Serotonin transporter inhibition and 5-HT2C receptor activation drive loss of cocaine-induced locomotor activation in DAT Val559 mice.
Dopamine (DA) signaling dysfunction is believed to contribute to multiple neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD). The rare DA transporter (DAT) coding substitution Ala559Val found in subjects with ADHD, bipolar disorder and autism, promotes anomalous DA efflux in vitro and, in DAT Val559 mice, leads to increased reactivity to imminent handling, waiting impulsivity, and enhanced motivation for reward. Here, we report that, in contrast to amphetamine and methylphenidate, which induce significant locomotor activation, cocaine administration to these mice elicits no locomotor effects, despite retention of conditioned place preference (CPP). Additionally, cocaine fails to elevate extracellular DA. Given that amphetamine and methylphenidate, unlike cocaine, lack high-affinity interactions with the serotonin (5-HT) transporter (SERT), we hypothesized that the lack of cocaine-induced hyperlocomotion in DAT Val559 mice arises from SERT blockade and augmented 5-HT signaling relative to cocaine actions on wildtype animals. Consistent with this idea, the SERT blocker fluoxetine abolished methylphenidate-induced locomotor activity in DAT Val559 mice, mimicking the effects seen with cocaine. Additionally, a cocaine analog (RTI-113) with greater selectivity for DAT over SERT retains locomotor activation in DAT Val559 mice. Furthermore, genetic elimination of high-affinity cocaine interactions at SERT in DAT Val559 mice, or specific inhibition of 5-HT2C receptors in these animals, restored cocaine-induced locomotion, but did not restore cocaine-induced elevations of extracellular DA. Our findings reveal a significant serotonergic plasticity arising in the DAT Val559 model that involves enhanced 5-HT2C signaling, acting independently of striatal DA release, capable of suppressing the activity of cocaine-sensitive motor circuits.


The spotlight of attention illuminates failed feature-based expectancies.
A well-replicated finding is that visual stimuli presented at an attended location are afforded a processing benefit in the form of speeded reaction times and increased accuracy (Mangun, ; Posner,). This effect has been described using a spotlight metaphor, in which all stimuli within the focus of spatial attention receive facilitated processing, irrespective of other stimulus parameters. However, the spotlight metaphor has been brought into question by a series of combined expectancy studies that demonstrated that the behavioral benefits of spatial attention are contingent on secondary feature-based expectancies (Kingstone,). The present work used an event-related potential (ERP) approach to reveal that the early neural signature of the spotlight of spatial attention is not sensitive to the validity of secondary feature-based expectancies.


An Efficient Three-Dimensional Convolutional Neural Network for Inferring Physical Interaction Force from Video.
Interaction forces are traditionally predicted by a contact type haptic sensor. In this paper, we propose a novel and practical method for inferring the interaction forces between two objects based only on video data-one of the non-contact type camera sensors-without the use of common haptic sensors. In detail, we could predict the interaction force by observing the texture changes of the target object by an external force. For this purpose, our hypothesis is that a three-dimensional (3D) convolutional neural network (CNN) can be made to predict the physical interaction forces from video images. In this paper, we proposed a bottleneck-based 3D depthwise separable CNN architecture where the video is disentangled into spatial and temporal information. By applying the basic depthwise convolution concept to each video frame, spatial information can be efficiently learned; for temporal information, the 3D pointwise convolution can be used to learn the linear combination among sequential frames. To validate and train the proposed model, we collected large quantities of datasets, which are video clips of the physical interactions between two objects under different conditions (illumination and angle variations) and the corresponding interaction forces measured by the haptic sensor (as the ground truth). Our experimental results confirmed our hypothesis; when compared with previous models, the proposed model was more accurate and efficient, and although its model size was 10 times smaller, the 3D convolutional neural network architecture exhibited better accuracy. The experiments demonstrate that the proposed model remains robust under different conditions and can successfully estimate the interaction force between objects.


Reconstitution of bacterial photosynthetic unit in a lipid bilayer studied by single-molecule spectroscopy at 5 K.
As a model of photosynthetic unit (PSU), self-assembled aggregates of pigment-protein complexes from photosynthetic bacteria were prepared in a lipid bilayer by reconstitution of the light-harvesting 2 (LH2) complex and light-harvesting 1-reaction center (LH1-RC) complex through detergent removal of their micelles in the presence of lipids. By performing polarization-controlled fluorescence and fluorescence-excitation spectroscopy on single aggregates at a temperature of 5 K, the composition of individual aggregates was determined and excitation energy transfer (EET) between constituent complexes was observed. LH2 and LH1-RC from a bacterium, Rhodobacter (Rb.) sphaeroides, were found to form a trimeric aggregate in which EET takes place from one LH2 to two LH1-RCs. In contrast, a heterodimer of LH2 and LH1-RC in which EET works was found to assemble from a combination of complexes of different bacterial species, that is, LH2 from Rb. sphaeroides and LH1-RC from Rhodopseudomonas (Rps.) palustris.


Children with autism spectrum disorder show pronoun reversals in interpretation.
Pronoun reversals, saying you when meaning I, in children with autism spectrum disorder (ASD) are generally viewed as manifesting in early development and speech production only. This study investigates pronoun reversals in later development (age 6-12) in interpretation in 48 Dutch-speaking children with ASD and 43 typically developing (TD) peers. We contrasted children's interpretation of I and you in indirect and direct speech reports, with the latter type requiring an additional perspective shift. To examine which cognitive processes are involved in pronoun interpretation, additional tasks were administered to measure Theory of Mind (ToM) understanding, cognitive inhibition, cognitive flexibility, and working memory. We found that children with ASD showed more problems than TD children interpreting pronouns in direct speech, resulting in pronoun reversals in interpretation. Children with ASD hardly improved with age. Older children with ASD thus showed more pronoun reversals than did their TD peers. ToM understanding, working memory, IQ, and verbal ability, but not inhibition and flexibility, were associated with pronoun interpretation. ToM understanding in particular was associated with correct pronoun interpretation in older TD children relative to younger TD children, but this improvement was not found in children with ASD. These findings indicate that pronoun reversals most likely result from perspective-shifting difficulties. We conclude that pronoun reversals are more pronounced in individuals with ASD, occur beyond early development, and require sufficient cognitive resources. The relation with ToM understanding, but not inhibition and flexibility, suggests that pronoun reversals are best classified as a social communication problem in the diagnosis of ASD. (PsycINFO Database Record


Critical limb ischaemia: a case against Consensus II.
Critical limb ischaemia (CLI) is a serious clinical condition that often immediately precedes limb loss. The Consensus Documents of 1989 and 1991 attempted to define CLI and give direction to its investigation and management. Whilst the need for such a consensus was clear and should be supported we believe the definition of CLI as documented in the Consensus Documents I and II recommendation number I is wrong. We present evidence from 140 patients with severe limb ischaemia taken from the PARTNER Group studies to support our request for an amendment to the ankle pressure recommendation from < or = 50 mmHg to >50 mmHg and big toe pressure from < or = 30 mmHg to >30 mmHg for the purpose of conducting clinical trials and to include Doppler index and tcPO2 as additional parameters. We also believe that the current document may be actually excluding the only group of patients likely to benefit from drug treatment or other interventions and that the above amendment should be prioritized.


Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases.
Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications. To evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs. In this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center. Four cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases. Overall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations. Our findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.


A longitudinal study of quality of life of elderly with mandibular implant-supported fixed prostheses.
To verify the consequences of implant-supported fixed oral rehabilitation on the quality of life (QL) of elderly individuals. Fifteen patients were studied, being 10 females and five males; all were aged >60 years, were completely edentulous, wore removable dentures on both arches, and were treated with implant-supported fixed dentures. Three QL questionnaires were applied, two related to the oral conditions (Oral Impact on Daily Performance - OIDP - and Oral Health Impact Profile, short version - OHIP-14) and one dealing with global aspects (World Health Organization Quality of Life - WHOQOL-BREF), before 3, 6, and 18 months after surgical placement of implants. Scores in the OIDP and OHIP-14 questionnaires were better after dental treatment. The WHOQOL-BREF was less sensitive, confirming the higher reliability of specific questionnaires (focal) compared with general questions in such situations. Treatment with implant-supported fixed prostheses improved QL in the elderly; these effects are better detected by specific instruments focused on the subject.


Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions.
The effects of a 10-day course of moderate-dose (10 mg/kg/day) or high-dose (20 mg/kg/day) trimethoprim therapy on serum creatinine, measured creatinine clearance, urinary creatinine excretion, and serum folate were studied in 20 healthy volunteers. Serum creatinine concentrations increased significantly during trimethoprim therapy, began to decrease near day 10, and returned to baseline during the washout phase at both dosage levels. At the same time, measured creatinine clearance and urine creatinine changed in the opposite direction. No clinical or statistical differences were noted between changes in the moderate- versus the high-dose phases. Serum folate concentration decreases during high-dose trimethoprim therapy were statistically significant. Adverse drug reactions in the two groups were statistically different during the first study period, with the high-dose group having a 75% incidence rate and the moderate-dose group having an 11% incidence rate (P < 0.02). Serum creatinine, measured creatinine clearance, and urinary creatinine excretion demonstrated statistically, but not clinically, significant changes during trimethoprim therapy. In addition, high-dose trimethoprim caused significantly more adverse drug reactions than moderate-dose trimethoprim in normal volunteers.


Antimosquito property of Petroselinum crispum (Umbellifereae) against the pyrethroid resistant and susceptible strains of Aedes aegypti (Diptera: Culicidae).
The increasing and widespread resistance to conventional synthetic insecticides in vector populations has underscored the urgent need to establish alternatives in the mosquito management system. This study was carried out with the aim to investigate the antimosquito property, larvicidal and adulticidal potential, of plant products against both the pyrethroid-susceptible and resistant strains of Aedes aegypti. Seventeen plant products, including essential oils and ethanolic extracts, were obtained by steam distillation and extraction with 95 % ethanol, respectively. Their larvicidal activity was screened, using World Health Organization (WHO) procedures against A. aegypti, Muang Chiang Mai-susceptible (MCM-S) strain. The most effective product was a candidate for investigating larvicidal and adulticidal potential against three laboratory strains of A. aegypti, comprising MCM-S, Pang Mai Dang-resistant (PMD-R), and Upakut-resistant (UPK-R). Potential toxicity of the plant candidate was compared with that of synthetic temephos, permethrin, and deltamethrin. Chemical constituents of the most effective plant product also were analyzed by gas chromatography-mass spectrometry (GC-MS). Results obtained from the preliminary screening revealed the varying larvicidal efficacy of plant-derived products against MCM-S A. aegypti, with mortality ranging from 0 to 100 %. The larvicidal activity of seven effective plant products was found to be dose dependent, with the highest efficacy established from Petroselinum crispum fruit oil, followed by oils of Foeniculum vulgare, Myristica fragrans, Limnophila aromatica, Piper sarmentosum, Curcuma longa, and M. fragrans ethanolic extract (LC50 values of 43.22, 44.84, 47.42, 47.94, 49.19, 65.51, and 75.45 ppm, respectively). Essential oil of P. crispum was then investigated further and proved to be a promising larvicide and adulticide against all strains of A. aegypti. The pyrethroid-resistant strains of both PMD-R and UPK-R A. aegypti showed significant resistance to temephos, permethrin, and deltamethrin in either the larval or adult stage. Interestingly, high susceptibility to P. crispum oil was observed in the larvae and adults of MCM-S, which are pyrethroid-susceptible A. aegypti, and comparable to those of the pyrethroid-resistant strains, PMD-R and UPK-R. GC-MS analysis of P. crispum oil demonstrated that 19 compounds, accounting for 98.25 % of the whole oil, were identified, with the main constituents being thymol (42.41 %), p-cymene (27.71 %), and γ-terpinene (20.98 %). In conclusion, the profound larvicidal and adulticidal potential of P. crispum oil promises to form a new larvicide and adulticide against either the pyrethroid-susceptible or resistant strain of A. aegypti. Consequently, P. crispum oil and its constituents can be used or incorporated with other chemicals/measures in integrated mosquito management for controlling A. aegypti, particularly in localities with high levels of pyrethroid and organophosphate resistance.


Positive end-expiratory pressure during mechanical ventilation of the lungs. A new vlave.
A valve is described which will provide positive end-expiratory pressure during mechanical ventilation of the lungs. The authors will be pleased to supply further details of specification and production on request.


Developing a standardized faculty evaluation in an emergency medicine residency.
Quality educators are a core component of successful residency training. A structured, consistent, validated evaluation of clinical educators is important to improve teaching aptitude, further faculty development, and improve patient care. The authors sought to identify specific domains of instructional quality and to develop a composite instrument for assessing instructional quality. The study setting is a 3-year residency program. Residents rated the quality of faculty member instruction using an 18-item survey twice over a 2-year period (2004-2005). Each survey item used a 9-point scale. Factor analysis employing a Varimax rotation identified domains of instructional performance. Cronbach's alpha was used to assess the internal consistency of the identified domains. There were 29 faculty members evaluated. Using 2004 data, five domains of instructional quality were identified that explained 92.5% of the variation in survey responses (χ(2) = 2.33, P = 0.11). These were: Competency and Professionalism (30% of variation), Commitment to Knowledge and Instruction (23%), Inclusion and Interaction (17%), Patient Focus (13%), and Openness to Ideas (9%). Competency and Professionalism included appropriate care, effective patient communication, use of new techniques, and ethical principles. Commitment to Knowledge and Instruction included research, mentoring, feedback, and availability. Inclusion and Interaction included procedural participation and bedside teaching. Patient Focus included compassion, effective care, and sensitivity to diverse populations. Openness to Ideas included enthusiasm and receptivity of new ideas. These five domains were consistent in the 2005 data (Cronbach's alpha 0.68-0.75). A five-domain instrument consistently accounted for variations in faculty teaching performance as rated by resident physicians. This instrument may be useful for standardized assessment of instructional quality.


Predicting performance and performance satisfaction: mindfulness and beliefs about the ability to deal with social barriers in sport.
This research investigates the role of beliefs about the ability to deal with specific social barriers and its relationships to mindfulness, football performance, and satisfaction with one's own and team performance. Study 1 aimed at eliciting these social barriers. Study 2 tested (i) whether self-efficacy referring to social barriers would predict performance over and above task-related self-efficacy and collective efficacy and (ii) the mediating role of self-efficacy to overcome social barriers in the relationship between mindfulness and performance. Participants were football (soccer) players aged 16-21 years (Study 1: N=30; Study 2: N=101, longitudinal sample: n=88). Study 1 resulted in eliciting 82 social barriers referring to team, peer leadership, and coaches. Study 2 showed that task-related self-efficacy and collective efficacy explained performance satisfaction at seven-month follow-up, whereas self-efficacy referring to social barriers explained shooting performance at seven-month follow-up. Indirect associations between mindfulness and performance were found with three types of self-efficacy referring to social barriers, operating as parallel mediators. Results provide evidence for the role of beliefs about the ability to cope with social barriers and show a complex interplay between different types of self-efficacy and collective efficacy in predicting team sport performance.


Adaptation and Validation of the Screening Tool of Older People's Prescriptions Instrument for the Indonesian Population.
In this study, we aimed to prepare and validate an Indonesian version for the Screening Tool of Older People's Prescriptions (STOPP), which is an instrument to identify inappropriate medications for elderly patients. The Indonesian version of STOPP (STOPP_INA) was developed using modified transcultural adaptation guidelines from the American Academy of Orthopedic Surgeons. Our method consisted of translating original STOPP into Indonesian (forwardly translation), synthesis of forward translation, translation into English and synthesis of back translation, a review by the copyright holder of STOPP, a review by the expert team, pretest, revision of STOPP_INA, field test, and psychometric analysis of the final version of the questionnaire. The study design for this part was quasi-experimental with purposive sampling for members of the translator's team, expert's team, and respondents in the pretest, but they were different from field testing that used purposive and postsurvey sampling for respondents. Content validity and face validity were used to construct the validity of STOPP_INA by assessing item-level content validity and correlation between items and total values. Internal consistency was measured with Cronbach's alpha coefficient. The expert panel agreed on a list of 81 criteria. Five (62.50%) of expert team members agreed and could be continued to the field test without revision of STOPP_INA and 3 (37.50%) agreed with a revision. The research subjects in the psychometric test had 230 respondents, 5 (2.17%) resigned, with an average of item-level content validity index of 0.99. The construct validity analysis showed that 5-item criteria are "not valid," namely in A1, A3, B7, B10, and C3. Reliability analysis showed the Cronbach's Alpha and Cronbach's Alpha Based on Standardized Items were 0.978 and 0.979. The expert team was be agreed on 81 criteria (100%) of adaptation of STOPP version 2 criteria. There were 5 criteria that not valid statistically, they could not be removed from the instrument because they can influence content and construct of the instrument. The STOPP_INA has been developed for the Indonesian population, currently being tested in clinical practice against elderly patients undergoing hospitalization.


Biotransformations of drugs and foreign chemicals in the human fetal-placental unit.
Several communications pertaining to research on human fetal drug biotransformation have appeared in the literature in the past 3 to 4 years (Aranda et al. 1979; Cresteil et al. 1982; Pacifici et al. 1981; Pacifici and Rane 1982, 1983; Schroeter and Amon 1983). In general, research in this area has produced no major recent surprises, but it has confirmed, extended, and supported the earliest findings through those of the mid-1970s and has served to expand our understanding of these important systems. The important aspects of our current knowledge may be summarized very briefly as follows: Each of the major drug metabolic reactions (oxidations, reductions, hydrolyses, and conjugations) can be catalyzed at generally low rates by enzymes present in human fetal and placental tissues. Reaction rates appear, in general, to increase with advancing gestational age. Placental xenobiotic-biotransforming monooxygenases display a high sensitivity to the effects of MC-type (methylcholanthrene) but not PB-type (phenobarbital) inducing agents during the later stages of gestation. Responsivity is minimal during early gestation. Monooxygenases in other fetal tissues (liver, adrenal gland, etc.) appear to respond minimally to inducing agents, at least during the earlier stages of gestation. Glucuronyl transferase activities appear to be very low in all fetal and placental tissues. Epoxide hydrolase, glutathione S-transferase, and sulfotransferase (and perhaps others) activities can be relatively high in prenatal primate hepatic tissues but, at present, are difficult to predict. Some of these may respond to environmental inducers in situ, but solid evidence for this is still lacking.(ABSTRACT TRUNCATED AT 250 WORDS)


A Collaborative In Situ Simulation-based Pediatric Readiness Improvement Program for Community Emergency Departments.
More than 30 million children are cared for across 5,000 U.S. emergency departments (EDs) each year. Most of these EDs are not facilities designed and operated solely for children. A Web-based survey provided a national and state-by-state assessment of pediatric readiness and noted a national average score was 69 on a 100-point scale. This survey noted wide variations in ED readiness with scores ranging from 61 in low-pediatric-volume EDs to 90 in the high-pediatric-volume EDs. Additionally, the mean score at the state level ranged from 57 (Wyoming) to 83 (Florida) and for individual EDs ranged from 22 to 100. The majority of prior efforts made to improve pediatric readiness have involved providing Web-based resources and online toolkits. This article reports on the first year of a program that aimed to improve pediatric readiness across community hospitals in our state through in situ simulation-based assessment facilitated by our academic medical center. The primary aim was to improve the pediatric readiness scores in the 10 participating hospitals. The secondary aim was to explore the correlation of simulation-based performance of hospital teams with pediatric readiness scores. This interventional study measured the Pediatric Readiness Survey (PRS) prior to and after implementation of an improvement program. This program consisted of three components: 1) in situ simulations, 2) report-outs, and 3) access to online pediatric readiness resources and content experts. The simulations were conducted in situ (in the ED resuscitation bay) by multiprofessional teams of doctors, nurses, respiratory therapists, and technicians. Simulations and debriefings were facilitated by an expert team from a pediatric academic medical center. Three scenarios were conducted for all teams and include: a 6-month-old with respiratory failure, an 8-year-old with diabetic ketoacidosis (DKA), and a 6-month-old with supraventricular tachycardia (SVT). A performance score was calculated for each scenario. The improvement of PRS was compared before and after the simulation program. The correlation of the simulation performance of each hospital and the PRS was calculated. Forty-one multiprofessional teams from 10 EDs in Indiana participated in the study, five were of medium pediatric volume and five were medium- to high-volume EDs. The PRS significantly improved from the first to the second on-site verification assessment (58.4 ± 4.8 to 74.7 ± 2.9, p = 0.009). Total adherence scores to scenario guidelines were 54.7, 56.4, and 62.4% in the respiratory failure, DKA, and SVT scenarios, respectively. We found no correlation between simulation performance and PRS scores. Medium ED pediatric volume significantly predicted higher PRS scores compared to medium-high pediatric ED volume (β = 8.7; confidence interval = 0.72-16.8, p = 0.034). Our collaborative improvement program that involved simulation was associated with improvement in pediatric readiness scores in 10 EDs participating statewide. Future work will focus on further expanding of the network and establishing a national model for pediatric readiness improvement.


Confined-Enhanced Raman Spectroscopy.
In 1997, the discovery of single molecule-surface enhanced Raman spectroscopy (SM-SERS) rekindled broad interests owing to its ultrahigh enhancement factor up to the 1014-1015 level. However, regretfully, the advantage of SM-SERS with an ultralow detection limit has not yet been fully utilized in commercialized applications. Here, we report a strategy, which we name confined-enhanced Raman spectroscopy, in which the overall Raman properties can be remarkably improved with in situ-formed active nanoshell on the surface of silver or gold nanoparticles. The nanoshell can confine and anchor molecules onto the surface of plasmonic nanoparticles and avoid desorption from hot spots so that the "on and off" blinking effect can be eliminated. It is the first time the single-molecule detection of analytes with super sensitivity, high stability, and reproducibility based on gold nanoparticles has been realized. In addition, this strategy is suitable for SERS detection in diverse molecule systems, including biomedical diagnosis, catalytic reaction, etc.


Self-esteem in children with attention and/or learning deficits: the importance of gender.
Our objective was to analyze self-esteem in children within a spectrum of attention disorders, that is, besides attention deficit hyperactivity disorder (ADHD), also children with subthreshold ADHD and even milder attention deficits and/or learning problems. From a population-based group of 10-11-year-old children in a Swedish municipality those with ADHD/subthreshold ADHD (n = 30) and those with milder attention and/or learning problems (n = 64) were targeted for the study. The children completed the 'I think I am' scale, reflecting physical appearance, scholastic competence, mental well-being, relationships to parents and to others and global self-esteem. Data from boys and girls were compared and related to the parents' and teachers' ratings on the two dimensions of the Conners' 10-item questionnaire (impulsive-restless behaviour and emotional lability) and to the children's cognitive levels. Significant gender differences were found, girls reporting lower self-esteem concerning mental well-being and poorer relationships with parents and peers. However, children with ADHD/subthreshold ADHD did not report significantly lower global self-esteem when compared to a reference population. Self-esteem in children with attention, behaviour and/or learning problems has to be carefully evaluated, especially in girls, and measures are needed to prevent a trajectory towards adolescent psychopathology.


Describing, explaining or predicting mental health care costs: a guide to regression models. Methodological review.
Analysis of the patterns of variation in health care costs and the determinants of these costs (including treatment differences) is an increasingly important aspect of research into the performance of mental health services. To encourage both investigators of the variation in health care costs and the consumers of their investigations to think more critically about the precise aims of these investigations and the choice of statistical methods appropriate to achieve them. We briefly describe examples of regression models that might be of use in the prediction of mental health costs and how one might choose which one to use for a particular research project. If the investigators are primarily interested in explanatory mechanisms then they should seriously consider generalised linear models (but with careful attention being paid to the appropriate error distribution). Further insight is likely to be gained through the use of two-part models. For prediction we recommend regression on raw costs using ordinary least-square methods. Whatever method is used, investigators should consider how robust their methods might be to incorrect distributional assumptions (particularly in small samples) and they should not automatically assume that methods such as bootstrapping will allow them to ignore these problems.


[Bioavailability of 3 theophylline delayed-release preparations. Comparison of theophylline concentrations in the serum and saliva in the steady state].
The absolute and relative bioavailability of three sustained release theophylline preparations marketed in Switzerland was tested in 11 healthy volunteers. The mean absolute bioavailability in the steady state in 4 to 6 volunteers was 88% (range 52-127%) for Euphyllin retard 350 mg, 93% (78-106%) for Phyllotemp retard 225 mg and 131% (78-169%) for Theolair SR 175 mg. There was no significant difference (p less than 0.05) in absolute or relative bioavailability between the three preparations. The concentration-time curves in a dosing interval showed adequate sustained release properties for all three preparations. The mean ratio between the concentration of theophylline in serum and saliva was surprising constant. Moreover, each volunteer appeared to have an individual fixed serum/saliva ratio. This ratio was independent of the theophylline preparation or the serum concentration. Knowledge of the individual serum/saliva ratio may allow calculation of the serum level from noninvasive tests in saliva during long-term treatment.


Is mitochondrial DNA copy number associated with clinical characteristics and prognosis in gastric cancer?
Alterations in mitochondrial DNA (mtDNA) have been studied in various cancers. However, the clinical value of mtDNA copy number (mtCN) alterations in gastric cancer (GC) is poorly understood. In the present study, we investigated whether alterations in mtCNs might be associated with clinicopathological parameters in GC cases. mtCN was measured in 109 patients with GC by quantitative real-time PCR. Then, correlations with clinicopathological characteristics were analyzed. mtCN was elevated in 64.2% of GC tissues compared with paired, adjacent, non-cancerous tissue. However, the observed alterations in mtCN were not associated with any clinicopathological characteristics, including age, gender, TN stage, Lauren classification, lymph node metastasis, and depth of invasion. Moreover, Kaplan-Meier survival curves revealed that mtCN was not significantly associated with the survival of GC patients. In this study, we demonstrated that mtCN was not a significant marker for predicting clinical characteristics or prognosis in GC.


Vascular superoxide production by NAD(P)H oxidase: association with endothelial dysfunction and clinical risk factors.
Superoxide anion plays important roles in vascular disease states. Increased superoxide production contributes to reduced nitric oxide (NO) bioactivity and endothelial dysfunction in experimental models of vascular disease. We measured superoxide production by NAD(P)H oxidase in human blood vessels and examined the relationships between NAD(P)H oxidase activity, NO-mediated endothelial function, and clinical risk factors for atherosclerosis. Endothelium-dependent vasorelaxations and direct measurements of vascular superoxide production were determined in human saphenous veins obtained from 133 patients with coronary artery disease and identified risk factors. The predominant source of vascular superoxide production was an NAD(P)H-dependent oxidase. Increased vascular NAD(P)H oxidase activity was associated with reduced NO-mediated vasorelaxation. Furthermore, reduced endothelial vasorelaxations and increased vascular NAD(P)H oxidase activity were both associated with increased clinical risk factors for atherosclerosis. Diabetes and hypercholesterolemia were independently associated with increased NADH-dependent superoxide production. The association of increased vascular NAD(P)H oxidase activity with endothelial dysfunction and with clinical risk factors suggests an important role for NAD(P)H oxidase-mediated superoxide production in human atherosclerosis. The full text of this article is available at http://www.circresaha.org.


[Factors associated with metabolic syndrome in administrative workers in the oil industry].
This is a cross-sectional study seeking to identify the factors associated with metabolic syndrome in administrative workers of an oil company. A total of 1,387 workers were examined, including their anthropometric and biochemical data, lifestyle, demographic and socioeconomic characteristics. Metabolic syndrome was defined in accordance with the First Set of Brazilian Guidelines for the Diagnosis and Treatment of Metabolic Syndrome. Factors associated with MS were examined by univariate and multivariate logistic regression models and 15% of the workers had MS symptoms. Multivariate analysis revealed that gender (OR=3.4; IC 95% 2.1- 5.5), age (OR=3.8; IC 95% 1.5-9.4) and smoking (current and past) (OR=1.6; CI 95% 1.2-2.3), were associated with metabolic syndrome. In conclusion, the prevalence of MS in administrative workers of the oil industry is high, especially among males, smokers, ex-smokers and those aged 40 years or more. Possibly, the greatest value of this diagnosis is to make it possible to identify workers with severe metabolic changes, which would justify the implementation of immediate intervention to reduce the identified risk factors. In this sense, actions aiming to promote a healthy lifestyle can be developed by the companies, in order to enhance the health and quality of life of their employees.


A Prospective Longitudinal Study of Caregivers of Community Dwelling Persons with Severe Dementia (PISCES): Study Protocol.
Although many persons with severe dementia (PWSDs) are cared for at home by their family caregivers, few studies have assessed end of life (EOL) care experiences of PWSDs. We present the protocol for the PISCES study (Panel study Investigating Status of Cognitively impaired Elderly in Singapore) which aims to describe the clinical course, health care utilization, and expenditures for community-dwelling PWSDs; and perceived burden, coping, resilience, anticipatory and prolonged grief among their caregivers. This ongoing multi-center prospective longitudinal study is recruiting primary informal caregivers of 250 PWSDs from major restructured public hospitals, community hospitals, home care foundations, and hospices in Singapore. Caregivers are surveyed every four months for two years or until the PWSD passes away and then at eight weeks and six months post-death to assess the bereavement of the caregiver. Survey questionnaires included validated tools to assess PWSDs' quality of life, suffering, behaviors, functional status, resource utilization; and caregiver's satisfaction with care, awareness of prognosis, care preferences, resilience, coping, perceived burden, distress, positive aspects of caregiving, anticipatory grief, and bereavement adjustment. We also conduct qualitative in-depth interviews with a sub-sample of caregivers. The survey data is being linked with medical and billing records of PWSDs. The study has been approved by an ethics board. Results from the study will be disseminated through publications and presentations targeting researchers, policy makers and clinicians interested in understanding and improving EOL care for PWSDs and their caregivers.


The therapeutic efficacy of sacroiliac joint blocks with triamcinolone acetonide in the treatment of sacroiliac joint dysfunction without spondyloarthropathy.
Prospective case series. The study aimed to investigate the therapeutic efficacy of sacroiliac joint (SIJ) blocks with triamcinolone acetonide in patients with SIJ pain without spondyloarthropathy. Numerous studies have demonstrated that SIJ blocks with corticosteroid/anesthetic provide long-term pain relief in seronegative spondyloarthropathy. However, only one report on SIJ dysfunction patients without spondyloarthropathy shows promising results. We conducted a prospective observational study of patients at a University Spine Center from March 2005 to May 2006. The above mentioned SIJ blocks were performed in 150 patients, and dual SIJ blocks confirmed SIJ pain in 39 patients (26%). Twenty-six patients (66.7%) experienced significant pain reduction for more than 6 weeks; the overall mean duration of pain reduction in these responders was 36.8 +/- 9.9 weeks. SIJ blocks were ineffective in 13 patients (33.3%); the mean duration of pain reduction in these patients was 4.4 +/- 1.8 weeks. Univariate analysis revealed that treatment failure was significantly associated with a history of lumbar/lumbosacral fusion (P = 0.03). SIJ blocks with triamcinolone acetonide are beneficial for some patients with SIJ pain without spondyloarthropathy. The SIJ blocks showed a long-lasting efficacy in two-thirds of the patients; however, the duration of its efficacy was shorter in patients with a history of lumbar/lumbosacral fusion. These findings suggest the need for further studies.


Brain activity during a motor learning task: an fMRI and skin conductance study.
Measuring electrodermal activity (EDA) during fMRI is an effective means of studying the influence of task-related arousal, inferred from autonomic nervous system activity, on brain activation patterns. The goals of this study were: (1) to measure reliable EDA from healthy individuals during fMRI involving an effortful unilateral motor task, (2) to explore how EDA recordings can be used to augment fMRI data analysis. In addition to conventional hemodynamic modeling, skin conductance time series data were used as model waveforms to generate activation images from fMRI data. Activations from the EDA model produced significantly different brain regions from those obtained with a standard hemodynamic model, primarily in the insula and cingulate cortices. Onsets of the EDA changes were synchronous with the hemodynamic model, but EDA data showed additional transient features, such as a decrease in amplitude with time, and helped to provide behavioral evidence suggesting task difficulty decreased with movement repetition. Univariate statistics also confirmed that several brain regions showed early versus late session effects. Partial least squares (PLS) multivariate analysis of EDA and fMRI data provided complimentary, additional insight on how the motor network varied over the course of a single fMRI session. Brain regions identified in this manner included the insula, cingulate gyrus, pre- and postcentral gyri, putamen and parietal cortices. These results suggest that recording EDA during motor fMRI experiments provides complementary information that can be used to improve the fMRI analysis, particularly when behavioral or task effects are difficult to model a priori.


Translation of rat intestinal RNA yields two alkaline phosphatases.
After translation of total rat intestinal RNA, immunoprecipitation using monospecific antiserum against rat intestinal alkaline phosphatase yielded two polypeptides in the adult duodenum and jejunum (molecular masses 62 and 65 kDa). Immunoprecipitation of both bands was blocked by a single purified alkaline phosphatase. In the adult ileum and in the entire small intestine of suckling pups, only the 62 kDa translation product was found. After fat feeding, translated alkaline phosphatase increased by an amount proportionate to the increase in enzyme activity previously seen in the serum. A small fraction of nascent alkaline phosphatase was translocated into microsomal vesicles, producing peptides of 65 and 69 kDa. Tunicamycin-treated membranes demonstrated a different signal peptide for each translation product. N-Terminal sequencing of the translation products showed leucine residues at similar positions, but overlap with the mature protein sequence was not demonstrated. On the basis of these data, we propose the presence of two mRNAs encoding alkaline phosphatase in the rat intestine.


Mapping low-resource contexts to prepare for lung health interventions in four countries (FRESH AIR): a mixed-method study.
Effectiveness of health programmes can be undermined when the implementation misaligns with local beliefs and behaviours. To design context-driven implementation strategies, we explored beliefs and behaviours regarding chronic respiratory disease (CRD) in diverse low-resource settings. This observational mixed-method study was conducted in Africa (Uganda), Asia (Kyrgyzstan and Vietnam) and Europe (rural Greece and a Roma camp). We systematically mapped beliefs and behaviours using the SETTING-tool. Multiple qualitative methods among purposively selected community members, health-care professionals, and key informants were triangulated with a quantitative survey among a representative group of community members and health-care professionals. We used thematic analysis and descriptive statistics. We included qualitative data from 340 informants (77 interviews, 45 focus group discussions, 83 observations of community members' households and health-care professionals' consultations) and quantitative data from 1037 community members and 204 health-care professionals. We identified three key themes across the settings; namely, (1) perceived CRD identity (community members in all settings except the rural Greek strongly attributed long-lasting respiratory symptoms to infection, predominantly tuberculosis); (2) beliefs about causes (682 [65·8%] of 1037 community members strongly agreed that tobacco smoking causes symptoms, this number was 198 [19·1%] for household air pollution; typical perceived causes ranged from witchcraft [Uganda] to a hot-cold disbalance [Vietnam]); and (3) norms and social structures (eg, real men smoke [Kyrgyzstan and Vietnam]). When designing context-driven implementation strategies for CRD-related interventions across these global settings, three consistent themes should be addressed, each with common and context-specific beliefs and behaviours. Context-driven strategies can reduce the risk of implementation failure, thereby optimising resource use to benefit health outcomes. European Commission Horizon 2020. For the Greek, Russian and Vietnamese translations of the abstract see Supplementary Materials section.


The economic geography of medical cannabis dispensaries in California.
The introduction of laws that permit the use of cannabis for medical purposes has led to the emergence of a medical cannabis industry in some US states. This study assessed the spatial distribution of medical cannabis dispensaries according to estimated cannabis demand, socioeconomic indicators, alcohol outlets and other socio-demographic factors. Telephone survey data from 5940 residents of 39 California cities were used to estimate social and demographic correlates of cannabis consumption. These individual-level estimates were then used to calculate aggregate cannabis demand (i.e. market potential) for 7538 census block groups. Locations of actively operating cannabis dispensaries were then related to the measure of demand and the socio-demographic characteristics of census block groups using multilevel Bayesian conditional autoregressive logit models. Cannabis dispensaries were located in block groups with greater cannabis demand, higher rates of poverty, alcohol outlets, and in areas just outside city boundaries. For the sampled block groups, a 10% increase in demand within a block group was associated with 2.4% greater likelihood of having a dispensary, and a 10% increase in the city-wide demand was associated with a 6.7% greater likelihood of having a dispensary. High demand for cannabis within individual block groups and within cities is related to the location of cannabis dispensaries at a block-group level. The relationship to low income, alcohol outlets and unincorporated areas indicates that dispensaries may open in areas that lack the resources to resist their establishment.


Filtering of intended motion for real-time tremor compensation in human upper limb using surface electromyography.
The recorded motion from (pathological) tremor patient may consist of the involuntary tremulous component and the intended motion. These two components have to be separated so that the actuation part will be able to suppress only the tremor. This paper proposes an algorithm to remove the intended motion by using an extended Kalman filter with the help of adaptive high-pass filter. The effectiveness of the algorithm is also shown in the presence of stimulation artifacts. It is part of the active pathological tremor compensation project for human upper limb.


The pattern of protein synthesis in spoIVC mutants of Bacillus subtilis resuspended in sporulation medium.
Two spoIVC mutants of Bacillus subtilis were labelled with [35S]methionine either at the time of resuspension in sporulation medium or 1, 2 or 3 h later, and radioactive proteins were detected after cell extracts had been subjected to two-dimensional gel electrophoresis. The mutants completed almost all of the changes in protein synthesis that occur in the wild-type in these conditions. A heavily labelled protein was found in the mutants that has also been observed in a spoO mutant but does not occur in the wild-type.


Precisely timing dissipative quantum information processing.
Dissipative engineering constitutes a framework within which quantum information processing protocols are powered by system-environment interaction rather than by unitary dynamics alone. This framework embraces noise as a resource and, consequently, offers a number of advantages compared to one based on unitary dynamics alone, e.g., that the protocols are typically independent of the initial state of the system. However, the time independent nature of this scheme makes it difficult to imagine precisely timed sequential operations, conditional measurements, or error correction. In this work, we provide a path around these challenges, by introducing basic dissipative gadgets which allow us to precisely initiate, trigger, and time dissipative operations while keeping the system Liouvillian time independent. These gadgets open up novel perspectives for thinking of timed dissipative quantum information processing. As an example, we sketch how measurement-based computation can be simulated in the dissipative setting.


Energy transfer in the major intrinsic light-harvesting complex from Amphidinium carterae.
Carbonyl carotenoids are important constituents of the antenna complexes of marine organisms. These carotenoids possess an excited state with a charge-transfer character (intramolecular charge transfer state, ICT), but many details of the carotenoid to chlorophyll energy transfer mechanisms are as yet poorly understood. Here, we employ femtosecond transient absorption spectroscopy to study energy transfer pathways in the intrinsic light-harvesting complex (LHC) of dinoflagellates, which contains the carbonyl carotenoid peridinin. Carotenoid to chlorophyll energy transfer efficiency is about 90% in the 530-550 nm region, where the peridinin S2 state transfers energy with an efficiency of 25-50%. The rest proceeds via the S1/ICT channel, and the major S1/ICT-mediated energy transfer pathway utilizes the relaxed S1/ICT state and occurs with a time constant of 2.6 ps. Below 525 nm, the overall energy transfer efficiency drops because of light absorption by another carotenoid, diadinoxanthin, that contributes only marginally to energy transfer. Instead, its role is likely to be photoprotection. In addition to the peridinin-Chl-a energy transfer, it was shown that energy transfer also occurs between the two chlorophyll species in LHC, Chl-c2, and Chl-a. The time constant characterizing the Chl-c2 to Chl-a energy transfer is 1.4 ps. The results demonstrate that the properties of the S1/ICT state specific for carbonyl carotenoids is the key to ensure the effective harvesting of photons in the 500-600 nm region, which is of vital importance to underwater organisms.


Idiomarina gen. nov., comprising novel indigenous deep-sea bacteria from the Pacific Ocean, including descriptions of two species, Idiomarina abyssalis sp. nov. and Idiomarina zobellii sp. nov.
Two bacterial strains, KMM 227T and 231T, were isolated from seawater samples collected from the north-western Pacific Ocean at a depth of 4000-5000 m and were characterized using polyphasic taxonomy. Both were Gram-negative, psychrotolerant, heterotrophic, aerobic and required NaCl for growth (0.6-15.0%). The temperature for growth was 4-30 degrees C. Both strains were rod-shaped, with a single flagellum. However, strain KMM 231T revealed a single long fimbrium. Cellular fatty acids detected in the isolates were predominantly odd-numbered and iso-branched, with 15 and 17 carbons (ca. 70%). Also present were saturated and monounsaturated straight-chain fatty acids. Results of phylogenetic analyses, employing three tree-making methods, strongly indicated that the two strains formed a distinct lineage within a clade containing the genera Alteromonas, Colwellia and Pseudoalteromonas, in the gamma-Proteobacteria. The two strains shared 16S rDNA sequence similarity of 96.9% and genomic DNA relatedness of 27%; the latter was determined by dot-blot hybridization. The strains were differentiated by the presence of fimbria, production of chitinase, ability to grow on 15% NaCl and BIOLOG profiles. Given the polyphasic evidence accumulated in this study, it is proposed that the two deep-sea isolates be classified in the genus Idiomarina gen. nov., as Idiomarina abyssalis sp. nov. (type strain is KMM 227T) and Idiomarina zobellii sp. nov. (type strain is KMM 231T).


Risk of Atherosclerotic Cardiovascular Diseases in various Ethnicities of Pakistan.
To estimate the risk of atherosclerotic cardiovascular diseases (ASCVD) in various ethnicities of Pakistan using Astronaut Cardiovascular Health and Risk Modification (Astro-CHARM) risk calculator and the Pooled Cohort Equations (PCE). Individuals of both gender between 40 to 65 years of age without pre-existing coronary artery disease from residents of Karachi were recruited through snowball sampling technique. Study was conducted at the National Institute of Cardiovascular Diseases, Karachi, Pakistan during January to June 2019. Ethnicity of the participants was categorized based on their mother tongue. Ten-year risk of ASCVD event was estimated using Astro-CHARM Calculator and PCE. Mean age of a total of 386 individuals was 49(±7.1) years and 45.3% (175) were females. Urdu-speaking individuals were 33.4%(129) of the sample, while, 18.4%(71) Pushtoons, 14%(54) Sindhi, 13%(50) Punjabi, 2.6%(10) Balochi, and remaining 18.7%(72) were of other ethnicities. High risk (≥7.5%) individuals were 20.7% (80/386) as per PCE and 11.1% (43/386) as per Astro-CHARM. As per Astro-CHARM, Sindhis' had the least risk of ten-years ASCVD event among all the ethnicities, while, Urdu-speakings' had the highest risk with mean rank of 145.18 vs. 216.50, p-value=0.001. A significant 10-years risk of first ASCVD event was observed in our population. ASCVD risk is alarmingly high in some ethnicities, such as Urdu-speaking, owing to the increased prevalence of traditional modifiable risk factors, such as diabetes and smoking.


Evolutionary constraints in variable environments, from proteins to networks.
Environmental changes can not only trigger a regulatory response, but also impose evolutionary pressures that can modify the underlying regulatory network. Here, we review recent approaches that are beginning to disentangle this complex interplay between regulatory and evolutionary responses. Systematic genetic reconstructions have shown how evolutionary constraints arise from epistatic interactions between mutations in fixed environments. This approach is now being extended to more complex environments and systems. The first results suggest that epistasis is affected dramatically by environmental changes and, hence, can profoundly affect the course of evolution. Thus, external environments not only define the selection of favored phenotypes, but also affect the internal constraints that can limit the evolution of these phenotypes. These findings also raise new questions relating to the conditions for evolutionary transitions and the evolutionary potential of regulatory networks.


Recursive segmentation and recognition templates for image parsing.
In this paper, we propose a Hierarchical Image Model (HIM) which parses images to perform segmentation and object recognition. The HIM represents the image recursively by segmentation and recognition templates at multiple levels of the hierarchy. This has advantages for representation, inference, and learning. First, the HIM has a coarse-to-fine representation which is capable of capturing long-range dependency and exploiting different levels of contextual information (similar to how natural language models represent sentence structure in terms of hierarchical representations such as verb and noun phrases). Second, the structure of the HIM allows us to design a rapid inference algorithm, based on dynamic programming, which yields the first polynomial time algorithm for image labeling. Third, we learn the HIM efficiently using machine learning methods from a labeled data set. We demonstrate that the HIM is comparable with the state-of-the-art methods by evaluation on the challenging public MSRC and PASCAL VOC 2007 image data sets.


The mismatch repair gene hMSH2 is mutated in the prostate cancer cell line LNCaP.
Mismatch repair genes are responsible for the coordinated correction of misincorporated nucleotides formed during DNA replication. Inactivating and inherited mutations in the prototypic mismatch repair gene hMSH2 have been described in a cancer predisposition syndrome known as hereditary nonpolyposis colon cancer. Patients with hereditary nonpolyposis colon cancer are at increased risk for colon cancer and extracolonic cancers such as upper tract transitional cell carcinoma but not prostate cancer. We investigated expression of hMSH2 in prostate cancer cell lines using genetic and molecular analysis. We used the 3 well described prostate cancer cell lines, DU145, LNCaP and PC3. Western blot analysis with monoclonal antibody to hMSH2 was used to assess expression. Southern blot and polymerase chain reaction of genomic DNA were used to identify genetic alterations in the hMSH2 gene. Single cell cloning, dinucleotide repeats and BAT-26 were used to assess the cell lines for microsatellite instability. The prostate cancer cell line LNCaP did not express hMSH2 and was found to have a homozygous deletion of hMSH2 exons 9 to 16, resulting in truncation of the protein. While microsatellite analysis did not reveal alterations at the BAT-26 locus, single cell cloning produced several LNCaP subclones with alteration at 1 dinucleotide repeat. The well described prostate cancer cell line LNCaP has a mutation in the hMSH2 gene, resulting in loss of expression and possible evidence of microsatellite instability. To our knowledge our finding is the first demonstration of a genetic alteration in hMSH2 in a prostate cancer cell line.


cDNA cloning and functional properties of human glutamate receptor EAA3 (GluR5) in homomeric and heteromeric configuration.
We have isolated a new member of the human glutamate receptor family from a fetal brain cDNA library. This cDNA clone, designated EAA3a, shares a 90% nucleotide identity with the previously reported rat GluR5-2b cDNA splice variant and differed from human GluR5-1d in the amino and carboxy terminal regions. Cell lines stably expressing EAA3a protein formed homomeric ligand-gated ion channels responsive, in order of decreasing affinity to domoate, kainate, L-glutamate and (RS)-alpha-amino-3-hydroxy-5- methylisoxazole-propionate (AMPA). Kainate-evoked currents showed partial desensitization that was reduced on incubation with concanavalin A (conA) but not cyclothiazide and were attenuated by the non-N-methyl-D-aspartate (NMDA) receptor antagonist CNQX (6-cyano-7-nitro-quinoxalinedione). Coexpression of EAA3a and human EAA1 cDNAs in HEK 293 cells formed a heteromeric channel with unique properties. Kainate and AMPA activated the heteromeric channel with significantly higher affinities than observed for EAA3a alone. Ligand binding studies with the recombinant EAA3a receptor expressed in mammalian cells indicated a high affinity kainate binding site (Kd = 120 +/- 15.0 nM). The relative potency of compounds in displacing [3H]-kainate binding to EAA3a receptor was: domoate > kainate > L-glutamate = quisqualate > 6,7-dinitroquinoxaline-2,3-dione (DNQX) = CNQX > AMPA > dihydrokainate > NMDA.


Cutaneous tuberculosis: diagnosis, histopathology and treatment - part II.
The evolution in the knowledge of tuberculosis' physiopathology allowed not only a better understanding of the immunological factors involved in the disease process, but also the development of new laboratory tests, as well as the establishment of a histological classification that reflects the host's ability to contain the infectious agent. At the same time, the increasing bacilli resistance led to alterations in the basic tuberculosis treatment scheme in 2009. This article critically examines laboratory and histological investigations, treatment regimens for tuberculosis and possible adverse reactions to the most frequently used drugs.


Giving Birth After Fertility Sparing Treatment for a Yolk Sac Tumour: Case Report.
Yolk Sac Tumours (YSTs) of the ovary, also called Endodermal Sinus Tumours (ESTs), are the second most common Malignant Ovarian Germ Cell Tumours (MOGCTs), after dysgerminomas. YSTs occur primarily in children and young women. We present a case report of a 20-year-old woman who had been diagnosed with YST (tumour diameter of 29 cm). The patient underwent fertility sparing surgery and was subsequently treated with adjuvant chemotherapy (four cycles of bleomycin, etoposide and cisplatin). Two years after the diagnosis of YST, she successfully gave birth to a healthy girl (birth weight 3,500 g, Apgar score of 9-10 and a spontaneous vaginal delivery). During pregnancy, she had microscopic hematuria and bilateral nephrolithiasis, was ultrasonographically diagnosed. The conception after fertility sparing treatment of YST is possible and the birth of a healthy child is feasible. There are no current guidelines for surveillance of such patients during pregnancy; however, structured pregnancy surveillance in such survivors seems necessary.


Occupational Hearing Loss from Non-Gaussian Noise.
Noise levels are truly continuous in relatively few occupations, with some degree of intermittency the most common condition. The sound levels of intermittent noise are often referred to as non-Gaussian in that they are not normally distributed in the time domain. In some conditions, intermittent noise affects the ear differently from continuous noise, and it is this assumption that underlies the selection of the 5-dB exchange rate (ER). The scientific and professional communities have debated this assumption over recent decades. This monograph explores the effect of non-Gaussian noise on the auditory system. It begins by summarizing an earlier report by the same author concentrating on the subject of the ER. The conclusions of the earlier report supported the more conservative 3-dB ER with possible adjustments to the permissible exposure limit for certain working conditions. The current document has expanded on the earlier report in light of the relevant research accomplished in the intervening decades. Although some of the animal research has supported the mitigating effect of intermittency, a closer look at many of these studies reveals certain weaknesses, along with the fact that these noise exposures were not usually representative of the conditions under which people actually work. The more recent animal research on complex noise shows that intermittencies do not protect the cochlea and that many of the previous assumptions about the ameliorative effect of intermittencies are no longer valid, lending further support to the 3-dB ER. The neurologic effects of noise on hearing have gained increasing attention in recent years because of improvements in microscopy and immunostaining techniques. Animal experiments showing damage to auditory synapses from noise exposures previously considered harmless may signify the need for a more conservative approach to the assessment of noise-induced hearing loss and consequently the practice of hearing conservation programs.


Temperature response of Rubisco kinetics in Arabidopsis thaliana: thermal breakpoints and implications for reaction mechanisms.
Enhancement of Rubisco kinetics could improve photosynthetic efficiency, ultimately resulting in increased crop yield. However, imprecise knowledge of the reaction mechanism and the individual rate constants limits our ability to optimize the enzyme. Membrane inlet mass spectrometry (MIMS) may offer benefits over traditional methods for determining individual rate constants of the Rubisco reaction mechanism, as it can directly monitor concentration changes in CO2, O2, and their isotopologs during assays. However, a direct comparison of MIMS with the traditional radiolabel method of determining Rubisco kinetic parameters has not been made. Here, the temperature responses of Rubisco kinetic parameters from Arabidopsis thaliana were measured using radiolabel and MIMS methods. The two methods provided comparable parameters above 25 °C, but temperature responses deviated at low temperature as MIMS-derived catalytic rates of carboxylation, oxygenation, and CO2/O2 specificity showed thermal breakpoints. Here, we discuss the variability and uncertainty surrounding breakpoints in the Rubisco temperature response and the relevance of individual rate constants of the reaction mechanisms to potential breakpoints.


Molecular composition of type VI collagen. Evidence for chain heterogeneity in mammalian tissues and cultured cells.
The chain composition and relative abundance of type VI collagen synthesized by cells cultured from foetal bovine nuchal ligament and skin were compared with those of the type VI collagen present in these foetal tissues. Immunoprecipitation of intact collagen VI from medium and cell layers of nuchal ligament fibroblasts and skin fibroblasts at confluence revealed collagen type VI molecules with a chain composition consistent with an [alpha 1(VI)alpha 2(VI)alpha 3(VI)] monomeric assembly. Maintenance of cells in a post-confluent quiescent state promoted a marked phenotypic change in these ratios, with increased concentrations of assemblies composed of equimolar ratios of alpha 1(VI) and alpha 2(VI) chains detected in the medium of these cultures. Analysis of steady-state concentrations of mRNA for alpha 1(VI) and alpha 2(VI) chains revealed these species to be present in increased abundance at post-confluence in all the cultures, but no corresponding increase was observed in the alpha 3(VI) mRNA. In order to assess the physiological significance of these observations, the chain composition of the collagen VI content of the corresponding foetal tissues was assessed by Western blotting after extraction in guanidinium isothiocyanate under reducing conditions. Extracts of nuchal ligament revealed a collagen VI chain composition consistent with a heterotrimeric chain assembly. In contrast, the skin extracts revealed an abundance of alpha 1(VI) and alpha 2(VI) chains with only traces of the alpha 3(VI) chain detected. Increased equimolar concentrations of the alpha 1(VI)-chain and alpha 2(VI)-chain mRNAs in skin again reflected the increased concentrations of these polypeptide chains. Type VI collagen was present in greater abundance both in the nuchal ligament and in the corresponding nuchal-ligament fibroblast cultures. The results indicate that the chain composition of type VI collagen is subject to modulation at the level of transcription as a result of variations in the proliferative state of the cells, and demonstrate that different isoforms of collagen VI occur in foetal development.


Survival After Simultaneous Pancreas-Kidney Transplantation in Type 1 Diabetes: The Critical Role of Early Pancreas Allograft Function.
Simultaneous pancreas-kidney transplantation (SPK) carries about a 7%-22% risk of technical failure, but the impact of early pancreas allograft loss on subsequent kidney graft and patient survival is not well-defined. We examined national transplant registry data for type 1 diabetic patients who received SPK between 2000 and 2021. Associations of transplant type (i.e., SPK, deceased-donor kidney transplant [DDKA], living-donor kidney transplant [LDKA]) with kidney graft failure and patient survival were estimated by multivariable inverse probability of treatment-weighted accelerated failure-time models. Compared to SPK recipients with a functioning pancreas graft 3 months posttransplant (SPK,P+), LDKA had 18% (Time Ratio [TR] 0.82, 95%CI: 0.70-0.95) less graft survival time and 18% (TR 0.82, 95%CI: 0.68-0.97) less patient survival time, DDKA had 23% (TR 0.77, 95%CI: 0.68-0.87) less graft survival time and 29% (TR 0.71, 95%CI: 0.62-0.81) less patient survival time, and SPK with early pancreas graft loss had 34% (TR 0.66, 95%CI: 0.56-0.78) less graft survival time and 34% (TR 0.66, 95%CI: 0.55-0.79) less patient survival time. In conclusion, SPK,P+ recipients have better kidney allograft and patient survival compared with LDKA and DDKA. Early pancreas graft failure results in inferior kidney and patient survival time compared to kidney transplant alone.


Extent and frequency of vessel oil spills in US marine protected areas.
Little is known about how marine protected areas (MPAs) may be vulnerable to vessel oil spills in the United States. This study investigated individual size, frequency, and total amount of vessel oil spilled in US MPAs, and how characteristics of MPAs and individual spill events influenced spills. Vessel oil spills in US waters (2002-06) and MPA boundaries were mapped. Total number and volume of oil spills inside and outside MPAs were computed. Results show that the presence of a MPA does not seem to prevent vessel oil spills or reduce the amount of oil spilled, and that a variety of MPA attributes (e.g., scale of protection, fishing restrictions, and others) and spill event characteristics (e.g., vessel type, year of spill, and others) affect oil spills inside and outside MPAs. These results can be used to develop MPA rules and marine transportation policies that reduce the vulnerability of sensitive resources to oil spills.


Identification of New QTL Contributing to Barley Yellow Dwarf Virus-PAV (BYDV-PAV) Resistance in Wheat.
Barley yellow dwarf (BYD) is a major virus disease which dramatically reduces wheat yield. Introducing BYD resistance genes into commercial varieties has been proven to be effective in reducing damage caused by barley yellow dwarf virus (BYDV). However, only one major resistance gene is readily deployable for breeding; Bdv2 derived from Thinopyrum intermedium is deployed as a chromosomal translocation. In this study, a double haploid (DH) population was developed from a cross between XuBYDV (introduced from China showing very good resistance to BYD) and H-120 (a BYD-sensitive Chinese accession), and was used to identify QTL for BYD resistance. The population was genotyped using an Infinium iSelect bead chip array targeting 90K gene-based SNPs. The disease resistance of DH lines inoculated with BYDV was assessed at the heading stage. The infections were assessed by tissue blot immunoassay (TBIA). Three new QTL were identified on chromosomes 5A, 6A, and 7A for both symptom and TBIA, with all three resistance alleles being inherited from XuBYDV. Some DH lines with the resistance alleles from all three QTL showed high level resistance to BYD. These new QTL will be useful in breeding programs for pyramiding BYD resistance genes.


Do women receive enough information to make informed choices about breast cancer screening?
Mammography screening has generated considerable professional and public debate. In this study, we investigate whether women receive sufficient information about the benefits and disadvantages of the Norwegian Breast Cancer Screening Program to enable them to make informed, independent choices. Informational material from the Norwegian Breast Cancer Screening Program for 1996, 2003, 2009 and 2017 was analysed and compared with information from the independent inquiry into the mammography screening programme headed by the Research Council of Norway. The criteria that are essential in order to make informed choices are as follows: benefit (absolute and relative reduction in mortality), disadvantages (false-positive results, overdiagnosis, overtreatment and anxiety), implementation (following invitation, recall, and findings requiring treatment), and limitations (interval cancer). Information provided to women has significantly improved from 1996 to 2017. Nevertheless, the information in 2017 lacks important details regarding the disadvantages of screening, such as overdiagnosis and overtreatment. The Norwegian Breast Cancer Screening Program does not provide sufficient information for women to be able to make informed, independent choices. Women are nudged to participate by prescheduled appointments, and the information is insufficiently balanced and nuanced.


Prosthodontic complications in a prospective clinical trial of single-stage implants at 36 months.
The present material reports on prosthodontic complications in a trial of 51 patients with prostheses supported by single-stage implants over a period of 36 months. One hundred eighty-six single-stage implants were placed in 51 patients over a 3-year period in 2 carefully controlled prospective clinical trials. Nineteen of the patients (103 implants) were completely edentulous and restored with a maxillary complete denture and a mandibular fixed-detachable complete prosthesis. Single metal-ceramic crowns or fixed partial dentures were fabricated for the remaining 32 patients (83 implants). The fixed restorations were either screw-retained or cemented. All patients/implants were followed for a minimum of 3 years. Complications in the edentulous patients included fracture of denture teeth, fracture of the maxillary denture, and occlusal screw loosening. Occlusal screw loosening and loss of the resin composite access plug were the only complications observed in the patients treated with screw-retained restorations. No complications were found in the patients restored with cemented restorations on solid abutments. Problems with prostheses were very common in the completely edentulous patients (13 of 19 patients encountered complications), possibly a result of increased bite force or inadequate laboratory technique. Tooth fractures were seen more frequently in men than in women. Complications occurred in only 5 of the 32 partially edentulous patients. Complications were associated with laboratory-related procedures rather than the implant system itself.


Small glandular proliferations on needle biopsies: most common benign mimickers of prostatic adenocarcinoma sent in for expert second opinion.
The current study aimed to determine the incidence of various benign mimickers of prostatic adenocarcinoma most commonly encountered in a busy consultation practice. All prostate needle biopsies from the consult service of one of the authors were prospectively evaluated over a 7-month period. Only cases with foci where the contributor questioned malignancy and which upon expert review the entire case was determined to be benign were included in this study. A total of 567 separate suspected atypical foci from 345 patients of a total of 4,046 patients (8.5%) received in consultation were identified. Of these, 281 foci (49.5%) had immunohistochemical (IHC) studies performed by the outside institution, which included high molecular weight cytokeratin (HMWCK) (n = 280), alpha-methylacyl-CoA racemase (AMACR) (P504s) (n = 45), and p63 (n = 34). The most common mimicker was partial atrophy (203 of 567; 35.8%). Technically adequate IHC for basal cells was performed in 117 cases of partial atrophy with patchy or patchy/negative staining seen in 102 of 117 (87%), with the remaining 13% of cases completely negative. A total of 15 of 19 (79%) cases of partial atrophy were positive with AMACR. Crowded benign glands, insufficiently crowded or numerous to warrant a diagnosis of adenosis, was the second most common mimicker (146 of 567; 25.7%). Crowded benign glands had patchy or patchy/negative IHC for basal cells in 66 of 81 (81%) cases with the remaining 19% of cases completely negative. A total of 7 of 11 (64%) cases of crowded glands were positive for AMACR. In the past, complete atrophy, adenosis, seminal vesicle, and granulomatous prostatitis were considered common mimickers of prostate cancer on prostatic needle biopsies. Our study shows that currently partial atrophy and crowded benign glands are the most common benign changes causing diagnostic difficulty and prompting consultation. Negative or patchy staining for basal cells and positive staining for AMACR may contribute to diagnostic difficulty in these entities.


Design and properties of multiple-emitter luminescent metal-organic frameworks.
Multi-emitter luminescent metal-organic frameworks (LMOFs) possess multiple emission bands that can cover a wider spectral region, which is a prerequisite for white-light emitting and multi-dimensional ratiometric fluorescent sensing. By taking advantage of the structure features of MOFs (e.g. hybrid structure, porosity) and the various luminescence origins of LMOFs, different emission sources can be designed and combined with each other into a homogeneous solid-state LMOF phase with the desired emission properties. This feature article reviews the recent development of multi-emitter LMOFs, and focuses on the design strategies for creating multi-emitter LMOFs based on at least two emission centers. The design strategies are classified into and discussed along six categories: type I metal-linker emitters, Type II multi-metal emitters, Type III multi-linker emitters, Type IV chromophore@LMOF (chromophore incorporated into an already luminescent MOF), Type V chromophores@MOF (multi-chromophores embedded into a non-emissive MOF) and Type VI multi-heterostructure LMOF emitters. The new class of Type VI includes core-shell structured LMOF⊃LMOF and nanostructured LMOF/LMOF thin films on a substrate. The good spatial separation between the different emitters in their own but chemically linked LMOF phase can retain their emission properties with less interference with the other emitters.


The dorsal diencephalic conduction system of zebrafish as a model of vertebrate brain lateralisation.
Lateralisation is an attractive and intriguing feature of the vertebrate CNS studied for decades in the different disciplines of the neurosciences. Due to the complexity of the phenomena and intrinsic limitations of the approaches used to date, it has been difficult to establish useful links between the different, and usually distant, levels of lateralisation e.g. between genetics, morphology, physiology and behaviour. Recently, the dorsal diencephalon of the teleost zebrafish has emerged as a valuable model to begin addressing this issue and as a result unravel the role of vertebrate CNS lateralisation. Zebrafish is a well-established genetic system that allows a 'bottom up' ('gene to behaviour') approach to the study of lateralisation. In fact, it is the single vertebrate system to date in which asymmetric gene expression in the brain has been directly linked to asymmetric morphology. Zebrafish offers several experimental advantages that allow the study of brain lateralisation using a wide range of experimental tools, from study of gene function through in vivo analysis of morphology and physiology to behavioural assessments. Altogether, these features will allow the establishment of operational links between lower (genetics and morphology) and upper (physiology and behaviour) levels of brain lateralisation.


Universal Imprints of a Pseudo-Nambu-Goldstone Higgs Boson.
A large class of models addressing the electroweak naturalness problem postulates the existence of new spontaneously broken global symmetries above the weak scale. The Higgs boson arises as a pseudo-Nambu-Goldstone boson (PNGB) whose interactions are nonlinear due to the presence of degenerate vacua. We argue that, once the normalization of the PNGB decay constant f is determined, the Higgs nonlinear interactions in the gauge sector are universal in the infrared and independent of the symmetry breaking pattern G/H, even after integrating out heavy composite resonances. We propose a set of "universal relations" in Higgs couplings with electroweak gauge bosons and in triple gauge boson couplings, which are unique predictions of the universal nonlinearity. Experimental measurements of these relations would serve as the litmus test of a PNGB Higgs boson.


Activator protein 2alpha associates with adenomatous polyposis coli/beta-catenin and Inhibits beta-catenin/T-cell factor transcriptional activity in colorectal cancer cells.
In most human colorectal cancers, mutations in the adenomatous polyposis coli gene (APC) or CTNNB1 constitutively activate the beta-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway. Here, we show that the transcription factor activator protein (AP)-2alpha inhibited a beta-catenin/TCF-responsive reporter in human embryonic kidney 293 cells and in two human colorectal cancer lines, despite the fact that beta-catenin and TCF-4 protein levels were unchanged in the nucleus. Co-immunoprecipitation studies revealed that AP-2alpha formed a complex with APC and beta-catenin and that AP-2alpha disrupted beta-catenin/TCF-4 interactions in the nucleus. Thus, AP-2alpha.APC.beta-catenin complex formation appears to suppress beta-catenin transactivation by shifting the pool of nuclear beta-catenin toward an inactive form, having reduced binding to TCF/LEF transcription factors. Glutathione S-transferase pull-down assays showed that AP-2alpha physically associated with APC rather than with beta-catenin, and the AP-2alpha binding site was identified in the N terminus of APC, involving both the heptad and armadillo repeat domains, whereas the APC binding site in AP-2alpha was in the basic region of the C-terminal DNA binding domain. These findings provide the first evidence for a specific interaction between the tumor suppressor protein APC and the transcription factor AP-2alpha, and they suggest a link between the Wnt signaling pathway and various other pathways of development and differentiation associated with AP-2alpha.


Transcriptomic analysis reveals a global alkyl-quinolone-independent regulatory role for PqsE in facilitating the environmental adaptation of Pseudomonas aeruginosa to plant and animal hosts.
The quorum sensing (QS) system of Pseudomonas aeruginosa constitutes a sophisticated genome-wide gene regulatory network employing both N-acylhomoserine lactone and 2-alkyl-4-quinolone (AQ) signal molecules. AQ signalling utilizes 2-heptyl-3-hydroxy-4-quinolone (PQS) and its immediate precursor, 2-heptyl-4-quinolone (HHQ). AQ biosynthesis requires the first four genes of the pqsABCDE operon and while the biochemical function of pqsE is not known, it is required for the production of secondary metabolites such as pyocyanin. To gain insights into the relationship between the AQ stimulon, the PqsE stimulon and the regulatory function of PqsE, we constructed a pqsE inducible mutant (pqsEind) and compared the transcriptomes of the induced and uninduced states with a pqsA mutant. Of 158 genes exhibiting altered expression in the pqsA mutant, 51% were also affected in the pqsE mutant. Following induction of pqsE, 237 genes were differentially expressed compared with the wild-type strain. In the pqsEind strain, pqsA was highly expressed but following induction both pqsA expression and AQ biosynthesis were repressed, revealing a negative autoregulatory role for PqsE. Furthermore, pqsE was required for swarming motility and virulence in plant and animal infection models in the absence of AQs, while mature biofilm development required both pqsA and pqsE. Taken together these data reveal that PqsE is a key regulator within the QS circuitry facilitating the environmental adaptation of P. aeruginosa.


Tenascin-X expression in tumor cells and fibroblasts: glucocorticoids as negative regulators in fibroblasts.
Tenascin-X has recently been shown to be a novel member of the tenascin family and its distribution is often reciprocal to that of tenascin-C in the developing mouse embryo. We have investigated the expression of tenascin-X in fibroblasts and carcinoma cells in culture. Tenascin-X protein was secreted in vitro in the conditioned media at an apparent molecular mass of approximately 450 kDa. In addition fibroblasts contained a major tenascin-X isoform of 220 kDa. On northern blots, a single major transcript with a size of approximately 13 kb was detected. No overexpression of tenascin-X protein was found in primary fibroblasts of the tenascin-C-gene knockout mice. Steroid hormone glucocorticoids, were found to downregulate tenascin-X mRNA levels and protein synthesis in fibroblasts but not carcinoma cells at physiological concentrations. None of the growth factors or cytokines examined affected the expression level of tenascin-X. As in vivo study, carcinoma cells were transplanted into nude mice. In contrast to the ubiquitous presence of tenascin-X in adult skin, expression of tenascin-X protein during tumorigenesis was found to be down-regulated considerably not only in tumor cells themselves but also in tumor stroma. These findings provide evidence that the expression of tenascin-X can be influenced by stromal-epithelial interactions. We have identified glucocorticoids as physiological inhibitors of tenascin-X and suggest that glucocorticoids may in part participate in the downregulation of tenascin-X in fibroblasts in vivo.


Climate changes modulated the history of Arctic iodine during the Last Glacial Cycle.
Iodine has a significant impact on promoting the formation of new ultrafine aerosol particles and accelerating tropospheric ozone loss, thereby affecting radiative forcing and climate. Therefore, understanding the long-term natural evolution of iodine, and its coupling with climate variability, is key to adequately assess its effect on climate on centennial to millennial timescales. Here, using two Greenland ice cores (NEEM and RECAP), we report the Arctic iodine variability during the last 127,000 years. We find the highest and lowest iodine levels recorded during interglacial and glacial periods, respectively, modulated by ocean bioproductivity and sea ice dynamics. Our sub-decadal resolution measurements reveal that high frequency iodine emission variability occurred in pace with Dansgaard/Oeschger events, highlighting the rapid Arctic ocean-ice-atmosphere iodine exchange response to abrupt climate changes. Finally, we discuss if iodine levels during past warmer-than-present climate phases can serve as analogues of future scenarios under an expected ice-free Arctic Ocean. We argue that the combination of natural biogenic ocean iodine release (boosted by ongoing Arctic warming and sea ice retreat) and anthropogenic ozone-induced iodine emissions may lead to a near future scenario with the highest iodine levels of the last 127,000 years.


NUCLEOPORIN85 is required for calcium spiking, fungal and bacterial symbioses, and seed production in Lotus japonicus.
In Lotus japonicus, seven genetic loci have been identified thus far as components of a common symbiosis (Sym) pathway shared by rhizobia and arbuscular mycorrhizal fungi. We characterized the nup85 mutants (nup85-1, -2, and -3) required for both symbioses and cloned the corresponding gene. When inoculated with Glomus intraradices, the hyphae managed to enter between epidermal cells, but they were unable to penetrate the cortical cell layer. The nup85-2 mutation conferred a weak and temperature-sensitive symbiotic phenotype, which resulted in low arbuscule formation at 22 degrees C but allowed significantly higher arbuscule formation in plant cortical cells at 18 degrees C. On the other hand, the nup85 mutants either did not form nodules or formed few nodules. When treated with Nod factor of Mesorhizobium loti, nup85 roots showed a high degree of root hair branching but failed to induce calcium spiking. In seedlings grown under uninoculated conditions supplied with nitrate, nup85 did not arrest plant growth but significantly reduced seed production. NUP85 encodes a putative nucleoporin with extensive similarity to vertebrate NUP85. Together with symbiotic nucleoporin NUP133, L. japonicus NUP85 might be part of a specific nuclear pore subcomplex that is crucial for fungal and rhizobial colonization and seed production.


The use of behavioral methods to predict spinal cord plasticity.
The mechanisms underlying recovery of function following damage to the CNS, although suspected, are virtually unknown. After damage to the adult cat spinal cord, recovery of motor behavior depends on which systems have been interrupted and which remain intact. For example, following hemisection, overground (voluntary) and reflex locomotion recover and, although a normal kinematic pattern recovers, accurate placement of the limb during locomotion does not return to normal levels. This recovery is associated with lowering of thresholds for postural reflexes suggesting that increased afferent input may compensate for diminished descending control. In contrast, after unilateral loss of afferent input by lumbosacral deafferentation, (L1-S2 dorsal roots cut) overground locomotion recovers but a permanently abnormal kinematic pattern is used; reflex locomotion (bipedal locomotion on a treadmill) does not recover at all in the deafferented hindlimb. The specificity of the recovery suggests that increased input from descending pathways, which is required for overground but not reflex locomotion may compensate for loss of afferent input. Anatomical sequellae of these two lesion types have been examined. Studies after hemisection support the notion of a permanently increased dorsal root input as mapped by monoclonal antibody 'rat 102'. This is associated with a transient increase in GAP-43 labeling in the dorsal horn. In contrast, after deafferentation an increase is found in the descending serotonergic input to the deafferented side. These observations suggest that recovery of specific locomotor behavior can be used to predict compensatory changes in spared pathways. For the study of the effects of transplants, we have used complete spinal transections in newborn kittens with transplantation of E26 cat spinal cord into the transection site. The normal kitten develops overground locomotion beginning the end of the first week postnatal but reflex locomotion is delayed until the end of the second week. After transection on the first day of life, with or without a transplant, reflex locomotion begins precociously. Overground locomotion fails to develop in transection-only animals but does develop in animals with transection and transplant. This locomotion although clearly abnormal, shows postnatal development in terms of weight support and lateral stability. Furthermore, there is some indication of coordination between fore and hind limbs. These observations suggest that the transplants permit the development of some descending control although the anatomical correlates of this sparing/recovery of function are uncertain; the transplant rescues neurons caudal to the transection and also permits regeneration of some descending pathways into the transplant and caudally into host spinal cord.


Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.
Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.


Treatment outcomes of chronic-phase chronic myeloid leukemia with resistance and/or intolerance to a 1st-line tyrosine kinase inhibitor in Japan: the results of the New TARGET study 2nd-line.
We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22-88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1-99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4-94.8%) and 87.2% (95% CI 78.1-93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.


[Regulation of the duration of expiratory phases in decerebrate cats].
The changes of durations of the first (postinspiratory, TPIA) and second (TE2) stages of expiration in hypercapnic hyperpnoea before and after bilateral vagotomy and after subsequent injection of pentabarbitone, were evaluated in 10 decerebrated cats. With vagal nerves intact, the hyperpnoea was accompanied by the diminution of the TPIA with no significant changes of the TE2. Vagotomy increased the TPIA. During the hyperpnoea, the TPIA did not change significantly in vagotomized cats whereas the TE2 increased. Pentobarbitone did not affect the TPIA but increased the TE2. Under these conditions, hypercapnia was accompanied by no significant changes of either the TPIA or TE2. The leading part in the regulation of expiratory duration in decerebrated cats seems to be played by the lung mechanoreceptors whose impulses reduce both the TPIA and TE2 in hyperpnoea. The lung stretch receptors impulses inhibit the postinspiratory activity. The TPIA and TE2 regulation is performed by separate central mechanisms. Postinspiratory activity is relatively resistant to pentabarbitone, although the latter delays the start of the next inspiration and obviously suppresses active expirations.


Forensic Post-Mortem Investigation in AAS Abusers: Investigative Diagnostic Protocol. A Systematic Review.
Anabolic-androgenic steroids (AASs) are a group of synthetic molecules derived from testosterone and its precursors. AASs are widely used illicitly by adolescents and athletes, especially by bodybuilders; AASs are among the most used drugs for improving physical performance, as well as for aesthetic purposes. The use of AASs by professional and recreational athletes is increasing worldwide. This review focused on deaths related to AAS abuse and to investigation of the autopsy results and histopathological findings using a rigorous methodology protocol covering: a complete autopsy, histological analysis, and a broad toxicological investigation. Moreover, we aimed to define an investigative diagnostic protocol supporting forensic pathologists during the post-mortem investigation of AAS abusers. This review was conducted using PubMed Central and Google Scholar databases to find articles published between 1 January 1968 and 30 June 2021, using the following key terms: "(anabolic-androgenic steroids) AND (autopsy); (anabolic-androgenic steroids) AND (forensic)". A total of 939 articles were screened and 926 did not meet the inclusion criteria. In conclusion, 14 articles were included in this systematic review, reporting 137 fatal cases of AAS abuse in total. The histopathologic studies showed myocardial damage characterized by myocyte hypertrophy, focal myocyte damage with myofibrillar loss, interstitial fibrosis, mostly subepicardial, and small vessel disease. Indeed, in AAS-related cases, autopsy plays a pivotal role in the study of AAS adverse effects and organ damage related to their use or abuse. This systematic review aimed to define a specific workflow in death cases related to AASs, suggesting important future insights to better clarify sudden deaths related to AASs, such as the use of miRNAs. The forensic community needs a unified approach in cases of suspected death related to the use of AASs. There are several occasions to apply this workflow, for example in cases of death of bodybuilders and of young people who die in gymnasiums or during sports activities.