Genomic and genetic definition of a functional human centromere.
The definition of centromeres of human chromosomes requires a complete genomic understanding of these regions. Toward this end, we report integration of physical mapping, genetic, and functional approaches, together with sequencing of selected regions, to define the centromere of the human X chromosome and to explore the evolution of sequences responsible for chromosome segregation. The transitional region between expressed sequences on the short arm of the X and the chromosome-specific alpha satellite array DXZ1 spans about 450 kilobases and is satellite-rich. At the junction between this satellite region and canonical DXZ1 repeats, diverged repeat units provide direct evidence of unequal crossover as the homogenizing force of these arrays. Results from deletion analysis of mitotically stable chromosome rearrangements and from a human artificial chromosome assay demonstrate that DXZ1 DNA is sufficient for centromere function. Evolutionary studies indicate that, while alpha satellite DNA present throughout the pericentromeric region of the X chromosome appears to be a descendant of an ancestral primate centromere, the current functional centromere based on DXZ1 sequences is the product of the much more recent concerted evolution of this satellite DNA.


Does the General Strain Theory Explain Gambling and Substance Use?
General Strain Theory (GST: Agnew Criminology 30:47-87, 1992) posits that deviant behaviour results from adaptation to strain and the consequent negative emotions. Empirical research on GST has mainly focused on aggressive behaviours, while only few research studies have considered alternative manifestations of deviance, like substance use and gambling. The aim of the present study is to test the ability of GST to explain gambling behaviours and substance use. Also, the role of family in promoting the adoption of gambling and substance use as coping strategies was verified. Data from 266 families with in mean 8 observations for each group were collected. The multilevel nature of the data was verified before appropriate model construction. The clustered nature of gambling data was analysed by a two-level Hierarchical Linear Model while substance use was analysed by Multivariate Linear Model. Results confirmed the effect of strain on gambling and substance use while the positive effect of depressive emotions on these behaviours was not supported. Also, the impact of family on the individual tendency to engage in addictive behaviours was confirmed only for gambling.


Use of statins in patients with chronic hepatitis C.
Hepatitis C is a leading cause of liver failure and transplantation in the United States and a major public health issue. Studies have shown that patients with hepatitis C are at an increased risk of cardiovascular disease, which make statins of particular benefit in this patient population. However, the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) lists active or chronic liver disease as an absolute contraindication to statin therapy. The available literature regarding the safety of statins in this patient population is limited, but has not shown clinically significant differences in aminotransferase elevations or evidence of hepatotoxicity in patients with hepatitis C who have received statins versus those who have not. Statins should continue to be avoided in advanced end-stage liver disease, as there is a lack of safety data in these patients and drug metabolism would be severely compromised. Treatment with statins can be used in those with chronic, stable hepatitis C with elevated cardiac risk or a previous cardiac event.


Biochemical and functional characterization of soluble multivalent MHC L(d)/Fc gamma 1 and L(d)/Fc mu chimeric proteins loaded with specific peptides.
Central to the specificity of the immune system is the interaction between the T cell receptor and the major histocompatibility complex (MHC)-peptide ligand complex. To better understand the nature of this interaction, and to investigate possible avenues for specific therapeutic intervention, we have produced soluble recombinant molecules that can modulate antigen-specific T cells. Our approach involved the construction of recombinant murine genes composed of the MHC class I gene H-2L(d) and the Fc portion of immunoglobulin (Ig) heavy chain genes mu or gamma1. Stable transfectants of these L(d)/Fc gamma1 and L(d)/Fc mu genes generated correctly spliced transcripts and were capable of secreting chimeric protein. Immunoprecipitation analyses demonstrated the presence of chimeric L(d)/ Fc gamma1 and L(d)/Fc mu monomers of approximately 69 kDa and 90 kDa, respectively, as well as chimeric dimers under nonreducing conditions. The capacity of L(d)/Ig molecules to bind specific peptide ligands was demonstrated using radiolabeled peptides or with monoclonal reagents that specifically identify peptide-induced conformational changes in the L(d) ligand binding site. Soluble divalent L(d)/Fc gamma1 molecules were loaded with the murine cytomegalovirus-derived peptide and other L(d)-specific peptide ligands and subsequently isolated and purified. Peptide-loaded L(d)/Fc gamma1 molecules were capable of inhibiting the response of class I-restricted T cells in vitro in a peptide-specific fashion. The development of soluble multivalent chimeric proteins that possess unique properties of both the MHC class I and Ig molecules provides a valuable reagent for the study of potential mechanisms of in vitro and in vivo immune modulation.


Prenatal Exposure to Famine and Risk for Development of Psychopathology in Adulthood: A Meta-Analysis.
Prenatal famine, resulting in intrauterine malnutrition, impacts offspring psychopathology later in adulthood. In addition, the specific impact of intrauterine malnutrition of different psychopathology differs by the timing of the exposure. Using a meta-analysis, the current study assessed the specific risk of developing affective, psychotic, and personality disorders. Studies were identified using PubMed and PsycINFO. Studies met the following criteria for inclusion in the analysis: availability in peer-reviewed English journals, use of human subjects, prenatal exposure to famine, and psychopathology in adulthood defined by diagnostic criteria as an outcome. Fixed effect relative risks (RRs) were calculated for affective, psychotic, and personality domains. Furthermore, timing of exposure was assessed as an effect modifier in our analysis, defined by the index trimester at the height of famine. Our meta-analysis found that adults exposed in utero during the 1st trimester were at a significant increased risk of psychotic disorders (RR=1.46, 95% CI=1.08, 1.97, p=0.014), and personality disorders (RR=2.31, 95% CI=1.36, 3.92, p=0.002). Those exposed during the 2nd trimester were at a significant increased risk of affective disorders (RR=1.45, 95% CI=1.22, 1.72, p<0.0001), and psychotic disorders (RR=1.46, 95% CI=1.13, 1.89, p=0.004). Similarly, those exposed in the 3rd trimester were at a significant increased risk of affective disorders (RR=1.33, 95% CI=1.13, 1.57, p=0.0001), and psychotic disorders RR=1.47, 95% CI=1.10, 1.97, p=0.010). Our findings suggest that there is differential risk across the different domains of psychopathology by trimester of exposures. This meta-analysis underscores the need for further investigation into the mechanisms underlying prenatal maternal nutrition and offspring psychopathology where magnitude of elevated risk differs by the exposure timing during pregnancy.


Suicide and attempted suicide in France: results of a general practice sentinel network, 1999-2001.
The continuous surveillance of suicide and attempted suicide cases was added to the tasks of the French Sentinel Network of General Practitioners (GPs) in 1999. In 2001, 9700 suicides were estimated to have occurred and an estimated 61 500 attempted suicide cases were diagnosed by GPs, representing approximately 40% of cases nationwide. The majority of suicide and attempted suicide cases involved women (67%) and 43% of all cases involved patients aged 25-44 years. The fatality rate increased with age. About 80% of GPs complied with the current recommendation to refer patients who had attempted suicide to hospital.


Genotype/phenotype correlations in complement factor H deficiency arising from uniparental isodisomy.
We report a male infant who presented at 8 months of age with atypical hemolytic uremic syndrome (aHUS) responsive to plasma therapy. Investigation showed him to have complement factor H (CFH) deficiency associated with a homozygous CFH mutation (c.2880delT [p.Phe960fs]). Mutation screening of the child's parents revealed that the father was heterozygous for this change but that it was not present in his mother. Chromosome 1 uniparental isodisomy of paternal origin was confirmed by genotyping chromosome 1 SNPs. CD46 SNP genotyping was undertaken in this individual and another patient with CFH deficiency associated with chromosome 1 uniparental isodisomy. This showed a homozygous aHUS risk haplotype (CD46GGAAC) in the patient with aHUS and a homozygous glomerulonephritis risk haplotype (CD46AAGGT) in the patient with endocapillary glomerulonephritis. We also showed that FHL-1 (factor H-like protein 1) was present in the patient with aHUS and absent in the patient with glomerulonephritis. This study emphasizes that modifiers such as CD46 and FHL-1 may determine the kidney phenotype of patients who present with homozygous CFH deficiency.


Clinical profile and outcome in a large sample of children and adolescents with obsessive-compulsive disorder: A chart review from a tertiary care center in India.
Obsessive-compulsive disorder (OCD) is a common psychiatric illness in children and adolescents. Till date, the sample sizes in the Indian studies have been relatively small. The present study is a retrospective chart review of a large sample of children and adolescents diagnosed with OCD in a tertiary care center. The objectives of this study were to characterize the clinical profile and to evaluate outcome of OCD in children and adolescents. Fear of contamination and washing/cleaning compulsions were the most common presenting symptoms. Most of the patients were male with two-thirds having a comorbid disorder. Major depressive disorder was the most common comorbid disorder. The rates of attention deficit hyperactivity disorder, disruptive behavioral disorders, and tic disorders were low when compared to Western studies. One-third of the patients received adequate trial of serotonin reuptake inhibitors and 36% received cognitive behavior therapy. Fifty-four percent of patients had a poor outcome with hospitalization, longer duration of illness, earlier onset of OC symptoms, and family history of OCD being the predictors of poor outcome. The present study of a large sample of patients with juvenile OCD highlights the low rate of comorbid disruptive behavior disorders as reported in the earlier Indian studies and a favorable short-term outcome in approximately 56% of the patients.


C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.
Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.


Benchmarking empirical models for THMs formation in drinking water systems: An application for decision support in Barcelona, Spain.
Drinking water treatment plants (DWTPs) face changes in raw water quality, which affect the formation of disinfection by-products. Several empirical modelling approaches have been reported in the literature, but most of them have been developed with lab-scale data, which may not be representative of real water systems. Therefore, the application of these models for real-time operation of DWTPs might be limited. At the present study, multiple linear regression (MLR) and multi-layer perceptrons (MLP) were benchmarked using field-scale data for predicting the THMs formation in a case-study DWTP in Barcelona, Spain. After fitting the studied models, MLR exhibited good fit with the validation data set (R2 = 0.88 and MAE = 4.0 μg·L-1) and described the most plausible input-output relationships with field-scale data. The MLR predictive model was incorporated into an environmental decision support system (EDSS) for assessing the THMs formation at two critical points of the distribution network. A Monte Carlo scheme was applied for quantifying uncertainty of model predictions at these points, considering low and high water quality scenarios and different degrees of treatment by an electrodialysis reversal process. The results show that the use of the proposed EDSS can help in real operation of complex drinking water systems, which face important changes in water quality throughout the year.


The distribution of NADPH-diaphorase-labelled interneurons and the role of nitric oxide in the swimming system of Xenopus laevis larvae.
The possible involvement of the free radical gas nitric oxide (NO) in the modulation of spinal rhythm-generating networks has been studied using Xenopus laevis larvae. Using NADPH-diaphorase histochemistry, three putative populations of nitric oxide synthase (NOS)-containing cells were identified in the brainstem. The position and morphology of the largest and most caudal population suggested that a proportion of these neurons is reticulospinal. The possible contribution of nitrergic neurons to the control of swimming activity was examined by manipulating exogenous and endogenous NO concentrations in vivo with an NO donor (SNAP, 100-500 micromol l(-)(1)) and NOS inhibitors (l-NAME and l-NNA, 0.5-5 mmol l(-)(1)), respectively. In the presence of SNAP, swim episode duration decreased and cycle period increased, whereas the NOS inhibitors had the opposite effects. We conclude from these data that the endogenous release of NO from brainstem neurons extrinsic to the spinal cord of Xenopus laevis larvae exerts a continuous modulatory influence on swimming activity, functioning like a 'brake'. Although the exact level at which NO impinges upon the swimming rhythm generator has yet to be determined, the predominantly inhibitory effect of NO suggests that the underlying mechanisms of NO action could involve modulation of synaptic transmission and/or direct effects on neuronal membrane properties.


An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis.
To identify genetic associations between allograft inflammatory factor 1 (AIF1) and systemic sclerosis (SSc), or its subsets, using a single nucleotide polymorphism (SNP) in a replicate case-control study. The frequencies of alleles and genotypes of an SNP, rs2269475, for the AIF1 gene were examined in two large independent cohorts of SSc patients (n = 1015 total), and compared with two groups of normal controls (n = 893 total). Both cases and controls were stratified by ethnicity (Caucasian, African American and Hispanic) and by autoantibody status [anti-centromere antibodies (ACA) and anti-topoisomerase I antibody (ATA)]. The minor T allele and CT/TT genotype frequencies of the AIF1 SNP were not observed more frequently in SSc patients of the three ethnic groups (individually or combined) when compared with controls. On the other hand, T and CT/TT frequencies were significantly increased in ACA-positive Caucasian SSc patients, and all ACA-positive SSc patients (the three ethnic groups combined), when compared with ACA-negative SSc patients and with normal controls, with odds ratios of approximately 1.5. The data demonstrate a genetic association between AIF1 and the ACA-positive subset of SSc. This polymorphism is a non-synonymous substitution and therefore likely to represent an important functional change in AIF1. Since vascular pathology is a prominent feature in ACA-positive SSc patients, the observed association with a vasculotrophic inflammatory gene is biologically plausible and warrants further research.


Geographic distributions and origins of human head lice (Pediculus humanus capitis) based on mitochondrial data.
Human head lice (Pediculus humanus capitis) are subdivided into 3 deeply divergent mitochondrial clades (Clades A, B, and C), each having unique geographical distributions. Determining the evolutionary history and geographic distribution of these mitochondrial clades can elucidate the evolutionary history of the lice as well as their human hosts. Previous data suggest that lice belonging to mitochondrial Clade B may have originated in North America or Asia; however, geographic sampling and sample sizes have been limited. With newly collected lice, we calculate the relative frequency, geographic distribution, and genetic diversity of louse mitochondrial clades to determine the geographic origin of lice belonging to Clade B. In agreement with previous studies, genetic diversity data support a North American origin of Clade B lice. It is likely that lice belonging to this mitochondrial clade recently migrated to other geographic localities, e.g., Europe and Australia, and, if not already present, may disperse further to occupy all geographic regions.


Multiple Past Concussions in High School Hockey Players: Examining Cognitive Functioning and Symptom Reporting.
To investigate (1) if there are meaningful differences in baseline preseason cognitive functioning or symptom reporting between high school ice hockey players with and without prior concussions and (2) determine which health history variables predict symptom reporting. Cross-sectional study. High schools across the state of Maine. Participants were 1616 male high school ice hockey players (mean age = 15.6 years; SD = 1.5 years) who completed baseline testing between 2009 and 2015. Athletes were grouped according to their self-reported concussion history [0 (n = 1136), 1 (n = 321), 2 (n = 112), or 3+ (n = 47) previous concussions]. Cognitive functioning was measured by the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) battery, and symptom ratings were obtained from the Post-Concussion Symptom Scale. There were no statistically significant differences between groups in cognitive functioning as measured by ImPACT. The group with ≥3 prior concussions endorsed higher total symptom scores, but the effect sizes were small and not statistically significant. In a multivariate model, prior treatment for headaches (not necessarily migraines), prior treatment for a psychiatric condition, and prior treatment for substance/alcohol use all significantly predicted total symptom scores, with concussion history being the weakest independent predictor. Players with a history of prior concussions performed similarly to players with no prior concussions on cognitive testing. Health history factors were more strongly associated with symptom reporting than concussion history.


[Ecological correlation studies on standardized incidence ratios of malignant neoplasms contracted from different sources of drinking water supply].
Ecological correlation analysis was made between the source of drinking water and standardized incidence ratios (SIRs) of malignant neoplasms registered in Niigata, Japan. The purpose of this study was to find out some clues for generating a working hypothesis that the contamination of drinking water with environmental chemicals especially of endocrine disrupting chemicals in big rivers may be related to the occurrence of cancers. Sources of drinking water in the year 1974 were classified into two categories; one from the Shinano and Agano and their down-stream rivers, and the other from small rivers flowing into these big rivers, rivers originating from the mountain areas, underground and reservoirs (The other group). After excluding registered cases under 20 years of age, the registry data (1992-94) were sub-divided into two categories according to the source of drinking water. The SIRs were calculated by using two different standard populations; Niigata total and "The other group". All of the sites were examined in the former standard. In the latter case, however, 12 and 9 sites in males and females, respectively were selected based on the assumption that the expected numbers in each age group totaled 5 or over when there were more than 200 registered patients as a total. Concerning the judgment for the significant association in the former standard, we considered the presence of positive associations when both of the SIRs in the two categories were significantly different from the Niigata total population (p < 0.05 by chi 2 test). Of the 33 sites in males, the following sites were correlated with the source of drinking water; tongue, colon, rectum, gallbladder, etc., prostate, kidney, etc. and all sites. Of 35 sites in females, those were the colon, gallbladder, etc., bronchus and lung, breast, corpus uteri, thyroid and all sites. Of the 12 and 9 respective sites subjected to the second analysis, positive associations were observed in the following: esophagus, colon, rectum, liver, gallbladder, etc., bronchus and lung, prostate, bladder and all sites in males, and colon, rectum, gallbladder, etc., bronchus and lung, breast and all sites in females. Final conclusion, however, should be waived until the consistency of association can be confirmed by using more reliable incidence data, because the difference in the death certificates only (DCO) rate between the two groups might have played as a bias. The use of mortality data may be an alternative way to evaluate the present findings in terms of the consistency of association.


Intratumoral oncolytic virus V937 plus ipilimumab in patients with advanced melanoma: the phase 1b MITCI study.
Intratumoral administration of V937, a bioselected, genetically unmodified coxsackievirus A21, has previously demonstrated antitumor activity in patients with advanced melanoma as monotherapy and in combination with the programmed cell death 1 (PD-1) antibody pembrolizumab. We report results from an open-label, single-arm, phase 1b study (NCT02307149) evaluating V937 plus the cytotoxic T-lymphocyte antigen 4 inhibitor ipilimumab in patients with advanced melanoma. Adult patients (aged ≥18 years) with histologically confirmed metastatic or unresectable stage IIIB/C or IV melanoma received intratumoral V937 on days 1, 3, 5, 8, and 22 and every 3 weeks (Q3W) thereafter for up to 19 sets of injections plus intravenous ipilimumab 3 mg/kg Q3W administered for four doses starting on day 22. Imaging was performed at screening, on days 43 and 106 and every 6 weeks thereafter; response was assessed by immune-related response criteria per investigator assessment. Primary endpoints were safety in all treated patients and objective response rate (ORR) in all treated patients and in patients with disease that progressed on prior anti-PD-1 therapy. Fifty patients were enrolled and treated. ORR was 30% (95% CI 18% to 45%) among all treated patients, 47% (95% CI 23% to 72%) among patients who had not received prior anti-PD-1 therapy, and 21% (95% CI 9% to 39%) among patients who had experienced disease progression on prior anti-PD-1 therapy. Tumor regression occurred in injected and non-injected lesions. Median immune-related progression-free survival was 6.2 months (95% CI 3.5 to 9.0 months), and median overall survival was 45.1 months (95% CI 28.3 months to not reached). The most common treatment-related adverse events (AEs) were pruritus (n=25, 50%), fatigue (n=22, 44%), and diarrhea (n=16, 32%). There were no V937-related dose-limiting toxicities and no treatment-related grade 5 AEs. Treatment-related grade 3 or 4 AEs, all of which were considered related to ipilimumab, occurred in 14% of patients (most commonly dehydration, diarrhea, and hepatotoxicity in 4% each). Responses associated with intratumoral V937 plus ipilimumab were robust, including in the subgroup of patients who had experienced disease progression on prior anti-PD-1 therapy. Toxicities were manageable and consistent with those of the individual monotherapies.


Identification of human NK cells that are deficient for signaling adaptor FcRγ and specialized for antibody-dependent immune functions.
NK cells respond to tumor and virus-infected cells directly through several activation receptors, including natural cytotoxicity receptors, or indirectly through the activating Fc receptor CD16 for antibody-coated cells. Triggering of NK-cell effector functions through these receptors depends on physically associated transmembrane signaling adaptors, such as FcRγ (also known as FcεRIγ) and CD3ζ, both of which have been traditionally believed to be expressed by all mature NK cells. However, we have identified a distinct subset of human NK cells that are deficient for FcRγ expression but express normal levels of CD3ζ. FcRγ-deficient NK cells were readily detectable in about one-third of the healthy individuals examined. The deficiency was confined to the CD56(dim) population and was due to low FcRγ mRNA. FcRγ-deficient NK cells displayed dramatically reduced expression of the natural cytotoxicity receptors NKp46 and NKp30 but still expressed substantial levels of CD16. Compared to FcRγ-expressing NK cells, FcRγ-deficient NK cells showed poor direct reactivity toward tumor targets as measured by cytokine production and degranulation. Unexpectedly, however, FcRγ-deficient NK cells exhibited significantly more robust responsiveness upon stimulation through CD16, particularly for cytokine production, compared to FcRγ-expressing NK cells. Thus, our study reveals FcRγ-deficient NK cells as a novel subset of human NK cells that have remarkably potent responses toward antibody-coated targets. These findings also illustrate a differential contribution of FcRγ and CD3ζ for the expression and functional activity of their associated receptors.


Botulinum toxin as a biological weapon: medical and public health management.
The Working Group on Civilian Biodefense has developed consensus-based recommendations for measures to be taken by medical and public health professionals if botulinum toxin is used as a biological weapon against a civilian population. The working group included 23 representatives from academic, government, and private institutions with expertise in public health, emergency management, and clinical medicine. The primary authors (S.S.A. and R.S.) searched OLDMEDLINE and MEDLINE (1960-March 1999) and their professional collections for literature concerning use of botulinum toxin as a bioweapon. The literature was reviewed, and opinions were sought from the working group and other experts on diagnosis and management of botulism. Additional MEDLINE searches were conducted through April 2000 during the review and revisions of the consensus statement. The first draft of the working group's consensus statement was a synthesis of information obtained in the formal evidence-gathering process. The working group convened to review the first draft in May 1999. Working group members reviewed subsequent drafts and suggested additional revisions. The final statement incorporates all relevant evidence obtained in the literature search in conjunction with final consensus recommendations supported by all working group members. An aerosolized or foodborne botulinum toxin weapon would cause acute symmetric, descending flaccid paralysis with prominent bulbar palsies such as diplopia, dysarthria, dysphonia, and dysphagia that would typically present 12 to 72 hours after exposure. Effective response to a deliberate release of botulinum toxin will depend on timely clinical diagnosis, case reporting, and epidemiological investigation. Persons potentially exposed to botulinum toxin should be closely observed, and those with signs of botulism require prompt treatment with antitoxin and supportive care that may include assisted ventilation for weeks or months. Treatment with antitoxin should not be delayed for microbiological testing.


Depression during Pregnancy : Overview of Clinical Factors.
Depression during pregnancy is common, affecting an estimated 20% of women. However, conflicting data exist concerning the outcomes of this disorder. Thus, we reviewed studies that presented evidence for the use of antidepressants and those that examined untreated depression during the gestational period, in terms of clinical and epidemiological aspects.Observational studies have provided reassuring evidence of the safety of antidepressant use during pregnancy. However, due to the reluctance of healthcare providers to prescribe and patients to take medication during the obstetric period, approximately three-quarters of those diagnosed with depression remain untreated. Furthermore, healthcare providers apparently do not recognise the disorder in up to 50% of pregnant women who experience depression. Increased antidepressant dosing during pregnancy may be required to maintain euthymia; however, guidelines for effective dosing levels are absent. Consequently, many patients remain inadequately treated. Substantial maternal and fetal morbidity including substance abuse, functional impairment, increased risk of postnatal depression, and poor pregnancy outcomes have resulted from untreated depression.The consequences of those outcomes are likely to be associated with substantial clinical, social and economic burdens. An incidence-based assessment of the consequences of prenatal depression would be useful in order to: (i) establish the impact on the quality of life of these patients and their families; (ii) assess the associated economic burden on individual families and the healthcare system; and (iii) to provide epidemiological data to enable the provision of suitable management strategies for these patients.


Moving inwards, moving outwards, moving upwards: the role of spirituality during the early stages of breast cancer.
The paper reflects on a study which explored the role of spirituality in the lives of women during the first year after being diagnosed with breast cancer. The study utilised a qualitative method (hermeneutic phenomenology) designed to provide rich and thick understanding of women's experiences of breast cancer and to explore possible ways in which spirituality may, or may not, be beneficial in enabling coping and enhancing quality of life. The paper draws on the thinking of David Hay and Viktor Frankl to develop a model of spirituality that includes, but is not defined by, religion and that has the possibility to facilitate effective empirical enquiry. It outlines a threefold movement - inwards, outwards and upwards - that emerged from in-depth interviews with women who have breast cancer. This framework captures something of the spiritual movement that women went through on their cancer journeys and offers some pointers and possibilities for better and more person-centred caring approaches that include recognition of the spiritual dimension of women's experiences for the management of those with breast cancer.


Baby booms and busts: waves in fertility patterns.
Fertility curves sometimes resemble sea waves. During periods that the fertility age patterns change, according to whatever reason, 'this sea' may become very turbulent. Also other sea-like phenomena, for example tsunamis, are discernible in fertility behaviour. This article gives a short overview of the relationships between age of the mother and the birth of her children by birth order, and the similarities with sea wave behaviour. We look at fertility behaviour from two perspectives: children born per calendar year versus mother's year of birth. Evidence comes from three European countries in the past decades. Politicians should keep distant from trying to change fertility levels as that easily can lead to regrettable waves in age group sizes.


Conversion of recent-onset atrial fibrillation with intravenous amiodarone: a meta-analysis of randomized controlled trials.
To evaluate efficacy and safety of intravenous amiodarone for conversion of recent-onset atrial fibrillation. MEDLINE search of published, randomized, controlled trials assessing the efficacy and safety of intravenous amiodarone in recent-onset (< 7 days) atrial fibrillation, supplemented with searches of reference lists of identified articles and bibliographies of secondary and tertiary review articles. The identified trials were eligible for meta-analysis if they met the following criteria: patients had recent-onset atrial fibrillation; patients were randomized to intravenous amiodarone, placebo, or another antiarrhythmic agent; no other antiarrhythmic agent except digoxin was administered simultaneously with intravenous amiodarone or other active treatments; the number and percentage of conversions to sinus rhythm after treatment began were reported; and the number and type of adverse drug reactions occurring after treatment began were reported. Eighteen randomized controlled trials, including active control cohorts and placebo cohorts, met inclusion criteria. Atrial fibrillation was spontaneous in 13 trials, postoperative in 4, and combined spontaneous and postoperative in 1. A total of 550 patients received intravenous amiodarone, 451 received other antiarrhythmic therapy, and 202 received placebo. Unadjusted averages for cardioversion were as follows: intravenous amiodarone, 417 (76%) of 550 patients; other antiarrhythmics, 324 (72%) of 451 patients; and placebo, 121 (60%) of 202 patients. Pooled estimates of cardioversion for active cohort studies were 72.1% for intravenous amiodarone and 71.9% for other antiarrhythmics (p=0.84). Pooled estimates of cardioversion for placebo cohort studies were 82.4% for intravenous amiodarone and 59.7% for placebo (p=0.03). Unadjusted averages for adverse event rates were intravenous amiodarone, 94 (17%) of 550 patients; other antiarrhythmics, 63 (14%) of 451 patients; and placebo, 23 (11%) of 202 patients. Pooled estimates of adverse event rates for active cohort studies were 12.2% for intravenous amiodarone and 14.0% for other antiarrhythmics (p=0.64). Pooled estimates of adverse event rates for placebo cohort studies were 26.8% for intravenous amiodarone and 10.8% for placebo (p=0.02). The most common adverse drug reactions reported with intravenous amiodarone were infusion phlebitis, bradycardia, and hypotension. The efficacy and safety profile of intravenous amiodarone is similar to that of other antiarrhythmics for cardioversion of recent-onset atrial fibrillation. Intravenous amiodarone is significantly more effective than placebo but is associated with significantly higher frequency of adverse events, although most were not considered to be dose limiting.


Immortal data: a qualitative exploration of patients' understandings of genomic data.
As ambitions to 'mainstream' genetic and genomic medicine in the UK advance, patients are increasingly exposed to information about genomic data. Unlike the results of many other medical investigations which are linked to the time of sample collection, genomic testing provides immortal data that do not change across time, and may have relevance for relatives and generations far beyond the patient's own lifespan. This immortality raises new ethical challenges for healthcare professionals, patients and families alike, such as ensuring consent for possible future interpretations; determining when genomic data are best sought (at birth, on illness etc) and reinterpreted; and balancing the confidentiality of patients and duties of care towards others. This paper reports on qualitative work exploring the perspectives of patients and relatives participating in genomic testing, and suggests that their engagements with this immortality are shaped by: the contrast between the simplicity of sample provision and information gathered; understandings of heritability; and notions of genomic data as a collective resource. We discuss the implications this holds for practice and argue that the immortality of genomic data must take a more prominent position in patient and healthcare professional interactions.


VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.
Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells.


Ecological niche modeling in Maxent: the importance of model complexity and the performance of model selection criteria.
Maxent, one of the most commonly used methods for inferring species distributions and environmental tolerances from occurrence data, allows users to fit models of arbitrary complexity. Model complexity is typically constrained via a process known as L1 regularization, but at present little guidance is available for setting the appropriate level of regularization, and the effects of inappropriately complex or simple models are largely unknown. In this study, we demonstrate the use of information criterion approaches to setting regularization in Maxent, and we compare models selected using information criteria to models selected using other criteria that are common in the literature. We evaluate model performance using occurrence data generated from a known "true" initial Maxent model, using several different metrics for model quality and transferability. We demonstrate that models that are inappropriately complex or inappropriately simple show reduced ability to infer habitat quality, reduced ability to infer the relative importance of variables in constraining species' distributions, and reduced transferability to other time periods. We also demonstrate that information criteria may offer significant advantages over the methods commonly used in the literature.


Development of chronic pain following severe accidental injury. Results of a 3-year follow-up study.
Motor vehicle accidents (MVA) and work-related injuries are two of the more common causes of chronic pain. Nevertheless, there is little evidence on predicting factors regarding the development of chronic pain following physical injury. The present study investigated temporal associations between accident-related factors, psychological factors [symptoms of posttraumatic stress disorder (PTSD), anxiety, depression, coping], and the development of chronic pain in a sample of individuals who had sustained severe accidental injuries (N=90). Assessments were performed within 1 month of the accident, and at 6, 12, and 36 months post trauma. A total of 40 individuals (44%) reported accident-related pain 3 years after the accident. Individuals with chronic pain showed significantly more symptoms of PTSD, depression, and anxiety, more disability, and more days off work. Analysis of temporal associations between psychological variables and the development of chronic pain indicated that the separation of the pain from the nonpain group mostly occurred between 6 (T2) and 12 months (T3). Differences were much less pronounced at T1. The prevalence of chronic pain in severely injured patients 3 years after the accident is considerably high. The development of chronic pain is more related to psychological factors, particularly PTSD symptoms, in the aftermath of the accident, as compared to sociodemographic and accident-related variables at the time of the accident. These findings may be helpful to elucidate the problems in predicting chronic pain conditions in injured subjects and to recognize the onset of a chronic pain condition more reliably.


Novel plasma biomarker surrogating cerebral amyloid deposition.
Alzheimer's disease (AD) is the most common and devastating dementia. Simple and practical biomarkers for AD are urgently required for accurate diagnosis and to facilitate the development of disease-modifying interventions. The subjects for the study were selected on the basis of PiB amyloid imaging by PET. Forty PiB-positive (PiB+) individuals, including cognitively healthy controls (HC), and mild cognitive impairment and AD individuals, and 22 PiB-negative (PiB-) HC participated. Employing our novel highly sensitive immunoprecipitation-mass spectrometry, we measured plasma amyloid β-proteins (Aβs; Aβ1-40 and Aβ1-42) and Aβ-approximate peptides (AβAPs), which were cleaved from amyloid precursor protein (APP). Among the AβAPs, APP669-711 appeared to be a good reference for deciphering pathological change of Aβ1-42. We evaluated the performance of the ratio of APP669-711 to Aβ1-42 (APP669-711/Aβ1-42) as a biomarker. APP669-711/Aβ1-42 significantly increased in the PiB+ groups. The sensitivity and specificity to discriminate PiB+ individuals from PiB- individuals were 0.925 and 0.955, respectively. Our plasma biomarker precisely surrogates cerebral amyloid deposition.


Revealing the radiative and non-radiative relaxation rates of the fluorescent dye Atto488 in a λ/2 Fabry-Pérot-resonator by spectral and time resolved measurements.
Using a Fabry-Pérot-microresonator with controllable cavity lengths in the λ/2-regime, we show the controlled modification of the vibronic relaxation dynamics of a fluorescent dye molecule in the spectral and time domain. By altering the photonic mode density around the fluorophores we are able to shape the fluorescence spectrum and enhance specifically the probability of the radiative transitions from the electronic excited state to distinct vibronic excited states of the electronic ground state. Analysis and correlation of the spectral and time resolved measurements by a theoretical model and a global fitting procedure allows us to reveal quantitatively the spectrally distributed radiative and non-radiative relaxation dynamics of the respective dye molecule under ambient conditions at the ensemble level.


The role of iron nitrides in the Fe-N-C catalysis system towards the oxygen reduction reaction.
Fe-N-C series catalysts are always attractive for their high catalytic activity towards the oxygen reduction reaction (ORR). However, they usually consist of various components such as iron nitrides, metallic iron, iron carbides, N-doped carbon and Fe-N4 moieties, leading to controversial contributions of these components to the catalysis of the ORR, especially iron nitrides. In this work, to investigate the function of iron nitrides, FexN nanoparticles (NPs) embedded in mesoporous N-doped carbon without Fe-N4 moieties are designed and constructed by a simple histidine-assisted method. Herein, the use of histidine can increase the N and Fe contents in the product. The obtained catalyst exhibits excellent ORR catalytic activity which is very close to that of the commercial Pt/C catalyst in alkaline electrolytes. Combining the catalytic activity, structural characterization (especially from Mössbauer spectroscopy), and the results of DFT calculations for adsorption energies of oxygen on the main surfaces of Fe2N including ε-Fe2N and ζ-Fe2N, it can be deduced that Fe2N NPs as active species make a contribution to the ORR catalysis, of which ε-FexN (x ≤ 2.1) is more active than ζ-Fe2N. In addition, we find that there exists an obvious synergistic effect between Fe2N NPs and N-doped carbon, leading to the greatly enhanced ORR catalytic activity.


Senior citizens as rescuers: Is reduced knowledge the reason for omitted lay-resuscitation-attempts? Results from a representative survey with 2004 interviews.
Resuscitation (CPR) provided by a bystander prior to the arrival of the emergency services is a beneficial factor for surviving a cardiac arrest (CA). Our registry-based data show, that older patients receive bystander-CPR less frequently. Little is known on possible reasons for this finding. We sought to investigate the hypothesis that awareness of CPR measures is lower in older laypersons being a possible reason for less CPR-attempts in senior citizens. 1206 datasets on bystander resuscitations actually carried out were analyzed for age-dependent differences. Subsequently, we investigated whether the knowledge required carrying out bystander-CPR and the self-confidence to do so differ between younger and older citizens using computer-assisted telephone interviewing. 2004 interviews were performed and statistically analyzed. A lower level of knowledge to carry out bystander-CPR was seen in older individuals. For example, 82.4% of interviewees under 65 years of age, knew the correct emergency number. In this group, 66.6% named CPR as the relevant procedure in CA. Among older individuals these responses were only given by 75.1% and 49.5% (V = 0.082; P < 0.001 and V = 0.0157; P < 0.001). Additionally, a difference concerning participants' confidence in their own abilities was detectable. 58.0% of the persons younger than 65 years were confident that they would detect a CA in comparison to 44.6% of the participants older than 65 years (V = 0.120; P < 0.001). Similarly, 62.7% of the interviewees younger than 65 were certain to know what to do during CPR compared to 51.3% of the other group (V = 0.103; P < 0.001). Lower levels of older bystanders' knowledge and self-confidence might provide an explanation for why older patients receive bystander-CPR less frequently. Further investigation is necessary to identify causal connections and optimum ways to empower bystander resuscitation.


Test-retest reliability of wideband reflectance measures in infants under screening and diagnostic test conditions.
The main goal of this study was to examine the test-retest reliability of wideband reflectance (WBR) measures collected from infants in screening and diagnostic hearing test environments. In addition, the results of WBR testing for infants who passed and failed otoacoustic emission (OAE) screening were examined to determine whether these measures distinguished between the two groups. Repeated WBR measures were collected from two groups of infants, one group tested in an outpatient hearing screening setting and the other group in a diagnostic test setting. For a total of 127 infants and a control group of 10 adults, repeated WBR measurements were made with the probe left in place between the two tests (T1 and T2) and after reinsertion of the probe (T3) for a total of 3 measurements. Test-retest differences were calculated for each individual across one-third octave frequency bands, and the mean and 90th percentile were calculated by subject group and OAE results. WBR patterns were also compared between infants who passed versus failed OAE screening. Mean test-retest differences were smaller for the diagnostic group than for the screening group. Test-retest differences were largest for the reinsertion condition and for the frequencies below 500 Hz. While the low frequencies were variable, the test-retest differences were smallest in the mid-frequency range which is thought to be the frequency range most sensitive to middle ear dysfunction. Test-retest performance did not differ between infants who passed or failed OAE screening. However, infants who failed OAE screening had significantly higher WBR in the range from 630 to 2000 Hz than infants who passed OAE screening. Test-retest performance was poor for frequencies below 500 Hz, but in general test-retest differences were small across the important mid-frequency range. Reinsertion of the probe between repeated tests yielded larger and more variable test-retest differences. Careful monitoring of probe fit and testing while infants are in a quiet state appears to be critical for obtaining reliable WBR results. Analysis of WBR results indicated significantly higher reflected energy in the mid-frequency range for infants who failed OAE screening than for those who passed OAE screening. Although conclusions are limited by the fact that the true status of the middle ear and cochlea were not known for the infants in this study, this result may indicate that a number of these infants failed OAE screening due to transient or permanent middle ear dysfunction which was detected by WBR.


TCF7L2 variants associate with CKD progression and renal function in population-based cohorts.
Genetic variants may increase susceptibility to both diabetes and kidney disease. Whether known diabetes-associated variants in the transcription factor 7-like 2 (TCF7L2) gene are associated with chronic kidney disease (CKD) progression and markers of kidney function is unknown. Participants of the Atherosclerosis Risk in Communities Study (ARIC; n = 11,061 self-identified white and n = 4014 black), Framingham Heart Offspring Cohort (FHS; n = 2468), and Heredity and Phenotype Intervention Heart Study (HAPI; n = 861) were genotyped at five (ARIC) and two (FHS) common TCF7L2 variants. The diabetes-conferring risk alleles at rs7903146 and rs7901695 were significantly associated with CKD progression among ARIC participants overall and among those without baseline diabetes. The overall adjusted hazard ratios per rs7903146 T allele were 1.17 (95% confidence interval [CI] 1.04 to 1.32) for white individuals and 1.20 (95% CI 1.03 to 1.41) for black individuals. Similarly, the overall hazard ratios per rs7901695 C allele were 1.19 (95% CI 1.06 to 1.34) for white individuals and 1.27 (95% CI 1.09 to 1.48) for black individuals. The FHS cohort supported these results: The rs7903146 T allele was significantly associated with lower estimated GFR (P = 0.01) and higher cystatin C (P = 0.004) in adjusted analyses overall and among those without diabetes. In the HAPI cohort, the rs7901695 C allele was significantly associated with lower estimated GFR in adjusted analyses (P = 0.049), as were several variants upstream and downstream of TCF7L2 (P < 0.003). No identified variant in the ARIC or FHS cohorts was associated with albuminuria. In conclusion, several population-based samples suggest that variants in the TCF7L2 gene are associated with reduced kidney function or CKD progression, overall and specifically among participants without diabetes.


Atrial Fibrillation and Metabolic Syndrome: Understanding the Connection.
Metabolic syndrome, a constellation of conditions including obesity, dyslipidemia, hypertension and insulin resistance, has increased to epidemic proportions. Metabolic syndrome has been recognized as a risk factor for cardiovascular morbidity and is likely related to the epidemic of cardiovascular diseases. Perhaps not coincidentally, its growth in incidence has paralleled that of atrial fibrillation. Various components of metabolic syndrome have been known to have a role in the pathogenesis of atrial fibrillation. With the conglomeration of components seen in the metabolic syndrome, the risk for atrial fibrillation increases greatly. Several studies have elucidated the role of metabolic syndrome in the development of atrial fibrillation. Its role on the atrial substrate makes it an important determinant of progression of disease and failure of therapeutic strategies such as catheter ablation. Control of the various components of metabolic syndrome may ultimately lead to better outcomes in atrial fibrillation patients.


The Candida albicans INT1 gene facilitates cecal colonization in endotoxin-treated mice.
Increased intestinal colonization with Candida albicans is believed to be a major predisposing factor to systemic candidiasis. Previous evidence has implicated the C. albicans INT1 gene in hyphal development, epithelial adherence, and mouse virulence. The effect of INT1 on mouse cecal colonization was measured using a parent strain (CAF2, INT1/INT1), an int1 deletion homozygote (CAG3, int1/int1), and a heterozygous reintegrant (CAG5, int1/int1 + INT1). Forty-eight hours after oral inoculation of 10(7) C. albicans into normal mice, only low numbers of each strain were recovered from the cecal flora. In mice pretreated with oral bacitracin/streptomycin, cecal colonization of each C. albicans strain was increased compared to the corresponding strain inoculated into untreated mice, with the CAF2 parent strain greater (P < 0.01) than the two mutant strains, and with the heterozygous and homozygous mutants not different from each other. In mice pretreated with parenteral lipopolysaccharide (LPS), in addition to oral antibiotics, numbers of cecal CAF2, CAG5, and CAG3 were increased (P < 0.01) compared to the corresponding strain inoculated into mice treated with antibiotics alone. In LPS-treated mice, numbers of cecal C. albicans CAF2 (INT1/INT1) were greater (P < 0.05) than C. albicans CAG3 (int1/int1). Thus, parenteral LPS had an additive effect on C. albicans cecal colonization in antibiotic-treated mice, and the presence of two functional copies of the INT1 gene appeared to facilitate colonization in both antibiotic-treated mice and in mice treated with antibiotics plus parenteral endotoxin.


Fossils of uncertain affinity from the upper devonian of iowa.
Thousands of specimens of the enigmatic fossil Gluteus minimus (new genus, newt species) occur in a 5-centimeter-thick interval within the Maple Mill Shale and in equivalent deposits of the Devonian of eastern Iowa. They are roughly lenticular. bilobed fossils up to 11 millimeters in diamiter and 8 milllimeters thic. These objects consistently asymmetrical in the same direction. defy placement in any known higher taxon when their morphology. histology, and apatitic composition considered.


Being the Family Caregiver of a Patient With Dementia During the Coronavirus Disease 2019 Lockdown.
Background: Family caregivers of patients with dementia are at high risk of stress and burden, and quarantine due to the coronavirus disease 2019 (COVID-19) pandemic may have increased the risk of psychological disturbances in this population. The current study was carried out during the national lockdown declared in March 2020 by the Italian government as a containment measure of the first wave of the coronavirus pandemic and is the first nationwide survey on the impact of COVID-19 lockdown on the mental health of dementia informal caregivers. Methods: Eighty-seven dementia centers evenly distributed on the Italian territory enrolled 4,710 caregiver-patient pairs. Caregivers underwent a telephone interview assessing classical symptoms of caregiver stress and concern for the consequences of COVID-19 infection on patient's health. We calculated prevalence of symptoms and regressed them on various potential stress risk factors: caregivers' sociodemographic characteristics and lifestyle, patients' clinical features, and lockdown-related elements, like discontinuity in medical care. Results: Approximately 90% of caregivers reported at least one symptom of stress, and nearly 30% reported four or more symptoms. The most prevalent symptoms were concern for consequences of COVID-19 on patient's health (75%) and anxiety (46%). The main risk factors for stress were identified as a conflicting relationship with the patient and discontinuity in assistance, but caregiver's female sex, younger age, lower education, and cohabitation with the patient also had an impact. Availability of help from institutions or private individuals showed a protective effect against sense of abandonment but a detrimental effect on concern about the risk for the patient to contract COVID-19. The only protective factor was mild dementia severity, which was associated with a lower risk of feeling isolated and abandoned; type of dementia, on the other hand, did not affect stress risk. Conclusion: Our results demonstrate the large prevalence of stress in family caregivers of patients with dementia during the COVID-19 pandemic and have identified both caregivers and situations at a higher risk of stress, which should be taken into account in the planning of interventions in support of quarantined families and patients.


Suicidal behaviour on subway systems: a review of the epidemiology.
Suicide on subway systems is a public health challenge that has been reported in urban centers worldwide. Our objective was to analyze studies of suicide on subway systems, develop a profile of characteristics that are suggestive of association with suicides or attempts, and show how this profile can inform prevention. A literature review involving epidemiology studies and studies relating to subway suicide was conducted. Twenty-eight studies were included in this review. Across studies, characteristics were not often assessed for risk factor status, although several characteristics were remarkably similar. Those attempting suicide on the subway appear to be affected by serious mental illness and have contact with mental health services before the suicidal behavior. Several characteristics may be shared among this population, emphasizing the potential for prevention in clinical and public health domains. Well-designed studies that utilize robust data collection and statistical methods are needed to establish the risk status associated with these characteristics.


Assessment of the anti-inflammatory, analgesic and sedative effects of oleuropein from Olea europaea L.
More and more studies show that inflammation, pain and insomnia have become the main common diseases. Effective treatments of inflammation, pain and insomnia have become an issue of primary concern in clinical practice. Oleuropein (OLE), the main phenolic component of Mediterranean extra virgin olive oil, has shown many pharmacological properties. In the present study, the anti-inflammatory effect of OLE was firstly evaluated using RAW264.7 macrophages subjected to stimulation with lipopolysaccharide (LPSC). The results obtained revealed that OLE caused significant and dose-dependent downregulation of nitric (NO), COX-2, inducible NO synthase iNOS, and the inflammation-associated cytokines IL-6 and TNF-α. From the mechanism, the expression of COX-2, cytokines IL-6 and TNF-α OLE is closely related to analgesic and sedation effect. Further evaluations showed significant analgesic and sedative effects of OLE in tail-flick test and sedation test conducted in SD rats in vivo. All these results indicate that OLE has anti-inflammatory, analgesic and sedative effects both in vitro and in vivo.


Reciprocal Relations between the Trajectories of Mothers' Harsh Discipline, Responsiveness and Aggression in Early Childhood.
Theoretical advances in the study of the development of aggressive behaviors indicate that parenting behaviors and child aggression mutually influence one another. This study contributes to the body of empirical research in this area by examining the development of child aggression, maternal responsiveness, and maternal harsh discipline, using 5-year longitudinal data from a nationally representative sample of Turkish children (n = 1009; 469 girls and 582 boys). Results indicated that: (i) maternal responsiveness and harsh discipline at age 3 were associated with the subsequent linear trajectory of aggression; (ii) reciprocally, aggressive behaviors at age 3 were associated with the subsequent linear trajectories of these two types of parenting behaviors; (iii) deviations from the linear trajectories of the child and mother behaviors tended to be short lived; and, (iv) the deviations of child behaviors from the linear trajectories were associated with the subsequent changes in mother behaviors after age 5. These findings are discussed in the cultural context of this study.


Actin filaments as tension sensors.
The field of mechanobiology has witnessed an explosive growth over the past several years as interest has greatly increased in understanding how mechanical forces are transduced by cells and how cells migrate, adhere and generate traction. Actin, a highly abundant and anomalously conserved protein, plays a large role in forming the dynamic cytoskeleton that is so essential for cell form, motility and mechanosensitivity. While the actin filament (F-actin) has been viewed as dynamic in terms of polymerization and depolymerization, new results suggest that F-actin itself may function as a highly dynamic tension sensor. This property may help explain the unusual conservation of actin's sequence, as well as shed further light on actin's essential role in structures from sarcomeres to stress fibers.


Regionwide sharing for status 1 liver patients--beneficial impact on waiting time and pre- and posttransplant survival.
On August 21, 1999, Region 7 of the United Network for Organ Sharing (UNOS) adopted a policy of regionwide sharing of cadaver livers for UNOS Status 1 recipients. We examined what impact this policy had at our center on their waiting times, waiting list mortality, and outcomes. From January 1, 1995, through December 31, 2002, our center listed 39 patients for an emergent (Status 1) transplant, according to the current criteria for Status 1 listing: patients (adult and pediatric) with fulminant hepatic failure (FHF), hepatic artery thrombosis, or primary nonfunction early after a liver transplant, or critically ill pediatric patients with chronic liver disease. These 39 candidates were analyzed in 2 groups: those listed before regionwide sharing (Group I, n = 19) and those listed after (Group II, n = 20). Patient characteristics did not differ significantly between the 2 groups, including mean donor and recipient age, proportion of pediatric patients, and type of graft used (i.e., living or deceased donor, segmental or whole-organ). FHF was the most common cause of liver failure in both groups-74% versus 70% (P = ns). The next most common cause in both groups was hepatic artery thrombosis, followed by primary nonfunction. Most transplants used deceased donors; however, 2 of the transplants in Group I versus only 1 in Group II used living donors. Waiting list mortality (the patient death rate before a transplant could take place) was 32% in Group I versus only 5% in Group II (P =.03). The mean number of days on the waiting list was also substantially lower in Group II (2.9 days) than in Group I, (5.8 days) (P =.04). For patients who underwent a transplant, graft and patient survival rates at 6 months posttransplant were 69.2% in Group I versus 89.5% in Group II (P =.03). In conclusion, the introduction of regionwide sharing seems to have been of benefit for Status 1 patients at our center. They have a significantly lower risk of dying while waiting for a transplant and undergo one in a much shorter period of time.


Circuit topology of proteins and nucleic acids.
Folded biomolecules display a bewildering structural complexity and diversity. They have therefore been analyzed in terms of generic topological features. For instance, folded proteins may be knotted, have beta-strands arranged into a Greek-key motif, or display high contact order. In this perspective, we present a method to formally describe the topology of all folded linear chains and hence provide a general classification and analysis framework for a range of biomolecules. Moreover, by identifying the fundamental rules that intrachain contacts must obey, the method establishes the topological constraints of folded linear chains. We also briefly illustrate how this circuit topology notion can be applied to study the equivalence of folded chains, the engineering of artificial RNA structures and DNA origami, the topological structure of genomes, and the role of topology in protein folding.


A national approach for automated collection of standardized and population-based radiation therapy data in Sweden.
To develop an infrastructure for structured and automated collection of interoperable radiation therapy (RT) data into a national clinical quality registry. The present study was initiated in 2012 with the participation of seven of the 15 hospital departments delivering RT in Sweden. A national RT nomenclature and a database for structured unified storage of RT data at each site (Medical Information Quality Archive, MIQA) have been developed. Aggregated data from the MIQA databases are sent to a national RT registry located on the same IT platform (INCA) as the national clinical cancer registries. The suggested naming convention has to date been integrated into the clinical workflow at 12 of 15 sites, and MIQA is installed at six of these. Involvement of the remaining 3/15 RT departments is ongoing, and they are expected to be part of the infrastructure by 2016. RT data collection from ARIA®, Mosaiq®, Eclipse™, and Oncentra® is supported. Manual curation of RT-structure information is needed for approximately 10% of target volumes, but rarely for normal tissue structures, demonstrating a good compliance to the RT nomenclature. Aggregated dose/volume descriptors are calculated based on the information in MIQA and sent to INCA using a dedicated service (MIQA2INCA). Correct linkage of data for each patient to the clinical cancer registries on the INCA platform is assured by the unique Swedish personal identity number. An infrastructure for structured and automated prospective collection of syntactically interoperable RT data into a national clinical quality registry for RT data is under implementation. Future developments include adapting MIQA to other treatment modalities (e.g. proton therapy and brachytherapy) and finding strategies to harmonize structure delineations. How the RT registry should comply with domain-specific ontologies such as the Radiation Oncology Ontology (ROO) is under discussion.


Two-film reflection polarizers: theory and application.
An analysis is made of reflection polarizers consisting of two transparent films on an absorbing substrate. A method is described for determining the angles of incidence at which the reflectance of either component of polarization is extinguished. It is demonstrated that polarized light can be obtained over a finite range of incidence angles. This is in contrast to a polarizer having a single transparent film, where polarization occurs only at a specific angle of incidence. At each angle of incidence in the polarizing range, any one of a number of discrete thicknesses of the films can be used to obtain polarized light; and the procedures for finding these thicknesses are described. Numerical application of the theory was made for metallic substrates that range from good to intermediate reflectors. The results serve to illustrate most of the significant characteristics of two-film polarizers. It was shown that two-film systems can yield reasonably high values of the unextinguished component, with minimal sensitivity of the extinguished component to off-design conditions.


Liposome-mediated extracellular superoxide dismutase gene delivery protects against acute liver injury in mice.
Our previous study demonstrated that polycationic liposomes are highly stable in the bloodstream and represent an effective agent for liver gene delivery. We report here that liposome-mediated extracellular superoxide dismutase (EC-SOD) gene delivery successfully prevented acute liver injury in mice. The therapeutic efficacy of EC-SOD gene delivery by polycationic liposomes was determined against the toxicity of superoxide anions and hydroxyethyl radicals in HepG2 cells and in a mouse model of acute liver injury caused by D-galactosamine and lipopolysaccharide intoxication. Transfection of HepG2 cells with an EC-SOD plasmid led to a striking increase in superoxide dismutase activity in the medium. The transfected cells had much less cell death after reactive oxygen species exposure compared with untransfected or control plasmid-transfected cells. In a model of acute liver injury, serum alanine aminotransferase levels in mice receiving portal vein injections of EC-SOD lipoplexes were much lower than in those receiving normal saline, liposomes alone, or control lipoplexes. Liver histology confirmed that there was less cell death in the EC-SOD lipoplex-treated group. Quantitative reverse transcriptase polymerase chain reaction showed a 55-fold increase in human EC-SOD gene expression in the liver of mice injected with EC-SOD lipoplexes. Serum superoxide dismutase activity in EC-SOD lipoplex-treated mice was higher than in the control groups; this was associated with higher liver glutathione levels and reduced lipid peroxidation. In conclusion, polycationic liposome-mediated EC-SOD gene delivery protects against reactive oxygen species toxicity in vitro and against lipopolysaccharide-induced acute liver injury in D-galactosamine-sensitized mice.


Circular polarization intrinsic optical signal recording of stimulus-evoked neural activity.
Linear polarization intrinsic optical signal (LP-IOS) measurement can provide sensitive detection of neural activities in stimulus-activated neural tissues. However, the LP-IOS magnitude and signal-to-noise ratio (SNR) are highly correlated with the nerve orientation relative to the polarization plane of the incident light. Because of the complexity of orientation dependency, LP-IOS optimization and outcome interpretation are time consuming and complicated. In this study, we demonstrate the feasibility of circular polarization intrinsic optical signal (CP-IOS) measurement. Our theoretical modeling and experimental investigation indicate that CP-IOS magnitude and SNR are independent from the nerve orientation. Therefore, CP-IOS promises a practical method for polarization IOS imaging of complex neural systems.


Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
Mesenchymal stem cells have been recently described to localize to breast carcinomas, where they integrate into the tumour-associated stroma. However, the involvement of mesenchymal stem cells (or their derivatives) in tumour pathophysiology has not been addressed. Here, we demonstrate that bone-marrow-derived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly when this cell mixture is introduced into a subcutaneous site and allowed to form a tumour xenograft. The breast cancer cells stimulate de novo secretion of the chemokine CCL5 (also called RANTES) from mesenchymal stem cells, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. This enhanced metastatic ability is reversible and is dependent on CCL5 signalling through the chemokine receptor CCR5. Collectively, these data demonstrate that the tumour microenvironment facilitates metastatic spread by eliciting reversible changes in the phenotype of cancer cells.


Origin, Evolution, and Movement of Microlayer in Pool Boiling.
The microlayer thin film is visualized in situ in a vapor bubble during pool boiling. Contrary to current understanding, bubbles originate on hydrophilic and silane-coated hydrophobic surfaces without a three-phase contact line, i.e., the microlayer completely covers the bubble base. The occurrence of such a wetted bubble base is found to be dependent on the liquid-solid interaction. As the bubble grows in time, the film decreases in thickness, eventually forming the contact line and dry region. During this drying out process, curvature at the center of the microlayer shows a cyclical behavior due to competing Marangoni and capillary flows, and is characterized as a "dryout viscosity". After the dry region forms, the mechanism of contact line/microlayer movement of a single bubble on the hydrophilic surface is experimentally determined, and a generalized expression of energy required for its unpinning and movement is defined.


Functional self-assembled nanovesicles based on β-cyclodextrin, liposomes and adamantyl guanidines as potential nonviral gene delivery vectors.
Multicomponent self-assembled supramolecular nanovesicles based on an amphiphilic derivative of β-cyclodextrin and phosphatidylcholine liposomes (PC-liposomes) functionalized with four structurally different adamantyl guanidines were prepared and characterized. Incorporation efficiency of the examined adamantyl guanidines as well as size and surface charge of the prepared supramolecular nanovesicles was determined. Changes in the surface charge of the prepared nanovesicles confirmed that guanidinium groups were exposed on the surface. ITC and 1H NMR spectroscopy complemented by molecular dynamics (MD) simulations were used to elucidate the structural data and stability of the inclusion complexes of β-cyclodextrin and adamantyl guanidines (AG1-5). The results are consistent and point to a significant contribution of the guanylhydrazone residue to the complexation process for AG1 and AG2 with β-cyclodextrin. In order to evaluate the potential of the self-assembled supramolecular nanomaterial as a nonviral gene delivery vector, fluorescence correlation spectroscopy was used. It showed that the prepared nanovesicles functionalized with adamantyl guanidines AG1-4 effectively recognize and bind the fluorescently labelled DNA. Furthermore, gel electrophoretic assay confirmed the formation of nanoplexes of functionalized nanovesicles and plasmid DNA. These findings together suggest that the designed supramolecular nanovesicles could be successfully applied as nonviral gene delivery vectors.


Repeatability of 18F-FDG PET Radiomic Features in Cervical Cancer.
Knowledge of the intrinsic variability of radiomic features is essential to the proper interpretation of changes in these features over time. The primary aim of this study was to assess the test-retest repeatability of radiomic features extracted from 18F-FDG PET images of cervical tumors. The impact of different image preprocessing methods was also explored. Methods: Patients with cervical cancer underwent baseline and repeat 18F-FDG PET/CT imaging within 7 d. PET images were reconstructed using 2 methods: ordered-subset expectation maximization (PETOSEM) or ordered-subset expectation maximization with point-spread function (PETPSF). Tumors were segmented to produce whole-tumor volumes of interest (VOIWT) and 40% isocontours (VOI40). Voxels were either left at the default size or resampled to 3-mm isotropic voxels. SUV was discretized to a fixed number of bins (32, 64, or 128). Radiomic features were extracted from both VOIs, and repeatability was then assessed using the Lin concordance correlation coefficient (CCC). Results: Eleven patients were enrolled and completed the test-retest PET/CT imaging protocol. Shape, neighborhood gray-level difference matrix, and gray-level cooccurrence matrix features were repeatable, with a mean CCC value of 0.81. Radiomic features extracted from PETOSEM images showed significantly better repeatability than features extracted from PETPSF images (P < 0.001). Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT (P < 0.001). For most features (78.4%), a change in bin number or voxel size resulted in less than a 10% change in feature value. All gray-level emphasis and gray-level run emphasis features showed poor repeatability (CCC values < 0.52) when extracted from VOIWT but were highly repeatable (mean CCC values > 0.96) when extracted from VOI40Conclusion: Shape, gray-level cooccurrence matrix, and neighborhood gray-level difference matrix radiomic features were consistently repeatable, whereas gray-level run length matrix and gray-level zone length matrix features were highly variable. Radiomic features extracted from VOI40 were more repeatable than features extracted from VOIWT Changes in voxel size or SUV discretization parameters typically resulted in relatively small differences in feature value, though several features were highly sensitive to these changes.


Feedback-mediated reduction in glomerular filtration during acetazolamide infusion in insulin-dependent diabetic patients.
1. A sustained high glomerular filtration rate in diabetes mellitus is associated with increased proximal reabsorption, suggesting alterations in the tubuloglomerular feedback system. To test this hypothesis, renal function was studied in eight control subjects and 14 recent-onset euglycaemic insulin-dependent diabetic patients before and after infusion of the carbonic anhydrase inhibitor, acetazolamide (5 mg/kg body weight). 2. Acetazolamide induced a dramatic fall in glomerular filtration rate in both diabetic patients and control subjects (from 138 +/- 5 to 114 +/- 4 and from 127 +/- 3 to 113 +/- 2 ml min-1 1.73 m-2, respectively, P less than 0.0001). This fall in glomerular filtration rate was strongly correlated with the acetazolamide-induced decrease in absolute proximal reabsorption calculated by using lithium clearance. 3. To further assess the potential role of angiotensin II in the acetazolamide-induced tubulo-glomerular feedback response, 11 additional diabetic patients were investigated before and after the administration of acetazolamide plus the angiotensin-converting enzyme inhibitor, enalaprilat (1.25 mg intravenously). Despite the effective blockade of angiotensin II formation and a slight decrease in renal vascular resistance, the glomerular filtration rate fell significantly and by a similar magnitude as seen with acetazolamide alone. 4. These results indirectly suggest that there is an altered basal tubulo-glomerular feedback system in diabetic patients but a normal response to the increase in distal delivery. No convincing role for an angiotensin II-mediated effect on the afferent limb of the tubuloglomerular feedback response could be demonstrated.


Contemporary results following surgical repair of acute type a aortic dissection (AAAD): a single centre experience.
The study aims to define predictors of neurological dysfunction, 30-day mortality, long-term survival and quality of life following repair of acute type A aortic dissection (AAAD). Between 2000 and 2008, 65 patients underwent repair of AAAD. Sixty-four pre-, intra- and post-operative variables were studied. Mean follow-up was 26.6 months. The mean age was 61years; 60% were male and five had Marfan's syndrome. At presentation, ischaemic ECG changes were seen in 45%, malperfusion syndrome in 59%, moderate-severe aortic regurgitation in 48% and tamponade in 16%. EF was <40% in 17%. There was a delay of >12hours between diagnosis and operation in 64%. Axillary cannulation was performed in 37%. Cerebral protection was by hypothermic arrest (HCA) alone (19%), HCA with retrograde cerebral perfusion (RCP) (11%), or HCA with antegrade cerebral perfusion (ACP) (46%). The procedure was performed on cross-clamp in 24%. Full arch replacement was performed in 14% and concomitant coronary artery grafting was performed in 11%. Post-operative neurological dysfunction was present in 33.8%. The only significant predictor of poor neurological outcome was full arch replacement (p=0.04) on univariate analysis. In-hospital OR 30 mortality was 23.53%. Significant predictors of mortality were low ejection fraction (p=0.017) and post-operative renal failure (p=0.012). Long-term survival was 70% at two years, 50% at five years and 25% at nine years. Functional outcomes and long-term quality of life were assessed in 69% of patients who were alive at last follow-up. Ninety percent of patients reported minimal limitation on functional scores. Quality of life was assessed using the EQ-5D questionnaire. Forty-eight percent of patients recorded full health with an overall mean index of 0.854 (where the best possible score is 1) using the US preference weighted index score. Discharged patients have reasonable long-term survival and good quality of life.


Development of the family symptom inventory: a psychosocial screener for children with hematology/oncology conditions.
A growing body of literature has begun to underscore the importance of integrating family-based comprehensive psychological screening into standard medical care for children with oncology and hematology conditions. There are no known family-based measures designed to screen for clinically significant emotional and behavioral concerns in pediatric oncology and hematology patients. The aim of this study was to develop and evaluate the Family Symptom Inventory (FSI), a brief screener of patient and family member psychological symptoms. The FSI also screens for common comorbid physical symptoms (pain and sleep disturbance) and is designed for use at any point during treatment and follow-up. A total of 488 caregivers completed the FSI during regular hematology/oncology visits for 193 cancer, 219 sickle cell disease, and 76 hematology pediatric patients. Exploratory factor analysis, confirmatory factor analysis, and tests of reliability and preliminary validity were conducted. Exploratory factor analysis suggested a 34-item, 4-factor solution, which was confirmed in an independent sample using confirmatory factor analysis (factor loadings=0.49 to 0.88). The FSI demonstrated good internal reliability (α's=0.86 to 0.92) and good preliminary validity. Regular psychosocial screening throughout the course of treatment and follow-up may lead to improved quality of care for children with oncology and hematology conditions.


Occupying 'in-hospitable' spaces: Parental/primary-caregiver perceptions of the impact of repeated hospitalisation in children under two years of age.
The experience of having a child hospitalised is stressful and disrupts families in myriad ways; however, the experiences of parents/caregivers who encounter repeated admissions of a child with acute lower respiratory infections are under-researched. This project aims to explore these experiences, from a qualitative perspective, using the philosophical tenets of reflective lifeworld research. The research included 14 face-to-face interviews with parents, grandparents, or primary caregivers, of children who, whilst under two years of age, were admitted to hospital multiple times with a lower respiratory infection diagnosis. Many of the participants were from Māori or Samoan ethnic backgrounds. The findings of this single site study revealed that these parents/caregivers' experiences were characterised by feelings of powerlessness, offering descriptions of hospitals as harsh and difficult places to reside, they are 'in-hospitable'. The findings suggest that repeated hospitalisations created a cycle of stressful experiences that impacted both familial relationships and interactions with society. This study draws attention to this previously obscured population group, and calls health care practitioners and policy advisors to engage differently over issues involving families in similar positions.


Approaches to the Management of Acute Kidney Injury in Children.
Acute kidney injury (AKI) causes increased morbidity in critically ill children and damage to the kidney, a central mediator of homeostasis in the body, affects survival. The incidence of AKI in pediatrics is significant and despite alarming data, therapeutic interventions have failed to effect a meaningful difference in outcomes. In this review, we will discuss the epidemiology of AKI in pediatrics, treatment strategies attempted to date, experimental therapies targeting molecular patterns associated with AKI, and highlight the needed direction of AKI research and management. Prospective trials in pediatrics are needed to test the validity of diagnostic tools, to identify the point of most efficacious intervention, and to underscore the therapies that can be effective in the different downstream effects of AKI.


Correlating neurobehavioral performance with biomarkers of organophosphorous pesticide exposure.
There is compelling evidence that adverse neurobehavioral effects are associated with occupational organophosphorous pesticide (OP) exposure in humans. Behavioral studies of pesticide applicators, greenhouse workers, agricultural workers and farm residents exposed repeatedly over months or years to low levels of OPs reveal a relatively consistent pattern of neurobehavioral deficits. However, only two studies have demonstrated a link between neurobehavioral performance and current biomarkers of OP exposure including blood cholinesterase (ChE) activity and urinary levels of OP metabolites. A variety of reasons may explain why so few studies have reported such correlations, including differing individual and group exposure histories, differing methodologies for assessing behavior and exposure, and lack of a reliable index of exposure. Alternatively, these data may suggest that current biomarkers (ChE, urine metabolites) are neither predictive nor diagnostic of the neurobehavioral effects of chronic OP pesticide exposures. This review focuses on the evidence that neurobehavioral performance deficits are associated with occupational OP pesticide exposure and concludes that research needs to return to the basics and rigorously test the relationships between neurobehavioral performance and both current (ChE and urine metabolites) and novel (e.g., inflammation and oxidative stress) biomarkers using human and animal models. The results of such studies are critically important because OP pesticides are widely and extensively used throughout the world, including situations where exposure controls and personal protective equipment are not routinely used.


Effect of surgical intervention on middle-ear cholesteatoma with associated facial paralysis.
To investigate the presenting symptoms, intra-operative findings and long-term facial nerve function in patients treated for cholesteatoma with associated facial paralysis. Fifteen patients with facial paralysis due to middle-ear cholesteatoma who underwent tympanomastoidectomy surgery from February 2000 to February 2015 were retrospectively reviewed. After removal of the cholesteatoma, a limited area of the fallopian canal, in which facial nerve oedema or redness was evident, was opened. Incision of the epineural sheath for nerve decompression was not performed. Pre-operative House-Brackmann grade was grade II in two patients, grade III in four, grade IV in seven, grade V in one and grade VI in one. Facial nerve perineurium damage was observed in two patients with poor prognoses. All patients treated within the first 15 days after paralysis onset showed normal facial function at long-term follow up. Post-operative House-Brackmann grade was grade I in 11 patients, grade II in 1, grade III in 2 and grade VI in 1. Early surgical treatment is more likely to give good results, and poor outcomes are observed in patients with facial nerve perineurium damage.


Reconcilable differences: correcting medication errors at hospital admission and discharge.
Medication errors at the time of hospital admission and discharge are common and can lead to preventable adverse drug events. The objective of this study was to describe the potential impact of a medication reconciliation process to identify and rectify medication errors at the time of hospital admission and discharge. Sixty randomly selected patients were prospectively enrolled at the time of admission to a Canadian community hospital. At admission, patients' medication orders were compared with pre-admission medication use based on medication vials and interviews with patients, caregivers, and/or outpatient healthcare providers. At discharge, pre-admission and in-patient medications were compared with discharge orders and written instructions. All variances were discussed with the prescribing physician and classified as intended or unintended; unintended variances were considered to be medication errors. An internist classified the clinical importance of each unintended variance. Overall, 60% (95% CI 48 to 72) of patients had at least one unintended variance and 18% (95% CI 9 to 28) had at least one clinically important unintended variance. None of the variances had been detected by usual clinical practice before reconciliation was conducted. Of the 20 clinically important variances, 75% (95% CI 56 to 94) were intercepted by medication reconciliation before patients were harmed. Unintended medication variances at the time of hospital admission and discharge are common and clinically important. The medication reconciliation process identified and addressed most of these unintended variances before harm occurred. In this small study, medication reconciliation was a useful method for identifying and rectifying medication errors at times of transition. Reconciliation warrants broader evaluation.


Beating heart on a chip: a novel microfluidic platform to generate functional 3D cardiac microtissues.
In the past few years, microfluidic-based technology has developed microscale models recapitulating key physical and biological cues typical of the native myocardium. However, the application of controlled physiological uniaxial cyclic strains on a defined three-dimension cellular environment is not yet possible. Two-dimension mechanical stimulation was particularly investigated, neglecting the complex three-dimensional cell-cell and cell-matrix interactions. For this purpose, we developed a heart-on-a-chip platform, which recapitulates the physiologic mechanical environment experienced by cells in the native myocardium. The device includes an array of hanging posts to confine cell-laden gels, and a pneumatic actuation system to induce homogeneous uniaxial cyclic strains to the 3D cell constructs during culture. The device was used to generate mature and highly functional micro-engineered cardiac tissues (μECTs), from both neonatal rat and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), strongly suggesting the robustness of our engineered cardiac micro-niche. Our results demonstrated that the cyclic strain was effectively highly uniaxial and uniformly transferred to cells in culture. As compared to control, stimulated μECTs showed superior cardiac differentiation, as well as electrical and mechanical coupling, owing to a remarkable increase in junction complexes. Mechanical stimulation also promoted early spontaneous synchronous beating and better contractile capability in response to electric pacing. Pacing analyses of hiPSC-CM constructs upon controlled administration of isoprenaline showed further promising applications of our platform in drug discovery, delivery and toxicology fields. The proposed heart-on-a-chip device represents a relevant step forward in the field, providing a standard functional three-dimensional cardiac model to possibly predict signs of hypertrophic changes in cardiac phenotype by mechanical and biochemical co-stimulation.


Stress potentiates early and attenuates late stages of visual processing.
Stress can fundamentally alter neural responses to incoming information. Recent research suggests that stress and anxiety shift the balance of attention away from a task-directed mode, governed by prefrontal cortex, to a sensory-vigilance mode, governed by the amygdala and other threat-sensitive regions. A key untested prediction of this framework is that stress exerts dissociable effects on different stages of information processing. This study exploited the temporal resolution afforded by event-related potentials to disentangle the impact of stress on vigilance, indexed by early perceptual activity, from its impact on task-directed cognition, indexed by later postperceptual activity in humans. Results indicated that threat of shock amplified stress, measured using retrospective ratings and concurrent facial electromyography. Stress also double-dissociated early sensory-specific processing from later task-directed processing of emotionally neutral stimuli: stress amplified N1 (184-236 ms) and attenuated P3 (316-488 ms) activity. This demonstrates that stress can have strikingly different consequences at different processing stages. Consistent with recent suggestions, stress amplified earlier extrastriate activity in a manner consistent with vigilance for threat (N1), but disrupted later activity associated with the evaluation of task-relevant information (P3). These results provide a novel basis for understanding how stress can modulate information processing in everyday life and stress-sensitive disorders.


Comparative sound detection abilities of four decapod crustaceans.
Sound perception and detection in decapod crustaceans is surprisingly poorly understood, even though there is mounting evidence for sound playing a critical role in many life history strategies. The suspected primary organ of sound perception is the paired statocysts at the base of the first antennal segment. To better understand the comparative sound detection of decapods, auditory evoked potentials were recorded from the statocyst nerve region of four species (Leptograpsus variegate, Plagusia chabrus, Ovalipes catharus, Austrohelice crassa) in response to two different auditory stimuli presentation methods, shaker table (particle acceleration) and underwater speaker (particle acceleration and pressure). The results showed that there was significant variation in the sound detection abilities between all four species. However, exposure to the speaker stimuli increased all four species sound detection abilities, in terms of both frequency bandwidth and sensitivity, compared with shaker table-derived sound detection abilities. This indicates that there is another sensory mechanism in play as well as the statocyst system. Overall, the present research provides comparative evidence of sound detection in decapods and indicates underwater sound detection in this animal group was even more complex than previously thought.


Emergence of infections with Schistosoma mansoni in the Dhofar Governorate, Oman.
Infections with Schistosoma mansoni were identified in an area of Dhofar (Oman), where this parasite had been virtually absent during recent years and was reported only very sporadically before 1992. In the present survey, performed late in 2001, between 1 and 13% of children (n=519) were found to excrete eggs (one Kato-Katz-smear) in four schools, from four different villages, but no infections were detected in additional five schools (n=281). Infections were light (<72 eggs/g of faeces) in 19 of the 36 children found infected. Serologic examination of sera (n=511) was done by ELISA (based on soluble worm antigen) and immunofluorescence tests (IFT, based on cryostat sections of adult S. mansoni). The prevalence according to serological tests was between 3 and 43% in the four schools with infected children. Positive test results were taken to reflect active infections, since false positive reactions could largely be excluded. According to ultrasound (US) examinations performed on 96 individuals (children and adults) from the four villages, livers were normal in all except three cases of mild pathology, which could be assigned to schistosomiasis mansoni (pattern C, ages 32-40 years). All data suggest that transmission of S. mansoni has been re-introduced only recently in Dhofar and that this emergence of schistosomiasis is limited to at most a few foci.


Birds of Two Oceans? Trans-Andean and Divergent Migration of Black Skimmers (Rynchops niger cinerascens) from the Peruvian Amazon.
Seasonal flooding compels some birds that breed in aquatic habitats in Amazonia to undertake annual migrations, yet we know little about how the complex landscape of the Amazon region is used seasonally by these species. The possibility of trans-Andes migration for Amazonian breeding birds has largely been discounted given the high geographic barrier posed by the Andean Cordillera and the desert habitat along much of the Pacific Coast. Here we demonstrate a trans-Andes route for Black Skimmers (Rynchops niger cinerascens) breeding on the Manu River (in the lowlands of Manu National Park, Perú), as well as divergent movement patterns both regionally and across the continent. Of eight skimmers tracked with satellite telemetry, three provided data on their outbound migrations, with two crossing the high Peruvian Andes to the Pacific. A third traveled over 1800 km to the southeast before transmissions ended in eastern Paraguay. One of the two trans-Andean migrants demonstrated a full round-trip migration back to its tagging location after traveling down the Pacific Coast from latitude 9° South to latitude 37° S, spending the austral summer in the Gulf of Arauco, Chile. This is the first documentation of a trans-Andes migration observed for any bird breeding in lowland Amazonia. To our knowledge, this research also documents the first example of a tropical-breeding waterbird migrating out of the tropics to spend the non-breeding season in the temperate summer, this being the reverse pattern with respect to seasonality for austral migrants in general.