RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1.
Improved clinical predictors for disease progression are needed for localised prostate cancer, since only a subset of patients develop recurrent or refractory disease after first-line treatment. Therefore, we undertook an unbiased analysis to identify RNA biomarkers associated with metastatic progression after prostatectomy. Prostate cancer samples from patients treated with radical prostatectomy at three academic institutions were analysed for gene expression by a high-density Affymetrix GeneChip platform, encompassing more than 1 million genomic loci. In a discovery cohort, all protein-coding genes and known long non-coding RNAs were ranked by fold change in expression between tumours that subsequently metastasised versus those that did not. The top ranked gene was then validated for its prognostic value for metastatic progression in three additional independent cohorts. 95% of the gene expression assays were done in a Clinical Laboratory Improvements Amendments certified laboratory facility. All genes were assessed for their ability to predict metastatic progression by receiver-operating-curve area-under-the-curve analyses. Multivariate analyses were done for the primary endpoint of metastatic progression, with variables including Gleason score, preoperative prostate-specific antigen concentration, seminal vesicle invasion, surgical margin status, extracapsular extension, lymph node invasion, and expression of the highest ranked gene. 1008 patients were included in the study: 545 in the discovery cohort and 463 in the validation cohorts. The long non-coding RNA SChLAP1 was identified as the highest-ranked overexpressed gene in cancers with metastatic progression. Validation in three independent cohorts confirmed the prognostic value of SChLAP1 for metastatic progression. On multivariate modelling, SChLAP1 expression (high vs low) independently predicted metastasis within 10 years (odds ratio [OR] 2·45, 95% CI 1·70-3·53; p<0·0001). The only other variable that independently predicted metastasis within 10 years was Gleason score (8-10 vs 5-7; OR 2·14, 95% CI 1·77-2·58; p<0·0001). We identified and validated high SChLAP1 expression as significantly prognostic for metastatic disease progression of prostate cancer. Our findings suggest that further development of SChLAP1 as a potential biomarker, for treatment intensification in aggressive prostate cancer, warrants future study. Prostate Cancer Foundation, National Institutes of Health, Department of Defense, Early Detection Research Network, Doris Duke Charitable Foundation, and Howard Hughes Medical Institute.


Human coronavirus HKU1 infection of primary human type II alveolar epithelial cells: cytopathic effects and innate immune response.
Because they are the natural target for respiratory pathogens, primary human respiratory epithelial cells provide the ideal in vitro system for isolation and study of human respiratory viruses, which display a high degree of cell, tissue, and host specificity. Human coronavirus HKU1, first discovered in 2005, has a worldwide prevalence and is associated with both upper and lower respiratory tract disease in both children and adults. Research on HCoV-HKU1 has been difficult because of its inability to be cultured on continuous cell lines and only recently it was isolated from clinical specimens using primary human, ciliated airway epithelial cells. Here we demonstrate that HCoV-HKU1 can infect and be serially propagated in primary human alveolar type II cells at the air-liquid interface. We were not able to infect alveolar type I-like cells or alveolar macrophages. Type II alveolar cells infected with HCoV-HKU1 demonstrated formation of large syncytium. At 72 hours post inoculation, HCoV-HKU1 infection of type II cells induced increased levels of mRNAs encoding IL29,CXCL10, CCL5, and IL-6 with no significant increases in the levels of IFNβ. These studies demonstrate that type II cells are a target cell for HCoV-HKU1 infection in the lower respiratory tract, that type II alveolar cells are immune-competent in response to infection exhibiting a type III interferon and proinflammatory chemokine response, and that cell to cell spread may be a major factor for spread of infection. Furthermore, these studies demonstrate that human alveolar cells can be used to isolate and study novel human respiratory viruses that cause lower respiratory tract disease.


The rational clinical examination. Does this patient have aortic regurgitation?
To review evidence as to the precision and accuracy of clinical examination for aortic regurgitation (AR). We conducted a structured MEDLINE search of English-language articles (January 1966-July 1997), manually reviewed all reference lists of potentially relevant articles, and contacted authors of relevant studies for additional information. Each study (n = 16) was independently reviewed by both authors and graded for methodological quality. Most studies assessed cardiologists as examiners. Cardiologists' precision for detecting diastolic murmurs was moderate using audiotapes (kappa = 0.51) and was good in the clinical setting (simple agreement, 94%). The most useful finding for ruling in AR is the presence of an early diastolic murmur (positive likelihood ratio [LR], 8.8-32.0 [95% confidence interval [CI], 2.8-32 to 16-63] for detecting mild or greater AR and 4.0-8.3 [95% CI, 2.5-6.9 to 6.2-11] for detecting moderate or greater AR) (2 grade A studies). The most useful finding for ruling out AR is the absence of early diastolic murmur (negative LR, 0.2-0.3 [95% CI, 0.1-0.3 to 0.2-0.4) for mild or greater AR and 0.1 [95% CI, 0.0-0.3] for moderate or greater AR) (2 grade A studies). Except for a test evaluating the response to transient arterial occlusion (positive LR, 8.4 [95% CI, 1.3-81.0]; negative LR, 0.3 [95% CI, 0.1-0.8]), most signs display poor sensitivity and specificity for AR. Clinical examination by cardiologists is accurate for detecting AR, but not enough is known about the examinations of less-expert clinicians.


Gonorrhoea diagnoses in a network of STI clinics in Spain during the period 2006-2010: differences by sex and transmission route.
Gonorrhoea infection is one of the most common bacterial sexually transmitted infections and an important cause of morbidity and serious complications. The objectives of this paper are: a) to describe gonorrhoea cases diagnosed in a network of 15 (out of 16) STI clinics in Spain during 2006-2010; b) to analyse differences among men who have sex with men (MSM), men who have sex exclusively with women (MSW) and women; and c) to evaluate factors associated to with HIV co-infection. All gonorrhoea cases diagnosed in the network were included (25.7% of total cases notified in Spain). Data were collected by clinical staff. Descriptive/bivariate analyses were carried out stratifying by sex and transmission category; association and trends were evaluated using the chi-square test. Factors associated with HIV co-infection were estimated using a logistic regression model. 2385 cases were included: 55.3% among MSM, 31.3% among MSW and 13.3% among females; cases among MSM increased from 55.8% in 2006 to 62.9% in 2010 while no trends were found among the other two groups.Most MSM cases were Spaniards (72%), aged 25-34 years (46%), 49% reported previous STI and 25% concurrent STI (excluding HIV); casual partners were the commonest source of infection, and 21% of cases had rectal gonorrhoea. MSW cases did not differ from MSM by age, origin or source of infection, but frequencies of prior or concurrent STI were lower. Female cases were younger than male, were mostly foreigners (58%), and 41% were sex workers; concurrent STI (other than HIV) were diagnosed in 30%; 20.4% had symptoms (72.5% and 89.2% in MSM and MSW), and pharyngeal location was present in 30%.HIV co-infection was highest in MSM (20.9%). Co-infection was associated with age > 35 years, low educational level, being Western European or Latin-American, being MSM, having previous or concurrent STI and reporting contact with an HIV-infected partner; it was inversely associated with female sex. Differences by sex, transmission route and origin should be considered when implementing care and preventive programmes for gonorrhoea, and MSM are a priority group for intervention, in particular HIV-infected MSM.


Mycoplasma genitalium in women with lower genital tract inflammation.
To examine the prevalence of Mycoplasma genitalium in a large number of female patients attending a sexually transmitted infections (STI) clinic and to determine if there is an association with signs or symptoms of lower genital tract inflammation (LGTI). Altogether, 7646 female patients who had symptoms or microscopic signs of LGTI or were perceived to be at high risk of exposure to an STI were tested for both M genitalium and Chlamydia trachomatis. Urethral and cervical smears were examined quantitatively for polymorphic mononuclear leucocytes (PMNLs). The prevalence of C trachomatis and M genitalium was 10.1% and 4.5%, respectively. We found a clear association between detecting M genitalium in first void urine (FVU) of patients and signs of urethral inflammation. The strongest association was between detecting M genitalium in FVU and number of PMNLs in urethral smears (n = 6790; OR 2.1; 95 % CI 1.5 to 2.9). The association was less significant between detecting M genitalium in cervical swabs and the number of PMNLs in urethral smears (n = 6785; OR 1.4; 95% CI 1.1 to 1.9), although cervical swabs gave higher sensitivity than FVU in detecting M genitalium (86% vs 62%). C trachomatis detection in FVU and cervical swabs was highly concordant and both significantly associated with urethritis (n = 6790; OR 3.6; 95% CI 3.0 to 4.4). This data support the hypothesis that M genitalium causes urethritis in women and that M genitalium infection of the genitourinary tract leads to different clinical manifestations depending on whether the site of infection is the urethral or the cervical epithelium.


A mathematical model for collagen fibre formation during foetal and adult dermal wound healing.
Adult dermal wounds, in contrast to foetal wounds, heal with the formation of scar tissue. A crucial factor in determining the nature of the healed tissue is the ratio of collagen 1 to collagen 3, which regulates the diameter of collagen fibres. We develop a mathematical model which focuses on the stimulus for collagen synthesis due to the secretion of the different isoforms of the regulatory chemical transforming growth factor beta. Numerical simulations of the model lead to a value of this ratio consistent with that of healthy tissue for the foetus but corresponding to scarring in adult wound healing. We investigate the effect of topical application of TGF beta isoforms during healing and determine the key parameters which control the difference between adult and foetal repair.


Observation of oscillatory surface reactions of riboflavin, trolox, and singlet oxygen using single carbon nanotube fluorescence spectroscopy.
Single-molecule fluorescent microscopy allows semiconducting single-walled carbon nanotubes (SWCNTs) to detect the adsorption and desorption of single adsorbate molecules as a stochastic modulation of emission intensity. In this study, we identify and assign the signature of the complex decomposition and reaction pathways of riboflavin in the presence of the free radical scavenger Trolox using DNA-wrapped SWCNT sensors dispersed onto an aminopropyltriethoxysilane (APTES) coated surface. SWCNT emission is quenched by riboflavin-induced reactive oxygen species (ROS), but increases upon the adsorption of Trolox, which functions as a reductive brightening agent. Riboflavin has two parallel reaction pathways, a Trolox oxidizer and a photosensitizer for singlet oxygen and superoxide generation. The resulting reaction network can be detected in real time in the vicinity of a single SWCNT and can be completely described using elementary reactions and kinetic rate constants measured independently. The reaction mechanism results in an oscillatory fluorescence response from each SWCNT, allowing for the simultaneous detection of multiple reactants. A series-parallel kinetic model is shown to describe the critical points of these oscillations, with partition coefficients on the order of 10(-6)-10(-4) for the reactive oxygen and excited state species. These results highlight the potential for SWCNTs to characterize complex reaction networks at the nanometer scale.


At the back stage of prenatal care: Japanese Ob-Gyns negotiating prenatal diagnosis.
In this article, I explore the reluctance of Japanese ob-gyns to discuss prenatal diagnosis (PND) tests with pregnant women. The analysis focuses on the culturally specific ways in which ob-gyns formulate their cautiousness and criticism toward PND while invoking a local moral economy. Analyzing ob-gyns' accounts, I show how the ambiguities of PND are constituted in a specific moment in Japanese culture, history, disability politics, and national reproductive policies and are formulated through local paradigms of thinking about pregnant women, their fetuses, and the process of becoming a person in Japanese society. Finally, I show how PND in Japan is pushed to a "back-stage" realm in which the diagnosis for fetal anomalies is practiced in secrecy.


Model-Based Evaluation of Methods for Respiratory Sinus Arrhythmia Estimation.
Respiratory sinus arrhythmia (RSA) refers to heart rate oscillations synchronous with respiration, and it is one of the major representations of cardiorespiratory coupling. Its strength has been suggested as a biomarker to monitor different conditions, and diseases. Some approaches have been proposed to quantify the RSA, but it is unclear which one performs best in specific scenarios. The main objective of this study is to compare seven state-of-the-art methods for RSA quantification using data generated with a model proposed to simulate, and control the RSA. These methods are also compared, and evaluated on a real-life application, for their ability to capture changes in cardiorespiratory coupling during sleep. A simulation model is used to create a dataset of heart rate variability, and respiratory signals with controlled RSA, which is used to compare the RSA estimation approaches. To compare the methods objectively in real-life applications, regression models trained on the simulated data are used to map the estimates to the same measurement scale. Results, and conclusion: RSA estimates based on cross entropy, time-frequency coherence, and subspace projections showed the best performance on simulated data. In addition, these estimates captured the expected trends in the changes in cardiorespiratory coupling during sleep similarly. An objective comparison of methods for RSA quantification is presented to guide future analyses. Also, the proposed simulation model can be used to compare existing, and newly proposed RSA estimates. It is freely accessible online.


Design of cohort studies in chronic diseases using routinely collected databases when a prescription is used as surrogate outcome.
There has been little research on design of studies based on routinely collected data when the clinical endpoint of interest is not recorded, but can be inferred from a prescription. This often happens when exploring the effect of a drug on chronic diseases. Using the LifeLink claims database in studying the possible anti-inflammatory effects of statins in rheumatoid arthritis (RA), oral steroids (OS) were treated as surrogate of inflammatory flare-ups. We compared two cohort study designs, the first using time to event outcomes and the second using quantitative amount of the surrogate. RA patients were extracted from the LifeLink database. In the first study, patients were split into two sub-cohorts based on whether they were using OS within a specified time window of the RA index date (first record of RA). Using Cox models we evaluated the association between time-varying exposure to statins and (i) initiation of OS therapy in the non-users of OS at RA index date and (ii) cessation of OS therapy in the users of OS at RA index date. In the second study, we matched new statin users to non users on age and sex. Zero inflated negative binomial models were used to contrast the number of days' prescriptions of OS in the year following date of statin initiation for the two exposure groups. In the unmatched study, the statin exposure hazard ratio (HR) of initiating OS in the 31451 non-users of OS at RA index date was 0.96(95% CI 0.9,1.1) and the statin exposure HR of cessation of OS therapy in the 6026 users of OS therapy at RA index date was 0.95 (0.87,1.05). In the matched cohort of 6288 RA patients the statin exposure rate ratio for duration on OS therapy was 0.88(0.76,1.02). There was digit preference for outcomes in multiples of 7 and 30 days. The 'time to event' study design was preferable because it better exploits information on all available patients and provides a degree of robustness toward confounding. We found no convincing evidence that statins reduce inflammation in RA patients.


Religious involvement and U.S. adult mortality.
We use recently released, nationally representative data from the National Health Interview Survey-Multiple Cause of Death linked file to model the association of religious attendance and sociodemographic, health, and behavioral correlates with overall and cause-specific mortality. Religious attendance is associated with U.S. adult mortality in a graded fashion: People who never attend exhibit 1.87 times the risk of death in the follow-up period compared with people who attend more than once a week. This translates into a seven-year difference in life expectancy at age 20 between those who never attend and those who attend more than once a week. Health selectivity is responsible for a portion of the religious attendance effect: People who do not attend church or religious services are also more likely to be unhealthy and, consequently, to die. However, religious attendance also works through increased social ties and behavioral factors to decrease the risks of death. And although the magnitude of the association between religious attendance and mortality varies by cause of death, the direction of the association is consistent across causes.


Stem cell therapy: a clinical trial of stroke.
The alarming disability burden and a high prevalence rate of stroke in India has encouraged the researchers to develop regenerative therapies to reduce clinical deficits. This study evaluates safety, feasibility and efficacy of autologous mononuclear and mesenchymal cell transplantation in stroke patients evaluated on clinical scores and functional imaging (fMRI and DTI). Forty (n=40) stroke patients were recruited with the inclusion criteria as: 3 months to 2 years of index event, power of hand muscles of at least 2; Brunnstrom stage: 2-5; conscious and comprehendible. Fugl Meyer (FM), modified Barthel Index (mBI), Medical Research Council (MRC) grade for strength, Ashworth tone scale and functional imaging was used for assessments at baseline, 8 weeks and 24 weeks. 50-60 million cells in 250 ml saline were infused intravenously over 2-3 h. The safety test profile was normal with no mortality or cell related adverse reactions in stem cell patients. Among outcome parameters, only modified Barthel Index (mBI) showed statistical significant improvement (p<0.05) in the stem cell group. An increased number of cluster activation in Brodmann areas BA 4, BA 6 was observed post stem cell infusion indicating neural plasticity. Autologous intravenous stem cell therapy is safe and feasible. Stem cells act as "scaffolds" for neural transplantation and may aid in repair mechanisms in stroke.


Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation.
Neuroligins (Nlgns) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlgn expression level. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlgn1 in CA1 mouse hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 hr selectively increased dendritic spine density and AMPA-receptor-mediated EPSCs in wild-type neurons, but not in Nlgn1 knock-out neurons or when endogenous Nlgn1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP in a Nlgn1-dependent manner. Combined with computer simulations, our data support a model by which Nlgn1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy highlights the impact of Nlgn1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.


Application of transdermal patches with new skin test reagents for detection of latent tuberculosis.
Introduction. Current intradermal tuberculin skin tests for latent tuberculosis infection (LTBI) based on purified protein derivative (PPD) have poor specificity.Aims. Developing a better skin test antigen as well as a simple skin patch test may improve and facilitate diagnostic performance.Methodology. Defined recombinant antigens that were unique to Mycobacterium tuberculosis (MTB), including two potential latency-associated antigens (ESAT-6 and Rv2653c) and five DosR-encoded latency proteins (Rv1996, Rv2031c, Rv2032, DevR and Rv3716c), were used as diagnostic skin test reagents in comparison with a standard PPD. The performance of the skin tests based on the detection of delayed-type hypersensitivity (DTH) reaction in guinea pigs sensitized to MTB and M. bovis bacille Calmette-Guérin (BCG) vaccine was evaluated.Results. The latency antigens Rv1996, Rv2031c, Rv2032 and Rv2653c and the ESAT-6 protein elicited less reactive DTH skin responses in MTB-sensitized guinea pigs than those resulting from PPD, but elicited no response in BCG-vaccinated guinea pigs. The remaining two latency antigens (DevR and Rv3716c) elicited DTH responses in both groups of animals, as did PPD. The reactivity of PPD in BCG-vaccinated guinea pigs was greater than that of any of the selected skin test reagents. Using stronger concentrations of selected skin test reagents in the patch test led to increased DTH responses that were comparable to those elicited by PPD in guinea pigs sensitized with MTB.Conclusion. Transdermal application of defined purified antigens might be a promising method for LTBI screening.


Factors associated with homicide recidivism in a 13-year sample of homicide offenders in Finland.
Data on persons known to have committed homicide during a 13-year period were studied to determine factors associated with increased risk of repeating homicide. Between 1981 and 1993, a total of 1,649 homicides were committed in Finland. In 1,089 cases (66 percent), the offenders received an exhaustive forensic psychiatric examination. Data from reports of these examinations were analyzed to determine whether mental disorder and other factors were associated with homicide recidivism. Thirty-six homicide recidivists were identified. Twenty-four were alcoholics, 23 had a personality disorder, in most cases combined with alcoholism, four had schizophrenia, and two had major depression. Homicidal behavior was ten times more likely in men who had committed a previous homicide than in the general male population. Alcoholism increased the odds ratio of additional homicidal behavior in male homicide offenders about 13 times, and schizophrenia increased the odds ratio more than 25 times. During their first year after release from prison, male homicide offenders were about 250 times more likely to commit homicide than members of the general male population. The data suggest that mentally abnormal offenders are overrepresented among homicide recidivists in Finland. The risk of repeat homicide appears to be very high during the first year after release from prison.


The long-term effectiveness of the International Child Development Programme (ICDP) implemented as a community-wide parenting programme.
Short-term effectiveness of the International Child Development Programme (ICDP) for parents in the general population has been studied. The aim of this paper was to investigate the longer term impact of the ICDP programme on parents looking for sustained changes 6-12 months after the programme. For this, a non-clinical caregiver group attending the ICDP programme (N = 79) and a non-attending comparison group (N = 62) completed questionnaires on parenting, psychosocial functioning, and child difficulties before, on completion and 6-12 months after the ICDP programme. Analyses compare changes in scores over time. The results revealed that the ICDP group showed significantly improved scores on parenting measures, less loneliness, and trends towards improved self-efficacy compared to the comparison group 6-12 months after programme completion. The ICDP group also reported that their children spent significantly less time on television and computer games and a trend towards fewer child difficulties. Key positive effects sustained over time but at a somewhat lower level, supporting community-wide implementation of ICDP as a general parenting programme. It is concluded that more intensive training with follow-up sessions should be considered to sustain and boost initial gains.


A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection. Results of the Veterans Affairs Cooperative Study.
Zidovudine is recommended for asymptomatic and early symptomatic human immunodeficiency virus (HIV) infection. The best time to initiate zidovudine treatment remains uncertain, however, and whether early treatment improves survival has not been established. We conducted a multicenter, randomized, double-blind trial that compared early zidovudine therapy (beginning at 1500 mg per day) with late therapy in HIV-infected patients who were symptomatic and had CD4+ counts between 0.2 x 10(9) and 0.5 x 10(9) cells per liter (200 to 500 per cubic millimeter) at entry. Those assigned to late therapy initially received placebo and began zidovudine when their CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter) or when the acquired immunodeficiency syndrome (AIDS) developed. During a mean follow-up period of more than two years, there were 23 deaths in the early-therapy group (n = 170) and 20 deaths in the late-therapy group (n = 168) (P = 0.48; relative risk [late vs. early], 0.81; 95 percent confidence interval, 0.44 to 1.59). In the early-therapy group, 28 patients progressed to AIDS, as compared with 48 in the late-therapy group (P = 0.02; relative risk, 1.76; 95 percent confidence interval, 1.1 to 2.8). Early therapy increased the time until CD4+ counts fell below 0.2 x 10(9) per liter (200 per cubic millimeter), and it produced more conversions from positive to negative for serum p24 antigen. Early therapy was associated with more anemia, leukopenia, nausea, vomiting, and diarrhea, whereas late therapy was associated with more skin rash. In symptomatic patients with HIV infection, early treatment with zidovudine delays progression to AIDS, but in this controlled study it did not improve survival, and it was associated with more side effects.


Antipsychotic dose and diminished neural modulation: a multi-site fMRI study.
The effect of antipsychotics on the blood oxygen level dependent signal in schizophrenia is poorly understood. The purpose of the present investigation is to examine the effect of antipsychotic medication on independent neural networks during a motor task in a large, multi-site functional magnetic resonance imaging investigation. Seventy-nine medicated patients with schizophrenia and 114 comparison subjects from the Mind Clinical Imaging Consortium database completed a paced, auditory motor task during functional magnetic resonance imaging (fMRI). Independent component analysis identified temporally cohesive but spatially distributed neural networks. The independent component analysis time course was regressed with a model time course of the experimental design. The resulting beta weights were evaluated for group comparisons and correlations with chlorpromazine equivalents. Group differences between patients and comparison subjects were evident in the cortical and subcortical motor networks, default mode networks, and attentional networks. The chlorpromazine equivalents correlated with the unimotor/bitemporal (rho=-0.32, P=0.0039), motor/caudate (rho=-0.22, P=0.046), posterior default mode (rho=0.26, P=0.020), and anterior default mode networks (rho=0.24, P=0.03). Patients on typical antipsychotics also had less positive modulation of the motor/caudate network relative to patients on atypical antipsychotics (t(77)=2.01, P=0.048). The results suggest that antipsychotic dose diminishes neural activation in motor (cortical and subcortical) and default mode networks in patients with schizophrenia. The higher potency, typical antipsychotics also diminish positive modulation in subcortical motor networks. Antipsychotics may be a potential confound limiting interpretation of fMRI studies on the disease process in medicated patients with schizophrenia.


Geomicrobiology of high-level nuclear waste-contaminated vadose sediments at the hanford site, washington state.
Sediments from a high-level nuclear waste plume were collected as part of investigations to evaluate the potential fate and migration of contaminants in the subsurface. The plume originated from a leak that occurred in 1962 from a waste tank consisting of high concentrations of alkali, nitrate, aluminate, Cr(VI), (137)Cs, and (99)Tc. Investigations were initiated to determine the distribution of viable microorganisms in the vadose sediment samples, probe the phylogeny of cultivated and uncultivated members, and evaluate the ability of the cultivated organisms to survive acute doses of ionizing radiation. The populations of viable aerobic heterotrophic bacteria were generally low, from below detection to approximately 10(4) CFU g(-1), but viable microorganisms were recovered from 11 of 16 samples, including several of the most radioactive ones (e.g., >10 microCi of (137)Cs/g). The isolates from the contaminated sediments and clone libraries from sediment DNA extracts were dominated by members related to known gram-positive bacteria. Gram-positive bacteria most closely related to Arthrobacter species were the most common isolates among all samples, but other phyla high in G+C content were also represented, including Rhodococcus and Nocardia. Two isolates from the second-most radioactive sample (>20 microCi of (137)Cs g(-1)) were closely related to Deinococcus radiodurans and were able to survive acute doses of ionizing radiation approaching 20 kGy. Many of the gram-positive isolates were resistant to lower levels of gamma radiation. These results demonstrate that gram-positive bacteria, predominantly from phyla high in G+C content, are indigenous to Hanford vadose sediments and that some are effective at surviving the extreme physical and chemical stress associated with radioactive waste.


[Trauma and anorexia nervosa: the association between trauma characteristics, PTSD and the duration of the eating disorder].
Research into the prevalence of various traumatic events in anorexia nervosa (AN) is sparse, with the findings from these studies varying. In addition, the number and age at which traumatic events occurred was not consistently included in previous studies.
 AIM: To study the prevalence of different types of traumatic events, whether they occurred in early childhood or not, the number of different events and their associations with PTSD symptoms, and the duration of the eating disorder among clinically admitted patients with AN.
 METHOD: In the admission department of an eating disorder clinic, 60 female patients with AN completed questionnaires about traumatic events and symptoms of PTSD during the first week of admission.
 RESULTS: Although physical violence during early childhood and traumatic sexual events in later childhood and adulthood were the most commonly reported, there was a variety of types of traumatic events that were frequently reported. In addition, patients who had experienced traumatic events at a young age and / or multiple types of traumatic events had a longer-lasting eating disorder.
 CONCLUSION: A thorough inventory of trauma in patients with eating disorders seems important, as this could play a role in maintaining an eating disorder.


Comprehension of Vernacular Features in Aphasia.
Insights from linguistic variation research illustrate a linguistically diverse population, in which even speakers who can be classified as speaking a "mainstream" variety have grammatical knowledge of vernacular or "nonmainstream" features. However, there is a gap in our knowledge regarding how vernacular features are comprehended in people with aphasia (PWA). This article presents the results of a pilot study exploring how PWA respond to linguistic stimuli that include the vernacular feature, negative concord (NC), often referred to by the more colloquial term double negative (e.g., I didn't do nothing, equivalent to I didn't do anything). Twelve PWA in the chronic stage of recovery each rated the naturalness and felicity of 48 critical sentences and 64 fillers, all of which contained two clauses, the second clause describing a consequence of the first. Ratings were analyzed using ordinal regression. PWA rated NC sentences as unacceptable, but felicitous-a pattern similar to that shown by neurologically intact adults in a previous study. These results suggest that PWA are sensitive to both social and linguistic information at levels similar to neurologically intact speakers. These results have implications for the integration of vernacular features into future research, assessment, and treatment protocols for PWA. https://doi.org/10.23641/asha.19027322.


Aerobic fitness, acute exercise and sleep in older men.
In the current study 12 aerobically fit and 12 sedentary older men underwent two nocturnal polysomnographic (PSG) studies. A control PSG was conducted following a day without aerobic activity, whereas a postexercise PSG study was conducted following an afternoon session of exhaustive aerobic exercise. In addition to deriving usual sleep parameters, a computer scoring program was used to count the number of individual electroencephalographic (EEG) slow waves in each PSG tracing. Multivariate and univariate analyses showed that the fit subjects had shorter sleep onset latencies, less wake time after onset, fewer discrete sleep episodes, fewer sleep stage shifts during the initial portion of the night, less stage 1 sleep, a higher sleep efficiency and more total slow waves during both PSGs than did the sedentary subjects. Although no main effects were found for the acute exercise challenge, post hoc analyses showed that high levels of body heating during exercise predicted increased sleep fragmentation for both fit and sedentary subjects. These findings provide initial support for the contention that exercise and fitness may have significant effects on the sleep of older men. However, results also suggest that high levels of body heating resulting from a single exercise challenge may have adverse effects. Implications of the study are discussed and suggestions for future research are provided.


Digital pen-based telemonitoring of elderly heart failure patients.
Considering that a majority of elderlies are non-users of computers and Internet we developed a telemonitoring system for elderly heart failure (HF) home care patients based on digital pen technology - a technology never used before by this patient group. We implemented the system in clinical use in a 13 months long study. Fourteen patients (mean/median age 84 years) with severe HF participated. They accepted the technology and performed daily reports of their health state using the digital pen and a Health Diary form. Via the system the clinicians detected all HF-related deteriorations at an early stage and thereby prevented hospital re-admissions for all patients during the study, implying improved symptom control and large cost savings.


Medical school and residency influence on choice of an academic career and academic productivity among US neurology faculty.
To evaluate the effectiveness of medical schools and neurology training programs in the United States by determining their contribution to academic neurology in terms of how many graduates choose academic careers and their respective influence on current medical knowledge through bibliometric analysis. Biographical information from current faculty members of neurology training programs in the United States was obtained through an Internet-based search of departmental Web sites. Collected variables included medical school attended, residency program completed, and current academic rank. For each faculty member, ISI Web of Science and Scopus h -indices were also collected. Data from academic neurologists from 120 training programs with 3249 faculty members were collected. All data regarding training program and medical school education were compiled and analyzed by the institution from which each individual graduated. The 20 medical schools and neurology residency training programs producing the greatest number of graduates remaining in academic practice and the mean h -indices are reported. More medical school graduates of the Columbia University College of Physicians and Surgeons chose to enter academic neurology practice than the graduates of any other institution. Analyzed by residency training program attended, New York Presbyterian Hospital (Columbia University), Mayo Clinic (Rochester, Minnesota), and Mount Sinai Medical Center (New York, New York) produced the most graduates remaining in academics. This retrospective, longitudinal cohort study examines through quantitative measures the academic productivity and rank of academic neurologists. The results demonstrate that several training programs excel in producing a significantly higher proportion of academically active neurologists.


Misattribution of self-generated speech in relation to hallucinatory proneness and delusional ideation in healthy volunteers.
When patients with hallucinations and delusions encounter their own distorted speech they tend to mistakenly attribute it to someone else. This external misattribution of self-generated material is thought to be associated with 'positive' psychotic symptoms. The aim of the present study was to examine this process in relation to the predisposition to hallucination-like experiences and unusual beliefs in a healthy population. Fifty-seven volunteers completed assessments of hallucination proneness and delusional ideation and performed a source-monitoring task. Participants listened to a series of pre-recorded words for which the source (self/non-self) and acoustic quality (undistorted/distorted) of the speech were varied across trials. Participants indicated whether the words were spoken in their own or another person's voice via a button press. Misattribution errors were greatest when participants made source judgements about their own distorted speech (p < 0.01) and were positively correlated with delusional ideation scores, particularly the level of conviction with which delusional ideas were held (p = 0.03), and there was a trend for a positive correlation with hallucination proneness scores. There was a negative correlation between unsure responses and delusional ideation when participants were processing their own distorted speech (p = -0.03). The misattribution of self-generated speech occurs in healthy individuals with high levels of psychotic-like experiences. This suggests that the same cognitive impairments may underlie psychotic phenomena in healthy individuals as in patients with psychotic disorders, consistent with a continuum model of psychosis.


Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease.
The neuropathological substrate of dementia in patients with Parkinson's disease is still under debate, particularly in patients with insufficient alternate neuropathology for other degenerative dementias. In patients with pure Lewy body Parkinson's disease, previous post-mortem studies have shown that dopaminergic and cholinergic regulatory projection systems degenerate, but the exact pathways that may explain the development of dementia in patients with Parkinson's disease remain unclear. Studies in rodents suggest that both the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways may functionally interact to regulate certain aspects of cognition, however, whether such an interaction occurs in humans is still poorly understood. In this study, we performed stereological analyses of the A9 and A10 dopaminergic neurons and Ch1, Ch2 and Ch4 cholinergic neurons located in the basal forebrain, along with an assessment of α-synuclein pathology in these regions and in the hippocampus of six demented and five non-demented patients with Parkinson's disease and five age-matched control individuals with no signs of neurological disease. Moreover, we measured choline acetyltransferase activity in the hippocampus and frontal cortex of eight demented and eight non-demented patients with Parkinson's disease, as well as in the same areas of eight age-matched controls. All patients with Parkinson's disease exhibited a similar 80-85% loss of pigmented A9 dopaminergic neurons, whereas patients with Parkinson's disease dementia presented an additional loss in the lateral part of A10 dopaminergic neurons as well as Ch4 nucleus basalis neurons. In contrast, medial A10 dopaminergic neurons and Ch1 and Ch2 cholinergic septal neurons were largely spared. Despite variable Ch4 cell loss, cortical but not hippocampal cholinergic activity was consistently reduced in all patients with Parkinson's disease, suggesting significant dysfunction in cortical cholinergic pathways before frank neuronal degeneration. Patients with Parkinson's disease dementia were differentiated by a significant reduction in hippocampal cholinergic activity, by a significant loss of non-pigmented lateral A10 dopaminergic neurons and Ch4 cholinergic neurons (30 and 55% cell loss, respectively, compared with neuronal preservation in control subjects), and by an increase in the severity of α-synuclein pathology in the basal forebrain and hippocampus. Overall, these results point to increasing α-synuclein deposition and hippocampal dysfunction in a setting of more widespread degeneration of cortical dopaminergic and cholinergic pathways as contributing to the dementia occurring in patients with pure Parkinson's disease. Furthermore, our findings support the concept that α-synuclein deposition is associated with significant neuronal dysfunction in the absence of frank neuronal loss in Parkinson's disease.


Sprint Start Kinetics of Amputee and Non-Amputee Sprinters.
The purpose of this study was to explore the relationship between the forces applied to the starting blocks and the start performances (SPs) of amputee sprinters (ASs) and non-amputee sprinters (NASs). SPs of 154 male and female NASs (100-m personal records [PRs], 9.58-14.00 s) and 7 male ASs (3 unilateral above knee, 3 unilateral below knee, 1 bilateral below knee; 100 m PRs, 11.70-12.70 s) with running specific prostheses (RSPs) were analysed during full-effort sprint starts using instrumented starting blocks that measured the applied forces in 3D. Using the NAS dataset and a combination of factor analysis and multiple regression techniques, we explored the relationship between force characteristics and SP (quantified by normalized average horizontal block power). Start kinetics were subsequently compared between ASs and NASs who were matched based on their absolute 100 m PR and their 100 m PR relative to the world record in their starting class. In NASs, 86% of the variance in SP was shared with five latent factors on which measured parameters related to force application to the rear and front blocks and the respective push-off directions in the sagittal plane of motion were loaded. Mediolateral force application had little influence on SP. The SP of ASs was significantly reduced compared to that of NASs matched on the basis of relative 100-m PR (-33.8%; d = 2.11, p < 0.001), while a non-significant performance reduction was observed when absolute 100-m PRs were used (-17.7%; d = 0.79, p = 0.09). These results are at least partially explained by the fact that force application to the rear block was clearly impaired in the affected legs of ASs.


Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33.
The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7, to within two centiMorgans of D2S152. This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5. These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases.


Hypoxia impairs primordial germ cell migration in zebrafish (Danio rerio) embryos.
As a global environmental concern, hypoxia is known to be associated with many biological and physiological impairments in aquatic ecosystems. Previous studies have mainly focused on the effect of hypoxia in adult animals. However, the effect of hypoxia and the underlying mechanism of how hypoxia affects embryonic development of aquatic animals remain unclear. In the current study, the effect of hypoxia on primordial germ cell (PGC) migration in zebrafish embryos was investigated. Hypoxic embryos showed PGC migration defect as indicated by the presence of mis-migrated ectopic PGCs. Insulin-like growth factor (IGF) signaling is required for embryonic germ line development. Using real-time PCR, we found that the mRNA expression levels of insulin-like growth factor binding protein (IGFBP-1), an inhibitor of IGF bioactivity, were significantly increased in hypoxic embryos. Morpholino knockdown of IGFBP-1 rescued the PGC migration defect phenotype in hypoxic embryos, suggesting the role of IGFBP-1 in inducing PGC mis-migration. This study provides novel evidence that hypoxia disrupts PGC migration during embryonic development in fish. IGF signaling is shown to be one of the possible mechanisms for the causal link between hypoxia and PGC migration. We propose that hypoxia causes PGC migration defect by inhibiting IGF signaling through the induction of IGFBP-1.


Correlation between cervical spine sagittal alignment and clinical outcome after cervical laminoplasty for ossification of the posterior longitudinal ligament.
The goal of this study was to determine the relationship between cervical spine sagittal alignment and clinical outcomes after cervical laminoplasty in patients with ossification of the posterior longitudinal ligament (OPLL). Fifty consecutive patients who underwent a cervical laminoplasty for OPLL between January 2012 and January 2013 and who were followed up for at least 1 year were analyzed in this study. Standing plain radiographs of the cervical spine, CT (midsagittal view), and MRI (T2-weighted sagittal view) were obtained (anteroposterior, lateral, flexion, and extension) pre- and postoperatively. Cervical spine alignment was assessed with the following 3 parameters: the C2-7 Cobb angle, C2-7 sagittal vertical axis (SVA), and T-1 slope minus C2-7 Cobb angle. The change in cervical sagittal alignment was defined as the difference between the post- and preoperative C2-7 Cobb angles, C2-7 SVAs, and T-1 slope minus C2-7 Cobb angles. Outcome assessments (visual analog scale [VAS], Oswestry Neck Disability Index [NDI], 36-Item Short-Form Health Survey [SF-36], and Japanese Orthopaedic Association [JOA] scores) were obtained in all patients pre- and postoperatively. The average patient age was 56.3 years (range 38-72 years). There were 34 male patients and 16 female patients. Cervical laminoplasty for OPLL helped alleviate radiculomyelopathy. Compared with the preoperative scores, improvement was seen in postoperative VAS and JOA scores. After laminoplasty, 35 patients had kyphotic changes, and 15 had lordotic changes. However, cervical sagittal alignment after laminoplasty was not significantly associated with clinical outcomes in terms of postoperative improvement of the JOA score (C2-7 Cobb angle: p = 0.633; C2-7 SVA: p = 0.817; T-1 slope minus C2-7 lordosis: p = 0.554), the SF-36 score (C2-7 Cobb angle: p = 0.554; C2-7 SVA: p = 0.793; T-1 slope minus C2-7 lordosis: p = 0.829), the VAS neck score (C2-7 Cobb angle: p = 0.263; C2-7 SVA: p = 0.716; T-1 slope minus C2-7 lordosis: p = 0.497), or the NDI score (C2-7 Cobb angle: p = 0.568; C2-7 SVA: p = 0.279; T-1 slope minus C2-7 lordosis: p = 0.966). Similarly, the change in cervical sagittal alignment was not related to the JOA (p = 0.604), SF-36 (p = 0.308), VAS neck (p = 0.832), or NDI (p = 0.608) scores. Cervical laminoplasty for OPLL improved radiculomyelopathy. Cervical laminoplasty increased the probability of cervical kyphotic alignment. However, cervical sagittal alignment and clinical outcomes were not clearly related.


Psychological processing of transplantation in lung recipients: a quantitative study of organ integration and the relationship to the donor.
Lung recipients undergo a complex psychological process, including organ integration and processing of attitudes towards the organ donor. Seventy-six lung recipients were asked to participate in a cross-sectional questionnaire study on the psychological processing of lung transplants. The questionnaire consisted of statements describing aspects of organ integration and the patient's relationship with the donor. Furthermore, chronic stress/psychological distress (Screening Scale of the Trier Inventory; Symptom Checklist SCL-K-9) and the emotional effects of transplantation/immunosuppression (Transplant Effects Questionnaire; Medication Experience Scale for Immunosuppressants) were assessed. In general, lung recipients perceive the transplant as part of themselves (97.4%) and not as a foreign object (90%). One-third of patients still have frequent thoughts about the donor, whilst the majority (80.3%) do not believe that they have adopted the donor's characteristic traits. Factor analysis reveals the two-dimensional structure of the questionnaire items 'organ integration' (factor 1) and 'relationship to the donor' (factor 2). Poor organ integration predicts low adherence, low disclosure and high feelings of guilt, whilst a close donor relationship predicts chronic stress and psychological distress. Poor organ integration and a close relationship to the donor should be borne in mind in psychosocial treatment regarding the patient's adherence behaviour and psychological distress.


Gaps in Guideline-Concordant Use of Diagnostic Tests Among Lung Cancer Patients.
Practice guidelines recommend routine use of pulmonary function tests (PFTs), computed tomography (CT), and positron emission tomography (PET) for the workup of resectable lung cancer patients. Little is known about the frequency of guideline concordance in routine practice. A cohort study (2007 to 2013) of 15,951 lung cancer patients undergoing lobectomy or pneumonectomy was conducted with MarketScan, a claims database of individuals with employer-provided health insurance. Guideline concordance was defined by claims for PFT within 180 days of resection and for CT and PET within 90 days of resection. Generalized linear models were used to evaluate temporal trends, patient characteristics, and costs associated with guideline-concordant care. Overall, 61% of patients received guideline-concordant care, increasing from 57% in 2007 to 66% in 2013 (p < 0.001). Compared with patients who received guideline-discordant care, patients with guideline-concordant care more frequently underwent repeat testing (PFT: 21% versus 12%, p < 0.001; CT: 46% versus 22%, p < 0.001; PET: 2.3% versus 1.1%, p < 0.001). Health plan-adjusted mean total test-related costs were higher among guideline-concordant patients who underwent repeat testing than patients who did not ($4,304 versus $3,454, p < 0.001). Forty percent of lung cancer patients treated with surgical procedures did not receive recommended noninvasive cancer staging and physiologic assessment before resection. Guideline concordance was associated with repeat testing, and repeat testing was associated with higher costs. These findings support the need for quality improvement interventions that can increase guideline concordance while curbing potential excess use of diagnostic tests.


Action of adrenalin on the circulation of the murine Plasmodium developing stages, in different blood compartments.
Adrenalin was used to investigate in vivo the circulation of the different stages of rodent Plasmodium present in the blood. A single dose of adrenalin injected to mice infected with P. yoelii resulted immediately in i) a diminution of the parasitaemia of approximately 50% in the peripheral large vessels (estimated in tail blood films), as well as in the capillaries (estimated in smears of blood collected from a fed Anopheles), and ii) an increased parasitaemia in blood collected by cardiac puncture from the right heart. The numbers of young stages of P. yoelii in the peripheral blood were initially somewhat reduced but, unexpectedly, midterm trophozoites were preferentially expelled from the peripheral blood into major organs like the heart. With P. vinckei, parasitaemia decreased only when midterm trophozoites predominated, and with P. chabaudi no effect was observed at any time. We propose that midterm trophozoites, by their increased surface area, as compared to rings, and their flexibility which contrasts with the rigid schizonts, are particularly susceptible to haemodynamic perturbations.


Pre and post-amputation mobility of trans-tibial amputees: correlation to medical problems, age and mortality.
This retrospective study compares pre and post-amputation mobility and the influence of age and associated medical problems. Data from the charts of 120 male patients who underwent unilateral trans-tibial (below-knee) amputation at the Dallas Veteran's Administration Hospital between June, 1983 and October, 1991, were collected and analyzed. Mobility was assessed with a six level scale developed by Volpicelli et al. (1983). The presence of cardiac disease, pulmonary disease (COPD), peripheral vascular disease (PVD), diabetes mellitus, degenerative joint disease, blindness, cerebral vascular accident (CVA), and age are correlated with changes in mobility after amputation. Older patients had more medical problems and lower post-amputation scores Individual medical problems did not influence mobility scores, but the presence of COPD and PVD lowered pre-amputation mobility scores. Cardiac disease and diabetes mellitus influenced post-amputation mobility scores by lowering them, either together or individually. Regardless of age, however, patients with more medical problems were poor ambulators. The cause of amputation per se did not influence mobility scores.


Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review.
Hereditary nonpolyposis colorectal cancer (HNPCC) dates to Warthin's description of family G, which he began studying in 1895. Warthin's observations were not fully appreciated until 1966 when two families with an autosomal dominant inheritance pattern of nonpolyposis colorectal cancer (CRC) and endometrial cancer were described. This condition was first termed the "cancer family syndrome" and was later renamed HNPCC. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome I, with hereditary predisposition for CRC having early (approximately 44 years) age of onset, a proclivity (70%) for the proximal colon, and an excess of synchronous and metachronous colonic cancers and Lynch syndrome II, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium. Transitional cell carcinoma of the ureter and renal pelvis and carcinomas of the stomach, small bowel, ovary, and pancreas also afflict some families. Current estimates indicate that HNPCC may account for as much as 6% of the total CRC burden. There are no known premonitory phenotypic signs or biomarkers of cancer susceptibility in the Lynch syndromes. This report will summarize current knowledge, with emphasis on the manner in which this knowledge can be employed effectively for diagnosis and management of HNPCC.


A preconcentrator chip employing μ-SPME array coated with in-situ-synthesized carbon adsorbent film for VOCs analysis.
We report the design, fabrication, and evaluation of a μ-preconcentrator chip that utilizes an array of solid-phase microextraction (SPME) needles coated with in-situ-grown carbon adsorbent film. The structure of the SPME needle (diameter=100 μm, height=250 μm) array inside the sampling chamber was fabricated using a deep reactive-ion etching (DRIE) process to enhance the attachable surface area for adsorbent film. Heaters and temperature sensors were fabricated onto the back of a μ-preconcentrator chip using lithography patterning and a metal lift-off process. The devices were sealed by anodic bonding and diced prior to the application of the adsorbent film. An adsorbent precursor, cellulose was dissolved in water and dynamically coated onto the SPME needle array. The coated cellulose film was converted into a porous carbon film via pyrolysis at 600 °C in a N(2) atmosphere. The surface area of the carbon adsorbent film was 308 m(2)/g, which is higher than that of a commercial adsorbent Carbopack X. A preconcentration factor as high as 13,637-fold was demonstrated using toluene. Eleven volatile organic compounds (VOCs) of different volatilities and functional groups were sampled and analyzed by GC-FID, and the desorption peak widths at half height were all less than 2.6 s after elution from a 15m capillary GC column. There was no sign of performance degradation after continuous operation for 50 cycles in air.


A method for testing association patterns of social animals.
Association indices were originally developed to describe species co-occurrences, but have been used increasingly to measure associations between individuals. However, no statistical method has been published that allows one to test the extent to which the observed association index values differ from those of a randomly associating population. Here, we describe an adaptation of a test developed by Manly (1995, Ecology, 76, 1109-1115), which uses the observed association data as a basis for a computer-generated randomization. The observed pattern of association is tested against a randomly created one while retaining important features of the original data, for example group size and sighting frequency. We applied this new method to test four data sets of associations from two populations of Hector's dolphin, Cephalorhynchus hectori, using the Half-Weight Index (HWI) as an example of a measure of association. The test demonstrated that populations with similar median HWI values showed clear differences in association patterns, that is, some were associating nonrandomly whereas others were not. These results highlight the benefits of using this new testing method in order to validate the analysis of association indices. Copyright 1998 The Association for the Study of Animal Behaviour.


Towards a worldwide wood economics spectrum.
Wood performs several essential functions in plants, including mechanically supporting aboveground tissue, storing water and other resources, and transporting sap. Woody tissues are likely to face physiological, structural and defensive trade-offs. How a plant optimizes among these competing functions can have major ecological implications, which have been under-appreciated by ecologists compared to the focus they have given to leaf function. To draw together our current understanding of wood function, we identify and collate data on the major wood functional traits, including the largest wood density database to date (8412 taxa), mechanical strength measures and anatomical features, as well as clade-specific features such as secondary chemistry. We then show how wood traits are related to one another, highlighting functional trade-offs, and to ecological and demographic plant features (growth form, growth rate, latitude, ecological setting). We suggest that, similar to the manifold that tree species leaf traits cluster around the 'leaf economics spectrum', a similar 'wood economics spectrum' may be defined. We then discuss the biogeography, evolution and biogeochemistry of the spectrum, and conclude by pointing out the major gaps in our current knowledge of wood functional traits.


Safety Assessment of Advanced Imaging Sequences I: Measurements.
A method for rapid measurement of intensities (I(spta)), mechanical index (MI), and probe surface temperature for any ultrasound scanning sequence is presented. It uses the scanner's sampling capability to give an accurate measurement of the whole imaging sequence for all emissions to yield the true distributions. The method is several orders of magnitude faster than approaches using an oscilloscope, and it also facilitates validating the emitted pressure field and the scanner's emission sequence software. It has been implemented using the experimental synthetic aperture real-time ultrasound system (SARUS) scanner and the Onda AIMS III intensity measurement system (Onda Corporation, Sunnyvale, CA, USA). Four different sequences have been measured: a fixed focus emission, a duplex sequence containing B-mode and flow emissions, a vector flow sequence with B-mode and flow emissions in 17 directions, and finally a SA duplex flow sequence. A BK8820e (BK Medical, Herlev, Denmark) convex array probe is used for the first three sequences and a BK8670 linear array probe for the SA sequence. The method is shown to give the same intensity values within 0.24% of the AIMS III Soniq 5.0 (Onda Corporation, Sunnyvale, CA, USA) commercial intensity measurement program. The approach can measure and store data for a full imaging sequence in 3.8-8.2 s per spatial position. Based on I(spta), MI, and probe surface temperature, the method gives the ability to determine whether a sequence is within U.S. FDA limits, or alternatively indicate how to scale it to be within limits.


Motor learning enhances perceptual judgment: a case for action-perception transfer.
Transfer from perception to action is well documented, for instance in the form of observational learning. Transfer from action to perception, on the other hand, has not been researched. Such action-perception transfer (APT) is compatible with several learning theories and has been predicted within the framework of common coding of perceptual and motor events (Prinz, 1992, 1997). Our first experiment aimed at an empirical evaluation of APT and involved motor practice of timed two-cycle arm movements on verbal command without visual feedback. In a transfer test, visual judgments of similar patterns had to be made. In addition, transfer from the visual to the motor task was studied. In Experiment 2 we separated kinesthetic aspects of motor practice from preparatory and efferent contributions to APT. The experiments provide evidence that transfer between perception and action is bi-directional. Transfer from perception to action and, more importantly, from action to perception was found. Furthermore, APT was equally pronounced for participants who had actively practiced movements during training and for passive participants who had received merely kinesthetic feedback about the movement. This kinesthetic-visual transfer is likely to be achieved via visuomotor-kinesthetic matching or via timekeeping mechanisms that are involved in both motor and visual performance.


Staphylococcus aureus osmoregulation: roles for choline, glycine betaine, proline, and taurine.
Choline, glycine betaine, and L-proline enhanced the growth of Staphylococcus aureus at high osmolarity (i.e., they acted as osmoprotectants) on various liquid and solid defined media, while an osmoprotective effect of taurine was shown only for cells growing on high-NaCl solid medium that lacked other osmoprotectants. Potassium pool levels were high, and there was little difference in levels in cells grown at different osmolarities. Glycine betaine accumulated to high levels in osmotically stressed cells, and choline was converted to glycine betaine. Proline and taurine also accumulated in response to osmotic stress but to lower levels than glycine betaine.


Differential limb scaling in the american alligator (Alligator mississippiensis) and its implications for archosaur locomotor evolution.
Bipedalism evolved multiple times within archosaurs, and relatively shorter forelimbs characterize both crocodyliforms and nonavian dinosaurs. Analysis of a comprehensive ontogenetic sequence of specimens (embryo to adult) of the sauropodomorph Massospondylus has shown that bipedal limb proportions result from negative forelimb allometry. We ask, is negative forelimb allometry a pattern basal to archosaurs, amplified in certain taxa to produce bipedalism? Given the phylogenetic position of extant crocodylians and their relatively shorter forelimb, we tested the hypothesis that prevalent negative forelimb allometry is present in Alligator mississippiensis from a sample of wild specimens from embryonic to adult sizes. Long bone lengths (humerus, radius, ulna, femur, tibia, fibula, third metapodials) were measured with their epiphyseal cartilage intact at all sizes. Our results show an overall isometric pattern for most elements regressed on femur length, humerus length, or total limb length. However, negative allometry was prevalent for the ulna, and the third metapodials scale with positive allometry embryonically. These data suggest that the general forelimb proportions in relation to the hindlimb do not change significantly with increasing size in A. mississippiensis. The negative allometry of the ulna and embryonicaly positive allometry of the third metapodials appears to be related to maintaining the functional integrity of the limbs. We show that this pattern is different from that of the sauropodomorph Massospondylus, and we suggest that if bipedalism in archosaurs is tied, in part, to negative forearm allometry, it was either secondarily lost through isometric scaling, or never developed in the ancestor of A. mississippiensis.


From descent with modification to the origins of novelty.
Descent with modification is the foundational framework of all of evolution. Yet evolutionary novelties are defined as lacking affinities to structures that already existed in the ancestral state, i.e. to somehow emerge in the absence of homology. We posit that reconciling both perspectives necessitates the existence of a type of innovation gradient that allows descent with modification to seed the initiation of a novel trait, which once in existence can then diversify into its variant forms. Recent work on diverse, textbook examples of morphological novelties illustrate the value of the innovation gradient concept. Innovations as profound and diverse as insect wings, beetle horns, and treehopper helmets derive from homologous source tissues instructed in their development by homologous gene regulatory networks. Yet rather than rendering these traits no longer novel, we posit that discoveries such as these call for a reassessment of the usefulness of defining evolutionary novelty as necessitating the absence of homology. Instead, we need to redirect our attention to how ancestral homologies scaffold and bias the innovation gradient to facilitate hotspots of innovation in some places, and deep conservation elsewhere.


Recent trends in the prevalence of overweight and obesity among Canadian children.
Previous studies have shown an increase in the prevalence of overweight and obesity among Canadian children from 23.3% to 34.7% during 1978-2004. We examined the most recent trends by applying current definitions of overweight and obesity based on World Health Organization (WHO) body mass index (BMI) thresholds and recently validated norms for waist circumference and waist:height ratio. We examined directly measured height and weight data from the Canadian Community Health Survey (2004-2005) and the Canadian Health Measures Survey (2009-2013). We calculated z scores for BMI, height and weight based on the 2014 WHO growth charts for Canada, including the new extension of weight-for-age beyond 10 years. To calculate z scores for waist circumference and waist:height ratios, we used new charts from the reference population in the US NHANES III (National Health and Nutrition Examination Survey, 1988-1994). Data were available for 14 014 children aged 3-19 years for the period 2004-2013. We observed a decline in the prevalence of overweight or obesity, from 30.7% (95% confidence interval [CI] 29.7% to 31.6%) to 27.0% (95% CI 25.3% to 28.7%) (p < 0.001) and stabilization in the prevalence of obesity at about 13%. These trends persisted after we adjusted for age, sex and race/ethnicity. Although they declined, the median z scores for BMI, weight and height were positive and higher than those in the WHO reference population. The z scores for waist circumference and waist:height ratio were negative, which indicated that the Canadian children had less central adiposity than American children in historic or contemporary NHANES cohorts. After a period of dramatic growth, BMI z scores and the prevalence of overweight or obesity among Canadian children decreased from 2004 to 2013, which attests to progress against this important public health challenge.


Percent Gleason pattern 4 in stratifying the prognosis of patients with intermediate-risk prostate cancer.
The Gleason score remains the most reliable prognosticator in men with prostate cancer. One of the recent important modifications in the Gleason grading system recommended from the International Society of Urological Pathology consensus conference is recording the percentage of Gleason pattern 4 in the pathology reports of prostate needle biopsy and radical prostatectomy cases with Gleason score 7 prostatic adenocarcinoma. Limited data have indeed suggested that the percent Gleason pattern 4 contributes to stratifying the prognosis of patients who undergo radical prostatectomy. An additional obvious benefit of reporting percent pattern 4 includes providing critical information for treatment decisions. This review summarizes and discusses available studies assessing the utility of the percentage of Gleason pattern 4 in the management of prostate cancer patients.


Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study.
We have previously reported that increased aggressive behavior in schizophrenic patients may be associated with a polymorphism at codon 158 of the catechol O-methyltransferase (COMT) gene that encodes a low enzyme activity variant. The finding has been replicated by one group, but not others. The discordant findings could be due to statistical errors or methodological issues in the assessment of aggressive/violent behavior. Consequently, additional studies are needed. Patients with schizophrenia (SZ) were assessed for violent behavior using the Lifetime History of Aggression (LHA) scale, an 11-item questionnaire that includes Aggression, Self-Directed Aggression, and Consequences/Antisocial Behavior subscales. DNA was genotyped for the COMT 158 polymorphism, as well as a functional polymorphism in the monoamine oxidase A (MAOA) gene promoter. Similar to our previously reported findings, a statistically significant association was found between aggressive behavior in SZ and the COMT 158 polymorphism; mean LHA scores were higher in subjects homozygous for 158Met, the low enzyme activity COMT variant (F(2,105) = 5.616, P = 0.005). Analysis of the major LHA subscales revealed that the association with 158Met was due to high scores on the Aggression, and Self-Directed Aggression subscales, but not the Consequences/Antisocial Behavior subscale. No significant association was detected for the MAOA gene alone. Our findings provide further support that COMT is a modifying gene that plays a role in determining interindividual variability in the proclivity for outward and self-directed aggressive behavior found in some schizophrenic patients.


Internet of Things Platform for Smart Farming: Experiences and Lessons Learnt.
Improving farm productivity is essential for increasing farm profitability and meeting the rapidly growing demand for food that is fuelled by rapid population growth across the world. Farm productivity can be increased by understanding and forecasting crop performance in a variety of environmental conditions. Crop recommendation is currently based on data collected in field-based agricultural studies that capture crop performance under a variety of conditions (e.g., soil quality and environmental conditions). However, crop performance data collection is currently slow, as such crop studies are often undertaken in remote and distributed locations, and such data are typically collected manually. Furthermore, the quality of manually collected crop performance data is very low, because it does not take into account earlier conditions that have not been observed by the human operators but is essential to filter out collected data that will lead to invalid conclusions (e.g., solar radiation readings in the afternoon after even a short rain or overcast in the morning are invalid, and should not be used in assessing crop performance). Emerging Internet of Things (IoT) technologies, such as IoT devices (e.g., wireless sensor networks, network-connected weather stations, cameras, and smart phones) can be used to collate vast amount of environmental and crop performance data, ranging from time series data from sensors, to spatial data from cameras, to human observations collected and recorded via mobile smart phone applications. Such data can then be analysed to filter out invalid data and compute personalised crop recommendations for any specific farm. In this paper, we present the design of SmartFarmNet, an IoT-based platform that can automate the collection of environmental, soil, fertilisation, and irrigation data; automatically correlate such data and filter-out invalid data from the perspective of assessing crop performance; and compute crop forecasts and personalised crop recommendations for any particular farm. SmartFarmNet can integrate virtually any IoT device, including commercially available sensors, cameras, weather stations, etc., and store their data in the cloud for performance analysis and recommendations. An evaluation of the SmartFarmNet platform and our experiences and lessons learnt in developing this system concludes the paper. SmartFarmNet is the first and currently largest system in the world (in terms of the number of sensors attached, crops assessed, and users it supports) that provides crop performance analysis and recommendations.


Narrow-band generation in random distributed feedback fiber laser.
Narrow-band emission of spectral width down to ~0.05 nm line-width is achieved in the random distributed feedback fiber laser employing narrow-band fiber Bragg grating or fiber Fabry-Perot interferometer filters. The observed line-width is ~10 times less than line-width of other demonstrated up to date random distributed feedback fiber lasers. The random DFB laser with Fabry-Perot interferometer filter provides simultaneously multi-wavelength and narrow-band (within each line) generation with possibility of further wavelength tuning.


The optimal schedule for self-monitoring of blood pressure by patients at home.
The optimal schedule for home blood pressure monitoring should represent the usual level of home blood pressure, give a reproducible value, and have prognostic ability. Therefore, outcome studies, as well as short-term trials assessing the reproducibility of home blood pressure, its stability over time and its relationship with ambulatory blood pressure should be taken into account. A review of this evidence suggests that the optimal schedule should be based on 12-14 measurements, and even more measurements up to 25 are desirable. Morning and evening measurements should be obtained, with at least duplicate measurements per occasion. Measurements on the initial day should preferably be discarded.


The Biaxial Double-Barrel Fibula Flap-A Simplified Technique for Fibula Maxillary Reconstruction.
Previously described techniques for microvascular fibula reconstruction of Brown Class II to IV maxillectomy defects are complex, require multiple osteotomies, result in a short pedicle, and inadequately reconstruct the dental alveolus in preparation for endosseous implants. This report describes a simplified technique for Brown Class II to IV defects that re-creates facial support, allows for dental reconstruction with appropriately positioned implants, and maintains adequate pedicle length. A retrospective chart review was performed of all patients with Brown Class II to IV maxillectomy defects immediately reconstructed with a biaxial double-barrel fibula flap technique. The reconstructive surgeon evaluated each patient at least 1 month after reconstruction for enophthalmos, facial symmetry, nasal patency, satisfactory jaw position, deglutition, intelligible speech, and intraoperative need for vein grafting. The sample was composed of 6 patients (mean age, 54 yr; range, 33 to 78 yr; 67% women) who underwent reconstruction with the biaxial double-barrel fibula flap technique for Brown Class II to IV defects. None of these patients required vein grafting. None of these patients had flap failure. Diagnoses for these patients were a hybrid odontogenic tumor (n = 1), squamous cell carcinoma (n = 3), adenoid cystic carcinoma (n = 1), and sinonasal melanoma (n = 1). All 6 patients had excellent facial contour and malar projection, regular oral intake, 100% intelligible speech, and a new maxillary skeletal Class I relation without need for intraoperative vein grafting. One patient developed enophthalmos related to inferior rectus sacrifice and removal of orbital fat. Complications included development of nasal synechia and occlusion of the maxillary sinus ostium (n = 1). The biaxial double-barrel fibula flap technique achieves the goals of providing adequate facial support and an alveolar segment amenable to implant dentistry. It allows for intelligible speech, deglutition, orbital support, and separation of the oronasal, orbital, and sinus cavities. In addition, it minimizes the need for vein grafting.


Echocardiography practice, training and accreditation in the intensive care: document for the World Interactive Network Focused on Critical Ultrasound (WINFOCUS).
Echocardiography is increasingly used in the management of the critically ill patient as a non-invasive diagnostic and monitoring tool. Whilst in few countries specialized national training schemes for intensive care unit (ICU) echocardiography have been developed, specific guidelines for ICU physicians wishing to incorporate echocardiography into their clinical practice are lacking. Further, existing echocardiography accreditation does not reflect the requirements of the ICU practitioner. The WINFOCUS (World Interactive Network Focused On Critical UltraSound) ECHO-ICU Group drew up a document aimed at providing guidance to individual physicians, trainers and the relevant societies of the requirements for the development of skills in echocardiography in the ICU setting. The document is based on recommendations published by the Royal College of Radiologists, British Society of Echocardiography, European Association of Echocardiography and American Society of Echocardiography, together with international input from established practitioners of ICU echocardiography. The recommendations contained in this document are concerned with theoretical basis of ultrasonography, the practical aspects of building an ICU-based echocardiography service as well as the key components of standard adult TTE and TEE studies to be performed on the ICU. Specific issues regarding echocardiography in different ICU clinical scenarios are then described. Obtaining competence in ICU echocardiography may be achieved in different ways - either through completion of an appropriate fellowship/training scheme, or, where not available, via a staged approach designed to train the practitioner to a level at which they can achieve accreditation. Here, peri-resuscitation focused echocardiography represents the entry level--obtainable through established courses followed by mentored practice. Next, a competence-based modular training programme is proposed: theoretical elements delivered through blended-learning and practical elements acquired in parallel through proctored practice. These all linked with existing national/international echocardiography courses. When completed, it is anticipated that the practitioner will have performed the prerequisite number of studies, and achieved the competency to undertake accreditation (leading to Level 2 competence) via a recognized National or European examination and provide the appropriate required evidence of competency (logbook). Thus, even where appropriate fellowships are not available, with support from the relevant echocardiography bodies, training and subsequently accreditation in ICU echocardiography becomes achievable within the existing framework of current critical care and cardiological practice, and is adaptable to each countrie's needs.


Evaluation of longevity modeling censored records in Nellore.
The aim of the present study was to evaluate the prediction ability of models that cope with longevity phenotypic expression as uncensored and censored in Nellore cattle. Longevity was defined as the difference between the dates of last weaned calf and cow birth. There were information of 77 353 females, being 61 097 cows with uncensored phenotypic information and 16 256 cows with censored records. These data were analyzed considering three different models: (1) Gaussian linear model (LM), in which only uncensored records were considered; and two models that consider both uncensored and censored records: (2) Censored Gaussian linear model (CLM); and (3) Weibull frailty hazard model (WM). For the model prediction ability comparisons, the data set was randomly divided into training and validation sets, containing 80% and 20% of the records, respectively. There were considered 10 repetitions applying the following restrictions: (a) at least three animals per contemporary group in the training set; and (b) sires with more than 10 progenies with uncensored records (352 sires) should have daughters in the training and validation sets. The variance components estimated using the whole data set in each model were used as true values in the prediction of breeding values of the animals in the training set. The WM model showed the best prediction ability, providing the lowest χ 2 average and the highest number of sets in which a model had the smallest value of χ 2 statistics. The CLM and LM models showed prediction abilities 2.6% and 3.7% less efficient than WM, respectively. In addition, the accuracies of sire breeding values for LM and CLM were lower than those obtained for WM. The percentages of bulls in common, considering only 10% of sires with the highest breeding values, were around 75% and 54%, respectively, between LM-CLM and LM-WM models, considering all sires, and 75% between LM-CLM and LM-WM, when only sires with more than 10 progenies with uncensored records were taken into account. These results are indicative of reranking of animals in terms of genetic merit between LM, CLM and WM. The model in which censored records of longevity were excluded from the analysis showed the lowest prediction ability. The WM provides the best predictive performance, therefore this model would be recommended to perform genetic evaluation of longevity in this population.


Glucagon binding to liver membranes of Mt-T-W15 tumor-bearing and hypophysectomized rats. A possible role for insulin and growth hormone.
To assess the effect of the endocrine environment and, more specifically, of growth hormone and insulin on glucagon receptors, we studied 125I-glucagon binding to liver membranes in five groups of rats: (1) controls, (2) streptozocin (STZ)-treated, (3) tumor-bearing (growth hormone-producing, Mt-T-W15), (4) STZ-treated tumor-bearing, and (5) hypophysectomized rats. Glucagon binding was decreased in tumor-bearing, hypophysectomized, and STZ-treated rats. Basal and glucagon-stimulated cAMP levels were determined in isolated hepatocytes. The basal cAMP levels were increased in STZ-treated, tumor-bearing, STZ-treated tumor-bearing, and hypophysectomized animals. All groups responded and produced more cAMP in response to glucagon stimulation, although the maximal response was greater in STZ-treated, tumor-bearing STZ-treated, and hypophysectomized groups than in the controls. Our data confirm that hyperglucagonemia downregulates the hepatic glucagon receptors and suggest that insulin and growth hormone may play a stimulatory role in their regulation. The results also suggest that the downregulation of glucagon receptors is not directly correlated to the basal or glucagon-stimulated cAMP levels.


Capsule structure changes associated with Cryptococcus neoformans crossing of the blood-brain barrier.
Cryptococcus neoformans is a yeast responsible for disseminated meningoencephalitis in patients with cellular immune defects. The major virulence factor is the polysaccharide capsule. We took advantage of a relevant murine model of disseminated meningoencephalitis to study the early events associated with blood-brain barrier (BBB) crossing. Mice were sacrificed at 1, 6, 24, and 48 hours post-intravenous inoculation, and classical histology, electron microscopy, and double immunofluorescence were used to study tissues and yeasts. Crossing of the BBB occurred early after inoculation, did not involve the choroid plexus but instead occurred at the level of the cortical capillaries, and caused early and severe damage to the structure of the microvessels. Seeding of the leptomeninges was not the primary event but occurred secondary to leakage of cortical pseudocysts. Organ invasion was associated with changes in cryptococcal capsule structure and cell size, which differed in terms of magnitude and kinetics, depending on both the organs involved, and potentially, on the bed structure of the local capillary. The rapid changes in capsule structure could contribute to inability of the host immune response to control cryptococcal infection in extrapulmonary spaces.


Understanding the bias dependence of low frequency noise in single layer graphene FETs.
This letter investigates the bias-dependent low frequency noise of single layer graphene field-effect transistors. Noise measurements have been conducted with electrolyte-gated graphene transistors covering a wide range of gate and drain bias conditions for different channel lengths. A new analytical model that accounts for the propagation of the local noise sources in the channel to the terminal currents and voltages is proposed in this paper to investigate the noise bias dependence. Carrier number and mobility fluctuations are considered as the main causes of low frequency noise and the way these mechanisms contribute to the bias dependence of the noise is analyzed in this work. Typically, normalized low frequency noise in graphene devices has been usually shown to follow an M-shape dependence versus gate voltage with the minimum near the charge neutrality point (CNP). Our work reveals for the first time the strong correlation between this gate dependence and the residual charge which is relevant in the vicinity of this specific bias point. We discuss how charge inhomogeneity in the graphene channel at higher drain voltages can contribute to low frequency noise; thus, channel regions nearby the source and drain terminals are found to dominate the total noise for gate biases close to the CNP. The excellent agreement between the experimental data and the predictions of the analytical model at all bias conditions confirms that the two fundamental 1/f noise mechanisms, carrier number and mobility fluctuations, must be considered simultaneously to properly understand the low frequency noise in graphene FETs. The proposed analytical compact model can be easily implemented and integrated in circuit simulators, which can be of high importance for graphene based circuits' design.


Finding the needles in the haystack: mapping constitutive proteolytic events in vivo.
Our quest to understand the complex inner workings of the cell depends on the development of new technologies that allow the study of global regulatory events as they happen within their native cellular environment. Post-translational processing of proteins by proteases is one such regulatory process that can control many aspects of basic cell biology. In this issue of the Biochemical Journal, Timmer et al. describe a new proteomic approach that can be used to globally monitor constitutive proteolytic events in vivo. Using bacterial, human, yeast and mouse cells, the authors show that this methodology provides a comprehensive map of constitutive trimming events mediated by regulatory proteases such as methionine aminopeptidase. This study also identifies previously uncharacterized processing events that highlight potential novel regulatory mechanisms mediated by proteolysis.


Sorption of arsenic from soil-washing leachate by surfactant-modified zeolite.
Post-treatment of leachate from soil-washing remedial actions may be necessary depending on the amounts of dissolved contaminants present. Uptake of arsenic species by surfactant-modified zeolite (SMZ) from a synthetic soil leachate (pH of approximately 12 [NaOH]) was measured as a test of SMZ as a post-treatment sorbent. Batch sorption isotherms were prepared using leachate to SMZ ratios from 40:1 to 4:1, and temperatures of 25 and 15 degrees C. Equilibrium levels of dissolved and total solution arsenic were similar. At each temperature, sorption appeared to reach a plateau or maximum, then decreased at the highest solution concentration, corresponding to the lowest amount of zeolite added (2.5 g). A maximum sorption value of 72.0 mmol of arsenic per kg of SMZ (5400 mg/kg) was observed at 25 degrees C, and 42.1 mmol/kg (3150 mg/kg) at 15 degrees C. Total arsenic recoveries varied from 74 to 125%. Surfactant-modified zeolite removed up to 97% of dissolved organic carbon and decolorized the leachate solutions. Excluding the points for the highest arsenic to SMZ ratio, the sorption isotherms were well described by the linearized form of the Langmuir equation, with coefficients of determination greater than 0.90 at both temperatures. Sorption of arsenic by SMZ is attributed to anion exchange with counterions on the surfactant head groups, and/or partitioning of organic carbon-complexed arsenic into the surfactant bilayer.


Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice.
Deregulated production of IL-17 and IL-21 plays a key pathogenic role in many autoimmune disorders. A delineation of the mechanisms that underlie the inappropriate synthesis of IL-17 and IL-21 in autoimmune diseases can thus provide important insights into potential therapies for these disorders. Here we have shown that the serine-threonine kinase Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) becomes activated in mouse T cells under Th17 skewing conditions and phosphorylates interferon regulatory factor 4 (IRF4), a transcription factor that is absolutely required for the production of IL-17 and IL-21. We furthermore demonstrated that ROCK2-mediated phosphorylation of IRF4 regulated the synthesis of IL-17 and IL-21 and the differentiation of Th17 cells. Whereas CD4+ T cells from WT mice activated ROCK2 physiologically under Th17 conditions, CD4+ T cells from 2 different mouse models of spontaneous autoimmunity aberrantly activated ROCK2 under neutral conditions. Moreover, administration of ROCK inhibitors ameliorated the deregulated production of IL-17 and IL-21 and the inflammatory and autoantibody responses observed in these autoimmune mice. Our findings thus uncover a crucial link among ROCK2, IRF4, and the production of IL-17 and IL-21 and support the idea that selective inhibition of ROCK2 could represent an important therapeutic regimen for the treatment of autoimmune disorders.


Mood and disruptive behavior disorders and symptoms in the offspring of patients with bipolar I disorder.
The study aimed to ascertain the prevalence of mood and disruptive behavior disorders and symptoms in 35 children of 29 adult outpatients with a DSM-IV diagnosis of bipolar I disorder, compared with 33 children of 29 healthy adults, matched with patients on age, socioeconomic status and education. The offspring of bipolar patients had a 9.48 fold higher risk of receiving a psychiatric diagnosis. While only two children of patients with bipolar disorder were diagnosed with a mood disorder, 30.9% displayed mild depressed mood, compared with 8.8% of the controls, a statistically significant difference. The bipolar offspring also scored significantly higher on the hyperactivity and conduct problems subscales as well as the ADHD index of the Conners' Teacher Rating Scale. The disruptive behavior and mood symptoms observed in early life in the offspring of bipolar patients may indicate the need for early psychosocial intervention.


Kallikrein 6 protease advances colon tumorigenesis via induction of the high mobility group A2 protein.
Kallikrein-related peptidase 6 (KLK6) overexpression is commonly observed in primary tumors of colorectal cancer (CRC) patients and has been associated with tumor aggressiveness, metastasis, and poor prognosis. We previously established a unique contribution of KLK6 in colon cancer metastasis via a specific network of microRNAs and mRNAs. Here we evaluated the cellular functions of KLK6 protease in Caco-2 colon adenocarcinoma cell line after introduction of the enzymatically active or inactive form of the enzyme. We found that proteolytically active KLK6 increased Caco-2 cells invasiveness in vitro and decreased the animal survival in the orthotopic colon cancer model. The active KLK6 induced phosphorylation of SMAD 2/3 proteins leading to the altered expression of the epithelial-mesenchymal transition (EMT) markers. KLK6 overexpression also induced the RNA-binding protein LIN28B and high-mobility group AT-hook 2 (HMGA2) transcription factor, two essential regulators of cell invasion and metastasis. In the CRC patients, KLK6 protein levels were elevated in the non-cancerous distant and adjacent tissues, compared to their paired tumor tissues (p < 0.0001 and p = 0.0157, respectively). Patients with mutant K-RAS tumors had significantly higher level of KLK6 protein in the luminal surface of non-cancerous distant tissue, compared to the corresponding tissues of the patients with K-RAS wild type tumors (p ≤ 0.05). Furthermore, KLK6 and HMGA2 immunohistochemistry (IHC) scores in patients' tumors and paired adjacent tissues positively correlated (Spearman correlation P < 0.01 and p = 0.03, respectively). These findings demonstrate the critical function of the KLK6 enzyme in colon cancer progression and its contribution to the signaling network in colon cancer.


Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response.
In the current study, we tested the central hypothesis that exposure to Delta-9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component in marijuana, can lead to enhanced growth of tumors that express low to undetectable levels of cannabinoid receptors by specifically suppressing the antitumor immune response. We demonstrated that the human breast cancer cell lines MCF-7 and MDA-MB-231 and the mouse mammary carcinoma 4T1 express low to undetectable levels of cannabinoid receptors, CB1 and CB2, and that these cells are resistant to Delta9-THC-induced cytotoxicity. Furthermore, exposure of mice to Delta9-THC led to significantly elevated 4T1 tumor growth and metastasis due to inhibition of the specific antitumor immune response in vivo. The suppression of the antitumor immune response was mediated primarily through CB2 as opposed to CB1. Furthermore, exposure to Delta9-THC led to increased production of IL-4 and IL-10, suggesting that Delta9-THC exposure may specifically suppress the cell-mediated Th1 response by enhancing Th2-associated cytokines. This possibility was further supported by microarray data demonstrating the up-regulation of a number of Th2-related genes and the down-regulation of a number of Th1-related genes following exposure to Delta9-THC. Finally, injection of anti-IL-4 and anti-IL-10 mAbs led to a partial reversal of the Delta9-THC-induced suppression of the immune response to 4T1. Such findings suggest that marijuana exposure either recreationally or medicinally may increase the susceptibility to and/or incidence of breast cancer as well as other cancers that do not express cannabinoid receptors and are resistant to Delta9-THC-induced apoptosis.