Determining the Genetic Architecture of Reproductive Stage Drought Tolerance in Wheat Using a Correlated Trait and Correlated Marker Effect Model.
Water stress during reproductive growth is a major yield constraint for wheat (Triticum aestivum L). We previously established a controlled environment drought tolerance phenotyping method targeting the young microspore stage of pollen development. This method eliminates stress avoidance based on flowering time. We substituted soil drought treatments by a reproducible osmotic stress treatment using hydroponics and NaCl as osmolyte. Salt exclusion in hexaploid wheat avoids salt toxicity, causing osmotic stress. A Cranbrook x Halberd doubled haploid (DH) population was phenotyped by scoring spike grain numbers of unstressed (SGNCon) and osmotically stressed (SGNTrt) plants. Grain number data were analyzed using a linear mixed model (LMM) that included genetic correlations between the SGNCon and SGNTrt traits. Viewing this as a genetic regression of SGNTrt on SGNCon allowed derivation of a stress tolerance trait (SGNTol). Importantly, and by definition of the trait, the genetic effects for SGNTol are statistically independent of those for SGNCon. Thus they represent non-pleiotropic effects associated with the stress treatment that are independent of the control treatment. QTL mapping was conducted using a whole genome approach in which the LMM included all traits and all markers simultaneously. The marker effects within chromosomes were assumed to follow a spatial correlation model. This resulted in smooth marker profiles that could be used to identify positions of putative QTL. The most influential QTL were located on chromosome 5A for SGNTol (126cM; contributed by Halberd), 5A for SGNCon (141cM; Cranbrook) and 2A for SGNTrt (116cM; Cranbrook). Sensitive and tolerant population tail lines all showed matching soil drought tolerance phenotypes, confirming that osmotic stress is a valid surrogate screening method.


CDH6 and HAGH protein levels in plasma associate with Alzheimer's disease in APOE ε4 carriers.
Many Alzheimer's disease (AD) genes including Apolipoprotein E (APOE) are found to be expressed in blood-derived macrophages and thus may alter blood protein levels. We measured 91 neuro-proteins in plasma from 316 participants of the Rotterdam Study (incident AD = 161) using Proximity Extension Ligation assay. We studied the association of plasma proteins with AD in the overall sample and stratified by APOE. Findings from the Rotterdam study were replicated in 186 AD patients of the BioFINDER study. We further evaluated the correlation of these protein biomarkers with total tau (t-tau), phosphorylated tau (p-tau) and amyloid-beta (Aβ) 42 levels in cerebrospinal fluid (CSF) in the Amsterdam Dementia Cohort (N = 441). Finally, we conducted a genome-wide association study (GWAS) to identify the genetic variants determining the blood levels of AD-associated proteins. Plasma levels of the proteins, CDH6 (β = 0.638, P = 3.33 × 10-4) and HAGH (β = 0.481, P = 7.20 × 10-4), were significantly elevated in APOE ε4 carrier AD patients. The findings in the Rotterdam Study were replicated in the BioFINDER study for both CDH6 (β = 1.365, P = 3.97 × 10-3) and HAGH proteins (β = 0.506, P = 9.31 × 10-7) when comparing cases and controls in APOE ε4 carriers. In the CSF, CDH6 levels were positively correlated with t-tau and p-tau in the total sample as well as in APOE ε4 stratum (P < 1 × 10-3). The HAGH protein was not detected in CSF. GWAS of plasma CDH6 protein levels showed significant association with a cis-regulatory locus (rs111283466, P = 1.92 × 10-9). CDH6 protein is implicated in cell adhesion and synaptogenesis while HAGH protein is related to the oxidative stress pathway. Our findings suggest that these pathways may be altered during presymptomatic AD and that CDH6 and HAGH may be new blood-based biomarkers.


Synchronous x-ray and radio mode switches: a rapid global transformation of the pulsar magnetosphere.
Pulsars emit from low-frequency radio waves up to high-energy gamma-rays, generated anywhere from the stellar surface out to the edge of the magnetosphere. Detecting correlated mode changes across the electromagnetic spectrum is therefore key to understanding the physical relationship among the emission sites. Through simultaneous observations, we detected synchronous switching in the radio and x-ray emission properties of PSR B0943+10. When the pulsar is in a sustained radio-"bright" mode, the x-rays show only an unpulsed, nonthermal component. Conversely, when the pulsar is in a radio-"quiet" mode, the x-ray luminosity more than doubles and a 100% pulsed thermal component is observed along with the nonthermal component. This indicates rapid, global changes to the conditions in the magnetosphere, which challenge all proposed pulsar emission theories.


Tissue-specific mutation accumulation in human adult stem cells during life.
The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small intestine, colon and liver of human donors with ages ranging from 3 to 87 years by sequencing clonal organoid cultures derived from primary multipotent cells. Our results show that mutations accumulate steadily over time in all of the assessed tissue types, at a rate of approximately 40 novel mutations per year, despite the large variation in cancer incidence among these tissues. Liver ASCs, however, have different mutation spectra compared to those of the colon and small intestine. Mutational signature analysis reveals that this difference can be attributed to spontaneous deamination of methylated cytosine residues in the colon and small intestine, probably reflecting their high ASC division rate. In liver, a signature with an as-yet-unknown underlying mechanism is predominant. Mutation spectra of driver genes in cancer show high similarity to the tissue-specific ASC mutation spectra, suggesting that intrinsic mutational processes in ASCs can initiate tumorigenesis. Notably, the inter-individual variation in mutation rate and spectra are low, suggesting tissue-specific activity of common mutational processes throughout life.


A comparison of small monetary incentives to convert survey non-respondents: a randomized control trial.
Maximizing response rates is critically important in order to provide the most generalizable and unbiased research results. High response rates reduce the chance of respondents being systematically different from non-respondents, and thus, reduce the risk of results not truly reflecting the study population. Monetary incentives are often used to improve response rates, but little is known about whether larger incentives improve response rates in those who previously have been unenthusiastic about participating in research. In this study we compared the response rates and cost-effectiveness of a $5 versus $2 monetary incentive accompanying a short survey mailed to patients who did not respond or refused to participate in research study with a face-to-face survey. 1,328 non-responders were randomly assigned to receive $5 or $2 and a short, 10-question survey by mail. Reminder postcards were sent to everyone; those not returning the survey were sent a second survey without incentive. Overall response rates, response rates by incentive condition, and odds of responding to the larger incentive were calculated. Total costs (materials, postage, and labor) and incremental cost-effectiveness ratios were also calculated and compared by incentive condition. After the first mailing, the response rate within the $5 group was significantly higher (57.8% vs. 47.7%, p<.001); after the second mailing, the difference narrowed by 80%, resulting in a non-significant difference in cumulative rates between the $5 and $2 groups (67.3% vs. 65.4%, respectively, p=.47). Regardless of incentive or number of contacts, respondents were significantly more likely to be male, white, married, and 50-75 years old. Total costs were higher with the larger versus smaller incentive ($13.77 versus $9.95 per completed survey). A $5 incentive provides a significantly higher response rate than a $2 incentive if only one survey mailing is used but not if two survey mailings are used.


Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.
To examine the effects of intranasal insulin administration on cognition, function, cerebral glucose metabolism, and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease (AD). Randomized, double-blind, placebo-controlled trial. Clinical research unit of a Veterans Affairs medical center. The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment (n = 64) or mild to moderate AD (n = 40). Intervention Participants received placebo (n = 30), 20 IU of insulin (n = 36), or 40 IU of insulin (n = 38) for 4 months, administered with a nasal drug delivery device (Kurve Technology, Bothell, Washington). Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score, and secondary measures included the Alzheimer Disease's Assessment Scale-cognitive subscale (ADAS-cog) score and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale. A subset of participants underwent lumbar puncture (n = 23) and positron emission tomography with fludeoxyglucose F 18 (n = 40) before and after treatment. Outcome measures were analyzed using repeated-measures analysis of covariance. Treatment with 20 IU of insulin improved delayed memory (P < .05), and both doses of insulin (20 and 40 IU) preserved caregiver-rated functional ability (P < .01). Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD (P < .05). Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group, but, in exploratory analyses, changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid. Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal, frontal, precuneus, and cuneus regions and insulin-minimized progression. No treatment-related severe adverse events occurred. These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD. Trial Registration clinicaltrials.gov Identifier: NCT00438568.


A miniature microcontroller curve tracing circuit for space flight testing transistors.
This paper describes a novel miniature microcontroller based curve tracing circuit, which was designed to monitor the environmental effects on Silicon Carbide Junction Field Effect Transistor (SiC JFET) device performance, while exposed to the low earth orbit environment onboard the International Space Station (ISS) as a resident experiment on the 7th Materials on the International Space Station Experiment (MISSE7). Specifically, the microcontroller circuit was designed to operate autonomously and was flown on the external structure of the ISS for over a year. This curve tracing circuit is capable of measuring current vs. voltage (I-V) characteristics of transistors and diodes. The circuit is current limited for low current devices and is specifically designed to test high temperature, high drain-to-source resistance SiC JFETs. The results of each I-V data set are transmitted serially to an external telemetered communication interface. This paper discusses the circuit architecture, its design, and presents example results.


Entropy and order in urban street networks.
Many complex networks erase parts of their geometry as they develop, so that their evolution is difficult to quantify and trace. Here we introduce entropy measures for quantifying the complexity of street orientations and length variations within planar networks and apply them to the street networks of 41 British cities, whose geometric evolution over centuries can be explored. The results show that the street networks of the old central parts of the cities have lower orientation/length entropies - the streets are more tightly ordered and form denser networks - than the outer and more recent parts. Entropy and street length increase, because of spreading, with distance from the network centre. Tracing the 400-year evolution of one network indicates growth through densification (streets are added within the existing network) and expansion (streets are added at the margin of the network) and a gradual increase in entropy over time.


Nonphotosynthetic pigments as potential biosignatures.
Previous work on possible surface reflectance biosignatures for Earth-like planets has typically focused on analogues to spectral features produced by photosynthetic organisms on Earth, such as the vegetation red edge. Although oxygenic photosynthesis, facilitated by pigments evolved to capture photons, is the dominant metabolism on our planet, pigmentation has evolved for multiple purposes to adapt organisms to their environment. We present an interdisciplinary study of the diversity and detectability of nonphotosynthetic pigments as biosignatures, which includes a description of environments that host nonphotosynthetic biologically pigmented surfaces, and a lab-based experimental analysis of the spectral and broadband color diversity of pigmented organisms on Earth. We test the utility of broadband color to distinguish between Earth-like planets with significant coverage of nonphotosynthetic pigments and those with photosynthetic or nonbiological surfaces, using both 1-D and 3-D spectral models. We demonstrate that, given sufficient surface coverage, nonphotosynthetic pigments could significantly impact the disk-averaged spectrum of a planet. However, we find that due to the possible diversity of organisms and environments, and the confounding effects of the atmosphere and clouds, determination of substantial coverage by biologically produced pigments would be difficult with broadband colors alone and would likely require spectrally resolved data.


Relationship Between Cognitive Functions and Insulin-degrading Enzyme in Individuals With Prediabetes.
Individuals with diabetes can develop cognitive impairment due to dysfunction of glucose metabolism; however, it remains unclear whether cognition becomes altered in the prediabetic stage. Substantial evidence links cognitive impairment in diabetes to aberrant serum insulin-degrading enzyme (s[IDE]) levels. This relationship remains to be investigated in individuals with prediabetes. To investigate the relationship between cognitive function and s[IDE] levels in individuals with prediabetes. The study group consisted of 47 individuals who had been diagnosed with prediabetes and 41 healthy controls. Cognitive functions were evaluated using the Montreal Cognitive Assessment (MoCA), and s[IDE] levels were measured using enzyme-linked immunosorbent assay. The MoCA total scores and s[IDE] levels of the individuals with prediabetes were significantly lower (P = 0.001, 0.006) than those of the controls, and the MoCA Attention measure of the individuals with prediabetes was also very low (P = 0.001). To determine cognitive impairment, we divided the prediabetics into two subgroups according to the MoCA cutoff value. Scores on all of the MoCA tests were significantly lower in the group with mild cognitive impairment (P < 0.05). There was no correlation between MoCA scores and s[IDE] levels (P > 0.05), but serum-fasting glucose levels showed a negative correlation with MoCA scores (P < 0.05, ρ = -0.287). Evidence of mild cognitive impairment was high in the individuals with prediabetes and showed a negative correlation with serum-fasting glucose levels but not with s[IDE] levels.


Evaluating how lethal management affects poaching of Mexican wolves.
Despite illegal killing (poaching) being the major cause of death among large carnivores globally, little is known about the effect of implementing lethal management policies on poaching. Two opposing hypotheses have been proposed in the literature: implementing lethal management may decrease poaching incidence (killing for tolerance) or increase it (facilitated illegal killing). Here, we report a test of the two opposed hypotheses that poaching (reported and unreported) of Mexican grey wolves (Canis lupus baileyi) in Arizona and New Mexico, USA, responded to changes in policy that reduced protections to allow more wolf-killing. We employ advanced biostatistical survival and competing risk methods to data on individual resightings, mortality and disappearances of collared Mexican wolves, supplemented with Bayes factors to assess the strength of evidence. We find inconclusive evidence for any decreases in reported poaching. We also find strong evidence that Mexican wolves were 121% more likely to disappear during periods of reduced protections than during periods of stricter protections, with only slight changes in legal removals by the agency. Therefore, we find strong support for the 'facilitated illegal killing' hypothesis and none for the 'killing for tolerance' hypothesis. We provide recommendations for improving the effectiveness of US policy on environmental crimes, endangered species and protections for wild animals. Our results have implications beyond the USA or wolves because the results suggest transformations of decades-old management interventions against human-caused mortality among wild animals subject to high rates of poaching.


DNA-binding domain of RCC1 protein is not essential for coupling mitosis with DNA replication.
The RCC1 protein that is required for coupling mitosis with the S phase has a DNA-binding domain in the N-terminal region outside the repeat. We found that RCC1 protein without any DNA-binding activity complemented the tsBN2 mutation with the same efficiency as that of intact RCC1 protein. In ts+ transformants of tsBN2 cells transfected with the RCC1 cDNA lacking the DNA-binding domain, an endogenous RCC1 disappeared at 39.5 degrees C, and the deleted RCC1 protein encoded by the transfected cDNA was found in the cytoplasm, but a significant amount of it was also found in the nuclei. This deleted RCC1 protein was eluted from the nuclei with the same concentration of NaCl and DNase I as was used for the intact RCC1 protein in BHK21 cells. Furthermore, the deleted RCC1 protein co-migrated with the nucleosome fraction on sucrose density gradient analysis. These results indicate that the RCC1 protein binds chromatin with the aid of other unknown protein(s). Thus, the DNA-binding domain of RCC1 protein is not essential for coupling between the S and M phases, but was shown instead to function as a nuclear translocation signal.


Mockingbird Morphing Music: Structured Transitions in a Complex Bird Song.
The song of the northern mockingbird, Mimus polyglottos, is notable for its extensive length and inclusion of numerous imitations of several common North American bird species. Because of its complexity, it is not widely studied by birdsong scientists. When they do study it, the specific imitations are often noted, and the total number of varying phrases. What is rarely noted is the systematic way the bird changes from one syllable to the next, often with a subtle transition where one sound is gradually transformed into a related sound, revealing an audible and specific compositional mode. It resembles a common strategy in human composing, which can be described as variation of a theme. In this paper, we present our initial attempts to describe the specific compositional rules behind the mockingbird song, focusing on the way the bird transitions from one syllable type to the next. We find that more often than chance, syllables before and after the transition are spectrally related, i.e., transitions are gradual, which we describe as morphing. In our paper, we categorize four common modes of morphing: timbre change, pitch change, squeeze (shortening in time), and stretch (lengthening in time). This is the first time such transition rules in any complex birdsong have been specifically articulated.


A cue-free method to probe human lighting biases.
People readily perceive patterns of shading as 3-D shapes. Owing to the generalised bas-relief ambiguity when extracting shape from shading, people must simultaneously estimate the shape of the surface and the nature of the light source. In many cases cues in the image will be insufficient to resolve all of the ambiguities present, and in such cases the human visual system may employ one of a number of prior assumptions based on ecology and experience. One such assumption is the lighting-from-above prior. Here, in the absence of extrinsic cues to lighting direction, ambiguous shading patterns are interpreted as if lit by a light source that is above the observer's head. Studies of this prior typically use ambiguous stimuli and observe perceptual biases. A degree of cueing is inherent to such methods. Participants see the shaded stimuli repeatedly and are asked to make shape judgments about them regardless of whether or not they actually perceive any 3-D shape. We wanted to access people's lighting prior more directly by establishing the template they would employ to detect a shaded object in the absence of any visual cue to object shape. To this end, we adopted a classification image approach.


A hierarchical latent stochastic differential equation model for affective dynamics.
In this article a continuous-time stochastic model (the Ornstein-Uhlenbeck process) is presented to model the perpetually altering states of the core affect, which is a 2-dimensional concept underlying all our affective experiences. The process model that we propose can account for the temporal changes in core affect on the latent level. The key parameters of the model are the average position (also called home base), the variances and covariances of the process, and the regulatory mechanisms that keep the process in the vicinity of the average position. To account for individual differences, the model is extended hierarchically. A particularly novel contribution is that in principle all parameters of the stochastic process (not only the mean but also its variance and the regulatory parameters) are allowed to differ between individuals. In this way, the aim is to understand the affective dynamics of single individuals and at the same time investigate how these individuals differ from one another. The final model is a continuous-time state-space model for repeated measurement data taken at possibly irregular time points. Both time-invariant and time-varying covariates can be included to investigate sources of individual differences. As an illustration, the model is applied to a diary study measuring core affect repeatedly for several individuals (thereby generating intensive longitudinal data).


DRUG ANTAGONISM BETWEEN LINCOMYCIN AND ERYTHROMYCIN.
An antagonistic action can be demonstrated between lincomycin, a new antibiotic, and erythromycin, when the two drugs are allowed to diffuse into the same area of an agar plate seeded with a strain of Staphylococcus which is resistant to erythromycin but sensitive to lincomycin. The increase in the minimum inhibitory concentrations of lincomycin in the presence of erythromycin may be significant in clinical application. The antagonism does not depend on a reaction between the two antibiotics, but appears to be the result of an altered metabolism stimulated by erythromycin on erythromycin-resistant staphylococci.


The effect of moisture on the flowability of pharmaceutical excipients.
The effect of moisture content on flowability of six pharmaceutical powders (microcrystalline cellulose (MCC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), polyvinylpyrrolidone (PVP), corn starch, and potato starch) was investigated. Powder flowability was measured using established static techniques and emerging dynamic avalanche behavior measurements. Static techniques did not provide enough resolution to clearly identify changes in flowability due to increasing powder moisture content. Avalanche time and its standard deviation showed that flowability of MCC, CMC, PVP, and potato starch decreased after a critical moisture content, flowability of corn starch increased and flowability did not significantly change for HPMC. The moisture decreased flowability by forming stronger interparticle liquid bridges and increased flowability by acting as a lubricant. The dynamic density of the celluloses and PVP decreased linearly with increasing moisture content as the particles swelled with water. The starches also swelled and decreased in dynamic density, but only after a moisture content corresponding to monolayer coverage of water around the particles was reached. As flowability and dynamic density change with moisture content, to ensure consistent production of high-quality tablets, the moisture content of the powders must be measured and controlled.


The cancer of bureaucracy: how it will destroy science, medicine, education; and eventually everything else.
Everyone living in modernizing 'Western' societies will have noticed the long-term, progressive growth and spread of bureaucracy infiltrating all forms of social organization: nobody loves it, many loathe it, yet it keeps expanding. Such unrelenting growth implies that bureaucracy is parasitic and its growth uncontrollable - in other words it is a cancer that eludes the host immune system. Old-fashioned functional, 'rational' bureaucracy that incorporated individual decision-making is now all-but extinct, rendered obsolete by computerization. But modern bureaucracy evolved from it, the key 'parasitic' mutation being the introduction of committees for major decision-making or decision-ratification. Committees are a fundamentally irrational, incoherent, unpredictable decision-making procedure; which has the twin advantages that it cannot be formalized and replaced by computerization, and that it generates random variation or 'noise' which provides the basis for natural selection processes. Modern bureaucracies have simultaneously grown and spread in a positive feedback cycle; such that interlinking bureaucracies now constitute the major environmental feature of human society which affects organizational survival and reproduction. Individual bureaucracies must become useless parasites which ignore the 'real-world' in order to adapt to rapidly-changing 'bureaucratic reality'. Within science, the major manifestation of bureaucracy is peer review, which - cancer-like - has expanded to obliterate individual authority and autonomy. There has been local elaboration of peer review and metastatic spread of peer review to include all major functions such as admissions, appointments, promotions, grant review, project management, research evaluation, journal and book refereeing and the award of prizes. Peer review eludes the immune system of science since it has now been accepted by other bureaucracies as intrinsically valid, such that any residual individual decision-making (no matter how effective in real-world terms) is regarded as intrinsically unreliable (self-interested and corrupt). Thus the endemic failures of peer review merely trigger demands for ever-more elaborate and widespread peer review. Just as peer review is killing science with its inefficiency and ineffectiveness, so parasitic bureaucracy is an un-containable phenomenon; dangerous to the extent that it cannot be allowed to exist unmolested, but must be utterly extirpated. Or else modernizing societies will themselves be destroyed by sclerosis, resource misallocation, incorrigibly-wrong decisions and the distortions of 'bureaucratic reality'. However, unfortunately, social collapse is the more probable outcome, since parasites can evolve more rapidly than host immune systems.


Single blastomere expression profiling of Xenopus laevis embryos of 8 to 32-cells reveals developmental asymmetry.
We have measured the expression of 41 maternal mRNAs in individual blastomeres collected from the 8 to 32-cell Xenopus laevis embryos to determine when and how asymmetry in the body plan is introduced. We demonstrate that the asymmetry along the animal-vegetal axis in the oocyte is transferred to the daughter cells during early cell divisions. All studied mRNAs are distributed evenly among the set of animal as well as vegetal blastomeres. We find no asymmetry in mRNA levels that might be ascribed to the dorso-ventral specification or the left-right axis formation. We hypothesize that while the animal-vegetal asymmetry is a consequence of mRNA gradients, the dorso-ventral and left-right axes specifications are induced by asymmetric distribution of other biomolecules, probably proteins.


Role of αA-crystallin-derived αA66-80 peptide in guinea pig lens crystallin aggregation and insolubilization.
Earlier we reported that low molecular weight (LMW) peptides accumulate in aging human lens tissue and that among the LMW peptides, the chaperone inhibitor peptide αA66-80, derived from α-crystallin protein, is one of the predominant peptides. We showed that in vitro αA66-80 induces protein aggregation. The current study was undertaken to determine whether LMW peptides are also present in guinea pig lens tissue subjected to hyperbaric oxygen (HBO) in vivo. The nuclear opacity induced by HBO in guinea pig lens is the closest animal model for studying age-related cataract formation in humans. A LMW peptide profile by mass spectrometry showed the presence of an increased amount of LMW peptides in HBO-treated guinea pig lenses compared to age-matched controls. Interestingly, the mass spectrometric data also showed that the chaperone inhibitor peptide αA66-80 accumulates in HBO-treated guinea pig lens. Following incubation of synthetic chaperone inhibitor peptide αA66-80 with α-crystallin from guinea pig lens extracts, we observed a decreased ability of α-crystallin to inhibit the amorphous aggregation of the target protein alcohol dehydrogenase and the formation of large light scattering aggregates, similar to those we have observed with human α-crystallin and αA66-80 peptide. Further, time-lapse recordings showed that a preformed complex of α-crystallin and αA66-80 attracted additional crystallin molecules to form even larger aggregates. These results demonstrate that LMW peptide-mediated cataract development in aged human lens and in HBO-induced lens opacity in the guinea pig may have common molecular pathways.


The treatment of impending and existing pathological femoral fractures using the long gamma nail.
The subtrochanteric region of the femur accounts for one-third of all pathological fractures requiring surgical intervention. The large forces occurring in this region and the possible non-occurrence of bony consolidation constitute a difficult problem to the trauma surgeon. The medical records and X-rays of 25 consecutive patients treated with the long gamma nail (LGN) for pathological (impending or existing) fractures of the femur were analysed retrospectively. Our results in the use of the LGN for pathological fractures of the femur have been good. We recommend an aggressive approach to the early stabilisation of impending fractures and the use of distal locking.


Antibiotic resistance correlates with transmission in plasmid evolution.
Conjugative (horizontally transmissible) plasmids are autonomous replicators, whose "self-interests" do not necessarily overlap with those of their hosts. This situation causes plasmids and bacteria to sometimes experience differing selection pressures. Escherichia coli plasmid pB15 contains genes for resistance to several antibiotics, including tetracycline. When plasmid-bearing cells were experimentally evolved in the laboratory, changes in resistance level in the unselected tetracycline marker coincided with changes in plasmid rates of vertical versus horizontal transmission. Here, we used minimum inhibitory assays that measure resistance levels as quantitative traits to determine phenotypic correlations among plasmid characters and to estimate divergence among plasmid lineages. Results suggested that plasmid-level evolution led to formation of two phenotypically dissimilar groups: virulent (highly infectious) and avirulent (weakly infectious) plasmids. In contrast, measures of carbon-source utilization, and fitness assays relative to a common competitor revealed that bacterial hosts generally converged in phenotypic performance, despite divergence among their associated plasmids. Preliminary sequence analyses suggested that divergence in plasmid conjugation was due to altered configurations of a shufflon region (a site-specific recombination system), where genetic rearrangements affect conjugative ability. Furthermore, we proposed that correlated resistance and transmission in pB15 derivatives were caused by a tetracycline-resistance transposon inserted into a transfer operon, allowing transcription from its promoter to simultaneously affect both plasmid resistance and transmission.


Evaluation of an intervention promoting emotion regulation skills for adults with persisting distress due to adverse childhood experiences.
This phase II trial evaluated psychosocial and health outcomes of an intervention designed to improve emotion regulation skills in adults suffering from Adverse Childhood Experiences (ACEs). The study utilized a pretest-posttest design in which 92 adults enrolled in the community-based program completed pretest measures, attended either a faith-based or secular version of the 12-week ACE Overcomers program, and then completed posttest measures. The theory-guided program involved group sessions providing education and skills training to improve emotion regulation, self-awareness, resilience, and social functioning. Pretest and posttest surveys included measures of emotional regulation (suppression, rumination, cognitive reappraisal, and mindfulness), resilience (ego resilience and general self-efficacy), emotional experiences (perceived stress, moods, and depressive symptoms), quality of life (the SF-36 domains), and physical symptoms and illness (symptom load and sick days). Analyses revealed significant improvements from pretest to posttest in all facets of emotion regulation (p < .01), psychological resilience (p < .001), mental well-being (p < .001) and physical symptoms and illness (p < .001), and in specific facets of quality of life (p < .001). The faith-based and secular versions of the program yielded comparable improvements in well-being. Improvements were comparable for older versus younger participants, except that younger participants reported greater improvements in perceived stress (p < .05). These preliminary findings support the application of an emotion regulation perspective to interventions for adults with high ACEs. The study, with its single-group design, represents a promising step in the translational research pathway and provides support for further studies utilizing comparison groups.


Joint mobility and motor development.
The association of joint hypermobility and motor development was sequentially investigated in 715 infants from the ages of 8 to 14 months. Seven joints were evaluated for mobility, and each infant underwent a physical and neurological examination. Parents were given a Denver Developmental Parents' Questionnaire. All subjects with a general developmental delay, systemic illness or syndrome were excluded. The infants were classified as having normal or delayed motor development with normal or delayed joint mobility. They were re-examined six months later. Multivariate statistical techniques was used for categorical analysis, and three joints were found to be significantly associated with motor delay at the first examination--hip abduction, elbow hyperextension, and foot dorsiflexion. Of the 715 infants, 126 had joint hypermobility and of these 38 (30.2%) had motor delay. Sixty four of 589 (10.9%) with normal joints had delayed motor development. Six months later 23 out of 35 of the group with joint hypermobility and 42 out of 53 of the group with normal joints had normal motor function. Joint hypermobility is associated with an increased incidence of motor delay in infancy. Over the ensuing six months most of the subjects will catch up. These findings, indicating a favourable prognosis, have implications regarding clinical assessment and parental counselling.


Hodgkin lymphoma risk following infectious and chronic inflammatory diseases: a large population-based case-control study from Sweden.
Patients with Hodgkin lymphoma (HL) have a well-characterized immune deficiency of T cell function, originally identified by increased susceptibility to certain infections. Epidemiological evidence has long pointed to infectious etiologies in younger HL patients. With the aim of expanding our knowledge on the potential role of pre-existing immune deficiency in HL and an infectious/inflammatory etiology, we conducted a comprehensive population-based case-control study in HL patients diagnosed in Sweden in the period 1965-2004, and their matched controls. In a large population-based study including 7,414 HL patients and 29,240 matched controls, we evaluated the subsequent risk of HL in relation to a broad range of infectious and inflammatory conditions, using unconditional logistic regression. A previous history of any reported infection was associated with an 11 % increased risk of HL (P < 0.05). More specifically, we found sinusitis (odds ratio = 1.81; 95 % confidence interval = 1.06-3.07), tuberculosis (1.76; 1.01-3.07), encephalitis (7.88; 1.97-31.5), and herpes zoster (2.20; 1.11-4.35) to be associated with excess HL risk. A personal prior history of chronic inflammatory condition was not associated with an increased risk of HL (0.94; 0.71-1.14). Our results suggest that underlying immune deficiency is a primary phenomenon in HL. Alternatively, certain infectious agents may be potential HL triggers.


Biogeochemical control of the coupled CO2-O 2 system of the Baltic Sea: a review of the results of Baltic-C.
Past, present, and possible future changes in the Baltic Sea acid-base and oxygen balances were studied using different numerical experiments and a catchment-sea model system in several scenarios including business as usual, medium scenario, and the Baltic Sea Action Plan. New CO2 partial pressure data provided guidance for improving the marine biogeochemical model. Continuous CO2 and nutrient measurements with high temporal resolution helped disentangle the biogeochemical processes. These data and modeling indicate that traditional understandings of the nutrient availability-organic matter production relationship do not necessarily apply to the Baltic Sea. Modeling indicates that increased nutrient loads will not inhibit future Baltic Sea acidification; instead, increased mineralization and biological production will amplify the seasonal surface pH cycle. The direction and magnitude of future pH changes are mainly controlled by atmospheric CO2 concentration. Apart from decreasing pH, we project a decreasing calcium carbonate saturation state and increasing hypoxic area.


Field sports and conservation in the United Kingdom.
Many natural habitats exist on privately owned land outside protected areas, but few governments can afford to enforce or subsidize conservation of this biodiversity. Even in some developed countries, conservation subsidy schemes have only achieved limited success. Fortunately, some landowners may be willing to accept management costs in return for other benefits, although this remains controversial when it involves the killing of charismatic species. For example, participants in British field sports, such as fox hunting and game-bird shooting, may voluntarily conserve important habitats that are required by quarry species. Here we report results from a multidisciplinary study that addressed this issue by focusing on three sites across central England. We found that landowners participating in field sports maintained the most established woodland and planted more new woodland and hedgerows than those who did not, despite the equal availability of subsidies. Therefore, voluntary habitat management appears to be important for biodiversity conservation in Britain. Current debates on the future of field sports in Britain, and similar activities globally, may benefit from considering their utility as incentives to conserve additional habitat on private land.


Development and evaluation of a theory-based physical activity guidebook for breast cancer survivors.
This study's objective was to develop and evaluate the suitability and appropriateness of a theory-based physical activity (PA) guidebook for breast cancer survivors. Guidebook content was constructed based on the theory of planned behavior (TPB) using salient exercise beliefs identified by breast cancer survivors in previous research. Expert judges completed the Maine Area Health Education Center's 18-item attribute checklist for evaluating written health information. Judges indicated that the PA guidebook achieved desirable attributes for the suitability and appropriateness of the guidebook. A subset of TPB expert judges completed items designed to determine the degree of match between the guidebook content and the respective TPB components. Mean item-content relevance ratings indicated at least a "very good match" between the PA guidebook content and the keyed TPB domains. Theoretically based PA information may be an effective strategy for increasing PA in breast cancer survivors at the population level.


Cost-effectiveness analysis of a low-fat diet in the prevention of breast and ovarian cancer.
Results of the Women's Health Initiative Randomized Controlled Dietary Modification Trial (WHI-DM) suggest that a low-fat diet may be associated with beneficial health outcomes for specific groups of women. The objective is to assess how cost-effective the WHI-DM would be if implemented as a public health intervention and under the sponsorship of private health insurers and Medicare. Breast and ovarian cancers are the health outcomes of interest. Two groups of WHI-DM participants form the target population for this analysis: participants consuming >36.8% of energy from fat at baseline, and participants at high risk for breast cancer with 32% or more of energy from fat at baseline. This study uses Markov cohort modeling, following societal and health care payer perspectives, with Monte Carlo simulations and one-way sensitivity analyses. WHI-DM records, nationally representative prices, and published estimates of medical care costs were the sources of cost information. Simulations were performed for hypothetical cohorts of women aged 50, 55, 60, 65, or 70 years at the beginning of the intervention. Effectiveness was estimated by quality-adjusted life years (QALYs) and the main outcome measure was the incremental cost-effectiveness ratio (ICER). Following the societal perspective, the ICERs for the 50-year old cohort are $13,773/QALY (95% confidence interval $7,482 to $20,916) for women consuming >36.8% of energy from fat at baseline and $10,544/QALY ($2,096 to $23,673) for women at high risk for breast cancer. The comparable ICER from a private health care payer perspective is $66,059/QALY ($30,155 to $121,087) and from a Medicare perspective, it is $15,051/QALY ($6,565 to $25,105). The WHI-DM is a cost-effective strategy for the prevention of breast and ovarian cancers in the target population, from both societal and Medicare perspectives. Private health care payers have a relative short timeframe to realize a return on investment, since after age 65 years the financial benefits associated with the prevention program would accrue to Medicare. For this reason, the intervention is not cost-effective from a private health care payer perspective.


Validating the Quality of Life After Brain Injury Through Rasch Analysis.
The Quality of Life after Brain Injury (QOLIBRI), a cross-cultural instrument, has been validated in several languages; however, traditional psychometric approaches have critical limitations. Therefore, we applied the Rasch model for validating the 37-item QOLIBRI scale among a Chinese population with traumatic brain injury. In total, 587 participants (mean age: 44.2 ± 15.4 years; women, 46.3%) were surveyed in neurosurgery departments at 6 hospitals in Taipei, Taiwan. The QOLIBRI. Of the 6 subscales of the QOLIBRI, 4 (cognition, self, daily life and autonomy, and social relationships) were unidimensional, valid, and reliable, whereas the remaining 2 (emotions and physical problems) exhibited poor unidimensionality, item and person reliability, and person-item targeting. Five items (energy, concentrating, getting out and about, sex life, and achievements) showed considerable differential item functioning among age groups, disability levels, and time since traumatic brain injury. According to item response theory, we identified psychometric issues in the emotions and physical problems subscales of the QOLIBRI as well as several differential item functioning items. Future research is required to determine whether similar results are observed in other language versions of the QOLIBRI or in other countries.


Beta-blocking agents during electroconvulsive therapy: a review.
Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent cardiovascular complications and may shorten seizure duration. This review evaluates studies that used beta-blocking agents during ECT to determine which agent has the most favourable outcomes on cardiovascular variables and seizure duration. A Medline database search was made using the combined keywords 'adrenergic beta-antagonists' and 'electroconvulsive therapy'. The search was restricted to double-blind randomized controlled trials and yielded 29 original studies. With the use of esmolol, significant attenuating effects were found on cardiovascular parameters in the first 5 min after stimulation; its shortening effects on seizure duration may be dose-related. With the use of labetalol, findings on cardiovascular effects were inconsistent during the first minutes after stimulation but were significant after 5 min and thereafter; seizure duration was scarcely studied. Landiolol attenuates heart rate but with inconsistent findings regarding arterial pressure (AP); seizure duration was mostly unaffected. Esmolol appears to be effective in reducing the cardiovascular response, although seizure duration may be affected with higher dosages. Landiolol can be considered a suitable alternative, but effects on AP need further investigation. Labetalol has been studied to a lesser extent and may have prolonged cardiovascular effects. The included studies varied in design, methodology, and the amount of exact data provided in the publications. Further study of beta-blocking agents in ECT is clearly necessary.


Novel patch-based systems for the localised delivery of ALA-esters.
In photodynamic therapy (PDT) a combination of visible light and a sensitising drug causes the destruction of selected cells. Aminolaevulinic acid (ALA) has been widely used in topical PDT for over 15 years. However, ALA does not possess favourable physicochemical properties for skin penetration. Consequently, the clearance rates for difficult to treat lesions, such as nodular basal cell carcinomas are relatively low. For the first time, equimolar concentrations of ALA, methyl-ALA (m-ALA) and hexyl-ALA (h-ALA) have been incorporated into a bioadhesive patch-based system. In vitro penetration studies into excised porcine skin revealed that ALA patches containing relatively high loadings (226.7 micromol cm(-2)) were associated with significantly greater tissue concentrations (70.7 micromol cm(-3)) than patches containing m-ALA (16.3 micromol cm(-3)) or h-ALA (17.4 micromol cm(-3)). ALA was also found to be the most efficient inducer of protoporphyrin (PpIX) fluorescence in mice, in vivo (maximum mean fluorescence: ALA=236.2 a.u., m-ALA=175.1 a.u., h-ALA=193.5 a.u.). However, when the lipophilic hexylester was formulated in a pressure sensitive adhesive (PSA) patch, significantly higher PpIX levels were achieved compared to all bioadhesive systems tested. Of major importance, PSA patches containing relatively low h-ALA loadings induced high PpIX levels, which were localised to the application area. This study has highlighted the importance of rational selection of both the active agent and the delivery system. Bioadhesive preparations containing ALA are ideal for delivery to moist environments; whereas h-ALA-loaded PSA systems may facilitate enhanced delivery to dry areas of skin. In addition, owing to the relatively low loadings of h-ALA required in PSA patches, the costs of clinical PDT may potentially be reduced.


Clinical interventions, implementation interventions, and the potential greyness in between -a discussion paper.
There is increasing awareness that regardless of the proven value of clinical interventions, the use of effective strategies to implement such interventions into clinical practice is necessary to ensure that patients receive the benefits. However, there is often confusion between what is the clinical intervention and what is the implementation intervention. This may be caused by a lack of conceptual clarity between 'intervention' and 'implementation', yet at other times by ambiguity in application. We suggest that both the scientific and the clinical communities would benefit from greater clarity; therefore, in this paper, we address the concepts of intervention and implementation, primarily as in clinical interventions and implementation interventions, and explore the grey area in between. To begin, we consider the similarities, differences and potential greyness between clinical interventions and implementation interventions through an overview of concepts. This is illustrated with reference to two examples of clinical interventions and implementation intervention studies, including the potential ambiguity in between. We then discuss strategies to explore the hybridity of clinical-implementation intervention studies, including the role of theories, frameworks, models, and reporting guidelines that can be applied to help clarify the clinical and implementation intervention, respectively. Semantics provide opportunities for improved precision in depicting what is 'intervention' and what is 'implementation' in health care research. Further, attention to study design, the use of theory, and adoption of reporting guidelines can assist in distinguishing between the clinical intervention and the implementation intervention. However, certain aspects may remain unclear in analyses of hybrid studies of clinical and implementation interventions. Recognizing this potential greyness can inform further discourse.


Demand in pediatric dentistry for sedation and general anesthesia by dentist anesthesiologists: a survey of directors of dentist anesthesiologist and pediatric dentistry residencies.
This study describes what training programs in pediatric dentistry and dental anesthesiology are doing to meet future needs for deep sedation/general anesthesia services required for pediatric dentistry. Residency directors from 10 dental anesthesiology training programs in North America and 79 directors from pediatric dentistry training programs in North America were asked to answer an 18-item and 22-item online survey, respectively, through an online survey tool. The response rate for the 10 anesthesiology training program directors was 9 of 10 or 90%. The response rate for the 79 pediatric dentistry training program directors was 46 of 79 or 58%. Thirty-seven percent of pediatric dentistry programs use clinic-based deep sedation/general anesthesia for dental treatment in addition to hospital-based deep sedation/general anesthesia. Eighty-eight percent of those programs use dentist anesthesiologists for administration of deep sedation/general anesthesia in a clinic-based setting. Pediatric dentistry residency directors perceive a future change in the need for deep sedation/general anesthesia services provided by dentist anesthesiologists to pediatric dentists: 64% anticipate an increase in need for dentist anesthesiologist services, while 36% anticipate no change. Dental anesthesiology directors compared to 2, 5, and 10 years ago have seen an increase in the requests for dentist anesthesiologist services by pediatric dentists reported by 56% of respondents (past 2 years), 63% of respondents (past 5 years), and 88% of respondents (past 10 years), respectively. Predicting the future need of dentist anesthesiologists is an uncertain task, but these results show pediatric dentistry directors and dental anesthesiology directors are considering the need, and they recognize a trend of increased need for dentist anesthesiologist services over the past decade.


Ca2+-dependent myosin II activation is required for uropod retraction during neutrophil migration.
Buffering of intracellular Ca2+ transients in human neutrophils leads to reduced motility due to defective uropod detachment on fibronectin and vitronectin-coated surfaces. Since one potential target of a rise in [Ca2+]i is the activation of myosin II, we characterized the role of myosin II during motility. Treatment of neutrophils with a myosin inhibitor (2,3-butanedione monoxime), or myosin light chain kinase inhibitors (ML-7, ML-9, or KT5926) resulted in impaired uropod retraction and a dose-dependent decrease in chemokinesis following stimulation with N-formyl-Met-Leu-Phe (fMLP). Treatment with ML-9 resulted in a redistribution of F-actin and talin to the non-retracted uropods, mimicking the redistribution observed during [Ca2+]i buffering. Impairment of uropod retraction and redistribution of F-actin and talin by myosin II inhibition was only observed on adhesive substrates such as fibronectin and not on poorly adhesive substrates such as human serum-coated glass. At higher concentrations of ML-9, cell polarization was inhibited and pseudopod extension occurred radially. Using an antibody specific for serine 19-phosphorylated regulatory light chain of myosin II, regions of activated myosin II were found at the leading edge as well as the uropod in motile fMLP-stimulated cells. [Ca2+]i depletion caused a 50% decrease in the level of serine 19-phosphorylated myosin II suggesting that activation of myosin II by intracellular Ca2+ transients may be an essential step in establishing a polarized pseudopod and providing the force required for uropod retraction during PMN motility on adhesive surfaces.


Review article: the therapeutic potential of 5-HT3 receptor antagonists in the treatment of irritable bowel syndrome.
There is evidence from studies, in both animals and humans, that 5-HT3 receptor blockade has potential value in the treatment of irritable bowel syndrome, particularly in those patients with diarrhoea-predominant bowel habits. New findings suggest that 5-HT3 receptors exist on gut afferent neurones and that their activation by locally released 5-HT leads to visceral nociceptive stimulation, in addition to increased neuronally-mediated motor and secretory activity. If this concept is validated, it will provide a rationale for the use of 5-HT3 receptor antagonists in patients with increased gut motility, reduced fluid absorption and low nociceptive thresholds leading to abdominal pain. Alosetron is a highly selective, potent 5-HT3 receptor antagonist which is well absorbed with a long pharmacodynamic half-life. Its ability to provide long-lasting blockade of 5-HT3 receptors throughout the body make it an ideal candidate within its class to evaluate the clinical hypothesis that sustained and ubiquitous 5-HT3 receptor blockade is of value in the treatment of IBS.


Decontaminating N95 and SN95 masks with ultraviolet germicidal irradiation does not impair mask efficacy and safety.
Inadequate supply of filtering facepiece respirators (FFRs) for healthcare workers during a pandemic such as the novel coronavirus outbreak (SARS-CoV-2) is a serious public health issue. The aim of this study was to synthesize existing data on the effectiveness of ultraviolet germicidal irradiation (UVGI) for N95 FFR decontamination. A systematic review (PROSPERO CRD42020176156) was conducted on UVGI in N95 FFRs using Embase, Medline, Global Health, Google Scholar, WHO feed, and MedRxiv. Two reviewers independently determined eligibility and extracted predefined variables. Original research reporting on function, decontamination, or mask fit following UVGI were included. Thirteen studies were identified, comprising 54 UVGI intervention arms and 58 N95 models. FFRs consistently maintained certification standards following UVGI. Aerosol penetration averaged 1.19% (0.70-2.48%) and 1.14% (0.57-2.63%) for control and UVGI arms, respectively. Airflow resistance for the control arms averaged 9.79 mm H2O (7.97-11.70 mm H2O) vs 9.85 mm H2O (8.33-11.44 mm H2O) for UVGI arms. UVGI protocols employing a cumulative dose >20,000 J/m2 resulted in a 2-log reduction in viral load. A >3-log reduction was observed in seven UVGI arms using >40,000 J/m2. Impact of UVGI on fit was evaluated in two studies (16,200; 32,400 J/m2) and no evidence of compromise was found. Our findings suggest that further work in this area (or translation to a clinical setting) should use a cumulative UV-C dose of 40,000 J/m2 or greater, and confirm appropriate mask fit following decontamination.


Spatial working memory in children with high-functioning autism: intact configural processing but impaired capacity.
Visual attention and visual working memory exert severe capacity limitations on cognitive processing. Impairments in both functions may exacerbate the social and communication deficits seen in children with an autism spectrum disorder (ASD). This study characterizes spatial working memory and visual attention in school-age children with high-functioning autism. Children with ASD, and age, gender, and IQ-matched typically developing (TD) children performed 2 tasks: a spatial working memory task and an attentive tracking task. Compared with TD children, children with ASD showed a more pronounced deficit in the spatial working memory task than the attentive tracking task, even though the latter placed significant demands on sustained attention, location updating, and distractor inhibition. Because both groups of children were sensitive to configuration mismatches between the sample and test arrays, the spatial working memory deficit was not because of atypical organization of spatial working memory. These findings show that attention and working memory are dissociable, and that children with ASD show a specific deficit in buffering visual information across temporal discontinuity.


Measuring situation awareness in emergency settings: a systematic review of tools and outcomes.
Nontechnical skills have an impact on health care outcomes and improve patient safety. Situation awareness is core with the view that an understanding of the environment will influence decision-making and performance. This paper reviews and describes indirect and direct measures of situation awareness applicable for emergency settings. Electronic databases and search engines were searched from 1980 to 2010, including CINAHL, Ovid Medline, Pro-Quest, Cochrane, and the search engine, Google Scholar. Access strategies included keyword, author, and journal searches. Publications identified were assessed for relevance, and analyzed and synthesized using Oxford evidence levels and the Critical Appraisal Skills Programme guidelines in order to assess their quality and rigor. One hundred and thirteen papers were initially identified, and reduced to 55 following title and abstract review. The final selection included 14 papers drawn from the fields of emergency medicine, intensive care, anesthetics, and surgery. Ten of these discussed four general nontechnical skill measures (including situation awareness) and four incorporated the Situation Awareness Global Assessment Technique. A range of direct and indirect techniques for measuring situation awareness is available. In the medical literature, indirect approaches are the most common, with situation awareness measured as part of a nontechnical skills assessment. In simulation-based studies, situation awareness in emergencies tends to be suboptimal, indicating the need for improved training techniques to enhance awareness and improve decision-making.


Developmental pharmacology of benzodiazepines under normal and pathological conditions.
Benzodiazepines are allosteric agonists of GABAA receptors (GABAAR), pentameric ligand-gated Cl(-) channels, which serve both an important neurodevelopmental role but are also the principal inhibitory system in the brain. However, their subunit composition, channel properties, and function, as well as their region-specific expression patterns, change through development. These processes have been extensively studied in rodents and to some extent confirmed in higher species. Specifically, GABAARs acquire faster kinetics with age and their pharmacology changes rendering them more sensitive to drugs that have higher affinity for α1 subunit-containing GABAARs, such as benzodiazepines, but also, their inhibitory function becomes more potent as they shift from having depolarising to hyperpolarising responses due to a shift in Cl(-) gradient and cation chloride cotransporter expression. Concerns have been raised about possible pro-apoptotic and paradoxical effects of benzodiazepines in the neonatal normal rat brain, although it is unclear, as yet, whether this extends to brains exposed to seizures. Growing evidence indicates that the pharmacology and physiology of GABAARs may be altered in the brain of rats or humans with seizures or epilepsy, or different aetiologies that predispose to epilepsy. These changes follow different paths, depending on sex, age, region, cell type, aetiology, or time-point specific factors. Identification of dynamic biomarkers that could enable these changes in vivo to be monitored would greatly facilitate the selection of more effective agonists with fewer side effects.


Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach.
Histone deacetylases (HDAC) contain eighteen isoforms that can be divided into four classes. Of these isoform enzymes, class IIa (containing HDAC4, 5, 7 and 9) target unique substrates, some of which are client proteins associated with epigenetic control. Class IIa HDACs are reportedly associated with some neuronal disorders, making HDACs therapeutic targets for treating neurodegenerative diseases. Additionally, some reported HDAC inhibitors contain hydroxamate moiety that chelates with zinc ion to become the cofactor of HDAC enzymes. However, the hydroxamate functional group is shown to cause undesirable effects and has poor pharmacokinetic profile. This study used in silico virtual screening methodology to identify several nonhydroxamate compounds, obtained from National Cancer Institute database, which potentially inhibited HDAC4. Comparisons of the enzyme inhibitory activity against a panel of HDAC isoforms revealed these compounds had strong inhibitory activity against class IIa HDACs, but weak inhibitory activity against class I HDACs. Further analysis revealed that a single residue affects the cavity size between class I and class IIa HDACs, thus contributing to the selectivity of HDAC inhibitors discovered in this study. The discovery of these inhibitors presents the possibility of developing new therapeutic treatments that can circumvent the problems seen in traditional hydroxamate-based drugs.


Helminths of the sand lizard, Lacerta agilis (Reptilia, Lacertidae), in the Palaearctic: faunal diversity and spatial patterns of variation in the composition and structure of component communities.
We studied variation in the structure of component communities of helminths in sand lizards, Lacerta agilis, from 30 localities in the Ukraine and Bulgaria. Thirty-five separate samples of lizards, with a total of 661 completely censused infracommunities, yielded 30 helminth species (4 cestodes, 10 trematodes, 3 acanthocephalans and 13 nematodes). In its range within the Ukraine, L. agilis serves as the final host for 13 species of which only 3 (S. lacertae, S. hoffmanni and P. molini) can be considered as lizard specialists. A characteristic feature of these helminth component communities was the large proportion of heteroxeneous helminth species for which L. agilis serves as paratenic host. Sand lizards in the meadow steppeland zone were primarily parasitized by larval helminths that represented a major proportion of the total number of all worms recovered while those sampled in the grassland/forest transition zone were characterized by substantially higher proportions of adult helminths using lizards as final hosts. However, L. agilis was parasitized by a much higher proportion of lizard specialists in the 'typical' habitats of the meadow steppeland zone as opposed to those located in 'marginal' habitats in the grassland/forest transition zone, where helminths were shared to a greater extent with amphibian hosts.


The association between night shift work and nutrition patterns among nurses: a literature review.
The shift work system may affect the temporal distribution of eating and diet quality. The paper aimed at reviewing a body of research examining the associations between night shift work and dietary habits among nurses. Data from the PubMed and Google Schoolar databases, as well as references lists in selected papers were searched. The authors used the following keywords: nurses, shift work, diet, nutrition. Papers published in English or Polish were selected for the review, and as many as 19 papers published in 2000-2017 were eventually identified. The studies varied greatly with respect to the study size, subjects' age and the duration of night shift work. The major problem was the heterogeneity of the tools used for dietary assessment. Self-administered questionnaires were used and analyses were rarely adjusted for confounders. Alcohol consumption was the most frequently analyzed aspect (N = 8 studies), followed by the total energy (N = 7), protein, fat (N = 6), and carbohydrate intake, coffee and fruit consumption (N = 5). The results showed quite a consistent association of night work with higher coffee (caffeine) consumption, as well as lower alcohol, and fruit and vegetables consumption. Few studies also reported more frequent snacks consumption, later time of the last meal, eating at night, meals irregularity, and a poorer diet quality among night shift nurses when compared to the reference. The review showed some poor nutritional habits among nurses working night shifts. However, the topic warrants further attention, owing to the relatively small number of the studies performed so far, and their numerous methodological limitations. Med Pr. 2019;70(3):363-76.


Microstructure and ferroelectricity of BaTiO3 thin films on Si for integrated photonics.
Significant progress has been made in integrating novel materials into silicon photonic structures in order to extend the functionality of photonic circuits. One of these promising optical materials is BaTiO3 or barium titanate (BTO) that exhibits a very large Pockels coefficient as required for high-speed light modulators. However, all previous demonstrations show a noticable reduction of the Pockels effect in BTO thin films deposited on silicon substrates compared to BTO bulk crystals. Here, we report on the strong dependence of the Pockels effect in BTO thin films on their microstructure, and provide guidelines on how to engineer thin films with strong electro-optic response. We employ several deposition methods such as molecular beam epitaxy and chemical vapor deposition to realize BTO thin films with different morphology and crystalline structure. While a linear electro-optic response is present even in porous, polycrystalline BTO thin films with an effective Pockels coefficient r eff = 6 pm V-1, it is maximized for dense, tetragonal, epitaxial BTO films (r eff = 140 pm V-1). By identifying the key structural predictors of electro-optic response in BTO/Si, we provide a roadmap to fully exploit the linear electro-optic effect in novel hybrid oxide/semiconductor nanophotonic devices.


Spatial Patterns and Spread of Potato Zebra Chip Disease in the Texas Panhandle.
Zebra chip (ZC) is a disease that is affecting potato production in the southwestern United States and in other countries, and which has been linked to potato psyllids (Bactericera cockerelli) that harbor the bacterial plant pathogen 'Candidatus Liberibacter solanacearum'. Until recently, the epidemiology of ZC was unknown, motivating research to elucidate the spatial and temporal patterns of ZC infections in potato fields. Studies were performed in multiple commercial potato fields located in the Texas Panhandle, wherein locations of ZC-affected potato plants were georeferenced or counted within large plots and along belt transects consisting of contiguous 10-by-10-m quadrats. By employing distance- and area-based spatial statistical methods, it was determined that locations of ZC infections in potato fields departed from a completely spatially random pattern, instead appearing as clusters comprising infected plants situated in close proximity to one another, with clusters interspersed with numerous solitary infections. Disease progress curves of ZC clusters were generally well described by exponential growth and quadratic polynomial models. Numbers of ZC infections within disease clusters gradually increased over multiple weeks, with foliar disease symptoms first appearing during the tuber bulking stage. ZC infections were not found to be continuously present across fields, because many quadrats along belt transects contained zero or only a few infections while others had numerous infections. Consequently, the frequency of ZC infections within belt transect quadrats was well described by negative binomial and zero-inflated negative binomial distributions, in agreement with observed clustering of infections and distance-based spatial statistical results.


The relationship between suicide risk and sexual orientation: results of a population-based study.
This study examined the relationship between sexual orientation and suicide risk in a population-based sample of adolescents. Participants were selected from a cross-sectional, statewide survey of junior and senior public high school students. All males (n = 212) and females (n = 182) who described themselves as bisexual/homosexual were compared with 336 gender-matched heterosexual respondents on three outcome measures: suicidal ideation, intent, and self-reported attempts. Logistic regression analyses were used to examine the association between sexual orientation and outcome measures with adjustment for demographic characteristics. Suicide attempts were reported by 28. 1 % of bisexual/homosexual males, 20.5% of bisexual/homosexual females, 14.5% of heterosexual females, and 4.2% of heterosexual males. For males, but not females, bisexual/homosexual orientation was associated with suicidal intent (odds ratio [OR] = 3.61 95% confidence interval [CI = 1.40, 9.36) and attempts (OR=7.10; 95% CI=3.05, 16.53). There is evidence of a strong association between suicide risk and bisexuality or homosexuality in males.


Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.
A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.


Assessment of the potential role of muscle spindle mechanoreceptor afferents in chronic muscle pain in the rat masseter muscle.
The phenotype of large diameter sensory afferent neurons changes in several models of neuropathic pain. We asked if similar changes also occur in "functional" pain syndromes. Acidic saline (AS, pH 4.0) injections into the masseter muscle were used to induce persistent myalgia. Controls received saline at pH 7.2. Nocifensive responses of Experimental rats to applications of Von Frey Filaments to the masseters were above control levels 1-38 days post-injection. This effect was bilateral. Expression of c-Fos in the Trigeminal Mesencephalic Nucleus (NVmes), which contains the somata of masseter muscle spindle afferents (MSA), was above baseline levels 1 and 4 days after AS. The resting membrane potentials of neurons exposed to AS (n = 167) were hyperpolarized when compared to their control counterparts (n = 141), as were their thresholds for firing, high frequency membrane oscillations (HFMO), bursting, inward and outward rectification. The amplitude of HFMO was increased and spontaneous ectopic firing occurred in 10% of acid-exposed neurons, but never in Controls. These changes appeared within the same time frame as the observed nocifensive behaviour. Ectopic action potentials can travel centrally, but also antidromically to the peripheral terminals of MSA where they could cause neurotransmitter release and activation of adjacent fibre terminals. Using immunohistochemistry, we confirmed that annulospiral endings of masseter MSA express the glutamate vesicular transporter VGLUT1, indicating that they can release glutamate. Many capsules also contained fine fibers that were labelled by markers associated with nociceptors (calcitonin gene-related peptide, Substance P, P2X3 receptors and TRPV1 receptors) and that expressed the metabotropic glutamate receptor, mGluR5. Antagonists of glutamatergic receptors given together with the 2(nd) injection of AS prevented the hypersensitivity observed bilaterally but were ineffective if given contralaterally. Low pH leads to changes in several electrical properties of MSA, including initiation of ectopic action potentials which could propagate centrally but could also invade the peripheral endings causing glutamate release and activation of nearby nociceptors within the spindle capsule. This peripheral drive could contribute both to the transition to, and maintenance of, persistent muscle pain as seen in some "functional" pain syndromes.


Hydrogenation of α-Pinene over Platinum Nanoparticles Reduced and Stabilized by Sodium Lignosulfonate.
A one-pot clean preparation procedure and catalytic performance of platinum nanoparticles (NPs) reduced and stabilized by sodium lignosulfonate in aqueous solution are reported. No other chemical reagents are needed during the metal reduction and stabilization step, thanks to the active participation of sodium lignosulfonate (SLS). UV-vis, Fourier transform infrared (FT-IR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), 1H NMR, 195Pt NMR, and two-dimensional heteronuclear single-quantum coherence (2D HSQC) NMR studies were thoroughly performed to analyze the formation, particle size, and main lattice planes of NPs, the valence-state changes of the metal, and structural changes of SLS. An ecofriendly selective synthesis of cis-pinane from an abundant renewable natural resource, α-pinene, was developed in the presence of the prepared Pt NP aqueous system. Furthermore, this catalyst system was proved to show easy recovery and stable reusability by five-run tests. The synergistic effect of SLS reduction and stabilization not only avoided the introduction of conventional reducing agents and stabilizers but also made full use of the byproducts of the pulp and paper industry. This proved to be an environmentally friendly method for converting the natural resource α-pinene to cis-pinane.


Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.
The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL). This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells). Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients. Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.


Aberrant mRNA processing of the maize Rp1-D rust resistance gene in wheat and barley.
The maize Rp1-D gene confers race-specific resistance against Puccinia sorghi (common leaf rust) isolates containing a corresponding avrRp1-D avirulence gene. An Rp1-D genomic clone and a similar Rp1-D transgene regulated by the maize ubiquitin promoter were transformed independently into susceptible maize lines and shown to confer Rp1-D resistance, demonstrating that this resistance can be transferred as a single gene. Transfer of these functional transgenes into wheat and barley did not result in novel resistances when these plants were challenged with isolates of wheat stem rust (P. graminis), wheat leaf rust (P. triticina), or barley leaf rust (P. hordei). Regardless of the promoter employed, low levels of gene expression were observed. When constitutive promoters were used for transgene expression, a majority of Rp1-D transcripts were truncated in the nucleotide binding site-encoding region by premature polyadenylation. This aberrant mRNA processing was unrelated to gene function because an inactive version of the gene also generated such transcripts. These data demonstrate that resistance gene transfer between species may not be limited only by divergence of signaling effector molecules and pathogen avirulence ligands, but potentially also by more fundamental gene expression and transcript processing limitations.


Towards research-tested smartphone applications for preventing breast cancer.
Efforts to prevent breast cancer and other chronic illnesses have focused on promoting physical activity, healthy diet and nutrition, and avoidance of excessive alcohol consumption. Smartphone applications (apps) offer a low-cost, effective strategy for breast cancer prevention in women through behavioral change. However, there are currently no research-tested smartphone apps for breast cancer prevention that are suitable for women with varying levels of health literacy and eHealth literacy. In this perspective, we consider modifiable risk factors for breast cancer in women in relation to the development of smartphone apps to promote healthy behaviors associated with breast cancer-risk reduction. First, we provide a summary of breast cancer risk factors that are modifiable through behavioral change including their corresponding relative risk. Second, we discuss scientific issues related to the development of smartphone apps for the primary prevention of breast cancer and offer suggestions for further research. Smartphone apps for preventing breast cancer should be tailored for women at different life stages (e.g., young women, women who are post-menopausal, and older women). Topics such as breastfeeding and oral contraceptives are appropriate for younger women. Weight management, physical activity, avoiding cigarette smoking, and dispelling breast cancer myths are appropriate for women of all ages. As women age, topics such as hormone replacement therapy or comorbid health conditions become more important to address. Apps for breast cancer prevention should be grounded in a behavioral theory or framework and should be suitable for people with varying levels of health literacy. Future developments in smartphone apps for breast cancer prevention should include apps that are tailored for specific cultural, racial, and ethnic groups.


Complementary needs behind complementary therapies in cancer patients.
Although many studies indicate that the use of complementary and alternative medicine by cancer patients is common and widespread, few studies have focused on unmet needs of patients using complementary therapies (CTs). The aim of the present study was to evaluate, through a quantitative approach, possible associations between the use of CTs and the presence of specific unmet needs in cancer patients. In six Italian oncology departments, 783 patients were interviewed about CTs use and completed the Needs Evaluation Questionnaire. Patients included in the study had different primary tumor sites and were in different phases of the disease and care process. At the time of the survey, 38.3% of patients were using one or more types of CTs. According to Needs Evaluation Questionnaire, the use of CTs was associated (p < .05) with the need to be more involved in therapeutic choices (40% vs. 31.7%), the need to have a better dialogue with clinicians (44.4% vs. 37.2%), and the need to have more economic-insurance information in relation to their illness (46.1% vs. 36.4%). Statistical significance was confirmed with multivariable analysis for the last two items, whereas three more needs were associated with the use of CTs after adjustment: to receive more explanation on treatments (46.8% vs. 41.0%), to receive more comprehensible information (38% vs. 31.9%), and to receive more attention from nurses (16% vs. 12.1%). Our study shows interesting differences regarding perceived needs between cancer patients who use and who do not use CTs. Unmet needs that are more expressed in CTs users should be known and, when possible, could be taken into account to improve both psychosocial interventions in the context of conventional care process and the quality of the relationship between patient and medical and nursing staff.


Antibiotics in third molar surgery.
The aim of this survey was to assess the knowledge and practice of Swiss dentists focusing on the use of antibiotics in prophylactic surgical removal of lower wisdom teeth. A postal survey was conducted among all 3288 dentists who are members of the Swiss Dental Society (SSO) representing nearly all dentists in Switzerland. The questionnaire consisted of 13 questions with mostly multiple-choice answers. Demographic profile, surgical experience, the use of antibiotics, and wound management, i.e. wound closure and the use of mouth rinse were assessed. A response rate of 55% was obtained. Most Swiss dentists perform surgical extractions in their practices. Of all dentists, 18.6% used antibiotics routinely, but a large variation was found comparing the three linguistic regions of Switzerland with the highest prescription rate of 48% in the French-speaking south-west of Switzerland. Fifty-two percent of dentists prescribed amoxicillin in a dose of 750 mg. Most often three daily doses were prescribed (47%). A postoperative regime was prescribed by 54.4% of dentists. French language (p=0.003), graduation from the university of Geneva (p=0.007), foreign diplomas (p<0.001), and dentists with diplomas awarded from 2001-2006 (p=0.004) showed a highly significant correlation with the use of antibiotics. In Switzerland, prophylactic antibiotics are used in third molar surgery. Antibiotic prescription however largely depends on geographical situation and dentist profiles. The assessment of antibiotic use in private practices is important in the light of growing evidence that antibiotic overuse may lead to development of multiresistant bacterial strains. In a second part results regarding wound management and mouth rinse will be presented.


Addressing stroke signs and symptoms through public education: the Stroke Heroes Act FAST campaign.
In 2003, only 18% of Massachusetts adults were aware of all signs and symptoms of stroke, but 80% would call 9-1-1 if they thought someone was having a stroke or heart attack. Because early recognition leads to early treatment and improved clinical outcomes, increasing symptom recognition could have an impact on stroke survival and stroke patients' quality of life. We conducted secondary research to identify messages with evidence-based effectiveness for communicating stroke signs and symptoms. From these results, a Stroke Heroes Act FAST animation was created and concept-tested. Non-Hispanic white and non-Hispanic black women aged 40 to 64 years received education on stroke signs and symptoms. Knowledge change about stroke signs and symptoms was calculated immediately following and 3 months after the education session. Using Stroke Heroes Act FAST educational materials that were developed, 72 women (mean age, 54 years; 15.5% were non-Hispanic blacks) received education about signs and symptoms of stroke and took the pretests and posttests to assess knowledge change. Immediately after the education session, significant increases were seen in the percentage of participants who recognized that facial droop (92% vs 99%, P = .02) and arm weakness or numbness (86% vs 97%, P = .004) were symptoms of stroke. Of the 65 participants who were given the 3-month follow-up survey, 100% remembered slurred speech and facial drooping as symptoms; 98.5% recalled arm weakness or numbness; and 97% would call 9-1-1 if they thought someone was having a stroke. None of these is a significant change from the posttest. The Stroke Heroes Act FAST kit may be a useful tool for improving knowledge of stroke signs and symptoms among adults.


Historical reconstruction of polychlorinated biphenyl (PCB) exposures for workers in a capacitor manufacturing plant.
We developed a semiquantitative job exposure matrix (JEM) for workers exposed to polychlorinated biphenyls (PCBs) at a capacitor manufacturing plant from 1946 to 1977. In a recently updated mortality study, mortality of prostate and stomach cancer increased with increasing levels of cumulative exposure estimated with this JEM (trend p values = 0.003 and 0.04, respectively). Capacitor manufacturing began with winding bales of foil and paper film, which were placed in a metal capacitor box (pre-assembly), and placed in a vacuum chamber for flood-filling (impregnation) with dielectric fluid (PCBs). Capacitors dripping with PCB residues were then transported to sealing stations where ports were soldered shut before degreasing, leak testing, and painting. Using a systematic approach, all 509 unique jobs identified in the work histories were rated by predetermined process- and plant-specific exposure determinants; then categorized based on the jobs' similarities (combination of exposure determinants) into 35 job exposure categories. The job exposure categories were ranked followed by a qualitative PCB exposure rating (baseline, low, medium, and high) for inhalation and dermal intensity. Category differences in other chemical exposures (solvents, etc.) prevented further combining of categories. The mean of all available PCB concentrations (1975 and 1977) for jobs within each intensity rating was regarded as a representative value for that intensity level. Inhalation (in microgram per cubic milligram) and dermal (unitless) exposures were regarded as equally important. Intensity was frequency adjusted for jobs with continuous or intermittent PCB exposures. Era-modifying factors were applied to the earlier time periods (1946-1974) because exposures were considered to have been greater than in later eras (1975-1977). Such interpolations, extrapolations, and modifying factors may introduce non-differential misclassification; however, we do believe our rigorous method minimized misclassification, as shown by the significant exposure-response trends in the epidemiologic analysis.


Perceptions of Indonesian general practitioners in maintaining standards of medical practice at a time of health reform.
There is little research on how GPs experience the demands of maintaining standards of medical practice in developing countries and what strategies might improve their capability to provide high-quality primary health care (PHC). This study aims to explore the underlying factors, which shape GPs' experience within the Indonesian PHC system and impact on their experience of professional practice. A grounded theory approach was applied using semi-structured interviews of 25 purposively selected GPs in West Sumatra, Indonesia. The interviews were analysed inductively through an iterative process of the interplay between empirical data, emerging analysis and theory development. Three major health care systems attribute shaped GPs' experiences of professional practice, including (i) a restricted concept of the PHC system, (ii) lack of regulation of private primary care practice conducted by GPs, midwives, nurses and specialists and (iii) low coverage and inappropriate policy of the health insurance system. The findings indicate that a major revision of current health care system is required with a focus on promoting the concept of PHC services to the population, redefining the role of the GP to deliver recognised best practice within available resources, changing the way GPs are remunerated by the public health system and the health insurance industry, policing of the regulations related to the scope of practice of other health care professionals, particularly midwives and nurses, and regulation of prescribing. GPs can be the champions of the PHC service that Indonesia needs, but it requires sustained systematic change.


Animal models of alcoholism: neurobiology of high alcohol-drinking behavior in rodents.
This review discusses efforts to develop rodent models for the study of neurobiological mechanisms underlying chronic alcohol drinking, alcoholism, and abnormal alcohol-seeking behavior. Selective breeding has produced stable lines of rats that reliably exhibit high and (for comparison purposes) low voluntary alcohol consumption. In addition, animal models of chronic ethanol self-administration have been developed in rodents, who do not have a genetic predisposition for high alcohol-seeking behavior, to explore environmental influences in ethanol drinking and the effects of physical dependence on alcohol self-administration. The selectively bred high-preference animals reliably self-administer ethanol by free-choice drinking and operantly respond for oral ethanol in amounts that produce pharmacologically meaningful blood alcohol concentrations (50 to 200 mg% and higher). In addition, the alcohol-preferring rats will self-administer ethanol by intragastric infusion. With chronic free-choice drinking, the high alcohol-preferring rats develop tolerance to the high-dose effects of ethanol and show signs of physical dependence after the withdrawal of alcohol. Compared with nonpreferring animals, the alcohol-preferring rats are less sensitive to the sedative-hypnotic effects of ethanol and develop tolerance more quickly to high-dose ethanol. Nonselected common stock rats can be trained to chronically self-administer ethanol following its initial presentation in a palatable sucrose or saccharin solution, and the gradual replacement of the sucrose or saccharin with ethanol (the sucrose/saccharin-fade technique). Moreover, rats that are trained in this manner and then made dependent by ethanol-vapor inhalation or liquid diet increase their ethanol self-administration during the withdrawal period. Both the selectively bred rats and common-stock rats demonstrate "relapse" and an alcohol deprivation effect following 2 or more weeks of abstinence. Systemic administration of agents that (1) increase synaptic levels of serotonin (5-HT) or dopamine (DA); (2) activate 5-HT1A, 5-HT2, D2, D3, or GABA(A) receptors; or (3) block opioid and 5-HT3 receptors decrease ethanol intake in most animal models. Neurochemical, neuroanatomical, and neuropharmacological studies indicate innate differences exist between the high alcohol-consuming and low alcohol-consuming rodents in various CNS limbic structures. In addition, reduced mesolimbic DA and 5-HT function have been observed during alcohol withdrawal in common stock rats. Depending on the animal model under study, abnormalities in the mesolimbic dopamine pathway, and/or the serotonin, opioid, and GABA systems that regulate this pathway may underlie vulnerability to the abnormal alcohol-seeking behavior in the genetic animal models.


Symptoms of hand-arm vibration syndrome in gas distribution operatives.
To survey the prevalence and severity of hand-arm vibration syndrome symptoms (HAVS), and to estimate past and current exposure to hand held vibrating tools in a sample of gas distribution operatives breaking and re-instating road surfaces. 153 gas distribution operatives (participation rate 81%) from three company districts were assessed by an administered questionnaire, a clinical examination, and a simple cold challenge test to the hands. Exposure histories were taken aided by a picture album of past and current tools. Information was obtained from several sources on the likely vibratory characteristics of those tools. Estimates were thus obtained of the frequency of blanching and neurological complaints in operatives, and of their lifetime hours of exposure and lifetime dose of vibration. On average, the sample had spent 16 years in employment involving use of vibratory tools. 24% had symptoms or signs of blanching after use of tools in the industry; 46% had troublesome persistent complaints of paraesthesiae or numbness, and these symptoms extended into the hands or arms in 18% of workers. In 5.9% the distribution of symptoms was suggestive of carpal tunnel syndrome; and of ulnar nerve entrapment in a further 3.9%. The risks of blanching and neurological complaints rose significantly with lifetime hours of use of vibrating tools and lifetime dose of vibration. Symptoms were generally mild and apparent only after a prolonged interval, but there were exceptions, and cases had occurred after lower recent exposures. It has been suggested that aspects of the gas distribution operative's work mitigate against the risk normally anticipated from use of pneumatic road breaking tools. By contrast our data suggest that symptoms of HAVS do occur, given sufficient exposure, a finding relevant not only to gas supply workers, but also to workers from other industries who break and repair road surfaces.


A bibliometric study of scientific research conducted on second-generation antipsychotic drugs in Singapore.
A bibliometric study was carried out to ascertain the volume and impact of scientific literature published on second-generation antipsychotic drugs (SGAs) in Singapore from 1997 to 2011. A search of the EMBASE and MEDLINE databases was performed to identify articles originating from Singapore that included the descriptors 'atypic* antipsychotic*', 'second-generation antipsychotic*', 'clozapine', 'risperidone', 'olanzapine', 'ziprasidone', 'quetiapine', 'sertindole', 'aripiprazole', 'paliperidone', 'amisulpride', 'zotepine', 'asenapine', 'iloperidone', 'lurasidone', 'perospirone' and 'blonanserin' in the article titles. Certain bibliometric indicators of production and dispersion (e.g. Price's Law on the increase of scientific literature, and Bradford's Law) were applied, and the participation index of various countries was calculated. The bibliometric data was also correlated with some social and health data from Singapore, such as the total per capita expenditure on health and gross domestic expenditure on research and development. From 1997 to 2011, a total of 51 articles on SGAs in Singapore were published. Our results suggested non-fulfilment of Price's Law (r = 0.0648 after exponential adjustment vs. r = 0.2140 after linear adjustment). The most widely studied drugs were clozapine (21 articles), risperidone (16 articles) and olanzapine (8 articles). Division into Bradford zones yielded a nucleus occupied by the Journal of Clinical Psychopharmacology (6 articles) and the Singapore Medical Journal(4 articles). The analysed material was published in a total of 30 journals, with the majority from six journals. Four of these six journals have an impact factor greater than 2. Publications on SGAs in Singapore are still too few to confirm an exponential growth of scientific literature.