antibodies directed against normal and malignant lymphoid cells. Monoclonal antibodies directed against normal cell types in the lymph node may be useful for assessing the integrity of lymphatic chains by immunolymphoscintigraphy or, more speculatively, for altering the status of regional immune function. The results presented here indicate that a low or intermediate antibody dose may optimize the signal:noise ratio for imaging. In Kk-negative animals, the percentage of dose taken up in the major organs was essentially independent of the dose administered; there was no evidence for saturable sites of nonspecific binding. These findings provide background for attempts to use antitumor antibodies via the lymphatic route. Specific binding to target cells (and any cross-reaction with normal tissues) would presumably be superimposed on the nonspecific pharmacology of the antibody in vivo.


Severity of lung involvement on chest X-rays in SARS-coronavirus-2 infected patients as a possible tool to predict clinical progression: an observational retrospective analysis of the relationship between radiological, clinical, and laboratory data.
To investigate the diagnostic accuracy of a chest X-ray (CXR) score and of clinical and laboratory data in predicting the clinical course of patients with SARS coronavirus 2 (SARS-CoV-2) infection. This is a pilot multicenter retrospective study including patients with SARS-CoV-2 infection admitted to the ERs in three hospitals in Italy between February and March of 2020. Two radiologists independently evaluated the baseline CXR of the patients using a semi-quantitative score to determine the severity of lung involvement: a score of 0 represented no lung involvement, whereas scores of 1 to 4 represented the first (less severe) to the fourth (more severe) quartiles regarding the severity of lung involvement. Relevant clinical and laboratory data were collected. The outcome of patients was defined as severe if noninvasive ventilation (NIV) or intubation was necessary, or if the patient died. Our sample comprised 140 patients. Most of the patients were symptomatic (132/138; 95.7%), and 133/140 patients (95.0%) presented with opacities on CXR at admission. Of the 140 patients, 7 (5.0%) showed no lung involvement, whereas 58 (41.4%), 31 (22.1%), 26 (18.6%), and 18 (12.9%), respectively, scored 1, 2, 3, and 4. In our sample, 66 patients underwent NIV or intubation, 37 of whom scored 1 or 2 on baseline CXR, and 28 patients died. The severity score based on CXR seems to be able to predict the clinical progression in cases that scored 0, 3, or 4. However, the score alone cannot predict the clinical progression in patients with mild-to-moderate parenchymal involvement (scores 1 and 2).


Basic perceptual changes that alter meaning and neural correlates of recognition memory.
It is difficult to pinpoint the border between perceptual and conceptual processing, despite their treatment as distinct entities in many studies of recognition memory. For instance, alteration of simple perceptual characteristics of a stimulus can radically change meaning, such as the color of bread changing from white to green. We sought to better understand the role of perceptual and conceptual processing in memory by identifying the effects of changing a basic perceptual feature (color) on behavioral and neural correlates of memory in circumstances when this change would be expected to either change the meaning of a stimulus or to have no effect on meaning (i.e., to influence conceptual processing or not). Abstract visual shapes ("squiggles") were colorized during study and presented during test in either the same color or a different color. Those squiggles that subjects found to resemble meaningful objects supported behavioral measures of conceptual priming, whereas meaningless squiggles did not. Further, changing color from study to test had a selective effect on behavioral correlates of priming for meaningful squiggles, indicating that color change altered conceptual processing. During a recognition memory test, color change altered event-related brain potential (ERP) correlates of memory for meaningful squiggles but not for meaningless squiggles. Specifically, color change reduced the amplitude of frontally distributed N400 potentials (FN400), implying that these potentials indicated conceptual processing during recognition memory that was sensitive to color change. In contrast, color change had no effect on FN400 correlates of recognition for meaningless squiggles, which were overall smaller in amplitude than for meaningful squiggles (further indicating that these potentials signal conceptual processing during recognition). Thus, merely changing the color of abstract visual shapes can alter their meaning, changing behavioral and neural correlates of memory. These findings are relevant to understanding similarities and distinctions between perceptual and conceptual processing as well as the functional interpretation of neural correlates of recognition memory.


Effects of increased opportunity for physical exercise and learning experiences on recognition memory and brain-derived neurotrophic factor levels in brain and serum of rats.
Studies with animal models showed that cellular, structural, and behavioral changes induced by environmental enrichment are related to increased levels of brain-derived neurotrophic factor (BDNF) in the brain. These evidence suggest that BDNF could be an interesting biomarker of the effects of lifestyle on cognition and other behavioral parameters in humans, mainly if the BDNF alterations in brain are accompanied by correspondent peripheral modifications, since human studies depend basically on the evaluation of this neurotrophin in serum or plasma. To test this hypothesis, we analyzed the effects of environmental enrichment on long-term memory for object recognition and on BDNF levels of hippocampus, frontal cortex, and serum of rats exposed to an experimental protocol that could be more easily translated to human intervention studies. Animals were maintained for 10 weeks in a social (standard laboratory conditions) or enriched (increased opportunity for physical exercise and learning experiences) condition. In the 7th week, they were submitted to behavioral testing (open field and novel object memory task), and at the end of the 10th week, they were killed and BDNF levels were analyzed. Animals maintained in the enriched condition showed enhanced performance on the memory task in the absence of any significant alteration in central or peripheral BDNF levels. The results of this study are important to highlight the need to develop experimental protocols using animal models that more closely resemble the characteristics of studies with humans and motivate more investigations to determine the conditions under which BDNF could be a biomarker of the effects of environment enrichment.


Physical and functional interactions among RNase E, polynucleotide phosphorylase and the cold-shock protein, CsdA: evidence for a 'cold shock degradosome'.
Escherichia coli contains at least five ATP-dependent DEAD-box RNA helicases which may play important roles in macromolecular metabolism, especially in translation and mRNA decay. Here we demonstrate that one member of this family, CsdA, whose expression is induced by cold shock, interacts physically and functionally with RNase E. Three independent approaches show that after a shift of cultures to 15 degrees C, CsdA co-purifies with RNase E and other components of the RNA degradosome. Moreover, functional assays using reconstituted minimal degradosomes prepared from purified components in vitro show that CsdA can fully replace the resident RNA helicase of the RNA degradosome, RhlB. In addition, under these conditions, CsdA displays RNA-dependent ATPase activity. Taken together, our data are consistent with a model in which CsdA accumulates during the early stages of cold acclimatization and subsequently assembles into degradosomes with RNase E synthesized in cold-adapted cultures. These findings show that the RNA degradosome is a flexible macromolecular machine capable of adapting to altered environmental conditions.


Formononetin attenuates hydrogen peroxide (H2O2)-induced apoptosis and NF-κB activation in RGC-5 cells.
Diabetic retinopathy is a common diabetic eye disease caused by changes in retinal ganglion cells (RGCs). Several studies suggest that the oxidative stress plays a role in the pathogenesis of diabetic retinopathy in adults. Formononetin is a flavone with powerful antioxidant properties that exists naturally in various plants and Chinese medicine. In the present study, an attempt has been made to investigate the antioxidative effects of formononetin on H2O2-induced apoptosis of RGC-5 cells. Exposure of retinal ganglion cells (RGCs) to the indicated concentrations of formononetin and H2O2 for 24 h, analyzed by MTT assay. Cells were stained with Annexin V-FITC and PI, analyzed by flow cytometry. And the level of superoxide anions, malondialdehyde (MDA, a marker of lipid peroxidation), 8-hydroxy-2-deoxyguanosine (8-OHdG, indicator of oxidative DNA damage) and MnSOD (manganese superoxide dismutase) activity were measured by kits. Formononetin reduced hydrogen peroxide (H2O2)-induced apoptosis and improved the levels or activity of indicators of oxidative stress. Formononetin also inhibited the activation of nuclear factor-kappaB (NF-κB), which is a significant transcription factor for RGC-5 apoptosis. Formononetin may be developed as a antioxidant drug to treat diabetic retinopathy.


Diagnosing Sarcopenia in Male Patients With Cirrhosis by Dual-Energy X-Ray Absorptiometry Estimates of Appendicular Skeletal Muscle Mass.
Ascites in cirrhotic patients interfere with accurate assessment of skeletal muscle when diagnosing sarcopenia. We hypothesized measurement of appendicular skeletal muscle index (ASMI) with dual-energy x-ray absorptiometry (DXA) improves the diagnosis of sarcopenia in cirrhotic patients as ASMI does not include the fluid-filled abdominal compartment. To evaluate if ASMI is influenced by ascites, lower limb edema (LLE) and predicts mortality alone or combined with handgrip strength (HGS) in cirrhotic patients. ASMI, HGS, and 36-month mortality were obtained in 144 men with cirrhosis. ASMI was compared before and after paracentesis in 20 men with ascites and to results from 20 matched controls. The prognostic value of ASMI alone and with HGS was tested in a survival. Survival probabilities were obtained for sarcopenia diagnosed by standard ASMI and HGS European Working Group on Sarcopenia in Older People (EWGSOP) cutoffs and a new cutoff calculated from our ASMI + HGS tertiles. ASMI did not change after paracentesis, was lower in patients than in controls (P < .001), and was not influenced by LLE (D = 0.30 kg/m2, P = .068; R2 = 2.40%). Mortality was influenced by ASMI and HGS (Pinteraction = 0.028). Sarcopenia diagnosed by EWGSOP was also diagnosed by our new cutoff; both predicted mortality with the latter more sensitive for mortality risk prediction (P = .011). DXA-measured ASMI is not influenced by ascites or LLE in cirrhotic patients; can diagnose low skeletal muscle/sarcopenia; and predicts mortality, particularly when combined with HGS.


Effect of gender on computerized electrocardiogram measurements in college athletes.
Broad criteria for classifying an electrocardiogram (ECG) as abnormal and requiring additional testing prior to participating in competitive athletics have been recommended for the preparticipation examination (PPE) of athletes. Because these criteria have not considered gender differences, we examined the effect of gender on the computerized ECG measurements obtained on Stanford student athletes. Currently available computer programs require a basis for "normal" in athletes of both genders to provide reliable interpretation. During the 2007 PPE, computerized ECGs were recorded and analyzed on 658 athletes (54% male; mean age, 19 +/- 1 years) representing 22 sports. Electrocardiogram measurements included intervals and durations in all 12 leads to calculate 12-lead voltage sums, QRS amplitude and QRS area, spatial vector length (SVL), and the sum of the R wave in V5 and S wave in V2 (RSsum). By computer analysis, male athletes had significantly greater QRS duration, PR interval, Q-wave duration, J-point amplitude, and T-wave amplitude, and shorter QTc interval compared with female athletes (all P < 0.05). All ECG indicators of left ventricular electrical activity were significantly greater in males. Although gender was consistently associated with indices of atrial and ventricular electrical activity in multivariable analysis, ECG measurements correlated poorly with body dimensions. Significant gender differences exist in ECG measurements of college athletes that are not explained by differences in body size. Our tables of "normal" computerized gender-specific measurements can facilitate the development of automated ECG interpretation for screening young athletes.


Acetate stimulates flux through the tricarboxylic acid cycle in rabbit renal proximal tubules synthesizing glutamine from alanine: a 13C NMR study.
Although glutamine synthesis has a major role in the control of acid-base balance and ammonia detoxification in the kidney of herbivorous species, very little is known about the regulation of this process. We therefore studied the influence of acetate, which is readily metabolized by the kidney and whose metabolism is accompanied by the production of bicarbonate, on glutamine synthesis from variously labelled [(13)C]alanine and [(14)C]alanine molecules in isolated rabbit renal proximal tubules. With alanine as sole exogenous substrate, glutamine and, to a smaller extent, glutamate and CO(2), were the only significant products of the metabolism of this amino acid, which was removed at high rates. Absolute fluxes through the enzymes involved in alanine conversion into glutamine were assessed by using a novel model describing the corresponding reactions in conjunction with the (13)C NMR, and to a smaller extent, the radioactive and enzymic data. The presence of acetate (5 mM) led to a large stimulation of fluxes through citrate synthase and alpha-oxoglutarate dehydrogenase. These effects were accompanied by increases in the removal of alanine, in the accumulation of glutamate and in flux through the anaplerotic enzyme pyruvate carboxylase. Acetate did not alter fluxes through glutamate dehydrogenase and glutamine synthetase; as a result, acetate did not change the accumulation of ammonia, which was negligible under both experimental conditions. We conclude that acetate, which seems to be an important energy-provider to the rabbit renal proximal tubule, simultaneously traps as glutamate the extra nitrogen removed as alanine, thus preventing the release of additional ammonia by the glutamate dehydrogenase reaction.


Prevalence of overweight and associated factors in under-five-year-old children in urban population in Brazil.
To estimate the prevalence of overweight in children under five years old from urban households and to investigate associated factors. Cross-sectional population-based study carried out in the five regions of Brazil with a sample of 6,397 children. The World Health Organization 2006 Growth Curves were used and children were considered overweight when Z-score was higher than two standard deviations of weight for height. The following variables were investigated: family income, mothers' education level, race, age, gender, number of siblings, weight at birth and duration of exclusive breastfeeding. Proportions were compared with the χ2 test and reasons of prevalence were calculated. Logistic regression was used for the adjusted analysis. The prevalence of overweight was of 12%. After adjustments, this prevalence was significantly higher among males (p = 0.030) and inversely proportional to the child's age (p = 0.032). White children presented 22% higher overweight prevalence than non-white ones. A linear direct association was verified between weight at birth and overweight (p = 0.000). Children who were breastfed until 120 days presented 34% more prevalence of overweight when compared to the ones who were breastfed for a longer time. Overweight prevalence was higher in male, under one year old, white children, with more than 3,500 grams of weight at birth and who were exclusively breastfed until 120 days.


Pancreatic cancer: unreliability of frozen section in diagnosis.
Thirty-two patients with a resectable mass in the head of the pancreas had pancreaticoduodenectomy for suspected or proven cancer. Twenty-eight proved to have cancer (15 periampullary and 13 pancreatic), and four had pancreatitis. The five-year survival for periampullary and pancreatic cancer was 25% and 0%, respectively. The operative mortality was 19%. There were no false-positive frozen section diagnoses. Seventy-five percent with negative frozen section proved to have cancer, of which 17% were five-year survivors. Surgical judgment based on clinical findings may be more reliable than a negative frozen section in the diagnosis of suspected malignancy. Pancreaticoduodenectomy can be done on the basis of clinical judgment when no tumor is seen on frozen section of a mass in the head of the pancreas.


Time transfer using multi-channel GPS receivers.
This report is on time transfer experiments using a Global Positioning System (GPS) receiver constructed using a commercial GPS "engine" and a standard PC. The receiver measures the time difference between the local clock and a 1 pps signal synchronized to GPS time using data from up to 8 satellites. The receiver also reports the difference between GPS time as estimated using each of the satellites being tracked and the composite output pulses that have a rate of 1 Hz (1 pps signal). These data can be used to construct the standard 13-minute tracks as defined in the BIPM standard; the same data also can be averaged in other ways that make better use of the multi-channel capabilities of the hardware. The 13-minute averages can be directly compared with standard time-transfer receivers using common-view analysis. The results of the tests suggest that the methods currently used for national and international time and frequency coordination should be re-examined, and an alternative approach based on multi-channel receivers is suggested that should be more flexible, simpler, and easier to operate than the current system.


Reassembly of Excitable Domains after CNS Axon Regeneration.
Action potential initiation and propagation in myelinated axons require ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Disruption of these domains after injury impairs nervous system function. Traditionally, injured CNS axons are considered refractory to regeneration, but some recent approaches challenge this view by showing robust long-distance regeneration. However, whether these approaches allow remyelination and promote the reestablishment of AIS and nodes of Ranvier is unknown. Using mouse optic nerve crush as a model for CNS traumatic injury, we performed a detailed analysis of AIS and node disruption after nerve crush. We found significant disruption of AIS and loss of nodes within days of the crush, and complete loss of nodes 1 week after injury. Genetic deletion of the tumor suppressor phosphatase and tensin homolog (Pten) in retinal ganglion cells (RGCs), coupled with stimulation of RGCs by inflammation and cAMP, dramatically enhanced regeneration. With this treatment, we found significant reestablishment of RGC AIS, remyelination, and even reassembly of nodes in regions proximal, within, and distal to the crush site. Remyelination began near the retina, progressed distally, and was confirmed by electron microscopy. Although axons grew rapidly, remyelination and nodal ion channel clustering was much slower. Finally, genetic deletion of ankyrinG from RGCs to block AIS reassembly did not affect axon regeneration, indicating that preservation of neuronal polarity is not required for axon regeneration. Together, our results demonstrate, for the first time, that regenerating CNS axons can be remyelinated and reassemble new AIS and nodes of Ranvier. We show, for the first time, that regenerated CNS axons have the capacity to both remyelinate and reassemble the axon initial segments and nodes of Ranvier necessary for rapid and efficient action potential propagation.


HFE genotype affects exosome phenotype in cancer.
Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment. Exosomes have been demonstrated to contribute to the oncogenic effect on the surrounding tumor environment and also mediate resistance to therapy. The effect of genotype on exosomal phenotype has not yet been explored. We interrogated exosomes from human neuroblastoma cells that express wild-type or mutant forms of the HFE gene. HFE, one of the most common autosomal recessive polymorphisms in the Caucasian population, originally associated with hemochromatosis, has also been associated with increased tumor burden, therapeutic resistance boost, and negative impact on patient survival. Herein, we demonstrate that changes in genotype cause major differences in the molecular and functional properties of exosomes; specifically, HFE mutant derived exosomes have increased expression of proteins relating to invasion, angiogenesis, and cancer therapeutic resistance. HFE mutant derived exosomes were also shown to transfer this cargo to recipient cells and cause an increased oncogenic functionality in those recipient cells.


Skeletal muscle satellite cell proliferation in response to members of the fibroblast growth factor family and hepatocyte growth factor.
Fibroblast growth factors (FGF) have the ability to regulate satellite cell proliferation in culture and in muscle tissue, but the specific FGF receptors (FGFR) expressed by adult rat muscle satellite cells and the action of members of the FGF family have not been assessed. Therefore, the expression of FGF receptors 1-4 was examined in proliferating satellite cells in culture, and the effects of eight members of the fibroblast growth factor family (FGFs1, 2, 4, 5, 6, 7, 8, and 9) on adult rat muscle satellite cells were evaluated. In addition, the interactions of FGFs with hepatocyte growth factor (HGF) were described. Of the eight FGFs evaluated, 1, 2, 4, 6, and 9 significantly (P < 0.05) stimulated proliferation above control. FGFs5, 7, and 8 displayed no mitogenic activity. Furthermore, combinations of HGF with FGFs2, 4, 6, or 9 stimulated satellite cell proliferation above that of optimal concentrations of HGF alone. Expression of four FGFR genes was detected in satellite cell cultures by reverse-transcription-polymerase chain reaction (RT-PCR). FGFR1 and FGFR4 were the most prominent forms expressed, and FGFR2 was only expressed at low levels. FGFR3 was difficult to detect. FGFR1 and FGFR2 were also expressed in muscle-derived fibroblasts, but FGFR4 and FGFR3 were not. In proliferating cultures of satellite cells, HGF, insulin-like growth factor I (IGF-I) and FGF1 stimulated significantly (P < 0.05) higher levels of FGFR1 message content, relative to control conditions, and platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor (IGF-II) significantly (P < 0.05) depressed FGFR1 expression. During the activation period of satellite cell growth in culture (0-48 h), FGFR1 message content significantly (P < 0.05) increased from less than 1,000 copies per cell to approximately 5,000 copies per cell between 18 and 48 h, and HGF treatment significantly (P < 0.05) accelerated the accumulation of FGFR1 message during this period.


Hedgehog signaling in cancer stem cells: a focus on hematological cancers.
The stem cell paradigm was first demonstrated in hematopoietic stem cells. Whilst classically it was cytokines and chemokines which were believed to control stem cell fate, more recently it has become apparent that the stem cell niche and highly conserved embryonic pathways play a key role in governing stem cell behavior. One of these pathways, the hedgehog signaling pathway, found in all organisms, is vitally important in embryogenesis, performing the function of patterning through early stages of development, and in adulthood, through the control of somatic stem cell numbers. In addition to these roles in health however, it has been found to be deregulated in a number of solid and hematological malignancies, components of the hedgehog pathway being associated with a poor prognosis. Further, these components represent viable therapeutic targets, with inhibition from a drug development perspective being readily achieved, making the hedgehog pathway an attractive potential therapeutic target. However, although the concept of cancer stem cells is well established, how these cells arise and the factors which influence their behavior are not yet fully understood. The role of the hedgehog signaling pathway and its potential as a therapeutic target in hematological malignancies is the focus of this review.


Cancer during pregnancy: A qualitative study of healthcare experiences of Australian women.
To identify features enhancing the quality of healthcare experiences for women with gestational cancer, and explore the impact of the heterogeneous Australian healthcare system on those experiences. Semi-structured, qualitative interviews were conducted with women diagnosed with any cancer during pregnancy in the last five years. Recruitment occurred during 2018-2019 via social media and professional, clinical and community networks. Questions related to women's experiences of their healthcare, wellbeing and psychosocial needs. Interviews were analysed thematically. Study participants (n = 23) received treatment in the private sector (n = 10), public sector (n = 8), or both (n = 5). Five interview themes were found: Control over healthcare; Trust in clinicians, hospitals and systems; Coordination of care; An uncommon diagnosis; Holistic, future-oriented care. Women were most likely to have had a positive healthcare experience when (a)care was well-coordinated and adjusted to meet their unique needs/challenges, and (b)women perceived their care went beyond their immediate medical needs and encompassed future psychosocial wellbeing, including preparation for postpartum challenges. Existing 'usual care' in the public and/or private sector for both the pregnancy and the cancer is insufficient to meet these women's needs. Prioritising psychological wellbeing including psychosocial needs, and communication and planning around fertility and postnatal challenges are essential for this population.


A fair comparison between ultrathin crystalline-silicon solar cells with either periodic or correlated disorder inverted pyramid textures.
Fabrication of competitive solar cells based on nano-textured ultrathin silicon technology is challenging nowadays. Attention is paid to the optimization of this type of texture, with a lot of simulation and experimental results published in the last few years. While previous studies discussed mainly the local features of the surface texture, we highlight here the importance of their filling fraction. In this work, we focus on a fair comparison between a technologically realizable correlated disorder pattern of inverted nano-pyramids on an ultrathin crystalline-silicon layer, and its periodically patterned counterpart. A fair comparison is made possible by defining an equivalent periodic structure for each hole filling fraction. Moreover, in order to be as realistic as possible, we consider patterns that could be fabricated by standard patterning techniques: hole-mask colloidal lithography, nanoimprint lithography and wet chemical etching. Based on numerical simulations, we show that inverted nano-pyramid patterns with correlated disorder provide typically greater efficiency than their periodic counterparts. However, the hole filling fraction of the etched pattern plays a crucial role and may limit the benefits of the correlated disorder due to experimental restrictions on pattern fabrication.


Emotion-induced impairments in speeded word recognition tasks.
Recent studies show that emotional stimuli impair the identification of subsequently presented, briefly flashed stimuli. In the present study, we investigated whether emotional distractors (primes) impaired target processing when presentation of the target stimulus was not impoverished. In lexical decision, animacy decision, rhyme decision, and nonword naming, targets were presented in such a manner that they were clearly visible (i.e., targets were not masked and presented until participants responded). In all tasks taboo-sexual distractors caused a slowdown in responding to the subsequent neutral target. Our results indicate that the detrimental effects of emotional distractors are not confined to paradigms in which visibility of the target is limited. Moreover, impairments were obtained even when semantic processing of stimuli was not required.


The use of standardized uptake values for assessing FDG uptake with PET in oncology: a clinical perspective.
Among clinicians who use positron emission tomography (PET), the standardized uptake value (SUV) is a popular semi-quantitative value that can be easily assessed whenever a PET study is performed under physiological and pathological conditions. It provides an index of regional tracer uptake normalized to the administered dose of tracer. The simplicity of SUV assessment contrasts with the complexity of full quantitative procedures requiring blood sampling and possibly dynamic scanning, which limits patient throughput and significantly increases the workload of a PET centre. Two main clinical conditions/variables affect the significance and usefulness of the SUV: the type and stage of the disease being assessed. Diagnosis, prognosis and therapy monitoring represent the possible uses of SUV. In the above clinical conditions an SUV may provide information about the single lesion in which it is assessed, but the utility of such information depends largely on its integration with all the available clinical and instrumental data.


Cellular Responses to Widespread DNA Replication Stress.
Replicative DNA polymerases are blocked by nearly all types of DNA damage. The resulting DNA replication stress threatens genome stability. DNA replication stress is also caused by depletion of nucleotide pools, DNA polymerase inhibitors, and DNA sequences or structures that are difficult to replicate. Replication stress triggers complex cellular responses that include cell cycle arrest, replication fork collapse to one-ended DNA double-strand breaks, induction of DNA repair, and programmed cell death after excessive damage. Replication stress caused by specific structures (e.g., G-rich sequences that form G-quadruplexes) is localized but occurs during the S phase of every cell division. This review focuses on cellular responses to widespread stress such as that caused by random DNA damage, DNA polymerase inhibition/nucleotide pool depletion, and R-loops. Another form of global replication stress is seen in cancer cells and is termed oncogenic stress, reflecting dysregulated replication origin firing and/or replication fork progression. Replication stress responses are often dysregulated in cancer cells, and this too contributes to ongoing genome instability that can drive cancer progression. Nucleases play critical roles in replication stress responses, including MUS81, EEPD1, Metnase, CtIP, MRE11, EXO1, DNA2-BLM, SLX1-SLX4, XPF-ERCC1-SLX4, Artemis, XPG, FEN1, and TATDN2. Several of these nucleases cleave branched DNA structures at stressed replication forks to promote repair and restart of these forks. We recently defined roles for EEPD1 in restarting stressed replication forks after oxidative DNA damage, and for TATDN2 in mitigating replication stress caused by R-loop accumulation in BRCA1-defective cells. We also discuss how insights into biological responses to genome-wide replication stress can inform novel cancer treatment strategies that exploit synthetic lethal relationships among replication stress response factors.


Is there an intraspecific role for density-dependent colour change in the desert locust?
Attempts to uncover the adaptive significance of density-dependent colour polyphenism in the desert locust, Schistocerca gregaria (Orthoptera: Acrididae), have been unsuccessful. Desert locust juveniles can change colour as part of a phenotypically plastic response to changes in local population density known as phase polyphenism. They are typically cryptic in colour at low rearing density (solitarious phase), but become conspicuous at high density (gregarious phase). Recent evidence indicates that this colour change functions interspecifically as an aposematic signal. Other recent evidence, however, suggests that previous attempts to demonstrate an intraspecific function of gregarious coloration in mediating group interactions among locusts may have been confounded by the effects of multiple sensory cues. We reinvestigated the intraspecific function of density-dependent colour polyphenism and specifically controlled for potentially confounding olfactory and tactile cues. We found no effect of gregarious phase (yellow and black) coloration as either a gregarizing stimulus to behaviourally solitarious locusts or as a visual aggregation stimulus behaviourally to gregarious locusts. We did, however, find that nonmoving solitarious phase (green) coloration significantly increased the activity levels of behaviourally gregarious locusts. We cannot explain this result and its biological relevance remains unknown. In the absence of support for the intraspecific visual cue hypothesis, we favour an aposematic perspective on the function of density-dependent colour polyphenism in the desert locust. The aposematic perspective parsimoniously accounts for density-dependent changes in both colour and behaviour. Copyright 2000 The Association for the Study of Animal Behaviour.


Combined Pharmacological and Endoscopic Treatment for Worsening Gastroesophageal Varices in Patients with Cirrhosis.
At the present time, in patients with liver cirrhosis and gastroesophageal varices, primary prophylaxis of variceal bleeding made with combination therapy with non-selective β-blockers (NSBBs) and endoscopic band ligation (EBL) is not recommended. The aim of this study was to evaluate if patients with worsening varices while on NSBBs regimen benefit, in terms of bleeding and survival, from adding treatment with EBL. Patients with cirrhosis and endoscopic finding of gastroesophageal varices with high risk feature (increased variceal size and/or development of red signs) during primary prophylaxis with NSBBs, followed at the Unit of Internal Medicine and Hepatology, University and General Hospital of Padova, Italy, from 2012 to 2019, were retrospectively evaluated. When an increased bleeding risk of the varices was confirmed, patients maintained the pharmacological therapy alone or underwent also EBL. The primary endpoint of the study was the rate of variceal bleeding, the secondary endpoint was mortality at 30 months. Compared to patients treated only with NSBBs (n=56), in patients treated also with EBL (n=45), the 30-month probability of variceal bleeding (29.1% vs 5.1%; P =0.036) was significantly reduced, while the probability of survival was similar (59.6% vs 65.7%; P=0.61). On multivariate analysis, treatment with EBL was found to be a weak protective factor for mortality (HR 0.47, P=0.044). In patients with liver cirrhosis, when varices show endoscopic feature of increased haemorrhagic risk, adding EBL to NSBBs is effective in reducing the probability of first bleeding.


NeuCode labels for relative protein quantification.
We describe a synthesis strategy for the preparation of lysine isotopologues that differ in mass by as little as 6 mDa. We demonstrate that incorporation of these molecules into the proteomes of actively growing cells does not affect cellular proliferation, and we discuss how to use the embedded mass signatures (neutron encoding (NeuCode)) for multiplexed proteome quantification by means of high-resolution mass spectrometry. NeuCode SILAC amalgamates the quantitative accuracy of SILAC with the multiplexing of isobaric tags and, in doing so, offers up new opportunities for biological investigation. We applied NeuCode SILAC to examine the relationship between transcript and protein levels in yeast cells responding to environmental stress. Finally, we monitored the time-resolved responses of five signaling mutants in a single 18-plex experiment.


Development of a Simulation-Based Interprofessional Teamwork Assessment Tool.
The Accreditation Council for Graduate Medical Education (ACGME) Milestone projects required each specialty to identify essential skills and develop means of assessment with supporting validity evidence for trainees. Several specialties rate trainees on a milestone subcompetency related to working in interprofessional teams. A tool to assess trainee competence in any role on an interprofessional team in a variety of scenarios would be valuable and suitable for simulation-based assessment. We developed a tool for simulation settings that assesses interprofessional teamwork in trainees. In 2015, existing tools that assess teamwork or interprofessionalism using direct observation were systematically reviewed for appropriateness, generalizability, adaptability, ease of use, and resources required. Items from these tools were included in a Delphi method with multidisciplinary pediatrics experts using an iterative process from June 2016 to January 2017 to develop an assessment tool. Thirty-one unique tools were identified. A 2-stage review narrowed this list to 5 tools, and 81 items were extracted. Twenty-two pediatrics experts participated in 4 rounds of Delphi surveys, with response rates ranging from 82% to 100%. Sixteen items reached consensus for inclusion in the final tool. A global 4-point rating scale from novice to proficient was developed. A novel tool to assess interprofessional teamwork for individual trainees in a simulated setting was developed using a systematic review and Delphi methodology. This is the first step to establish the validity evidence necessary to use this tool for competency-based assessment.


Xenotransplantation of human cryopreserved parathyroid tissue isolated from parathyroid adenomas to normocalcemic rabbits.
Parathyroid allotransplantation is a new method for the treatment of permanent hypoparathyrodism. Adenoma cells are not used for transplantation because of the potential for functional or histopathologic transformation. In this study, we transplanted human adenomatous parathyroid cells to rabbits. Parathyroid adenoma tissue taken from a male patient was cryopreserved and transplanted into seven New Zealand white rabbits (mean weight, 3700±220 g; mean age, 4.5 months) under immunosuppression. The levels of parathormone, calcium and phosphorus were measured before and after transplantation, and the parathyroid cells were observed histopathologically. Mean parathyroid hormone level was 0.5 pg/dL before transplantation and 6.6 pg/dL after transplantation (p<0.05). Preoperative mean calciumlevel was 14.1 mg/dL, and mean phosporus level was 3.5 mg/dL before transplantation while these values were 14.4 mg/dL and 3.3 mg/dL, respectively, after transplantation (p>0.05). Morphologic transformation was not observed in parathyroid cells after transplantation. In short-term observation, adenomatous parathyroid cells can function without malignant transformation. In the future, the preliminary methodology in this study may serve as a safe alternative for allotransplantation into patients with permanent hypoparathyroidism.


Maturation of PNN and ErbB4 Signaling in Area CA2 during Adolescence Underlies the Emergence of PV Interneuron Plasticity and Social Memory.
Adolescence is a vulnerable period characterized by major cognitive changes. The mechanisms underlying the emergence of new cognitive functions are poorly understood. We find that a long-term depression of inhibitory transmission (iLTD) from parvalbumin-expressing (PV+) interneurons in the hippocampal area Cornu Ammonis 2 (CA2) is absent in young mice but emerges at the end of adolescence. We demonstrate that the maturation of both the perineuronal net (PNN) and signaling through ErbB4 is required for this plasticity. Furthermore, we demonstrate that social recognition memory displays the same age dependence as iLTD and is impaired by targeted degradation of the PNN or iLTD blockade in area CA2. Our data reveal an unusual developmental rule for plasticity at the PV+ interneuron transmission in area CA2 and indicate that this plasticity is involved in the emergence of higher cognitive function, such as social memory formation, in late adolescence.


Kupffer cell erythrophagocytosis and graft-versus-host hemolysis in liver transplantation.
Graft-versus-host hemolysis (GVHH) syndrome develops in approximately half of patients undergoing ABO-unmatched liver transplantation. The clinical and laboratory presentations of GVHH syndrome often mimic acute rejection, leading to liver biopsy for definitive diagnosis. The purpose of this study was to investigate if there are specific histological findings that permit diagnosis of GVHH syndrome and to assess the relationship between GVHH syndrome and rejection. Clinical and laboratory evidence of GVHH syndrome, results of liver biopsy, and clinical outcome were assessed in 30 ABO-unmatched liver transplant recipients. Biopsy results were compared with those of two control groups consisting of patients who had normal liver test findings (protocol biopsy) and rejection. Sixteen of the 30 patients (53%) had evidence of GVHH syndrome. Erythrophagocytosis was noted in each biopsy specimen, and the degree of phagocytosis correlated significantly with the amount of blood given after postoperative day 5 (r = 0.9; P < 0.02). Electron-microscopic studies performed randomly in 5 patients showed that the red cells were located in Kupffer cells. In contrast, erythrophagocytosis was minimal in the two control groups. Despite an incidence and severity of rejection similar to those in other liver transplant patients, serum transaminase levels were significantly higher in patients with GVHH syndrome. Erythrophagocytosis is a sensitive histological marker of GVHH syndrome. The severity of rejection and response to antirejection therapy should be monitored by markers other than transaminases in patients with GVHH syndrome.


Age at natural menopause in women exposed to diethylstilbestrol in utero.
Age at natural menopause is related to several health outcomes, including cardiovascular disease and overall mortality. Age at menopause may be influenced by the number of follicles formed during gestation, suggesting that prenatal factors could influence menopausal age. Diethylstilbestrol (DES), a nonsteroidal estrogen widely prescribed during the 1950s and 1960s, is related to reproductive tract abnormalities, infertility, and vaginal cancer in prenatally exposed daughters but has not been studied in relation to age at menopause. The authors used survival analyses to estimate the risk of natural menopause in 4,210 DES-exposed versus 1,829 unexposed US women based on responses to questionnaires mailed in 1994, 1997, and 2001. DES-exposed women were 50% more likely to experience natural menopause at any given age (hazard ratio = 1.49, 95% confidence interval: 1.28, 1.74). Among women for whom dose information was complete, there were dose-response effects, with a greater than twofold risk for those exposed to >10,000 mg. The causal mechanism for earlier menopause may be related to a smaller follicle pool, more rapid follicle depletion, or changes in hormone synthesis and metabolism in DES-exposed daughters. Age at menopause has been related, albeit inconsistently, to several exposures, but, to the authors' knowledge, this is the first study to suggest that a prenatal exposure may influence reproductive lifespan.


Metallization of Targeted Protein Assemblies in Cell-Derived Extracellular Matrix by Antibody-Guided Biotemplating.
Biological systems are composed of hierarchical structures made of a large number of proteins. These structures are highly sophisticated and challenging to replicate using artificial synthesis methods. To exploit these structures in materials science, biotemplating is used to achieve biocomposites that accurately mimic biological structures and impart functionality of inorganic materials, including electrical conductivity. However, the biological scaffolds used in previous studies are limited to stereotypical and simple morphologies with little synthetic diversity because of a lack of control over their morphologies. This study proposes that the specific protein assemblies within the cell-derived extracellular matrix (ECM), whose morphological features are widely tailorable, can be employed as versatile biotemplates. In a typical procedure, a fibrillar assembly of fibronectin-a constituent protein of the ECM-is metalized through an antibody-guided biotemplating approach. Specifically, the antibody-bearing nanogold is attached to the fibronectin through antibody-antigen interactions, and then metals are grown on the nanogold acting as a seed. The biomimetic structure can be adapted for hydrogen production and sensing after improving its electrical conductivity through thermal sintering or additional metal growth. This study demonstrates that cell-derived ECM can be an attractive option for addressing the diversity limitation of a conventional biotemplate.


Laparoscopic cholecystectomy in patients over 70 years of age: review of 176 cases.
We assessed the results of laparoscopic cholecystectomy in 176 patients over the age of 70 years. The study included all patients older than 70 years of age who underwent laparoscopic surgery cholelithiasis during the previous ten years. Variables studied included age, sex, type of operation (programmed/emergency), comorbidity, anesthetic risk, intraoperative cholangiography, conversion to open surgery, number of trocars, reoperation, residual choledocholithiasis, postoperative hospital stay, morbidity and mortality. The study included 176 patients (23.29% men and 76.71% women). The mean age was 74.86 years. The mean hospital stay was 1.27 days, with 16.98% morbidity and 0.56% mortality. Laparoscopic cholecystectomy is a safe procedure in older patients. It results in faster recovery, a shorter postoperative stay and lower rates of morbidity and mortality than open bile duct surgery.


Analysis and correction of compositional bias in sparse sequencing count data.
Count data derived from high-throughput deoxy-ribonucliec acid (DNA) sequencing is frequently used in quantitative molecular assays. Due to properties inherent to the sequencing process, unnormalized count data is compositional, measuring relative and not absolute abundances of the assayed features. This compositional bias confounds inference of absolute abundances. Commonly used count data normalization approaches like library size scaling/rarefaction/subsampling cannot correct for compositional or any other relevant technical bias that is uncorrelated with library size. We demonstrate that existing techniques for estimating compositional bias fail with sparse metagenomic 16S count data and propose an empirical Bayes normalization approach to overcome this problem. In addition, we clarify the assumptions underlying frequently used scaling normalization methods in light of compositional bias, including scaling methods that were not designed directly to address it. Compositional bias, induced by the sequencing machine, confounds inferences of absolute abundances. We present a normalization technique for compositional bias correction in sparse sequencing count data, and demonstrate its improved performance in metagenomic 16s survey data. Based on the distribution of technical bias estimates arising from several publicly available large scale 16s count datasets, we argue that detailed experiments specifically addressing the influence of compositional bias in metagenomics are needed.


Event- and context-specific normative misperceptions and high-risk drinking: 21st birthday celebrations and football tailgating.
Negative alcohol-related consequences often occur during specific events and in specific contexts (e.g., 21st birthday celebrations and tailgating parties). A lack of available event- and context-specific interventions suggests the need to better understand factors associated with heavy drinking in these contexts, with an eye toward developing specific interventions. The purpose of this research was to lay the foundation for developing personalized normative feedback interventions for 21st birthday celebratory drinking and tailgating drinking by evaluating whether students overestimate norms in these specific contexts, as they do more generally. Perceived descriptive norms and alcohol consumption were assessed at event- and context-specific levels in two studies. Study 1 included 119 students turning 21 years old who reported their 21st birthday drinking behavior and estimated the typical number of drinks consumed by students celebrating their 21st birthday. Study 2 included 140 undergraduates drawn from a stratified random sample who reported their behavior regarding drinking and tailgating and their perceived norms for typical drinking and tailgating behavior. Results from Study 1 revealed that students overestimated peer drinking during 21 st birthday celebrations, and this overestimation was associated with heavier drinking on one's own 21st birthday. In Study 2, students underestimated the percentage of tailgaters who drank but overestimated typical consumption. Overestimation was consistently associated with heavier drinking during tailgating. Successful correction of general normative misperceptions has been shown to reduce drinking in other research. Documentation of normative misperceptions for specific events and contexts provided by these results represents an important step in developing event- and context-specific interventions utilizing specific normative feedback.


Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.


The endotoxin hypothesis of neurodegeneration.
The endotoxin hypothesis of neurodegeneration is the hypothesis that endotoxin causes or contributes to neurodegeneration. Endotoxin is a lipopolysaccharide (LPS), constituting much of the outer membrane of gram-negative bacteria, present at high concentrations in gut, gums and skin and in other tissue during bacterial infection. Blood plasma levels of endotoxin are normally low, but are elevated during infections, gut inflammation, gum disease and neurodegenerative disease. Adding endotoxin at such levels to blood of healthy humans induces systemic inflammation and brain microglial activation. Adding high levels of endotoxin to the blood or body of rodents induces microglial activation, priming and/or tolerance, memory deficits and loss of brain synapses and neurons. Endotoxin promotes amyloid β and tau aggregation and neuropathology, suggesting the possibility that endotoxin synergises with different aggregable proteins to give different neurodegenerative diseases. Blood and brain endotoxin levels are elevated in Alzheimer's disease, which is accelerated by systemic infections, including gum disease. Endotoxin binds directly to APOE, and the APOE4 variant both sensitises to endotoxin and predisposes to Alzheimer's disease. Intestinal permeability increases early in Parkinson's disease, and injection of endotoxin into mice induces α-synuclein production and aggregation, as well as loss of dopaminergic neurons in the substantia nigra. The gut microbiome changes in Parkinson's disease, and changing the endotoxin-producing bacterial species can affect the disease in patients and mouse models. Blood endotoxin is elevated in amyotrophic lateral sclerosis, and endotoxin promotes TDP-43 aggregation and neuropathology. Peripheral diseases that elevate blood endotoxin, such as sepsis, AIDS and liver failure, also result in neurodegeneration. Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons. The endotoxin hypothesis is unproven, but if correct, then neurodegeneration may be reduced by decreasing endotoxin levels or endotoxin-induced neuroinflammation.


Miscellaneous Topics in Computer-Aided Drug Design: Synthetic Accessibility and GPU Computing, and Other Topics.
Computer-aided drug design is still a state-of-the-art process in medicinal chemistry, and the main topics in this field have been extensively studied and well reviewed. These topics include compound databases, ligand-binding pocket prediction, protein-compound docking, virtual screening, target/off-target prediction, physical property prediction, molecular simulation and pharmacokinetics/pharmacodynamics (PK/PD) prediction. Message and Conclusion: However, there are also a number of secondary or miscellaneous topics that have been less well covered. For example, methods for synthesizing and predicting the synthetic accessibility (SA) of designed compounds are important in practical drug development, and hardware/software resources for performing the computations in computer-aided drug design are crucial. Cloud computing and general purpose graphics processing unit (GPGPU) computing have been used in virtual screening and molecular dynamics simulations. Not surprisingly, there is a growing demand for computer systems which combine these resources. In the present review, we summarize and discuss these various topics of drug design.


The Genomic Revolution and Beliefs about Essential Racial Differences: A Backdoor to Eugenics?
Could the explosion of genetic research in recent decades affect our conceptions of race? In Backdoor to Eugenics, Duster argues that reports of specific racial differences in genetic bases of disease, in part because they are presented as objective facts whose social implications are not readily apparent, may heighten public belief in more pervasive racial differences. We tested this hypothesis with a multi-method study. A content analysis showed that news articles discussing racial differences in genetic bases of disease increased significantly between 1985 and 2008 and were significantly less likely than non-health-related articles about race and genetics to discuss social implications. A survey experiment conducted with a nationally representative sample of 559 adults found that a news-story vignette reporting a specific racial difference in genetic risk for heart attacks (the Backdoor Vignette) produced significantly greater belief in essential racial differences than did a vignette portraying race as a social construction or a no-vignette condition. The Backdoor Vignette produced beliefs in essential racial differences that were virtually identical to those produced by a vignette portraying race as a genetic reality. These results suggest that an unintended consequence of the genomic revolution may be the reinvigoration of age-old beliefs in essential racial differences.


Isolation and characterization of rabbit kidney brush borders.
1. Brush borders were isolated from rabbit kidney-cortex homogenates by rate-zonal centrifugation through a sucrose density gradient in a B-XIV zonal rotor, followed by differential centrifugation. 2. The method of preparation gave brush borders of high purity with a reasonable yield. The morphological appearance supported the evidence from enzymic and chemical investigations, that the brush borders were only slightly contaminated with endoplasmic reticulum, mitochondria, lysosomes and nuclei. 3. The molar ratio of cholesterol to phospholipid lay within the range found in other plasma membranes, but the carbohydrate content was double that found in liver plasma membranes. 4. Alkaline phosphatase, maltase, trehalase and aminopeptidase were major enzymic constituents of the brush borders, and had an approximately equal yield and enrichment, but none of these enzymes fulfilled the criteria for marker enzymes. 5. Mg(2+)-dependent and Na(+),K(+)-dependent adenosine triphosphatases, although found in brush borders, had low yields and low enrichments.


Observation on the saliva and salivary gland extract of Haemaphysalis spinigera and Rhipicephalus sanguineus sanguineus.
Intracutaneous injection of histamine acid phosphate (HAP) and salivary gland extract (SGE) of Haemaphysalis spinigera and Rhipicephalus sanguineus sanguineus into sensitized and nonsensitized rabbits previously injected intravenously with Evans blue indicated that the ticks' saliva contained a pharmacodynamic substance in addition to having antigenic properties. A primary skin reaction in nonsensitized rabbits produced by this pharmacodynamic substance within 30 min was amplified by a more extensive skin reaction in sensitized rabbits. It was postulated that, in concert with this pharmacodynamic component of the ticks' saliva, a histamine-blocking agent detected in the salivary gland of R. s. sanguineus would provide an efficient mechanism for regulating the quantity of tissue fluid available for the engorging tick, while simultaneously neutralizing the deleterious effects of excess pharmacodynamic substance in the host's tissues.


Regulation of epithelial sodium channels in urokinase plasminogen activator deficiency.
Epithelial sodium channels (ENaC) govern transepithelial salt and fluid homeostasis. ENaC contributes to polarization, apoptosis, epithelial-mesenchymal transformation, etc. Fibrinolytic proteases play a crucial role in virtually all of these processes and are elaborated by the airway epithelium. We hypothesized that urokinase-like plasminogen activator (uPA) regulates ENaC function in airway epithelial cells and tested that possibility in primary murine tracheal epithelial cells (MTE). Both basal and cAMP-activated Na(+) flow through ENaC were significantly reduced in monolayers of uPA-deficient cells. The reduction in ENaC activity was further confirmed in basolateral membrane-permeabilized cells. A decrease in the Na(+)-K(+)-ATPase activity in the basolateral membrane could contribute to the attenuation of ENaC function in intact monolayer cells. Dysfunctional fluid resolution was seen in uPA-disrupted cells. Administration of uPA and plasmin partially restores ENaC activity and fluid reabsorption by MTEs. ERK1/2, but not Akt, phosphorylation was observed in the cells and lungs of uPA-deficient mice. On the other hand, cleavage of γ ENaC is significantly depressed in the lungs of uPA knockout mice vs. those of wild-type controls. Expression of caspase 8, however, did not differ between wild-type and uPA(-/-) mice. In addition, uPA deficiency did not alter transepithelial resistance. Taken together, the mechanisms for the regulation of ENaC by uPA in MTEs include augmentation of Na(+)-K(+)-ATPase, proteolysis, and restriction of ERK1/2 phosphorylation. We demonstrate for the first time that ENaC may serve as a downstream signaling target by which uPA controls the biophysical profiles of airway fluid and epithelial function.


Comparisons of bacterial and archaeal communities in the rumen and a dual-flow continuous culture fermentation system using amplicon sequencing.
Dual-flow continuous culture (CC) fermenters are commonly used to study rumen fermentation in vitro. Research using culture-based and oligonucleotide techniques has shown that certain microbial populations within fermenters may be maintained at abundances similar to those observed in vivo. In this study, bacterial and archaeal communities in the rumen of dairy cattle and in a dual-flow CC fermentation system were compared using high-throughput amplicon sequencing targeting the V4 hypervariable region of 16S rRNA. We hypothesized that the in vitro system harbored a comparable bacterial and archaeal community to that observed in the rumen. Members of the Bacteroidetes and Firmicutes made up the 2 most abundant phyla in the rumen, inoculum, and fermenters and did not differ among sample types (P > 0.10). Similarly, Prevotellaceae, the most abundant family in all 3 sample types, did not differ based on source (P = 0.80). However, beta diversity analyses revealed that bacterial and archaeal communities differed between fermenters and rumen samples (P ≤ 0.001), but fermenter bacterial and archaeal communities stabilized by day 4 of each period. While the overall bacterial and archaeal community differs between natural rumens and those detected in in vitro fermenter systems, several prominent taxa were maintained at similar relative abundances suggesting that fermenters may provide a suitable environment in which to study shifts among the predominant members of the microbial community.


The middle cranial fossa: morphometric study and surgical considerations.
The anatomical features of the temporal bone can vary significantly among different individuals. These variations affect the operative view in middle cranial fossa surgery. We performed 18 middle fossa approaches in 9 cadaveric heads, with detailed morphological analysis, to identify unfavorable situations and reliable systems to avoid complications during surgery. We recorded linear, angular measurements and calculated areas. We performed a computed tomography (CT) scan with analysis of the amount of bone to remove in two temporal bones. We found that the location of the internal auditory canal (IAC) is the keystone of bone removal. We also found accuracy in the system suggested by E. and J. L. Garcia-Ibanez for its identification and that there is a smaller surgical window in female patients (statistically significant) that can be predicted on preoperative imaging studies. Our study also confirms significant individual variability in the mutual relationships of different surgical landmarks. We concluded that surgery of the middle fossa requires detailed understanding of the complex temporal bone anatomy. The surgeon has to be aware of extreme variability of the more commonly used anatomical landmarks. The method to identify the position of the IAC described by E. and J. L. Garcia-Ibanez seems to be the simplest and most reliable. When the surgical strategy includes an anterior petrosectomy, interindividual variability can critically affect the working area, particularly in females. The working area can be estimated on preoperative CT scans through the petrous bone.


Effects of intracellular free magnesium on calcium current in isolated cardiac myocytes.
Magnesium ions play a fundamental role in cellular function, but the effects of changes in the concentration of intracellular ionized magnesium ([Mg2+]i) on cell physiology have only recently received experimental attention. Increasing [Mg2+]i from 0.3 to 3.0 mM in cardiac cells by internal perfusion has only small effects on the basal voltage-gated calcium current (ICa) or on ICa elevated by dihydropyridine calcium channel agonists. In contrast, ICa elevated by cyclic adenosine monophosphate (cAMP)-dependent phosphorylation decreases by more than 50 percent. The effect of [Mg2+]i is not due to changes in the concentration of cAMP or in the velocity of phosphorylation but rather appears to be a direct effect on the phosphorylated channel or on channel dephosphorylation.


Awareness and control of canine leishmaniosis: A survey among Spanish and French veterinarians.
Zoonotic visceral leishmaniasis (ZVL) is a parasitic disease affecting dogs and humans, which is transmitted by female sandflies. Over the last decade, disease prevalence has increased fivefold in parts of southern Europe, where an estimated 2.5 million dogs are infected. This increase is mainly due to an expansion in sandfly distribution due to climate change and to the greater numbers of dogs travelling among European countries. To combat the spread of ZVL in Europe, international guidelines have been drawn up that describe strategies to prevent, control and monitor the disease. To investigate whether these strategies are being implemented in the field, we conducted an online survey among veterinarians in Spain (endemic for ZVL) and France (south: emerging; north: non-endemic). Of the 889 respondents, 459 veterinarians completed all questions. Although 60% of all veterinarians were aware of the current ZVL increase in Europe, 70% were not familiar with any guidelines for controlling the disease. Most of their preventive and treatment actions were, however, in line with intervention strategies recommended by the guidelines. From the veterinarians in this survey, 76% had received no reports regarding confirmed cases of canine leishmaniosis (CanL) or human visceral leishmaniasis in their region or country. The fact that 88% of confirmed cases of clinical CanL were not reported suggests inadequate disease monitoring and evaluation. We therefore recommend that an easy-to-use and accessible international online network be developed, where both veterinarians and physicians can report confirmed cases of leishmaniosis in dogs and humans. This is crucial for monitoring, controlling and preventing the further spread of ZVL in Europe at regional, national and international level.


Disruption of tolerance to the ataxic effect of ethanol by an extraneous stimulus.
According to a conditioning analysis, pharmacological conditional responses (CRs) contribute to tolerance. We previously reported that, as expected on the basis of this model, tolerance to the hypothermic effect of ethanol is attenuated by "external inhibition," for instance, by presentation of a novel stimulus (a strobe). However, results of more recent research indicate that novel stimuli augment the hypothermic effect of ethanol in rats receiving the drug for the first time. It is possible, therefore, that a novel stimulus apparently attenuates ethanol tolerance because it augments ethanol-hypothermia, rather than because it functions as an external inhibitor. Two experiments were designed to evaluate external inhibition of tolerance to another effect of ethanol-ataxia. Although the initial ataxic effect of the drug (unlike the hypothermic effect) is not enhanced by a novel stimulus, the stimulus reinstated ethanol-induced ataxia in tolerant rats. The results demonstrate external inhibition of ethanol tolerance in a preparation not confounded by the effects of the novel stimulus on initial responding to ethanol.


Mobilization of neural stem cells and generation of new neurons in 6-OHDA-lesioned rats by intracerebroventricular infusion of liver growth factor.
Neural stem cells with self-renewal and multilineage potential persist in the subventricular zone of the adult mammalian forebrain. These cells remain relatively quiescent but, under certain conditions, can be stimulated, giving rise to new neurons. Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and is useful for neuroregenerative therapies. The aim of this study was to investigate the potential neurogenic activity of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Proliferation was significantly increased in the subventricular zone and denervated striatum of rats receiving ICV LGF infusions, and 25% of the proliferating cells were doublecortin-positive neurons. Doublecortin-positive cells with the morphology of migrating neuroblasts were also observed in the dorsal and ventral regions of the striatum of LGF-infused animals. Moreover, some newly generated cells were neuronal nuclei-positive mature neurons. LGF also stimulated microglia and induced astrogliosis, both phenomena associated with generation and migration of new neurons in the adult brain. In summary, our study shows that LGF stimulates neurogenesis when applied intraventricularly in 6-hydroxydopamine-lesioned rats. Considering that this factor also promotes neuronal migration into damaged tissue, we propose LGF as a novel factor useful for neuronal replacement in neurodegenerative diseases.


Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis.
We describe two new monoclonal antibodies specific for the Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) that are suitable for the immunohistochemical analysis of routinely processed paraffin sections. These antibodies were applied to the immunohistochemical detection of LMP2A in Hodgkin's disease (HD). LMP2A-specific membrane staining was seen in the Hodgkin and Reed-Sternberg (HRS) cells of 22 of 42 (52%) EBV-positive HD cases, but not in 39 EBV-negative HD cases. In lymphoid tissues from patients with acute infectious mononucleosis (IM), interfollicular immunoblasts were shown to express LMP2A. This is the first demonstration of LMP2A protein expression at the single-cell level in EBV-associated lymphoproliferations in vivo. The detection of LMP2A protein expression in HD and IM is of importance in view of the proposed role of this protein for maintaining latent EBV infection and its possible contribution for EBV-associated transformation. Because LMP2A provides target epitopes for EBV-specific cytotoxic T cells, the expression of this protein in HRS cells has implications for the immunotherapeutic approaches to the treatment of HD.