The effects of cannabis and alcohol on simulated arterial driving: Influences of driving experience and task demand.
This study compared the effects of three doses of cannabis and alcohol (placebo, low and high doses), both alone and in combination, on the driving performance of young, novice drivers and more experienced drivers. Alcohol was administered as ethanol (95%) mixed with orange juice in doses of approximately 0, 0.4 and 0.6g/kg. Cannabis was administered by inhalation of smoke from pre-rolled cannabis cigarettes (supplied by the National Institute of Drug Abuse, USA). Active cigarettes contained 19 mg delta-9-THC. Using a counterbalanced design, the simulated driving performance of 25 experienced and 22 inexperienced drivers was tested under the nine different drug conditions in an arterial driving environment during which workload was varied through the drive characteristics as well as through the inclusion of a secondary task. High levels of cannabis generally induced greater impairment than lower levels, while alcohol at the doses used had few effects and did not produce synergistic effects when combined with cannabis. Both cannabis and alcohol were associated with increases in speed and lateral position variability, high dose cannabis was associated with decreased mean speed, increased mean and variability in headways, and longer reaction time, while in contrast alcohol was associated with a slight increase in mean speed. Given the limitations of the study, it is of great interest to further explore the qualitative impairments in driving performance associated with cannabis and alcohol separately and how these impairments may manifest in terms of crash characteristics.


Quantitative elementary mode analysis of metabolic pathways: the example of yeast glycolysis.
Elementary mode analysis of metabolic pathways has proven to be a valuable tool for assessing the properties and functions of biochemical systems. However, little comprehension of how individual elementary modes are used in real cellular states has been achieved so far. A quantitative measure of fluxes carried by individual elementary modes is of great help to identify dominant metabolic processes, and to understand how these processes are redistributed in biological cells in response to changes in environmental conditions, enzyme kinetics, or chemical concentrations. Selecting a valid decomposition of a flux distribution onto a set of elementary modes is not straightforward, since there is usually an infinite number of possible such decompositions. We first show that two recently introduced decompositions are very closely related and assign the same fluxes to reversible elementary modes. Then, we show how such decompositions can be used in combination with kinetic modelling to assess the effects of changes in enzyme kinetics on the usage of individual metabolic routes, and to analyse the range of attainable states in a metabolic system. This approach is illustrated by the example of yeast glycolysis. Our results indicate that only a small subset of the space of stoichiometrically feasible steady states is actually reached by the glycolysis system, even when large variation intervals are allowed for all kinetic parameters of the model. Among eight possible elementary modes, the standard glycolytic route remains dominant in all cases, and only one other elementary mode is able to gain significant flux values in steady state. These results indicate that a combination of structural and kinetic modelling significantly constrains the range of possible behaviours of a metabolic system. All elementary modes are not equal contributors to physiological cellular states, and this approach may open a direction toward a broader identification of physiologically relevant elementary modes among the very large number of stoichiometrically possible modes.


Bioaccessible arsenic in soils of former sugar cane plantations, Island of Hawaii.
Arsenical herbicides were used extensively for emergent weed control in Hawaiian sugar cane cultivation from 1913 to about 1950. As a result, surface soil arsenic concentrations average 280 mg kg(-1) across more than 60 km(2) of former sugar plantation land in the eastern portion of the Island of Hawaii. This study was conducted to elucidate the relationship between soil properties and arsenic bioaccessibility in the iron-rich volcanic soils. Soils are predominantly Andisols, formed by weathering of basaltic lava and tephra, with pedogenic solid phases consisting of short-range order iron oxyhydroxides, allophane-like aluminosilicates, and metal-humus compounds. These reactive solid phases strongly adsorb oxyanions, such as phosphate and arsenite/arsenate. High arsenic sorption capacity limits desorption and vertical migration within the soil column and prevents contamination of the underlying groundwater aquifer, despite high arsenic loading and precipitation rates. In vitro arsenic bioaccessibility, as measured by the SBRC gastric-phase test, ranges from 2% to 35% and averages 9% of total arsenic. Bioaccessible arsenic is higher in less weathered soils (Udifolists, Typic and Lithic Hydrudands) and lower in more weathered ash-dominant soils (Acrudoxic Hydrudands). Soil weathering indicators, such as reactive iron content, are strong predictors of arsenic bioaccessibility. Based on evidence from soil mineralogy, geochemistry and arsenic speciation, as well as limited soil arsenic bioavailability/bioaccessibility comparisons, risks to human health from direct contact (soil ingestion) are significantly reduced by low arsenic bioaccessibility. Nonetheless, some soils within former sugar cane cultivation areas contain bioaccessible arsenic concentrations exceeding Hawaii Department of Health risk-based action levels, and will require mitigating actions. Even higher levels of soil arsenic contamination have been identified at former pesticide storage and mixing areas, but are generally of localized extent.


Synthesis of crinane utilizing an allylic sulfoxide for the construction of a hydroindole ring via vinylogous C-N bond formation.
The synthesis of crinane is disclosed via intramolecular C-N bond formation by the displacement of an allylic sulfoxonium salt. The allylic sulfide precursor was synthesized by a ring-closing metathesis reaction. The quaternary carbon stereocenter was created by alkylation of a benzylic cyanide. The allyl sulfide 14 was prepared by adding vinylmagnesium bromide to an α-chlorosulfide.


Prevalence of Bruxism among the Students of Gulf Medical University: A Cross-Sectional Questionnaire Study.
Bruxism is a multifactorial phenomenon that involves grinding or clenching of teeth. The parafunctional habit includes abnormal tooth wear, tooth fracture, pain, and tooth mobility, along with headaches and facial muscle hypertrophy. It is imperative for students to be conscious of teeth grinding along with its possible causes. The student will be alert to visit the dentist if required and contribute to the recognition of etiological factors, to eliminate them. This study aims to find the prevalence and understanding of bruxism among Gulf Medical University (GMU) students. A cross-sectional, questionnaire-based study was conducted among 451 GMU students. The parameters for data collection were age, gender, prevalence, associated signs and symptoms, causes, genetic predisposition, time of day, and effect on the appearance of teeth. While 35.9% were unaware, 41.7% of our samples reported bruxism. The majority recognized temporomandibular joint and facial pain as causative, and 24.8% reported symptoms. Headache (26.4%) was prime and 7.5% were associated with fracture and abnormal tooth wear to bruxism (38.1%) experienced night bruxism. A significant number of students (32.4%) identified abnormal anterior teeth relationship as the cause and (64.3%) associated bruxism and esthetics. Nearly 41.7% of the students reported bruxism. Around 35.9% of the samples were uninformed. Nearly 20.8% believed that bruxism had genetic relevance. Nearly 51.9% of the participants were asymptomatic. Around 38.1% had night bruxism and 32.4% identified abnormal anterior teeth relationship as the cause. The majority of the sample (64.3%) connected bruxism to negative effects on teeth and esthetics.


Phospholipases and galactolipases trigger oxylipin-mediated wound-activated defence in the red alga Gracilaria chilensis against epiphytes.
We investigated the wound response of the commercially important red alga, Gracilaria chilensis, in order to obtain insight into its interaction with epiphytic pests. After wounding, the host releases free fatty acids as well as the hydroxylated eicosanoids, 8R-hydroxy eicosatetraenoic acid (8-HETE) and 7S,8R-dihydroxy eicosatetraenoic acid (7,8-di-HETE). While the release of free arachidonic acid and subsequent formation of 8-HETE is controlled by phospholipase A, 7,8-di-HETE production is independent of this lipase. This dihydroxylated fatty acid might be directly released from galactolipids. Physiologically relevant concentrations of oxylipins reduced spore settlement of Acrochaetium sp. (Rhodophyta, Acrochaetiaceae) and suppressed the development of hapteria in Ceramium rubrum (Rhodophyta, Ceramiaceae) when these model epiphytes were exposed to artificial surfaces that contained 8-HETE or 7,8-di-HETE. Thus, the immediate release of oxylipins can be seen as G. chilensis defence against epiphytes.


mCSM: predicting the effects of mutations in proteins using graph-based signatures.
Mutations play fundamental roles in evolution by introducing diversity into genomes. Missense mutations in structural genes may become either selectively advantageous or disadvantageous to the organism by affecting protein stability and/or interfering with interactions between partners. Thus, the ability to predict the impact of mutations on protein stability and interactions is of significant value, particularly in understanding the effects of Mendelian and somatic mutations on the progression of disease. Here, we propose a novel approach to the study of missense mutations, called mCSM, which relies on graph-based signatures. These encode distance patterns between atoms and are used to represent the protein residue environment and to train predictive models. To understand the roles of mutations in disease, we have evaluated their impacts not only on protein stability but also on protein-protein and protein-nucleic acid interactions. We show that mCSM performs as well as or better than other methods that are used widely. The mCSM signatures were successfully used in different tasks demonstrating that the impact of a mutation can be correlated with the atomic-distance patterns surrounding an amino acid residue. We showed that mCSM can predict stability changes of a wide range of mutations occurring in the tumour suppressor protein p53, demonstrating the applicability of the proposed method in a challenging disease scenario. A web server is available at http://structure.bioc.cam.ac.uk/mcsm.


A novel tool for high-throughput screening of granulocyte-specific antibodies using the automated flow cytometric granulocyte immunofluorescence test (Flow-GIFT).
Transfusion-related acute lung injury (TRALI) is a severe complication related with blood transfusion. TRALI has usually been associated with antibodies against leukocytes. The flow cytometric granulocyte immunofluorescence test (Flow-GIFT) has been introduced for routine use when investigating patients and healthy blood donors. Here we describe a novel tool in the automation of the Flow-GIFT that enables a rapid screening of blood donations. We analyzed 440 sera from healthy female blood donors for the presence of granulocyte antibodies. As positive controls, 12 sera with known antibodies against anti-HNA-1a, -b, -2a; and -3a were additionally investigated. Whole-blood samples from HNA-typed donors were collected and the test cells isolated using cell sedimentation in a Ficoll density gradient. Subsequently, leukocytes were incubated with the respective serum and binding of antibodies was detected using FITC-conjugated antihuman antibody. 7-AAD was used to exclude dead cells. Pipetting steps were automated using the Biomek NXp Multichannel Automation Workstation. All samples were prepared in the 96-deep well plates and analyzed by flow cytometry. The standard granulocyte immunofluorescence test (GIFT) and granulocyte agglutination test (GAT) were also performed as reference methods. Sixteen sera were positive in the automated Flow-GIFT, while five of these sera were negative in the standard GIFT (anti-HNA 3a, n = 3; anti-HNA-1b, n = 1) and GAT (anti-HNA-2a, n = 1). The automated Flow-GIFT was able to detect all granulocyte antibodies, which could be only detected in GIFT in combination with GAT. In serial dilution tests, the automated Flow-GIFT detected the antibodies at higher dilutions than the reference methods GIFT and GAT. The Flow-GIFT proved to be feasible for automation. This novel high-throughput system allows an effective antigranulocyte antibody detection in a large donor population in order to prevent TRALI due to transfusion of blood products.


Communication, training, well-being, and commitment across nurse generations.
Within a context of global nurse shortages, replacing nurses is difficult; training and retention is a critical concern for healthcare management. Similarities and differences in the impact of supervisor-nurse relationships upon satisfaction with training and development, well-being and affective commitment were examined across 3 different nursing generations in Australia. Nine hundred nurses from 7 private hospitals (small, medium, and large) across Australia responded. Path analysis, using an ordinary least squares approach, and multivariate analysis were used to test the hypotheses. Three factors accounted for almost half the variance of Generation Xs' and Baby Boomers' and a third of Generation Ys' affective commitment. Practical implications for hospital management include differences in generations and the pivotal role of nurse supervisors. For all 3 generations of nurses, supervisor-subordinate communication relationships are important because they contribute to satisfaction with training and development and well-being, but also significantly impact affective commitment.


Strongly enhanced Raman scattering of Cu-phthalocyanine sandwiched between graphene and Au(111).
Graphene and flat gold have both been argued to enhance Raman scattering of molecular adsorbates through a chemical mechanism. Here we show that these two effects can add to each other. For Cu-phthalocyanine in between graphene and Au(111) on mica a Raman enhancement up to 68-fold has been observed.


Computer/Mobile Device Screen Time of Children and Their Eye Care Behavior: The Roles of Risk Perception and Parenting.
This study assessed the computer/mobile device screen time and eye care behavior of children and examined the roles of risk perception and parental practices. Data were obtained from a sample of 2,454 child-parent dyads recruited from 30 primary schools in Taipei city and New Taipei city, Taiwan, in 2016. Self-administered questionnaires were collected from students and parents. Fifth-grade students spend more time on new media (computer/smartphone/tablet: 16 hours a week) than on traditional media (television: 10 hours a week). The average daily screen time (3.5 hours) for these children exceeded the American Academy of Pediatrics recommendations (≤2 hours). Multivariate analysis results showed that after controlling for demographic factors, the parents with higher levels of risk perception and parental efficacy were more likely to mediate their child's eye care behavior. Children who reported lower academic performance, who were from non-intact families, reported lower levels of risk perception of mobile device use, had parents who spent more time using computers and mobile devices, and had lower levels of parental mediation were more likely to spend more time using computers and mobile devices; whereas children who reported higher academic performance, higher levels of risk perception, and higher levels of parental mediation were more likely to engage in higher levels of eye care behavior. Risk perception by children and parental practices are associated with the amount of screen time that children regularly engage in and their level of eye care behavior.


A comparison of on-pack Quitline information formats.
Although tobacco packages have evolved to feature health warnings and, in Australia, dissuasive colours, the format of on-pack cessation information has not changed. We compared how alternative Quitline information formats affected smokers' perceptions and choice behaviours, and their likelihood of seeking cessation support. We conducted an online study comprising a choice experiment using a two (number of panels) by three (panel position: above, middle, below) plus control (current format) design, and a between-subjects comparison of a two-panel format and the control. The sample comprised 608 New Zealand smokers. Relative to the current format, respondents regarded each test format as more effective in communicating cessation information (p<0.0001), particularly the two-panel formats. Respondents found the two-panel format tested via paired comparisons significantly easier to read, more visually salient and more likely than the control to encourage them and other smokers to consider quitting (all p<0.0001). Heat map comparisons showed that the Quitline number and affirming message were significantly more salient in the test format than in the current format (p<0.0001), although the headline and warning explanation were more salient in the control. Reformatting Quitline information could improve its visual salience and readability and capitalise on the dissonance that pictorial warning labels and plain packaging create. Enhancing stimuli that may prompt smokers to try and quit, affirming their decision to do so and prompting the use of cessation support could increase the number and success of quit attempts.


Oxidative damage to DNA related to survivorship and carotenoid-based sexual ornamentation in the common yellowthroat.
Carotenoid-based sexual ornaments are hypothesized to be reliable signals of male quality, based on an allocation trade-off between the use of carotenoids as pigments and their use in antioxidant defence against reactive oxygen species. Carotenoids appear to be poor antioxidants in vivo, however, and it is not clear whether variation in ornament expression is correlated with measures of oxidative stress (OXS) under natural conditions. We used single-cell gel electrophoresis to assay oxidative damage to erythrocyte DNA in the common yellowthroat (Geothlypis trichas), a sexually dichromatic warbler in which sexual selection favours components of the males' yellow 'bib'. We found that the level of DNA damage sustained by males predicted their overwinter survivorship and was reflected in the quality of their plumage. Males with brighter yellow bibs showed lower levels of DNA damage, both during the year the plumage was sampled (such that yellow brightness signalled current OXS) and during the previous year (such that yellow brightness signalled past OXS). We suggest that carotenoid-based ornaments can convey information about OXS to prospective mates and that further work exploring the proximate mechanism(s) linking OXS to coloration is warranted.


Reading errors made by children with low vision.
Previous research has shown that, on average, children with low vision lag their sighted peers in general reading development (in terms of speed, accuracy and comprehension). This study sought to examine this apparent lag by comparing the reading profiles of 25 normally sighted readers (mean age 8 years 8 months) with 25 low vision readers. The children were tested using a reading test (the Neale Analysis of Reading Ability, NARA) and were matched on the reading accuracy score produced by the test. Therefore in terms of the reading accuracy scores (and reading ages) derived from the NARA both groups were the same. The low vision readers were on average older than the normally sighted children (mean = 10 years, 5 months). When the reading profile (i.e. accuracy, comprehension and speed) was examined in the same analysis no significant effect was revealed [d.f. = 1, 48; F = 0.05; p > 0.1], but a general lag for these children is suggested (in keeping with previous research). However, a closer analysis of the reading error profile revealed the most common reading errors made by all readers in the analysis were either mispronunciations or substitutions. The low vision readers were more prone to making substitution errors than mispronunciations and the reverse was true for normally sighted readers [d.f. = 1, 48; F = 7.1; p < 0.05]. This indicates that the reading strategies adopted by low vision readers may differ from those of normally sighted readers of the same apparent reading ability.


[Validation of a questionnaire for epilepsy diagnosis in primary care services].
To evaluate the usefulness of a questionnaire in primary health care services for establishing the diagnosis of epilepsy in children from 1 to 10 years old and for classifying their epileptic seizures. This cross-sectional observational study was conducted in 2004. There were 204 children in the study (102 diagnosed with epilepsy and 102 without epilepsy). The children were randomly selected at the Regional Center of Epilepsies and the Vincent Corral Moscoso Hospital, which are both in the city of Cuenca, Ecuador. For the study, each child with epilepsy was matched with a child without epilepsy, in two age groups: 1 to 5 years old and 6 to 10 years old. Four students who were in their last academic year in the School of Medicine of Cuenca and who did not know the child's diagnosis utilized the questionnaire with a family member or other guardian of the child. The validity, sensitivity, specificity, positive predictive value, and negative predictive value of the questionnaire were calculated, with 95% confidence intervals (95% CIs). The clinical diagnosis carried out by specialists was used as the gold standard. The assessment showed that the questionnaire had good sensitivity (95.10%; 95% CI: 94.58%-95.61%) and good specificity (97.06%; 95% CI: 96.58%-97.59%). Validity was 96.08% (95% CI: 95.84%-96.36%), with a positive predictive value of 97.00% (95% CI: 96.48%-97.52%) and a negative predictive value of 95.19% (95% CI: 94.74%-95.74%). The level of agreement in the classification of the epileptic seizures carried out by the neurologists and by the medical students who used the questionnaire was satisfactory for the generalized seizures (kappa = 0.67). Upon testing for interobserver agreement among the specialists, the kappa value for the diagnoses was 0.80 among the neurologists and 0.89 among the pediatricians. The diagnostic questionnaire that was assessed has good sensitivity and adequate specificity, and, after brief training, primary health care general practitioners can use it to help them diagnose epileptic seizures.


Development of AR-V7 as a putative treatment selection marker for metastatic castration-resistant prostate cancer.
Prostate cancer cells demonstrate a remarkable "addiction" to androgen receptor (AR) signaling in all stages of disease progression. As such, suppression of AR signaling remains the therapeutic goal in systemic treatment of prostate cancer. A number of molecular alterations arise in patients treated with AR-directed therapies. These molecular alterations may indicate the emergence of treatment resistance and may be targeted for the development of novel agents for prostate cancer. The presence of functional androgen receptor splice variants may represent a potential explanation for resistance to abiraterone and enzalutamide, newer AR-directed agents developed to treat metastatic castration-resistant prostate cancer (mCRPC). In the last 8 years, many androgen receptor splice variants have been identified and characterized. Among these, androgen receptor splice variant-7 (AR-V7) has been investigated extensively. In AR-V7, the entire COOH-terminal ligand-binding domain of the canonical AR is truncated and replaced with a variant-specific peptide of 16 amino acids. Functionally, AR-V7 is capable of mediating constitutive nuclear localization and androgen receptor signaling in the absence of androgens, or in the presence of enzalutamide. In this review, we will focus on clinical translational studies involving detection/measurement of AR-V7. Methods have been developed to detect AR-V7 in clinical mCRPC specimens. AR-V7 can be reliably measured in both tissue and circulating tumor cells derived from mCRPC patients, making it possible to conduct both cross-sectional and longitudinal clinical correlative studies. Current evidence derived from studies focusing on detection of AR-V7 in mCRPC support its potential clinical utility as a treatment selection marker.


Durability of effect of massage therapy on blood pressure.
Pre-hypertension is considered as a cardiovascular disease predicator. Management of pre-hypertension is an appropriate objective for clinicians in a wide range of medical centers. Treatment of pre-hypertension is primarily non-pharmacological, one of which is massage therapy that is used to control the BP. This study aimed to evaluate the survival effect of Swedish massage (face, neck, shoulders, and chest) on BP of the women with pre-hypertension. This was a single-blind clinical trial study. Fifty pre-hypertensive women selected by simple random sampling which divided into control and test groups. The test group (25 patients) received Swedish massage 10-15 min, 3 times a week for 10 sessions and the control groups (25 patients) also were relaxed at the same environment with receiving no massage. Their BP was measured before and after each session and 72 h after finishing the massage therapy. Analyzing the data was done using descriptive and inferential statistical methods (Chi- square, Mann-Whitney, paired t-test and Student t-test) through SPSS software. The results indicated that mean systolic and diastolic BP in the massage group was significantly lower in comparison with the control group (P < 0.001). Evaluation of durability of the massage effects on BP also indicated that 72 h after finishing the study, still there was a significant difference between the test and control groups in systolic and diastolic BP (P < 0.001). Findings of the study indicated that massage therapy was a safe, effective, applicable and cost-effective intervention in controlling BP of the pre-hypertension women and it can be used in the health care centers and even at home.


Angiotensin II type 1 receptor-dependent oxidative stress mediates endothelial dysfunction in type 2 diabetic mice.
The mechanisms underlying the effect of the renin-angiotensin-aldosterone system (RAAS) inhibition on endothelial dysfunction in type 2 diabetes are incompletely understood. This study explored a causal relationship between RAAS activation and oxidative stress involved in diabetes-associated endothelial dysfunction. Daily oral administration of valsartan or enalapril at 10 mg/kg/day to db/db mice for 6 weeks reversed the blunted acetylcholine-induced endothelium-dependent dilatations, suppressed the upregulated expression of angiotensin II type 1 receptor (AT(1)R) and NAD(P)H oxidase subunits (p22(phox) and p47(phox)), and reduced reactive oxygen species (ROS) production. Acute exposure to AT(1)R blocker losartan restored the impaired endothelium-dependent dilatations in aortas of db/db mice and also in renal arteries of diabetic patients (fasting plasma glucose level > or =7.0 mmol/l). Similar observations were also made with apocynin, diphenyliodonium, or tempol treatment in db/db mouse aortas. DHE fluorescence revealed an overproduction of ROS in db/db aortas which was sensitive to inhibition by losartan or ROS scavengers. Losartan also prevented the impairment of endothelium-dependent dilatations under hyperglycemic conditions that were accompanied by high ROS production. The present study has identified an initiative role of AT(1)R activation in mediating endothelial dysfunction of arteries from db/db mice and diabetic patients.


Clinical Applicability of Monitoring Antihypertensive Drug Levels in Blood.
Dried blood spot (DBS) analysis is a novel analytical method for therapeutic drug monitoring to identify nonadherence to antihypertensive drugs. This study was conducted to evaluate the clinical applicability of measuring drug concentrations of 8 antihypertensive drugs, using DBS and venipuncture. Furthermore, this study aimed to provide more insight into the between-patient variability in drug concentrations. False-negative values from DBS compared with a venipuncture were determined to assess drug adherence. A generalized estimating equation was used to estimate the model parameters, including sex, dose, age, weight, and the time interval, between drug intake and sampling, on the Cplasma (drug concentration in plasma). No false-negative values were found when measuring nonadherence using DBS compared with venipuncture. A high variability in Cplasma between patients was observed, especially at peak concentrations with a fold change reaching from 2.3 to 35.2. The time of intake was significantly related to the height of the Cplasma in 7 of the 8 measured drugs with a P<0.05, but the influence of dose, weight, age, and sex on drug levels differed largely between the measured drugs. DBS is a reliable and convenient method to assess nonadherence to antihypertensive drugs in clinical practice. The Cplasma of the 8 antihypertensive drugs in this study show a large interindividual difference, and therefore, low plasma concentrations do not necessarily mean nonadherence. Nonadherence can only be confirmed if drug levels are undetectable, that is, values below the lower limit of detection.


Adductor canal compression syndrome.
Adductor canal syndrome is an unusual cause of acute arterial occlusion in younger men. It is the result of arterial compression by an abnormal musculotendinous band arising from the adductor magnus muscle and lying adjacent and superior to the adductor tendon. The pathogenetic mechanism of this syndrome resembles that of popliteal fossa entrapment and can become manifest after exercise. Since this syndrome occurs in younger men in whom acute arterial occlusion can lead to limb loss, recognition of the presence of apparent ischemic symptoms after exercise in an otherwise healthy young man is important. The treatment consists of the division of the abnormal band and restoration of arterial continuity by appropriate means. A search for bilateral lesions can help avoid future problems even when the symptoms are unilateral.


Big for small: Validating brain injury guidelines in pediatric traumatic brain injury.
Brain injury guidelines (BIG) were developed to reduce overutilization of neurosurgical consultation (NC) as well as computed tomography (CT) imaging. Currently, BIG have been successfully applied to adult populations, but the value of implementing these guidelines among pediatric patients remains unassessed. Therefore, the aim of this study was to evaluate the established BIG (BIG-1 category) for managing pediatric traumatic brain injury (TBI) patients with intracranial hemorrhage (ICH) without NC (no-NC). We prospectively implemented the BIG-1 category (normal neurologic examination, ICH ≤ 4 mm limited to one location, no skull fracture) to identify pediatric TBI patients (age, ≤ 21 years) that were to be managed no-NC. Propensity score matching was performed to match these no-NC patients to a similar cohort of patients managed with NC before the implementation of BIG in a 1:1 ratio for demographics, severity of injury, and type as well as size of ICH. Our primary outcome measure was need for neurosurgical intervention. A total of 405 pediatric TBI patients were enrolled, of which 160 (NC, 80; no-NC, 80) were propensity score matched. The mean age was 9.03 ± 7.47 years, 62.1% (n = 85) were male, the median Glasgow Coma Scale score was 15 (13-15), and the median head Abbreviated Injury Scale score was 2 (2-3). A subanalysis based on stratifying patients by age groups showed a decreased in the use of repeat head CT (p = 0.02) in the no-NC group, with no difference in progression (p = 0.34) and the need for neurosurgical intervention (p = 0.9) compared with the NC group. The BIG can be safely and effectively implemented in pediatric TBI patients. Reducing repeat head CT in pediatric patients has long-term sequelae. Likewise, adhering to the guidelines helps in reducing radiation exposure across all age groups. Therapeutic/care management, level III.


Auld lang syne: success predictors, change processes, and self-reported outcomes of New Year's resolvers and nonresolvers.
New Year's resolvers (n = 159) and comparable nonresolvers interested in changing a problem later (n = 123) were followed for six months via telephone interviews to determine their self-reported outcomes, predictors of success, and change processes. The two groups did not differ in terms of demographic characteristics, problem histories, or behavioral goals (weight loss, exercise program, and smoking cessation being the most prevalent). Resolvers reported higher rates of success than nonresolvers; at six months, 46% of the resolvers were continuously successful compared to 4% of the nonresolvers. Self-efficacy, skills to change, and readiness to change assessed before January 1 all predicted positive outcome for resolvers. Once into the new year, successful resolvers employed more cognitive-behavioral processes but fewer awareness-generating and emotion-enhancing processes than nonsuccessful resolvers. Discussion centers on the research and intervention opportunities afforded by the annual tradition of resolutions.


Growth temperature exerts differential physiological and transcriptional responses in laboratory and wine strains of Saccharomyces cerevisiae.
Laboratory strains of Saccharomyces cerevisiae have been widely used as a model for studying eukaryotic cells and mapping the molecular mechanisms of many different human diseases. Industrial wine yeasts, on the other hand, have been selected on the basis of their adaptation to stringent environmental conditions and the organoleptic properties that they confer to wine. Here, we used a two-factor design to study the responses of a standard laboratory strain, CEN.PK113-7D, and an industrial wine yeast strain, EC1118, to growth temperatures of 15 degrees C and 30 degrees C in nitrogen-limited, anaerobic, steady-state chemostat cultures. Physiological characterization revealed that the growth temperature strongly impacted the biomass yield of both strains. Moreover, we found that the wine yeast was better adapted to mobilizing resources for biomass production and that the laboratory yeast exhibited higher fermentation rates. To elucidate mechanistic differences controlling the growth temperature response and underlying adaptive mechanisms between the strains, DNA microarrays and targeted metabolome analysis were used. We identified 1,007 temperature-dependent genes and 473 strain-dependent genes. The transcriptional response was used to identify highly correlated gene expression subnetworks within yeast metabolism. We showed that temperature differences most strongly affect nitrogen metabolism and the heat shock response. A lack of stress response element-mediated gene induction, coupled with reduced trehalose levels, indicated that there was a decreased general stress response at 15 degrees C compared to that at 30 degrees C. Differential responses among strains were centered on sugar uptake, nitrogen metabolism, and expression of genes related to organoleptic properties. Our study provides global insight into how growth temperature affects differential physiological and transcriptional responses in laboratory and wine strains of S. cerevisiae.


Global diversity, population stratification, and selection of human copy-number variation.
In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide-variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.


Pseudomyxoma peritonei. Long-term patient survival with an aggressive regional approach.
The aims of this study were to analyze the natural history of patients with pseudomyxoma peritonei (PMP), evaluate clinical and pathologic variables as prognostic indicators, and review the authors' experience with different treatments. PMP is an unusual form of intra-abdominal neoplasm that presents with large amounts of extracellular mucin. Diffuse peritoneal spread occurs in most patients with PMP, and distant metastasis is infrequent. Debulking surgery, radiation therapy (radioisotope and external beam), and chemotherapy (both intraperitoneal and systemic) have all been advocated for optional patient management, but the variability of patients studied, the small patient numbers, and the prolonged course of this disease make the evaluation of results difficult. Fifty-six patients were treated for PMP at the Mayo Clinic between 1957 and 1983. The data were collected retrospectively. Univariate (log-rank test) and multivariate (Cox regression model) analyses were performed for disease recurrence and patient survival. Most patients with PMP had carcinomas of the appendix (52%) or ovary (34%). All gross tumor could be removed only in the 34% of patients with limited disease. Although tumor progression occurred in 76% of patients, the 1-, 5-, and 10-year survival rates were 98%, 53%, and 32%, respectively. Adverse predictors of patient survival included weight loss (p = 0.001), abdominal distention (p = 0.004), use of systemic chemotherapy (p = 0.005), diffuse disease (p = 0.038), and invasion of other organs (p = 0.04). Intraperitoneal chemotherapy (p = 0.009) and radioisotopes (p = 0.0043) both were effective in prolonging the recurrence time of symptomatic PMP. Although PMP is an indolent disease, aggressive surgical debulking followed by intraperitoneal radioisotopes and/or chemotherapy should be considered because of the diffuse peritoneal involvement.


Sharing data on DNA transfer, persistence, prevalence and recovery: Arguments for harmonization and standardization.
Sharing data between forensic scientists on DNA transfer, persistence, prevalence and recovery (TPPR) is crucial to advance the understanding of these issues in the criminal justice community. We present the results of a collaborative exercise on reporting forensic genetics findings given activity level propositions. This exercise outlined differences in the methodology that was applied by the participating laboratories, as well as limitations to the use of published data on DNA TPPR. We demonstrate how publication of experimental results in scientific journals can be further improved to allow for an adequate use of these data. Steps that can be taken to share and use these data for research and casework purposes are outlined, and the prospects for future sharing of data through publicly accessible databases are discussed. This paper also explores potential avenues to proceed with implementation and is intended to fuel the discussion on sharing data pertaining to DNA TPPR issues. It is further suggested that international standardization and harmonization on these topics will benefit the forensic DNA community as it has been achieved in the past with the harmonization of STR typing systems.


Pulse Shaping and Evolution in Normal-Dispersion Mode-Locked Fiber Lasers.
Fiber lasers mode locked with large normal group-velocity dispersion have recently achieved femtosecond pulse durations with energies and peak powers at least an order of magnitude greater than those of prior approaches. Several new mode-locking regimes have been demonstrated, including self-similar pulse propagation in passive and active fibers, dissipative solitons, and a pulse evolution that avoids wave breaking at high peak power but has not been reproduced by theoretical treatment. Here, we illustrate the main features of these new pulse-shaping mechanisms through the results of numerical simulations that agree with experimental results. We describe the features that distinguish each new mode-locking state and explain how the interplay of basic processes in the fiber produces the balance of amplitude and phase evolutions needed for stable high-energy pulses. Dissipative processes such as spectral filtering play a major role in normal-dispersion mode locking. Understanding the different mechanisms allows us to compare and contrast them, as well as to categorize them to some extent.


Metabolism of diazirine-modified N-acetylmannosamine analogues to photo-cross-linking sialosides.
Terminal sialic acid residues often mediate the interactions of cell surface glycoconjugates. Sialic acid-dependent interactions typically exhibit rapid dissociation rates, precluding the use of traditional biological techniques for complex isolation. To stabilize these transient interactions, we employ a targeted photo-cross-linking approach in which a diazirine photo-cross-linker is incorporated into cell surface sialylated glycoconjugates through the use of metabolic oligosaccharide engineering. We describe three diazirine-modified N-acetylmannosamine (ManNAc) analogues in which the length of the linker between the pyranose ring and the diazirine was varied. These analogues were each metabolized to their respective sialic acid counterparts, which were added to both glycoproteins and glycolipids. Diazirine-modified sialic acid analogues could be incorporated into both α2-3 and α2-6 linkages. Upon exposure to UV irradiation, diazirine-modified glycoconjugates were covalently cross-linked to their interaction partners. We demonstrate that all three diazirine-modified analogues were capable of competing with endogeneous sialic acid, albeit to varying degrees. We found that larger analogues were less efficiently metabolized, yet could still function as effective cross-linkers. Notably, the addition of the diazirine substituent interferes with metabolism of ManNAc analogues to glycans other than sialosides, providing fidelity to selectively incorporate the cross-linker into sialylated molecules. These compounds are nontoxic and display only minimal growth inhibition at the concentrations required for cross-linking studies. This report provides essential information for the deployment of photo-cross-linking analogues to capture and study ephemeral, yet essential, sialic acid-mediated interactions.


An improved labelling technique for monitoring microcrack growth in compact bone.
Fatigue-induced damage plays an important role in bone remodelling and in the formation of stress and fragility fractures. Recently, a technique has been developed (Lee, T.C. et al., Sequential labelling of microdamage in bone using chelating agents. Journal of Orthopedic Research, 18 (2000) 322-325) which allows microcrack growth in trabecular bone to be monitored by the application of a series of chelating fluorochromes, however, some limitations were identified with the process. The aims of this study were to refine the method of detection using these agents in order to determine the optimal sequence of application and the optimal concentrations which allowed all the agents to fluoresce equally brightly using UV epifluorescence. A chemical analysis process, ion chromatography, followed by validation tests on bone samples showed that the optimal sequence of application and concentration of each agent was alizarin complexone (0.0005 M) followed by xylenol orange (0.0005 M), calcein (0.0005 M) and calcein blue (0.0001 M). A fifth agent, oxytetracycline was excluded from the study after recurring problems were found with its ability to chelate exposed calcium when applied in sequence with the other agents. This work has developed a sequential labelling technique, which allows for microcrack propagation during fatigue testing of bone specimens to be monitored without the problem of chelating agent substitution occurring.


Gender inequality during the COVID-19 pandemic: Income, expenditure, savings, and job loss.
The COVID-19 outbreak has brought unprecedented disruptions to the global economies and has led to income loss and high unemployment rates. But scant, if any, evidence exists on gender gaps in economic outcomes such as income, expenditure, savings, and job loss in a multi-country setting. We investigate the impacts of COVID-19 on gender inequality in these outcomes using data from a six-country survey that covers countries in different geographical locations and at various income levels. Our findings suggest that women are 24 percent more likely to permanently lose their job than men because of the outbreak. Women also expect their labor income to fall by 50 percent more than men do. Perhaps because of these concerns, women tend to reduce their current consumption and increase savings. Factors such as the different participation rates in work industries for men and women may take an important part in explaining these gender gaps. Our estimates also point to country heterogeneity in these gender differences that is likely due to varying infection rates and shares of women in the labor force.


Yeast β-Glucan Modulates Inflammation and Waist Circumference in Overweight and Obese Subjects.
Increased inflammation occurs with excessive adiposity and yeast β-glucan modulates immune responses. This study investigated the potential effect of yeast β-glucan on inflammatory cytokines in overweight/obese people. A randomized, double blinded, placebo-controlled, clinical trial design enrolled 44 overweight/obese participants with body mass index ≥23 kg/m2, randomized to two groups receiving β-glucan 477 mg/capsule (n = 22) or placebo (n = 22) orally for six weeks. At weeks one to two, participants received 1 β-glucan or placebo capsule/day and at four weeks two tablets/day. Anthropometric changes, lipid profiles, liver and renal functions, and inflammatory cytokines were measured. β-glucan reduced waist circumference (p = 0.037) and blood pressure (p = 0.006) compared with controls after six weeks of intervention. No statistical significance between groups was observed for triglyceride, cholesterol, lipid profile, liver and renal function, or energy and nutrient intake compared with controls at week six. β-glucan increased interlukin-10 (IL-10), an anti-inflammatory cytokine, by 23.97% from baseline at week two (p < 0.001) and 31.12% at week six (p < 0.001) and was significantly increased compared with controls at week two (p < 0.001) until week six (p < 0.001). β-glucan reduced pro-inflammatory cytokines IL-6 at week six (p = 0.005) and tumor necrosis factor-α at week two (p = 0.037) compared with controls. Supplementation of yeast β-glucan for six weeks modulated pro-cytokines that accelerate overweight/obese comorbidities and reduced blood pressure as well as waist circumference, the strong risk factors for cardiovascular disease, in overweight/obese subjects. Thus, β-glucan might have the potential to decrease comorbid conditions associated with overweight/ obesity.


Early prediction and prevention of pre-eclampsia.
Pre-eclampsia remains an important cause of maternal and perinatal mortality. The ability to predict the most severe forms of pre-eclampsia would allow closer surveillance and earlier intervention to improve outcomes. Although no definitive preventative treatment has been found to date, it is likely that prospective treatments would need to start early in pregnancy to alter pathogenesis. Following recent advances in the understanding of the pathogenesis of this complex syndrome, new predictive tests are being evaluated. The most promising models incorporate biochemical and biophysical tests that combine assessments of placentation and maternal disease susceptibility.


Neuroprotective maraviroc monotherapy in simian immunodeficiency virus-infected macaques: reduced replicating and latent SIV in the brain.
HIV-associated neurocognitive deficits remain a challenge despite suppressive combined antiretroviral therapy. Given the association between HIV-induced central nervous system (CNS) disease and replication of HIV in immune-activated macrophages, CCR5 antagonists may attenuate CNS disease by modulating inflammatory signaling and by limiting viral replication. To establish whether initiating CCR5 inhibition during early infection altered CNS disease progression, outcomes were compared between simian immunodeficiency virus (SIV)-infected macaques treated with maraviroc (MVC) versus untreated SIV-infected macaques. Six SIV-infected rhesus macaques were treated with MVC monotherapy for 5 months beginning 24 days postinoculation; 22 SIV-infected animals served as untreated controls. SIV RNA levels in plasma, cerobrospinal fluid, and brain, and CNS expression of TNFα and CCL2 were measured by qRT-PCR. Immunostaining for CD68 and amyloid precursor protein in the brain was measured by image analysis. Plasma sCD163 was measured by ELISA. SIV RNA and proviral DNA levels in brain were markedly lower with MVC treatment, demonstrating CCR5 inhibition reduces CNS replication of SIV and may reduce the CNS latent viral reservoir. MVC treatment also lowered monocyte and macrophage activation, represented by CNS CD68 immunostaining and plasma sCD163 levels, and reduced both TNFα and CCL2 RNA expression in brain. Treatment also reduced axonal amyloid precursor protein immunostaining to levels present in uninfected animals, consistent with neuroprotection. CCR5 inhibitors may prevent neurologic disorders in HIV-infected individuals by reducing inflammation and by limiting viral replication in the brain. Furthermore, CCR5 inhibitors may reduce the latent viral reservoir in the CNS. Adding CCR5 inhibitors to combined antiretroviral regimens may offer multiple neuroprotective benefits.


Supplemental nurses are just as educated, slightly less experienced, and more diverse compared to permanent nurses.
In the past three decades, the shortage of nurses willing to work in hospitals has been a persistent challenge in the United States. Hiring supplemental registered nurses-nurses on short-term contracts obtained through an external staffing agency-has been common to fill gaps in nurse staffing. But there has been insufficient evidence about supplemental nurse workforce trends to inform workforce policy. To address this concern, we compared qualifications and characteristics of supplemental nurses with those of permanent nurses during 1984-2008. The two groups shared similar education levels in terms of possessing a baccalaureate or higher degree. Supplemental nurses were somewhat less experienced than permanent nurses, averaging fifteen years of experience in 2008 compared to eighteen years for permanent nurses. The supplemental nurse workforce was more diverse racially and ethnically and more likely to be male than the permanent nurse workforce. These data show that employing supplemental nurses could help meet the challenges of an aging nursing workforce, the projected future shortage of nurses, and an increasingly diverse US population.


A stochastic model for studying the laminar structure of cortex from MRI.
The human cerebral cortex is a laminar structure about 3 mm thick, and is easily visualized with current magnetic resonance (MR) technology. The thickness of the cortex varies locally by region, and is likely to be influenced by such factors as development, disease and aging. Thus, accurate measurements of local cortical thickness are likely to be of interest to other researchers. We develop a parametric stochastic model relating the laminar structure of local regions of the cerebral cortex to MR image data. Parameters of the model include local thickness, and statistics describing white, gray and cerebrospinal fluid (CSF) image intensity values as a function of the normal distance from the center of a voxel to a local coordinate system anchored at the gray/white matter interface. Our fundamental data object, the intensity-distance histogram (IDH), is a two-dimensional (2-D) generalization of the conventional 1-D image intensity histogram, which indexes voxels not only by their intensity value, but also by their normal distance to the gray/white interface. We model the IDH empirically as a marked Poisson process with marking process a Gaussian random field model of image intensity indexed against normal distance. In this paper, we relate the parameters of the IDH model to the local geometry of the cortex. A maximum-likelihood framework estimates the parameters of the model from the data. Here, we show estimates of these parameters for 10 volumes in the posterior cingulate, and 6 volumes in the anterior and posterior banks of the central sulcus. The accuracy of the estimates is quantified via Cramer-Rao bounds. We believe that this relatively crude model can be extended in a straightforward fashion to other biologically and theoretically interesting problems such as segmentation, surface area estimation, and estimating the thickness distribution in a variety of biologically relevant contexts.


Using deep belief network modelling to characterize differences in brain morphometry in schizophrenia.
Neuroimaging-based models contribute to increasing our understanding of schizophrenia pathophysiology and can reveal the underlying characteristics of this and other clinical conditions. However, the considerable variability in reported neuroimaging results mirrors the heterogeneity of the disorder. Machine learning methods capable of representing invariant features could circumvent this problem. In this structural MRI study, we trained a deep learning model known as deep belief network (DBN) to extract features from brain morphometry data and investigated its performance in discriminating between healthy controls (N = 83) and patients with schizophrenia (N = 143). We further analysed performance in classifying patients with a first-episode psychosis (N = 32). The DBN highlighted differences between classes, especially in the frontal, temporal, parietal, and insular cortices, and in some subcortical regions, including the corpus callosum, putamen, and cerebellum. The DBN was slightly more accurate as a classifier (accuracy = 73.6%) than the support vector machine (accuracy = 68.1%). Finally, the error rate of the DBN in classifying first-episode patients was 56.3%, indicating that the representations learned from patients with schizophrenia and healthy controls were not suitable to define these patients. Our data suggest that deep learning could improve our understanding of psychiatric disorders such as schizophrenia by improving neuromorphometric analyses.


Separation of risks and benefits of seafood intake.
Fish and seafood provide important nutrients but may also contain toxic contaminants, such as methylmercury. Advisories against pollutants may therefore conflict with dietary recommendations. In resolving this conundrum, most epidemiologic studies provide little guidance because they address either nutrient benefits or mercury toxicity, not both. Impact on the same health outcomes by two exposures originating from the same food source provides a classical example of confounding. To explore the extent of this bias, we applied structural equation modeling to data from a prospective study of developmental methylmercury neurotoxicity in the Faroe Islands. Adjustment for the benefits conferred by maternal fish intake during pregnancy resulted in an increased effect of the prenatal methylmercury exposure, as compared with the unadjusted results. The dietary questionnaire response is likely to be an imprecise proxy for the transfer of seafood nutrients to the fetus, and this imprecision may bias the confounder-adjusted mercury effect estimate. We explored the magnitude of this bias in sensitivity analysis assuming a range of error variances. At realistic imprecision levels, mercury-associated deficits increased by up to 2-fold when compared with the unadjusted effects. These results suggest that uncontrolled confounding from a beneficial parameter, and imprecision of this confounder, may cause substantial underestimation of the effects of a toxic exposure. The adverse effects of methylmercury exposure from fish and seafood are therefore likely to be underestimated by unadjusted results from observational studies, and the extent of this bias will be study dependent.


Risk factors for pregnancy failure in patients with anti-phospholipid syndrome treated with conventional therapies: a multicentre, case-control study.
To identify the risk factors associated with pregnancy failure in patients with APS treated with conventional therapy. A multicentre, case-control study was conducted to compare APS patients with successful and unsuccessful pregnancy outcomes. We retrospectively considered 410 pregnancies of women diagnosed with primary APS. The study focused on 57 unsuccessful pregnancies (considered the study population) and 57 successful pregnancies (considered the control population) matched for age and therapy. All the patients had been treated with conventional protocol treatments including low-dose aspirin and/or heparin. The clinical and laboratory features of the two groups of women diagnosed with APS were compared. The independent risk factors for pregnancy failure were: (i) the presence of SLE or other autoimmune diseases [odds ratio (OR) 6.0; 95% CI 1.7, 20.8; P = 0.01]; (ii) history of both thrombosis and pregnancy morbidity (OR 12.1; 95% CI 1.3, 115.3; P = 0.03); and (iii) triple [Immunoglobulin (Ig) G/IgM aCLs plus IgG/IgM anti-β(2) glycoprotein I antibodies plus LA] aPL positivity (OR 4.1; 95% CI 1.0, 16.7; P = 0.05). APS patients diagnosed on the basis of a single positive test and/or history of pregnancy morbidity alone were generally found to have successful pregnancies. It would seem from these findings that the risk of pregnancy failure in APS women planning to conceive can be stratified on the basis of some specific clinical and laboratory features.


Effect of superior cervical ganglionectomy on the ultrastructure of pinealocytes in the Djungarian hamster (Phodopus sungorus): quantitative study.
Superior cervical ganglia are of crucial importance in regulating the secretion of the pineal hormone melatonin. Changes in pineal morphology have been observed in many mammalian species after sympathectomy. Therefore, we decided to investigate the ultrastructure of Djungarian hamster pinealocytes following superior cervical ganglionectomy. Eight adult female Djungarian hamsters (Phodopus sungorus) were used in this study. The superior cervical ganglia were removed bilaterally in four animals, whereas the other four animals served as sham-operated controls. The pineal glands were removed four weeks after the operation and processed for electron microscopic study. The cross-sectional areas of pinealocyte and its nucleus, and relative volume of mitochondria, Golgi apparatus, lysosomes, granular endoplasmic reticulum, and glycogen particles as well as the numbers of dense-core vesicles and "synaptic" ribbons were estimated using a digital analyzer connected on-line to IBM-PC computer. Statistical analysis of the data was performed using Student's t test and Snedecor F test. Significant reduction in the cross-sectional areas of the pinealocyte and its nucleus as well as in the relative volumes of mitochondria and glycogen particles was observed after superior cervical ganglionectomy in comparison with sham-operated controls. Sympathectomy resulted also in reduction of the number of dense-core vesicles. On the contrary 2,5 fold increase in the number of "synaptic" ribbons was observed in ganglionectomized animals in comparison to sham-operated controls. Deprivation of sympathetic innervation leads in Djungarian hamsters not only to suppression of melatonin synthesis and secretions but, as appears from our studies, induces also morphological changes suggesting lower metabolic and secretory activity of pinealocytes.


Morphological and neurohistological changes in adolescent rats administered with nicotine during intrauterine life.
Tobacco smoking has been linked to many preventable diseases affecting various organs and systems of the body, including the brain. The current study was conducted to demonstrate the histological changes observable in the cerebral cortex of young Wistar rats exposed to nicotine during gestation. Vaginal smearing was conducted for the female Wistar rats to determine their oestrous cycle, after which they were exposed to male rats overnight, for mating. Pregnancy was confirmed and the pregnant rats were divided into 3 groups based on the 3 trimesters (A, B, C), with each group having a control and a treated subgroup. The Control Groups (A1, B1, C1) were given 0.1 ml of normal saline i. p., while the Treated Groups (A2, B2, C2) received 0.06 mg/kg/0.1 ml of nicotine intra-peritoneally. Treatment was for a period of 6 days only within each trimester for all subgroups. The pregnant animals were allowed to litter, and at postnatal day 35 they were sacrificed. The skull was dissected to expose and remove the brain; the temporal and parietal cortices were excised and fixed in 4% paraformaldehyde for histological tissue preparation, using cresyl fast violet staining techniques. Exposure of the developing brain to nicotine during gestation resulted in various degrees of abnormalities in the cytoarchitecture of the parietal and temporal cortices of young rats. The gestational period of nicotine exposure and specific cortical affectation are important factors to consider while investigating neurological abnormalities in offspring of tobacco smokers.


Fifteen-minute music intervention reduces pre-radiotherapy anxiety in oncology patients.
Oncology patients may respond to radiation treatment with anxiety expressed as stress, fear, depression, and frustration. This study aimed to investigate effects of music intervention on reducing pre-radiotherapy anxiety in oncology patients. Quasi-experimental study with purposeful sampling was conducted in the Department of Radiation Oncology, at Far Eastern Memorial Hospital, Taipei, Taiwan. Subjects were assigned into a music group (n = 100) receiving 15 min of music therapy prior to radiation and a control group (n = 100) receiving 15 min rest prior to radiation. Both groups were evaluated for pre- and post-test anxiety using the State-Trait Anxiety Inventory. Physiological indicators of anxiety were measured pre- and post-test. Baseline State/Trait scores and vital signs were comparable between groups (P > 0.05). Mean change in pre- and post-test State/Trait scores showed significant decreases from baseline to post-test in both groups (all P < 0.05). A statistically significant difference was observed between music therapy and control groups in mean change of State anxiety scores (mean decreases 7.19 and 1.04, respectively; P < 0.001) and Trait anxiety scores (mean decreases 2.77 and 1.13, respectively; P = 0.036). In vital signs, both groups had significant decreases in pre- and post-test heart rate and respiration rate (P < 0.05). A statistically significant difference in mean change of systolic pressure was found between music and control groups (-5.69 ± 0.41 mmHg vs. -0.67 ± 1.29 mmHg, respectively; P = 0.009). Music therapy decreased State anxiety levels, Trait anxiety levels and systolic blood pressure in oncology patients who received the intervention prior to radiotherapy.


Consent in the time of COVID-19.
The COVID-19 pandemic crisis has necessitated widespread adaptation of revised treatment regimens for both urgent and routine medical problems in patients with and without COVID-19. Some of these alternative treatments maybe second-best. Treatments that are known to be superior might not be appropriate to deliver during a pandemic when consideration must be given to distributive justice and protection of patients and their medical teams as well the importance given to individual benefit and autonomy. What is required of the doctor discussing these alternative, potentially inferior treatments and seeking consent to proceed? Should doctors share information about unavailable but standard treatment alternatives when seeking consent? There are arguments in defence of non-disclosure; information about unavailable treatments may not aid a patient to weigh up options that are available to them. There might be justified concern about distress for patients who are informed that they are receiving second-best therapies. However, we argue that doctors should tailor information according to the needs of the individual patient. For most patients that will include a nuanced discussion about treatments that would be considered in other times but currently unavailable. That will sometimes be a difficult conversation, and require clinicians to be frank about limited resources and necessary rationing. However, transparency and honesty will usually be the best policy.


Voting contagion: Modeling and analysis of a century of U.S. presidential elections.
Social influence plays an important role in human behavior and decisions. Sources of influence can be divided as external, which are independent of social context, or as originating from peers, such as family and friends. An important question is how to disentangle the social contagion by peers from external influences. While a variety of experimental and observational studies provided insight into this problem, identifying the extent of contagion based on large-scale observational data with an unknown network structure remains largely unexplored. By bridging the gap between the large-scale complex systems perspective of collective human dynamics and the detailed approach of social sciences, we present a parsimonious model of social influence, and apply it to a central topic in political science-elections and voting behavior. We provide an analytical expression of the county vote-share distribution, which is in excellent agreement with almost a century of observed U.S. presidential election data. Analyzing the social influence topography over this period reveals an abrupt phase transition from low to high levels of social contagion, and robust differences among regions. These results suggest that social contagion effects are becoming more instrumental in shaping large-scale collective political behavior, with implications on democratic electoral processes and policies.


One small step for a yeast--microevolution within macrophages renders Candida glabrata hypervirulent due to a single point mutation.
Candida glabrata is one of the most common causes of candidemia, a life-threatening, systemic fungal infection, and is surpassed in frequency only by Candida albicans. Major factors contributing to the success of this opportunistic pathogen include its ability to readily acquire resistance to antifungals and to colonize and adapt to many different niches in the human body. Here we addressed the flexibility and adaptability of C. glabrata during interaction with macrophages with a serial passage approach. Continuous co-incubation of C. glabrata with a murine macrophage cell line for over six months resulted in a striking alteration in fungal morphology: The growth form changed from typical spherical yeasts to pseudohyphae-like structures - a phenotype which was stable over several generations without any selective pressure. Transmission electron microscopy and FACS analyses showed that the filamentous-like morphology was accompanied by changes in cell wall architecture. This altered growth form permitted faster escape from macrophages and increased damage of macrophages. In addition, the evolved strain (Evo) showed transiently increased virulence in a systemic mouse infection model, which correlated with increased organ-specific fungal burden and inflammatory response (TNFα and IL-6) in the brain. Similarly, the Evo mutant significantly increased TNFα production in the brain on day 2, which is mirrored in macrophages confronted with the Evo mutant, but not with the parental wild type. Whole genome sequencing of the Evo strain, genetic analyses, targeted gene disruption and a reverse microevolution experiment revealed a single nucleotide exchange in the chitin synthase-encoding CHS2 gene as the sole basis for this phenotypic alteration. A targeted CHS2 mutant with the same SNP showed similar phenotypes as the Evo strain under all experimental conditions tested. These results indicate that microevolutionary processes in host-simulative conditions can elicit adaptations of C. glabrata to distinct host niches and even lead to hypervirulent strains.


Use of TNF blockers and other targeted therapies in rare refractory immune-mediated inflammatory diseases: evidence-based or rational?
Evidence-based medicine implies that clinical decision making should be based on external research evidence when available. This external evidence includes, but is certainly not restricted to, randomised controlled trials (RCTs). The development of powerful but often expensive targeted therapies for immune-mediated inflammatory diseases (IMIDs) is one of the major successes of evidence-based medicine but, paradoxically, also threatens the traditional RCT-based approach. Indeed, the increasing availability of these drugs decreases the number of patients available for RCTs, questions the ethical basis for the use of placebo groups and raises the issue of cost-efficacy. These considerations become even more important in rare phenotypically diverse and potentially life- or organ-threatening IMIDs such as sarcoidosis, Behçet's disease and uveitis. Using the successful application of tumour necrosis factor blockade in these diseases as an example, this review defends the concept that pathophysiological insights in cellular and molecular disease pathways as well as limited case series are valid sources of external evidence for the rational use of targeted therapies in these rare refractory conditions. If authors fail to redefine their concept of rational therapy along the lines of not only evidence-based but also pathophysiology-based and practice-based medicine, they may underestimate the potential of novel drugs in rare refractory IMIDs and thereby jeopardise the health of their patients.


Clinical and radiologic features and their relationships with neurofunctional scores in patients with acute cerebellar infarct.
Cerebellar infarct is a rare condition with very nonspecific clinical features. The aim of this study was to assess the full spectrum of the clinical characteristics, neuroimaging findings and neurofunctional analyses of cerebellar infarction, and the relationship between them. Data were collected from 59 patients admitted to our department during an 8-year period. We retrospectively analyzed the relationship between demographic characteristics, clinical symptomatology, etiological factors, functional condition, vascular distribution, frequency of subcortical white matter lesions (WMLs), and concomitant lesion outside the cerebellum in patients with acute cerebellar infarct (ACI) at time of admission. The mean age in our series was 65.2 years, with most being male (57.6%). The posterior inferior cerebellar (PICA) artery was the most commonly affected territory at 62.7%. There was concomitant lesion outside the cerebellum in 45.7%. The main etiology in PICA was cardioembolism. While mean National Institutes of Health Stroke Scale on admission was 2.08 ± 1.67 in study group, modified Rankin Scale (mRS) on admission was detected to be mRS1 (n: 44, 74.5%) and mRS2 (n: 12, 20.3%) most frequently. Fourteen (35%) patients were detected to be in Fazekas stage 0; 11 (27.5%) patients in Fazekas stage 1; 6 (15%) patients in Fazekas stage 2; and 9 (22.5%) patients in Fazekas stage 3. Cerebellar infarct is very heterogeneous. The other cerebral area infarcts which accompany ACI negatively affect neurologic functional scores. Although it is difficult to detect the relationship between WMLs and neurologic functional severity, timely detection of risk factors and their modulation may be associated with prevention and treatability of WMLs, and this may be one of the important points for prevention of stroke-related disability.


Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice.
Adriamycin (ADR) is a commonly used chemotherapeutic agent that also produces significant tissue damage. Mutations to mitochondrial DNA (mtDNA) and reductions in mtDNA copy number have been identified as contributors to ADR-induced injury. ADR nephropathy only occurs among specific mouse inbred strains, and this selective susceptibility to kidney injury maps as a recessive trait to chromosome 16A1-B1. Here, we found that sensitivity to ADR nephropathy in mice was produced by a mutation in the Prkdc gene, which encodes a critical nuclear DNA double-stranded break repair protein. This finding was confirmed in mice with independent Prkdc mutations. Overexpression of Prkdc in cultured mouse podocytes significantly improved cell survival after ADR treatment. While Prkdc protein was not detected in mitochondria, mice with Prkdc mutations showed marked mtDNA depletion in renal tissue upon ADR treatment. To determine whether Prkdc participates in mtDNA regulation, we tested its genetic interaction with Mpv17, which encodes a mitochondrial protein mutated in human mtDNA depletion syndromes (MDDSs). While single mutant mice were asymptomatic, Prkdc/Mpv17 double-mutant mice developed mtDNA depletion and recapitulated many MDDS and ADR injury phenotypes. These findings implicate mtDNA damage in the development of ADR toxicity and identify Prkdc as a MDDS modifier gene and a component of the mitochondrial genome maintenance pathway.


Robot-assisted partial nephrectomy in cystic tumours: analysis of the Vattikuti Global Quality Initiative in Robotic Urologic Surgery (GQI-RUS) database.
To evaluate the outcomes of robot-assisted partial nephrectomy (RAPN) in cystic tumours, analysing a large, multi-institutional, retrospective series of RAPN, as limited data are available about the outcome of RAPN in cystic tumours. We evaluated 465 patients who received RAPN for either cystic or solid tumours from 2010 to 2013 and included in the multi-institutional, retrospective Vattikuti Global Quality Initiative in Robotic Urologic Surgery (GQI-RUS) database. Univariable and multivariable linear and logistic regression models addressed the association of cystic tumours with perioperative outcomes. In all, 54 (12%) tumours were cystic. Cystic tumours were associated with significantly lower operative time (t -3.9; P < 0.001), once adjusted for the effect of covariates, whereas blood loss and warm ischaemia time were similar. Postoperative any grade complications were recorded in 66 solid (16%) and nine cystic (17%) tumours (P = 0.08). In multivariable analysis, cystic tumours were not associated with a significantly lower risk of any grade postoperative complications [odds ratio (OR) 0.9; P = 0.8]. Similarly, presence of tumours with cystic features was not associated with a significantly different risk of high-grade postoperative complications (OR 2.2; P = 0.1). Prevalence of cancer histology and positive surgical margin rates were similar in cystic and solid tumours. Cystic tumours were not associated with significantly different postoperative estimated glomerular filtration rate (t 0.4; P = 0.7), once adjusted for the effect of covariates. RAPN can be performed in cystic renal tumours with perioperative, pathological, and functional outcomes similar to those achievable in solid tumours.


Evidence for bioavailability of Au nanoparticles from soil and biodistribution within earthworms (Eisenia fetida).
Because Au nanoparticles (NPs) are resistant to oxidative dissolution and are easily detected, they have been used as stable probes for the behavior of nanomaterials within biological systems. Previous studies provide somewhat limited evidence for bioavailability of Au NPs in food webs, because the spatial distribution within tissues and the speciation of Au was not determined. In this study, we provide multiple lines of evidence, including orthogonal microspectroscopic techniques, as well as evidence from biological responses, that Au NPs are bioavailable from soil to a model detritivore (Eisenia fetida). We also present limited evidence that Au NPs may cause adverse effects on earthworm reproduction. This is perhaps the first study to demonstrate that Au NPs can be taken up by detritivores from soil and distributed among tissues. We found that primary particle size (20 or 55 nm) did not consistently influence accumulated concentrations on a mass concentration basis; however, on a particle number basis the 20 nm particles were more bioavailable. Differences in bioavailability between the treatments may have been explained by aggregation behavior in pore water. The results suggest that nanoparticles present in soil from activities such as biosolids application have the potential to enter terrestrial food webs.


Water-use efficiency and relative growth rate mediate competitive interactions in Sonoran Desert winter annual plants.
A functional approach to investigating competitive interactions can provide a mechanistic understanding of processes driving population dynamics, community assembly, and the maintenance of biodiversity. In Sonoran Desert annual plants, a trade-off between relative growth rate (RGR) and water-use efficiency (WUE) contributes to species differences in population dynamics that promote long-term coexistence. Traits underlying this trade-off explain variation in demographic responses to precipitation as well as life history and phenological patterns. Here, we ask how these traits mediate competitive interactions. • We conducted competition trials for three species occupying different positions along the RGR-WUE trade-off axis and compared the effects of competition at high and low soil moisture. We compared competitive effect (ability to suppress neighbors) and competitive response (ability to withstand competition from neighbors) among species. • The RGR-WUE trade-off predicted shifts in competitive responses at different soil moistures. The high-RGR species was more resistant to competition in high water conditions, while the opposite was true for the high-WUE species. The intermediate RGR species tended to have the strongest impact on all neighbors, so competitive effects did not scale directly with differences in RGR and WUE among competitors. • Our results reveal mechanisms underlying long-term variation in fitness: high-RGR species perform better in years with large, frequent rain events and can better withstand competition under wetter conditions. The opposite is true for high-WUE species. Such resource-dependent responses strongly influence community dynamics and can promote coexistence in variable environments.


Electrochemical growth mechanism of nanoporous platinum layers.
Porous platinum is a frequently used catalyst material in electrosynthesis and a robust broadband absorber in thermoelectrics. Pore size distribution and localization determine its properties by a large extent. However, the pore formation mechanism during the growth of the material remains unclear. In this work we elucidate the mechanism underlying electrochemical growth of nanoporous platinum layers and its control by ionic concentration and current density during electrolysis. The electrode kinetics and reduction steps of PtCl4 on platinum electrodes are investigated by cyclic voltammetry and impedance measurements. Cyclic voltammograms show three reduction steps: two steps relate to the platinum cation reduction, and one step relates to the hydrogen reduction. Hydrogen is not involved in the reduction of PtCl4, however it enables the formation of nanopores in the layers. These findings contribute to the understanding of electrochemical growth of nanoporous platinum layers in isopropanol with thickness of 100 nm to 500 nm.


In-Vivo Evaluation of Microultrasound and Thermometric Capsule Endoscopes.
Clinical endoscopy and colonoscopy are commonly used to investigate and diagnose disorders in the upper gastrointestinal tract and colon, respectively. However, examination of the anatomically remote small bowel with conventional endoscopy is challenging. This and advances in miniaturization led to the development of video capsule endoscopy (VCE) to allow small bowel examination in a noninvasive manner. Available since 2001, current capsule endoscopes are limited to viewing the mucosal surface only due to their reliance on optical imaging. To overcome this limitation with submucosal imaging, work is under way to implement microultrasound (μUS) imaging in the same form as VCE devices. This paper describes two prototype capsules, termed Sonocap and Thermocap, which were developed respectively to assess the quality of μUS imaging and the maximum power consumption that can be tolerated for such a system. The capsules were tested in vivo in the oesophagus and small bowel of porcine models. Results are presented in the form of μUS B-scans as well as safe temperature readings observed up to 100 mW in both biological regions. These results demonstrate that acoustic coupling and μUS imaging can be achieved in vivo in the lumen of the bowel and the maximum power consumption that is possible for miniature μUS systems.


Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients.
Type 1 diabetes is a cell-mediated autoimmune disease characterized by autoantibody and peripheral blood mononuclear cell (PBMC) reactivity to islet cell proteins. Type 2 diabetes is not an autoimmune disease but rather results from both insulin resistance and a nonautoimmune insulin secretory defect. There is, however, a group of phenotypic type 2 diabetic patients who have islet autoantibodies that are similar to those of type 1 diabetic patients. In this study, we investigated, using cellular immunoblotting, whether type 2 diabetic patients positive for islet autoantibodies have PBMC responses to islet proteins. We observed that autoantibody negative (Ab-) type 2 diabetic patients (n = 9) and normal control subjects (n = 12) demonstrated PBMCs responsive to 0-3 molecular weight regions. In contrast, autoantibody positive (Ab+) type 2 diabetic patients (n = 11) demonstrated PBMC responses to 3-18 molecular weight regions, similar to that of type 1 diabetic patients (responsive to 4-18 molecular weight regions). PBMCs from over 90% of the Ab+ type 2 and type 1 diabetic patients were observed to proliferate to islet proteins in the vicinity of 97 kDa. In contrast, 65-90% of type 1 diabetic patients had responsive PBMCs for islet proteins in most of the molecular weight regions, whereas <60% of the Ab+ type 2 diabetic patients had PBMCs responsive to the same molecular weight proteins. Ab+ type 2 diabetic patients appear to be heterogeneous with respect to cellular reactivity to islet proteins. Some subjects demonstrate PBMC responses similar to those of "classic" type 1 diabetic patients, whereas others have PBMC responses potentially distinct from type 1 diabetic patients.


On dogs, people, and a rabies epidemic: results from a sociocultural study in Bali, Indonesia.
Previously free of rabies, Bali experienced an outbreak in 2008, which has since caused a large number of human fatalities. In response, both mass dog culling and vaccination have been implemented. In order to assess potential community-driven interventions for optimizing rabies control, we conducted a study exploring the relationship between dogs, rabies, and the Balinese community. The objectives of this study were to: i) understand the human-dog relationship in Bali; ii) explore local knowledge, attitudes, and practices (KAPs) relating to rabies; and iii) assess potential community-driven activities to optimize rabies control and surveillance. Conducted between February and June 2011, the study combined a questionnaire (n = 300; CI = 95 %; error margin = 5 %) and focus group discussions (FGDs) in 10 villages in the Denpasar, Gianyar, and Karangasem regencies. The questionnaire included a Likert scale to assess community knowledge and attitudes. For the knowledge assessment, three points were given for a correct answer, while wrong answers and uncertain answers were given zero points. For the attitudes assessment, three points were given for a positive answer, two points for a neutral answer, and one point for a negative answer. Respondent knowledge was categorized as good (score >40), fair (score 20-40), or poor (score <20), based on a maximum total score 60. Respondent attitudes were categorized as positive (score >26), neutral (score 13-26), or negative (score <13), based on a maximum total score of 39. Mixed-gender FGDs in each sub-village (banjar) were conducted, each involving 7-15 participants to complement the questionnaire results. On a follow-up research trip in mid-2013, the data analysis was triangulated and validated using semi-structured interviews. Questionnaire data were analyzed descriptively using SPSS 17.0, while qualitative data from interviews and FGDs were analyzed manually according to accepted methods of coding and memo writing. The chi-square test was then used to analyze the statistical relationships between knowledge and attitudes of the respondents. Out of the total 300 respondents, most were predominantly male (82 %), Hindu (99 %), married (96 %), older than 30 years of age (9 %), and owned dogs (72 %). Dog ownership was motivated by culture, personal taste, and function, with dogs was being used as guards (85 %) and companion animals (27 %), and was sometimes related to religious or traditional obligations (2 %). Relating to their culture and local beliefs, and eventually becoming their way of life, 79 % of respondents kept free-roaming dogs. With the rabies outbreak in Bali and Western breeds becoming more popular, more responsible dog ownership (leashing, confining, regular feeding) became more acceptable and changed community perceptions on keeping dogs, even though the sustainability of this practice cannot be gauged. In addition, the economic situation posed major problems in rural areas. The level of community knowledge about rabies and its associated control programs were generally fair and community attitudes were positive. However, community KAPs still need to be improved. A total of 74 % respondents reported to have vaccinated their dogs in 2011, but only few were found to report rabid animals to livestock officers (12 %) and a significant number believed that washing a bite wound was not important (62 %). Moreover, free-roaming dog practices and discarding of unwanted female puppies still continue and possibly create difficulties for rabies elimination as these practices potentially increase the stray dog population. We identified three major sociocultural aspects with potential for community-driven interventions to optimize current rabies elimination efforts: integrating local notions of ahimsa (non-violence) into education campaigns, engaging communities through the local banjar sociopolitical system, and working with traditional legal structures to increase local compliance with rabies control. The human-dog relationship in Bali is multifaceted. Due to the uniqueness of the culture and the local beliefs, and encouraged by a socioeconomic aspect, a number of local practices were found to be constituting risk factors for continued rabies spread. Community knowledge and attitudes, which can consequently result in behavioral changes, needs to be improved across different genders, ages, educational backgrounds, and roles in the community, regardless of the individual village's experiences with rabies. Furthermore, community-driven activities based on sociocultural conditioning and community capacity at the banjar and village levels, such as public awareness activities, vaccination, dog registration, dog population management, and rapid response to dog bites, were identified as being able to complement the rabies control program in Bali. The program also needs recognition or acknowledgement from governments, especially local government as well as regular mentoring to improve and sustain community participation.


Attentional modulation of word recognition by children in a dual-task paradigm.
This study investigated an account of limited short-term memory capacity for children's speech perception in noise using a dual-task paradigm. Sixty-four normal-hearing children (7-14 years of age) participated in this study. Dual tasks were repeating monosyllabic words presented in noise at 8 dB signal-to-noise ratio and rehearsing sets of 3 or 5 digits for subsequent serial recall. Half of the children were told to allocate their primary attention to word repetition and the other half to remembering digits. Dual-task performance was compared to single-task performance. Limitations in short-term memory demands required for the primary task were measured by dual-task decrements in nonprimary tasks. Results revealed that (a) regardless of task priority, no dual-task decrements were found for word recognition, but significant dual-task decrements were found for digit recall; (b) most children did not show the ability to allocate attention preferentially to primary tasks; and (c) younger children (7- to 10-year-olds) demonstrated improved word recognition in the dual-task conditions relative to their single-task performance. Seven- to 8-year-old children showed the greatest improvement in word recognition at the expense of the greatest decrement in digit recall during dual tasks. Several possibilities for improved word recognition in the dual-task conditions are discussed.


Prediction of the equilibrium structures and photomagnetic properties of the Prussian blue analogue RbMn[Fe(CN)6] by density functional theory.
A periodic density functional theory method using the B3LYP hybrid exchange-correlation potential is applied to the Prussian blue analogue RbMn[Fe(CN)6] to evaluate the suitability of the method for studying, and predicting, the photomagnetic behavior of Prussian blue analogues and related materials. The method allows correct description of the equilibrium structures of the different electronic configurations with regard to the cell parameters and bond distances. In agreement with the experimental data, the calculations have shown that the low-temperature phase (LT; Fe(2+)(t(6)2g, S = 0)-CN-Mn(3+)(t(3)2g e(1)g, S = 2)) is the stable phase at low temperature instead of the high-temperature phase (HT; Fe(3+)(t(5)2g, S = 1/2)-CN-Mn(2+)(t(3)2g e(2)g, S = 5/2)). Additionally, the method gives an estimation for the enthalpy difference (HT <--> LT) with a value of 143 J mol(-1) K(-1). The comparison of our calculations with experimental data from the literature and from our calorimetric and X-ray photoelectron spectroscopy measurements on the Rb0.97Mn[Fe(CN)6]0.98 x 1.03 H2O compound is analyzed, and in general, a satisfactory agreement is obtained. The method also predicts the metastable nature of the electronic configuration of the high-temperature phase, a necessary condition to photoinduce that phase at low temperatures. It gives a photoactivation energy of 2.36 eV, which is in agreement with photoinduced demagnetization produced by a green laser.


IQM: an extensible and portable open source application for image and signal analysis in Java.
Image and signal analysis applications are substantial in scientific research. Both open source and commercial packages provide a wide range of functions for image and signal analysis, which are sometimes supported very well by the communities in the corresponding fields. Commercial software packages have the major drawback of being expensive and having undisclosed source code, which hampers extending the functionality if there is no plugin interface or similar option available. However, both variants cannot cover all possible use cases and sometimes custom developments are unavoidable, requiring open source applications. In this paper we describe IQM, a completely free, portable and open source (GNU GPLv3) image and signal analysis application written in pure Java. IQM does not depend on any natively installed libraries and is therefore runnable out-of-the-box. Currently, a continuously growing repertoire of 50 image and 16 signal analysis algorithms is provided. The modular functional architecture based on the three-tier model is described along the most important functionality. Extensibility is achieved using operator plugins, and the development of more complex workflows is provided by a Groovy script interface to the JVM. We demonstrate IQM's image and signal processing capabilities in a proof-of-principle analysis and provide example implementations to illustrate the plugin framework and the scripting interface. IQM integrates with the popular ImageJ image processing software and is aiming at complementing functionality rather than competing with existing open source software. Machine learning can be integrated into more complex algorithms via the WEKA software package as well, enabling the development of transparent and robust methods for image and signal analysis.


A prospective 4-year naturalistic follow-up of treatment and outcome of 300 bipolar I and II patients.
Because randomized clinical trials in bipolar disorder include restricted study populations, the possibilities for generalizing to real-world bipolar patients are limited. Naturalistic long-term data can add valuable information about the diversity of treatment and outcome in bipolar disorder. After discharge from a psychiatric community hospital, 300 consecutively admitted patients with ICD-10 bipolar I (n = 158) and II (n = 142) disorder were followed up naturalistically for 4 years. Patients were assessed with regard to time to relapse, relapse polarity in relation to index episode, prophylactic effects of prescribed medication, prescribing behaviors, and medication adherence. Drugs were chosen by the treating psychiatrists on the basis of clinical judgment. Prescribed medications included lithium, carbamazepine, valproate, lamotrigine, antidepressants, and atypical antipsychotics, all of which were compared as a single mood stabilizer or in combination with at least 2 prophylactic agents. The study was conducted from 2000 through 2008. 204 of 300 patients (68%) relapsed within 4 years, with a mean of 208 days (SD = 356.2) until the next affective episode. Relapses correlated in a statistically significant manner with the index episode (χ²₄ = 57.48, P = .000; bipolar I: χ²₄ = 20.19, P = .000; bipolar II: χ²₄ = 106.82, P = .000). A Kaplan survival analysis showed that lithium in monotherapy statistically significantly delayed time to the next affective relapse (P = .002). Survival (time to relapse) was also statistically significantly reduced when prophylactic medication was changed by the psychiatrist (P = .000) or stopped by the patient (P = .001). In general, no differences in tested parameters were seen between the bipolar I and II groups. Our data confirm a high risk of relapse in a naturalistic setting. Lithium seems to offer some advantage over other medication over the long-term treatment of bipolar I and II disorder. Patients tend to relapse with the same polarity as their index episode; this emphasizes the importance of the polarity concept. Changing of medications by the psychiatrist and stopping of medication by the patient appear to be risk factors for an earlier affective relapse. ClinicalTrials.gov identifier: NCT01792128.


Linear differentiation of cytotoxic effectors into memory T lymphocytes.
A central question in immunology is the origin of long-lived T cell memory that confers protection against recurrent infection. The differentiation of naïve T cell receptor transgenic CD8+ cells into effector cytotoxic T lymphocytes (CTLs) and memory CD8+ cells was studied. Memory CD8+ cells that were generated after strong antigenic stimulation were the progeny of cytotoxic effectors and retained antigen-specific cytolytic activity 10 weeks after adoptive transfer to antigen-free recipient mice. Thus, potential vaccines based on CTL memory will require the differentiation of naïve cells into post-effector memory T cells.


The use of in vitro technics to study drug-induced pancytopenia.
The confirmation of drug-induced marrow aplasia is difficult since rechallenging the patient can lead to serious morbidity. We used marrow-culture technics to challenge in vitro the bone marrow of a patient with marrow aplasia after ingestion of quinidine. There was no clinical or laboratory evidence of quinidine-mediated destruction of erythrocytes, leukocytes or platelets. By contrast, use of quinidine in combination with the patient's serum substantially inhibited in vitro growth of allogeneic marrow granulocytic and erythroid series. Furthermore, use of quinidine in combination with acute-phase serum (but not acute-phase serum alone or quinidine in combination with recovery-phase serum) inhibited growth of the patient's marrow. This observation suggests that both a transient serum factor and quinidine were responsible for the marrow aplasia. These technics could be applied with minimal risk to similar patients and would permit in vitro rechallenge with the suspected drug.