Comparative computational analysis of pluripotency in human and mouse stem cells.
Pluripotent cells can be subdivided into two distinct states, the naïve and the primed state, the latter being further advanced on the path of differentiation. There are substantial differences in the regulation of pluripotency between human and mouse, and in humans only stem cells that resemble the primed state in mouse are readily available. Reprogramming of human stem cells into a more naïve-like state is an important research focus. Here, we developed a pipeline to reanalyze transcriptomics data sets that describe both states, naïve and primed pluripotency, in human and mouse. The pipeline consists of identifying regulated start-ups/shut-downs in terms of molecular interactions, followed by functional annotation of the genes involved and aggregation of results across conditions, yielding sets of mechanisms that are consistently regulated in transitions towards similar states of pluripotency. Our results suggest that one published protocol for naïve human cells gave rise to human cells that indeed share putative mechanisms with the prototypical naïve mouse pluripotent cells, such as DNA damage response and histone acetylation. However, cellular response and differentiation-related mechanisms are similar between the naïve human state and the primed mouse state, so the naïve human state did not fully reflect the naïve mouse state.


An isotope (18O, 15N, and 2H) technique to investigate the metal ion interactions between the phosphoryl group and amino acid side chains by electrospray ionization mass spectrometry.
Cationic metal ion-coordinated N-diisopropyloxyphosphoryl dipeptides (DIPP-dipeptides) were analyzed by electrospray ionization multistage tandem mass spectrometry (ESI-MS(n)). Two novel rearrangement reactions with hydroxyl oxygen or carbonyl oxygen migrations were observed in ESI-MS/MS of the metallic adducts of DIPP-dipeptides, but not for the corresponding protonated DIPP-dipeptides. The possible oxygen migration mechanisms were elucidated through a combination of MS/MS experiments, isotope ((18)O, (15)N, and (2)H) labeling, accurate mass measurements, and density functional theory (DFT) calculations at the B3LYP/6-31 G(d) level. It was found that lithium and sodium cations catalyze the carbonyl oxygen migration more efficiently than does potassium and participation through a cyclic phosphoryl intermediate. In addition, dipeptides having a C-terminal hydroxyl or aromatic amino acid residue show a more favorable rearrangement through carbonyl oxygen migration, which may be due to metal cation stabilization by the donation of lone pair of the hydroxyl oxygen or aromatic π-electrons of the C-terminal amino acid residue, respectively. It was further shown that the metal ions, namely lithium, sodium, and potassium cations, could play a novel directing role for the migration of hydroxyl or carbonyl oxygen in the gas phase. This discovery suggests that interactions between phosphorylated biomolecules and proteins might involve the assistance of metal ions to coordinate the phosphoryl oxygen and protein side chains to achieve molecular recognition.


Re-evaluating ethical concerns in planned emergency research involving critically ill patients: an interpretation of the guidance document from the United States Food and Drug Administration.
U.S. federal regulations require that certain ethical elements be followed to protect human research subjects. The location and clinical circumstances of a proposed research study can differ substantially and can have significant implications for these ethical considerations. Both the location and clinical circumstances are particularly relevant for research in intensive care units (ICUs), where patients are often unable to provide informed consent to participate in a proposed research intervention. Our goal is to elaborate on the updated 2013 U.S. Food and Drug Administration (FDA) guidance document regarding an exemption from the requirement of obtaining informed consent from patients or their surrogates and to address certain elements within that document, thereby assisting clinicians in developing a framework for emergency research in accordance with the regulatory bodies at their own institutions and in the United States. Review of the 2011 and updated FDA guidance document on exemption from informed consent. The current process of obtaining informed consent within ICUs needs to be revisited, especially for research in which timely informed consent is not likely. In particular, the process of obtaining informed consent may not be appropriate or even ethical for critically ill patients in extremis who require an intervention for which there is no current acceptable standard of care and clinical equipoise exists. We provide clinicians with a viewpoint that further elaborates on the FDA guidance document. The viewpoints provided herein are those of the authors and are therefore inherently limited by the personal views of a selected few. Other clinicians or researchers may not interpret the FDA guidelines in a similar manner. Moreover, the discussion of a guideline document is a limitation in and of itself. The guidelines set forth by the FDA are precisely that-guidelines. Therefore, they may not be followed as outlined in the guidance document within one's own institution. Our goal is that, by elaborating on the guidelines for planned research involving human subjects in the ICU, institutional regulatory bodies may gain a better understanding in drafting their own document when faced with a clinician or a researcher who wishes to conduct planned research in an ICU. We believe that the interpretations provided will allow clinicians to safely undertake planned research in ICUs without endangering the main tenets of ethical research involving human participants. This research is needed for the advancement of care in the critically ill.


Chordoma of the mobile spine: fifty years of experience.
A consecutive series of 52 chordomas of the mobile spine observed over a 50-year period includes a retrospective review of 15 cases treated prior to 1991 and a prospective group of 37 cases treated from 1991 to 2002. This series reviews epidemiologic issues as well as clinical patterns of spinal chordomas. We attempt to correlate tumor extent, treatment, and outcomes over time. Chordoma is the most frequent primary tumor of the mobile spine. Due to slow growth, both initial symptoms and recurrences after treatment arise later, making it difficult to evaluate the effectiveness of treatment protocols. A prospective series of 37 cases is compared with a retrospective group of 15 patients observed between 1954 and 1991. In the prospective study, all patients had imaging studies, and oncologic and surgical staging. When en bloc resection was not feasible, intralesional extracapsular excision was combined with radiation therapy. The prospective patients were clinically evaluated and imaged. Patients in the retrospective group were evaluated by chart and available images; of these, only one en bloc resection (intralesional margin) was performed. Survivors were all evaluated clinically and had radiographic studies. Forty-eight patients were available for long-term follow-up. Four died due to post-operative complications, and six due to disease less than 2 years after treatment. Forty-two patients were followed over 2 years; 26 patients had over 5 years follow-up. All patients having radiation alone, intralesional excision, or a combination had recurrences in less than 2 years, and died in some cases after a long survival with symptomatic disease. Intralesional extracapsular excision with radiation had a high rate of recurrence (12 of 16 at average 30 months), but 3 patients are continuously disease-free (CDF) at mean 52 months and 5 are alive with disease at average 69 months (ranging 24 to 146). Twelve of 18 patients having en bloc resection are CDF at average 8 years (48 to 155 months). The remaining 6 recurred and of these 1 died. All of these (6) had been previously treated and/or had en bloc resections with contaminated margins. The only treatment protocol associated with CDF at follow-up longer than 5 years is margin-free en bloc resection.


Molecular analysis of nuc-1+, a gene controlling phosphorus acquisition in Neurospora crassa.
In response to phosphorus starvation, Neurospora crassa makes several enzymes that are undetectable or barely detectable in phosphate-sufficient cultures. The nuc-1+ gene, whose product regulates the synthesis of these enzymes, was cloned and sequenced. The nuc-1+ gene encodes a protein of 824 amino acids with a predicted molecular weight of 87,429. The amino acid sequence shows homology with two yeast proteins whose functions are analogous to that of the NUC-1 protein. Two nuc-1+ transcripts of 3.2 and 3.0 kilobases were detected; they were present in similar amounts during growth at low or high phosphate concentrations. The nuc-2+ gene encodes a product normally required for NUC-1 function, and yet a nuc-2 mutation can be complemented by overexpression of the nuc-1+ gene. This implies physical interactions between NUC-1 protein and the negative regulatory factor(s) PREG and/or PGOV. Analysis of nuc-2 and nuc-1; nuc-2 strains transformed by the nuc-1+ gene suggests that phosphate directly affects the level or activity of the negative regulatory factor(s) controlling phosphorus acquisition.


What does Neural Plasticity Tell us about Role of Primary Visual Cortex (V1) in Visual Awareness?
The complete loss of visual awareness resulting from a lesion to the primary visual cortex (V1) suggests that this region is indispensable for conscious visual perception. There are however a number cases of conscious perception in the absence of V1 which appear to challenge this conclusion. These include reports of patients with bilateral V1 lesions sustained at an early age whose conscious vision has spontaneously recovered, as well as stroke patients who have recovered some conscious vision with the help of rehabilitation programs. In addition, the phenomenon of hemianopic completion and percepts induced by brain stimulation suggest that V1 may not be necessary for conscious perception in all circumstances. Furthermore, that the visual abilities in the cat are associated with the recovery of normal extrastriate tuning properties rather than emulation of V1 functions suggests that there is nothing unique about the functional properties of this region in visual awareness. Rather, the dramatic effect of a V1 lesion on visual awareness may be due to its role in providing the majority of extrastriate visual input, the loss of which abolishes normal neural responsiveness throughout the visual cortex.


Genomic identification in the historical case of the Nicholas II royal family.
Accurate unambiguous identification of ancient or historical specimens can potentially be achieved by DNA analysis. The controversy surrounding the fate of the last Russian Emperor, Nicholas II, and his family has persisted, in part, because the bodies of 2 children, Prince Alexei and 1 of his sisters, have not been found. A grave discovered in 1991 contained remains putatively identified as those of the Russian Royal family. However, not all family members were represented. Here, we report the results of genomic analyses of new specimens, the human remains of 2 burned skeletons exhumed from a grave discovered in July 2007, and the results of a comprehensive genomic analysis of remains from the 1991 discovery. Additionally, approximately 117 years old archival blood specimens from Nicholas II were obtained and genotyped, which provided critical material for the specific determination of individual identities and kinship identifications. Results of genotypic analyses of damaged historical specimens were evaluated alongside samples from descendants of both paternal and maternal lineages of the European Royal families, and the results conclusively demonstrate that the recently found remains belong to children of Nicholas II: Prince Alexei and his sister. The results of our studies provide unequivocal evidence that the remains of Nicholas II and his entire family, including all 5 children, have been identified. We demonstrate that convergent analysis of complete mitochondrial genome sequences combined with nuclear DNA profiles is an efficient and conclusive method for individual and kinship identification of specimens obtained from old historic relics.


From Genes to Networks: The Regulatory Circuitry Controlling Candida albicans Morphogenesis.
Candida albicans is a commensal yeast of most healthy individuals, but also one of the most prevalent human fungal pathogens. During adaptation to the mammalian host, C. albicans encounters different niches where it is exposed to several types of stress, including oxidative, nitrosative (e.g., immune system), osmotic (e.g., kidney and oral cavity) stresses and pH variation (e.g., gastrointestinal (GI) tract and vagina). C. albicans has developed the capacity to respond to the environmental changes by modifying its morphology, which comprises the yeast-to-hypha transition, white-opaque switching, and chlamydospore formation. The yeast-to-hypha transition has been very well characterized and was shown to be modulated by several external stimuli that mimic the host environment. For instance, temperature above 37 ℃, serum, alkaline pH, and CO2 concentration are all reported to enhance filamentation. The transition is characterized by the activation of an intricate regulatory network of signaling pathways, involving many transcription factors. The regulatory pathways that control either the stress response or morphogenesis are required for full virulence and promote survival of C. albicans in the host. Many of these transcriptional circuitries have been characterized, highlighting the complexity and the interconnections between the different pathways. Here, we present the major signaling pathways and the main transcription factors involved in the yeast-to-hypha transition. Furthermore, we describe the role of heat shock transcription factors in the morphogenetic transition, providing an edifying example of the complex cross talk between pathways involved in morphogenesis and stress response.


Dynamic instabilities of microwaves generated with optoelectronic oscillators.
We introduce a time-domain model to study the dynamics of optoelectronic oscillators. We show that, due to the interaction between nonlinearity and time delay, the envelope amplitude of ultrapure microwaves generated by optoelectronic oscillators can turn unstable when the gain is increased beyond a given critical value. Our analytical predictions are confirmed by numerical simulations and experiments.


Does episiotomy prevent perineal trauma and pelvic floor relaxation?
To compare the outcomes of the current practice of liberally or routinely employing episiotomy to prevent perineal tears and pelvic floor relaxation (control group) to a policy of restricting episiotomy use to specific fetal and maternal indications (experimental group). A randomized controlled trial (RCT). Three university hospitals in Montreal. Seven hundred three low-risk women enrolled at 30 to 34 weeks of gestation were randomized late in labor to the designated trial arm, by parity, and followed up to 3 months postpartum. Antepartum and postpartum information on perineal trauma and pain, pelvic floor symptoms (urinary incontinence), and sexual activity was collected through the use of standard questionnaires; pelvic floor function was measured by electromyographic (EMG) perineometry. Restricting episiotomy use in primiparous women was associated with similar sutured perineal trauma to the liberal or routine approach. Multiparous women in the restricted episiotomy group more often gave birth with an intact perineum (31% compared with 19%, odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.09 to 3.16). All but one 3rd/4th-degree perineal tear was associated with median episiotomy (46 of 47 in primiparous women and 6 of 6 among multiparous women). No difference between trial groups was found in postpartum perineal pain, antepartum and 3-month postpartum EMG perineometry, and urinary and pelvic floor symptoms. We found no evidence that liberal or routine use of episiotomy prevents perineal trauma or pelvic floor relaxation. Virtually all severe perineal trauma was associated with median episiotomy. Restriction of episiotomy use among multiparous women resulted in significantly more intact perineums and less perineal suturing.


PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins.
Despite significant structural diversity, present evidence suggests that EWS/ETS fusion proteins promote oncogenesis by transcriptionally modulating a common set of target genes. In order to identify these genes, microarray expression analyses were performed on NIH 3T3 polyclonal populations expressing one of three EWS/ETS fusion genes. The majority of these genes can be grouped into seven functional categories, including cellular metabolism and signal transduction. The biologic significance of these target genes was pursued. The effects of modulating genes involved in metabolism were assessed by flux studies and demonstrated shifts in glucose utilization and lactate production as a result of EWS/FLI1 expression. The proto-oncogene coding for serine/threonine kinase PIM3 was found to one of several genes encoding signal transduction proteins that were up-regulated by EWS/ETS fusions. PIM3 was found to be expressed in a panel of human Ewing's family tumor cell lines. Forced expression of PIM3 promoted anchorage-independent growth. Coexpression of a kinase-deficient PIM3 mutant attenuated EWS/FLI1-mediated NIH 3T3 tumorigenesis in immunodeficent mice.


Transcutaneous bilirubinometry in very low birthweight infants.
To evaluate whether transcutaneous bilirubinometry (TcB) would be a reliable and efficient screening technique for hyperbilirubinaemia in very low birthweight (VLBW, < or =1500 g) infants in an intensive care unit setting. TcB measurements (Minolta Airshield Jaundice Meter JM-102, Osaka, Japan) were obtained immediately before or within 10 min following routine blood sampling for plasma bilirubin concentration measurements in 124 VLBW infants not receiving phototherapy. The relationship between the two techniques was analysed by linear regression analysis. A plasma bilirubin > or =150 micromol/l was defined as hyperbilirubinaemia. The sensitivity and specificity of possible TcB cut-off readings to detect hyperbilirubinaemia was evaluated. There was a significant correlation between the measurements of both techniques (p < 0.0001, r = 0.68). In the present study, a TcB cut-off reading of 14 would have reduced the need for plasma bilirubin measurements by 26% without missing true hyperbilirubinaemia. The data suggest that TcB will improve VLBW infant care in an intensive care unit setting by reducing the need for invasive bilirubin concentration measurements.


Honorary authorship.
This issue of Archives of Physical Medicine and Rehabilitation includes an article by Rajasekaran et al that addresses the persistent, difficult, and unsettled issue of unwarranted authorship as it applies to physical medicine and rehabilitation. The findings that it exists and that its frequency is similar to the 25% to 50% rates reported in other medical specialties are discouraging but, unfortunately, not surprising. They do, however, warrant discussion. This commentary attempts to do so and begins with a review of Rajasekaran's findings. It then proceeds to compare them with other work in the literature and concludes with a discussion of (1) why unwarranted authorship matters; (2) if it matters, why does it matter; and (3) what we as authors, editors, and the publishing world can do about it. Our goal is to give us all an improved understanding of the situation as well a little more backbone when dealing with the pressures associated with both overt and covert suggestions for the inclusion of authors that we may believe are unwarranted.


Nausea and vomiting of pregnancy: cost effective pharmacologic treatments.
Nausea and vomiting of pregnancy (NVP) can range from morning sickness to moderate NVP to hyperemesis gravidarum (HG). If it is left unmanaged, health plans may pay for expensive unproven outpatient therapies that are not necessary for treatment of simple morning sickness or moderate NVP. Meanwhile, patients with serious hyperemesis gravidarum whose treatment is delayed may suffer needlessly, ending up with multiple hospitalizations or emergency room (ER) visits. Two expensive, heavily marketed outpatient therapies with scant supportive evidence in the treatment of NVP have recently emerged and some health plans are providing coverage without a thorough review of the medical evidence or cost implications. Health plans may have an opportunity to save a significant amount and to improve member satisfaction by utilizing evidence-based knowledge of pharmacologic interventions that are driven, in order, by known safety, proven efficacy, and cost effectiveness.


Central projections of antennular chemosensory and mechanosensory afferents in the brain of the terrestrial hermit crab (Coenobita clypeatus; Coenobitidae, Anomura).
The Coenobitidae (Decapoda, Anomura, Paguroidea) is a taxon of hermit crabs that includes two genera with a fully terrestrial life style as adults. Previous studies have shown that Coenobitidae have evolved a sense of spatial odor localization that is behaviorally highly relevant. Here, we examined the central olfactory pathway of these animals by analyzing central projections of the antennular nerve of Coenobita clypeatus, combining backfilling of the nerve with dextran-coupled dye, Golgi impregnations and three-dimensional reconstruction of the primary olfactory center, the antennular lobe. The principal pattern of putative olfactory sensory afferents in C. clypeatus is in many aspects similar to what have been established for aquatic decapod crustaceans, such as the spiny lobster Panulirus argus. However, there are also obvious differences that may, or may not represent adaptations related to a terrestrial lifestyle. In C. clypeatus, the antennular lobe dominates the deutocerebrum, having more than one thousand allantoid-shaped subunits. We observed two distinct patterns of sensory neuron innervation: putative olfactory afferents from the aesthetascs either supply the cap/subcap region of the subunits or they extend through its full depth. Our data also demonstrate that any one sensory axon can supply input to several subunits. Putative chemosensory (non-aesthetasc) and mechanosensory axons represent a different pathway and innervate the lateral and median antennular neuropils. Hence, we suggest that the chemosensory input in C. clypeatus might be represented via a dual pathway: aesthetascs target the antennular lobe, and bimodal sensilla target the lateral antennular neuropil and median antennular neuropil. The present data is compared to related findings in other decapod crustaceans.


Decadelong profile of women in ophthalmic publications.
In recent decades, there has been an increase in the number of women practicing medicine. We believe this shift may be reaching academic publications in ophthalmology and changing gender trends. To determine whether there has been an increase in women publishing academic articles and editorials in ophthalmology during the past decade. In this observational retrospective study, 3 ophthalmology journals were sampled from 2000 and 2010 for at least 100 articles per journal, per year, and all editorials published in both years. Data reviewed included the authors' gender, number of authors, number of references, subspecialty, and country of origin. Publication by women authors. The primary outcome measure was an increase in women publishing in ophthalmology. The hypothesis was formulated before data collection. Our analysis included 671 original articles (336 from 2000 and 335 from 2010) and 89 editorials. The percentage of original articles with a woman as first author increased from 23.2% in 2000 to 32.5% in 2010, a difference of 9.3% (95% CI, 23.3%-32.5%; P = .005). The percentage of original articles with a woman last author increased from 16.4% in 2000 to 24.2% in 2010, a difference of 7.8% (95% CI, 16.4%-24.2%; P = .01). The percentage of original articles with a woman first author increased in Asia from 1.2% in 2000 to 8.4% in 2010, a difference of 7.2% (95% CI, 1.2%-8.4%; P < .001). The percentage of articles with a woman last author increased in Europe from 2.2% in 2000 to 7.5% in 2010, a difference of 5.3% (95% CI, 2.2%-7.5%; P < .001) and in Asia from 0% in 2000 to 6.0% in 2010, a difference of 6.0% (95% CI, 0%-6%; P < .001). Editorials were written predominantly by men: 33 of 38 editorials (87%) in 2000 and 46 of 51 (90%) in 2010, a difference of 3% (95% CI, 87%-90%; P = .62), showing a trend toward decreased editorial authorship by women during the past decade. Our data suggest an increase in women publishing original investigations in ophthalmic literature, but no increase in editorial authorship.


Reverse engineering directed gene regulatory networks from transcriptomics and proteomics data of biomining bacterial communities with approximate Bayesian computation and steady-state signalling simulations.
Network inference is an important aim of systems biology. It enables the transformation of OMICs datasets into biological knowledge. It consists of reverse engineering gene regulatory networks from OMICs data, such as RNAseq or mass spectrometry-based proteomics data, through computational methods. This approach allows to identify signalling pathways involved in specific biological functions. The ability to infer causality in gene regulatory networks, in addition to correlation, is crucial for several modelling approaches and allows targeted control in biotechnology applications. We performed simulations according to the approximate Bayesian computation method, where the core model consisted of a steady-state simulation algorithm used to study gene regulatory networks in systems for which a limited level of details is available. The simulations outcome was compared to experimentally measured transcriptomics and proteomics data through approximate Bayesian computation. The structure of small gene regulatory networks responsible for the regulation of biological functions involved in biomining were inferred from multi OMICs data of mixed bacterial cultures. Several causal inter- and intraspecies interactions were inferred between genes coding for proteins involved in the biomining process, such as heavy metal transport, DNA damage, replication and repair, and membrane biogenesis. The method also provided indications for the role of several uncharacterized proteins by the inferred connection in their network context. The combination of fast algorithms with high-performance computing allowed the simulation of a multitude of gene regulatory networks and their comparison to experimentally measured OMICs data through approximate Bayesian computation, enabling the probabilistic inference of causality in gene regulatory networks of a multispecies bacterial system involved in biomining without need of single-cell or multiple perturbation experiments. This information can be used to influence biological functions and control specific processes in biotechnology applications.


Integrating Ethics into the Physiology curriculum: a scale-up study in three medical colleges in Karnataka, South India.
A published pilot study showed the feasibility of integrating ethics into physiology in a single medical college. However, questions were raised about feasibility of scale-up and acceptance across different colleges. To assess feasibility of integrating ethics into Physiology, first year MBBS students of three medical colleges (n=449, College A=149; 59M, 90F; College B=150; 78M, 72F; College C=150; 48M, 102F) were exposed to the integrated ethics programme. Triggers related to theory or practicals were included. Faculty volunteers conducted the sessions with feedback from observers and students. Students across three colleges felt that the programme was relevant (92%-98%), effectively integrated (86%-98%) [significantly greater number of College A students: (p=0.003)], seldom interfered with physiology teaching (59%-66%). Greater number of students from College C followed by College B and A opined to continue the integrated programme for future years (p=0.004). A scale-up study of integration of ethics programme across different colleges was perceived to be feasible by students and observers.


Determination of (2)H-enrichment of rat brain interstitial fluid and rat plasma by headspace-gas-chromatography - quadrupole-mass-spectrometry.
(2)H2O as nonradioactive, stable marker substance is commonly used in preclinical and clinical studies and the precise determination of (2)H2O concentration in biological samples is crucial. However, aside from isotope ratio mass spectrometry (IRMS), only a very limited number of methods to accurately measure the (2)H2O concentration in biological samples are routinely established until now. In this study, we present a straightforward method to accurately measure (2)H-enrichment of rat brain interstitial fluid (ISF) and rat plasma to determine the relative recovery of a cerebral open flow microperfusion (cOFM) probe, using headspace-gas-chromatography - quadrupole-mass-spectrometry. This method is based on basic-catalyzed hydrogen/deuterium exchange in acetone and detects the (2)H-labelled acetone directly by the headspace GC-MS. Small sample volumes and limited number of preparation steps make this method highly competitive. It has been fully validated. (2)H enriched to 8800 ppm in plasma showed an accuracy of 98.9% and %Relative Standard Deviation (RSD) of 3.1 with n = 18 over three days and with two operators. Similar performance was obtained for cerebral ISF enriched to 1100 ppm (accuracy: 96.5%, %RSD: 3.1). With this highly reproducible method we demonstrated the successful employment of (2)H2O as performance marker for a cOFM probe.


Cortical and trabecular bone microarchitecture as an independent predictor of incident fracture risk in older women and men in the Bone Microarchitecture International Consortium (BoMIC): a prospective study.
Although areal bone mineral density (aBMD) assessed by dual-energy x-ray absorptiometry (DXA) is the clinical standard for determining fracture risk, most older adults who sustain a fracture have T scores greater than -2·5 and thus do not meet the clinical criteria for osteoporosis. Importantly, bone fragility is due to low BMD and deterioration in bone structure. We assessed whether indices of high-resolution peripheral quantitative CT (HR-pQCT) were associated with fracture risk independently of femoral neck aBMD and the Fracture Risk Assessment Tool (FRAX) score. We assessed participants in eight cohorts from the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazard ratios (HRs) to estimate the association between HR-pQCT bone indices (per 1 SD of deficit) and incident fracture, adjusting for age, sex, height, weight, and cohort, and then additionally for femoral neck DXA aBMD or FRAX. 7254 individuals (66% women and 34% men) were assessed. Mean baseline age was 69 years (SD 9, range 40-96). Over a mean follow-up of 4·63 years (SD 2·41) years, 765 (11%) participants had incident fractures, of whom 633 (86%) had femoral neck T scores greater than -2·5. After adjustment for age, sex, cohort, height, and weight, peripheral skeleton failure load had the greatest association with risk of fracture: tibia HR 2·40 (95% CI 1·98-2·91) and radius 2·13 (1·77-2·56) per 1 SD decrease. HRs for other bone indices ranged from 1·12 (95% CI 1·03-1·23) per 1 SD increase in tibia cortical porosity to 1·58 (1·45-1·72) per 1 SD decrease in radius trabecular volumetric bone density. After further adjustment for femoral neck aBMD or FRAX score, the associations were reduced but remained significant for most bone parameters. A model including cortical volumetric bone density, trabecular number, and trabecular thickness at the distal radius and a model including these indices plus cortical area at the tibia were the best predictors of fracture. HR-pQCT indices and failure load improved prediction of fracture beyond femoral neck aBMD or FRAX scores alone. Our findings from a large international cohort of men and women support previous reports that deficits in trabecular and cortical bone density and structure independently contribute to fracture risk. These measurements and morphological assessment of the peripheral skeleton might improve identification of people at the highest risk of fracture. National Institutes of Health National Institute of Arthritis Musculoskeletal and Skin Diseases.


Living Waste and the Labor of Toxic Health on American Factory Farms.
In the 1930s, erosion caused storms of dust to hurtle across the American Great Plains and Midwest. While agricultural conservation methods helped remediate this landscape, recent studies suggest the region is contending with a new type of particle cloud: desiccated fecal dust that renders the vitalities of factory farms airborne, potentially exposing those in their surrounds to various forms of illness while spreading antibiotic resistance genes. Thinking alongside these findings, and based on research within corporate hog farms, this article develops an ethnography of excrement by tracing the practices and knowledge of people who live and labor in proximity to late industrial lifeforms, such as confined pigs and resistance genes, and who are tasked with intimately shaping this unruly waste that has the potential to affect broader populations. In so doing, it analyzes the maintenance of American animals' toxic health alongside the politics of labor with complex anthropogenic materials.


Simulations of high-Q optical nanocavities with a gradual 1D bandgap.
High-quality cavities in hybrid material systems have various interesting applications. We perform a comprehensive modeling comparison on such a design, where confinement in the III-V material is provided by gradual photonic crystal tuning, a recently proposed method offering strong resonances. The III-V cavity couples to an underlying silicon waveguide. We report on the device properties using four simulation methods: finite-difference time-domain (FDTD), finite-element method (FEM), bidirectional eigenmode propagation (BEP) and aperiodic rigorous coupled wave analysis (aRCWA). We explain the major confinement and coupling effects, consistent with the simulation results. E.g. for strong waveguide coupling, we find quantitative discrepancies between the methods, which establishes the proposed high-index-contrast, lossy, 3D structure as a challenging modeling benchmark.


In-Flight Transmission of a SARS-CoV-2 Lineage B.1.617.2 Harbouring the Rare S:E484Q Immune Escape Mutation.
We describe a flight-associated infection scenario of seven individuals with a B.1.617.2 (Delta) lineage, harbouring an S:E484Q point mutation. In Sweden, at least 10% of all positive SARS-CoV-2 samples were sequenced in each county; the B.1.717.2 + S:E484Q combination was not detected in Sweden before and was imported within the scenario described in this report. The high transmission rate of the delta lineage combined with the S:E484Q mutation, associated with immune escape in other lineages, makes this specific genetic combination a possible threat to the global fight against the COVID-19 pandemic. Even within the Omicron wave, the B.1.617.2 + S:E484Q variant appeared in community samples in Sweden, as it seems that this combination has an evolutionary gain compared to other B.1.617.2 lineages. The here described genomic combination was not detectable with the common fasta file-based Pango-lineage analysis, hence increasing the probability of the true global prevalence to be higher.


Oral health training programs for community and professional health care workers in Nairobi East District increases identification of HIV-infected patients.
Better knowledge and skills for diagnosis and management of human immunodeficiency virus (HIV) related oral lesions by primary healthcare workers (PHWs) may increase recognition of HIV-related oral lesions (HROLs) and may improve implementation of HIV testing in Kenya. For this purpose training programs at health facility and community level were evaluated. A pre-post control-test group design in two administrative divisions of Nairobi East District was used. Clinical competencies of PHWs (n = 32 intervention, and n = 27 control) at health facility level were assessed 9 months after training, and after 6 months for community health workers, (CHWs) (n = 411 intervention and n = 404 control) using written questionnaires, clinical data and patient interviews. Effects on referral for HIV testing and actual HIV testing were assessed by comparing laboratory registries pre- and post training. PHWs in intervention (n = 27; 84%) and control (n = 15; 60%) divisions, and CHWs in intervention (n = 330; 80%) and control (189; 47%) divisions, completed all questionnaires. Trained PHWs significantly increased their knowledge of HROLs (p<0.02), frequency of oral examinations, diagnosis of HROLs and referral of patients with HROLs for HIV testing. Trained CHWs significantly gained knowledge about HROLs (p<0.02) and referred more patients with HROLs to health facilities. Overall percentage of HIV-positive test results was three-fold for HROLs compared to non-HROLs. Specifically, 70% of patients with oro pharyngeal candidiasis (OPC), the most commonly diagnosed HROL, were confirmed as being HIV-positive. Increase in overall HIV testing rates (1.6% pre-, 1.2% post training) and overall percentage of HIV-positive results (13% pre-, 16% post-intervention) was not significant. Training programs significantly increased PHW and CHW knowledge, recognition and management of HROLs but increased neither overall HIV testing rates nor overall percentage of positive tests. Speculation is that the health system and patient-related barriers seriously limit HIV testing. Netherlands Trial Register NTR2627 (date registered 22nd November 2010), and NTR2697 (date registered 13th January 2011).


Diversity dynamics of Phanerozoic terrestrial tetrapods at the local-community scale.
The fossil record provides one of the strongest tests of the hypothesis that diversity within local communities is constrained over geological timescales. Constraints to diversity are particularly controversial in modern terrestrial ecosystems, yet long-term patterns are poorly understood. Here we document patterns of local richness in Phanerozoic terrestrial tetrapods using a global data set comprising 145,332 taxon occurrences from 27,531 collections. We show that the local richness of non-flying terrestrial tetrapods has risen asymptotically since their initial colonization of land, increasing at most threefold over the last 300 million years. Statistical comparisons support phase-shift models, with most increases in local richness occurring: (1) during the colonization of land by vertebrates, concluding by the late Carboniferous; and (2) across the Cretaceous/Paleogene boundary. Individual groups, such as mammals, lepidosaurs and dinosaurs also experienced early increases followed by periods of stasis often lasting tens of millions of years. Mammal local richness abruptly tripled across the Cretaceous/Paleogene boundary, but did not increase over the next 66 million years. These patterns are consistent with the hypothesis that diversity is constrained at the local-community scale.


Epidemiology of decompensated heart failure in a single community in the northeastern United States.
Limited data are available describing the clinical characteristics, hospital treatment practices, and hospital and long-term death rates of patients hospitalized with decompensated heart failure (HF). To examine the descriptive epidemiology of acute HF in residents of a large New England metropolitan area during the 2 study years of 1995 and 2000, we reviewed the medical records of patients hospitalized with acute HF at 11 medical centers in the Worcester, Massachusetts, metropolitan area during 1995 and 2000 for purposes of collecting information about patients' sociodemographic and clinical characteristics, hospital management approaches, and hospital and postdischarge mortalities. The mean age of 4,537 residents of the Worcester metropolitan area hospitalized with decompensated HF was 76 years, 57% were women, and most study patients had been previously diagnosed with several co-morbidities. The average duration of hospitalization was 6.3 days and 6.8% of patients died during hospitalization. Diuretics (98%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (54%) were the most common medications used to treat acutely ill patients. The 1- and 5-year death rates of hospital survivors were 39% and 77%, respectively, with no change observed in these death rates between our 2 study years. In conclusion, the results of this observational study in residents of a central New England metropolitan area provide insights into the characteristics, treatment practices, and short- and long-term death rates associated with this increasingly prevalent clinical syndrome.


Recurrent tongue tip constriction in a captive giant anteater (Myrmecophaga tridactyla).
A male giant anteater (Myrmecophage tridactyla) was treated twice for tongue tip constrictions. Clinical signs were partial anorexia, soft stool, bleeding from the mouth, and intermittent lingual discomfort. In the first presentation, wood fibers constricting the distal part of the tongue were detected by endoscopy and were removed. In the second presentation, bands of collagenous fibers were identified and resected. Dietary elements were responsible for both cases: elongated wood fibers were present in peat, which was included as a supplement to improve stool consistency, and collagenous fibers originated from fascias of lean meat, which served as a protein source in this diet. Preventive measures included sieving of the peat to eliminate long fibers and grinding of the meat, respectively, prior to diet presentation. A homogenous diet, utilizing cellulose rather than peat and dry cat food rather than meat, will avoid tongue tip constriction as described in these cases.


Using stable-hydrogen isotopes to reveal immigration in an Arctic-breeding songbird population.
Knowledge of immigration and emigration rates is crucial for understanding of population dynamics, yet little is known about these vital rates, especially for arctic songbirds. We estimated immigration in an Arctic population of northern wheatears on Baffin Island, Canada, by the use of stable hydrogen isotopes in tail feathers (δ(2)HK). We assumed that δ(2)HK values of juvenile (hatch-year) feathers grown at the breeding grounds were representative of the local population, while those of breeding adults were indicative of where they grew their feathers during their post-breeding molt the previous year. The extent to which adult isotope values differ from those of juveniles provides an estimate of the minimum level of immigration into the breeding population. Mean δ(2)HK values did not differ in juvenile birds between years. Breeding adult birds did not differ significantly in mean δ(2)HK values compared to juveniles but did differ in their respective standard deviations, reflecting a significantly wider range of isotopic signatures in adults than in juveniles. Thirty-eight percent of the δ(2)HK values in adults were greater ± 2 SD of the mean δ(2)HK values of juveniles, suggesting that at least 38 % of the breeding adults were of non-local origin, thus immigrants from elsewhere. Although the use of stable isotopes has limitations, the use of stable-hydrogen isotopic markers has the potential to contribute valuable information towards understanding immigration rates in bird populations. In our study, hydrogen isotope measurements of the feathers of northern wheatears indicated a high rate of immigration into the breeding population, which is consistent with low return rates of banded breeding adults as well as implying high emigration rates of local breeders.


Assessment of median nerve with MR neurography by using diffusion-tensor imaging: normative and pathologic diffusion values.
To determine normative diffusion values of the median nerve at several anatomic locations in healthy men and women of variable age and to compare these normative values with those in patients with carpal tunnel syndrome. After ethics board approval and written informed consent were obtained, 45 healthy volunteers (30 women, 15 men) and 15 patients (10 women, five men) were studied. Volunteers were divided into three age groups. Magnetic resonance (MR) neurography with diffusion-tensor imaging (DTI) was performed in all study participants at 3.0 T by using a single-shot echo-planar imaging sequence (repetition time msec/echo time msec, 10 123/40; b=1200 sec/mm2). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the median nerve were determined by two readers at three locations: the levels of the distal radioulnar joint, pisiform bone, and hamate bone. Normative FA and ADC values were calculated for men and women, different age groups, and different anatomic locations. FA and ADC did not differ between men and women (P=.28 and P=.38, respectively). FA decreased and ADC increased when moving from proximal to distal locations (P<.001). FA decreased and ADC increased significantly with age (P<.001). There was a significant difference between healthy volunteers and patients with carpal tunnel syndrome (P<.001 for both FA and ADC). An FA threshold of 0.47 and an ADC threshold of 1.054×10(-3) mm2/sec might be used in the diagnosis of carpal tunnel syndrome. Normative diffusion values for MR neurography of the median nerve with DTI depend on the anatomic location and age but not on sex. Age-specific FA and ADC threshold values might be used to diagnose carpal tunnel syndrome.


Real-World Treatment Trends in Endovascular Stroke Therapy.
Background and Purpose- Recent landmark trials provided overwhelming evidence for effectiveness of endovascular stroke therapy (EST). Yet, the impact of these trials on clinical practice and effectiveness of EST among lower volume centers remains poorly characterized. Here, we determine population-level patterns in EST performance in US hospitals and compare EST outcomes from higher versus lower volume centers. Methods- Using validated diagnosis codes from data on all discharges from hospitals and Emergency Rooms in Florida (2006-2016) and the National Inpatient Sample (2012-2016) we identified patients with acute ischemic stroke treated with EST. The primary end point was good discharge outcome defined as discharge to home or acute rehabilitation facility. Multivariate regressions adjusted for medical comorbidities, intravenous tPA (tissue-type plasminogen activator) usage and annual hospital stroke volume were used to evaluate the likelihood of good outcome over time and by annual hospital EST volume. Results- A total of 3890 patients (median age, 73 [61-82] years, 51% female) with EST were identified in the Florida cohort and 42 505 (median age, 69 [58-79], 50% female) in the National Inpatient Sample. In both Florida and the National Inpatient Sample, the number of hospitals performing EST increased continuously. Increasing numbers of EST procedures were performed at lower annual EST volume hospitals over the studied time period. In adjusted multivariate regression, there was a continuous increase in the likelihood of good outcomes among patients treated in hospitals with increasing annual EST procedures per year (odds ratio, 1.1; 95% CI, 1.1-1.2 in Florida and odds ratio, 1.3; 95% CI, 1.2-1.4 in National Inpatient Sample). Conclusions- Analysis of population-level datasets of patients treated with EST from 2006 to 2016 demonstrated an increase in the number of centers performing EST, resulting in a greater number of procedures performed at lower volume centers. There was a positive association between EST volume and favorable discharge outcomes in EST-performing hospitals.


Shifts in leaf litter breakdown along a forest-pasture-urban gradient in Andean streams.
Tropical montane ecosystems of the Andes are critically threatened by a rapid land-use change which can potentially affect stream variables, aquatic communities, and ecosystem processes such as leaf litter breakdown. However, these effects have not been sufficiently investigated in the Andean region and at high altitude locations in general. Here, we studied the influence of land use (forest-pasture-urban) on stream physico-chemical variables (e.g., water temperature, nutrient concentration, and pH), aquatic communities (macroinvertebrates and aquatic fungi) and leaf litter breakdown rates in Andean streams (southern Ecuador), and how variation in those stream physico-chemical variables affect macroinvertebrates and fungi related to leaf litter breakdown. We found that pH, water temperature, and nutrient concentration increased along the land-use gradient. Macroinvertebrate communities were significantly different between land uses. Shredder richness and abundance were lower in pasture than forest sites and totally absent in urban sites, and fungal richness and biomass were higher in forest sites than in pasture and urban sites. Leaf litter breakdown rates became slower as riparian land use changed from natural to anthropogenically disturbed conditions and were largely determined by pH, water temperature, phosphate concentration, fungal activity, and single species of leaf-shredding invertebrates. Our findings provide evidence that leaf litter breakdown in Andean streams is sensitive to riparian land-use change, with urban streams being the most affected. In addition, this study highlights the role of fungal biomass and shredder species (Phylloicus; Trichoptera and Anchytarsus; Coleoptera) on leaf litter breakdown in Andean streams and the contribution of aquatic fungi in supporting this ecosystem process when shredders are absent or present low abundance in streams affected by urbanization. Finally, we summarize important implications in terms of managing of native vegetation and riparian buffers to promote ecological integrity and functioning of tropical Andean stream ecosystems.


Harmonization of Mangiferin on methylmercury engendered mitochondrial dysfunction.
Mangiferin (MGN), a C-glucosylxanthone abundantly found in mango plants, was studied for its potential to ameliorate methylmercury (MeHg) induced mitochondrial damage in HepG2 (human hepatocarcinoma) cell line. Cell viability experiments performed using 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) showed protective property of MGN in annulling MeHg-induced cytotoxicity. Conditioning the cells with optimal dose of MGN (50 µM) lowered MeHg-induced oxidative stress, calcium influx/efflux, depletion of mitochondrial trans-membrane potential and prevented mitochondrial fission as observed by decrease in Mitotracker red fluorescence, expression of pDRP1 (serine 616), and DRP1 levels. MGN pre-treated cells demonstrated elevation in the activities of glutathione (GSH), Glutathione-S-transferase (GST), Glutathione peroxidase (GPx), Glutathione reductase (GR), reduced levels of Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) and mitochondrial electron transport chain (ETC) enzyme complexes. In addition, the anti-apoptotic effect of MGN was clearly indicated by the reduction in MeHg-induced apoptotic cells analyzed by flowcytometric analysis after Annexin V-FITC/propidium iodide staining. In conclusion, the present work demonstrates the ability of a dietary polyphenol, MGN to ameliorate MeHg-mediated mitochondrial dysfunction in human hepatic cells in vitro. This hepatoprotective potential may be attributed predominantly to the free radical scavenging/antioxidant property of MGN, by facilitating the balancing of cellular Ca2+ ions, maintenance of redox homeostasis and intracellular antioxidant activities, ultimately preserving the mitochondrial function and cell viability after MeHg intoxication. As MeHg intoxication occurs over a period of time, continuous consumption of such dietary compounds may prove to be very useful in promoting human health. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 630-644, 2017.


Wolbachia Blocks Currently Circulating Zika Virus Isolates in Brazilian Aedes aegypti Mosquitoes.
The recent association of Zika virus with cases of microcephaly has sparked a global health crisis and highlighted the need for mechanisms to combat the Zika vector, Aedes aegypti mosquitoes. Wolbachia pipientis, a bacterial endosymbiont of insect, has recently garnered attention as a mechanism for arbovirus control. Here we report that Aedes aegypti harboring Wolbachia are highly resistant to infection with two currently circulating Zika virus isolates from the recent Brazilian epidemic. Wolbachia-harboring mosquitoes displayed lower viral prevalence and intensity and decreased disseminated infection and, critically, did not carry infectious virus in the saliva, suggesting that viral transmission was blocked. Our data indicate that the use of Wolbachia-harboring mosquitoes could represent an effective mechanism to reduce Zika virus transmission and should be included as part of Zika control strategies.


AliView: a fast and lightweight alignment viewer and editor for large datasets.
AliView is an alignment viewer and editor designed to meet the requirements of next-generation sequencing era phylogenetic datasets. AliView handles alignments of unlimited size in the formats most commonly used, i.e. FASTA, Phylip, Nexus, Clustal and MSF. The intuitive graphical interface makes it easy to inspect, sort, delete, merge and realign sequences as part of the manual filtering process of large datasets. AliView also works as an easy-to-use alignment editor for small as well as large datasets. AliView is released as open-source software under the GNU General Public License, version 3.0 (GPLv3), and is available at GitHub (www.github.com/AliView). The program is cross-platform and extensively tested on Linux, Mac OS X and Windows systems. Downloads and help are available at http://ormbunkar.se/aliview email@example.com Supplementary data are available at Bioinformatics online.


Ancestral Haplotype Mapping for GWAS and Detection of Signatures of Selection in Admixed Dairy Cattle of Kenya.
Understanding the genetic structure of adaptation and productivity in challenging environments is necessary for designing breeding programs that suit such conditions. Crossbred dairy cattle in East Africa resulting from over 60 years of crossing exotic dairy breeds with indigenous cattle plus inter se matings form a highly variable admixed population. This population has been subject to natural selection in response to environmental stresses, such as harsh climate, low-quality feeds, poor management, and strong disease challenge. Here, we combine two complementary sets of analyses, genome-wide association (GWA) and signatures of selection (SoS), to identify genomic regions that contribute to variation in milk yield and/or contribute to adaptation in admixed dairy cattle of Kenya. Our GWA separates SNP effects due to ancestral origin of alleles from effects due to within-population linkage disequilibrium. The results indicate that many genomic regions contributed to the high milk production potential of modern dairy breeds with no region having an exceptional effect. For SoS, we used two haplotype-based tests to compare haplotype length variation within admixed and between admixed and East African Shorthorn Zebu cattle populations. The integrated haplotype score (iHS) analysis identified 16 candidate regions for positive selection in the admixed cattle while the between population Rsb test detected 24 divergently selected regions in the admixed cattle compared to East African Shorthorn Zebu. We compare the results from GWA and SoS in an attempt to validate the most significant SoS results. Only four candidate regions for SoS intersect with GWA regions using a low stringency test. The identified SoS candidate regions harbored genes in several enriched annotation clusters and overlapped with previously found QTLs and associations for different traits in cattle. If validated, the GWA and SoS results indicate potential for SNP-based genomic selection for genetic improvement of smallholder crossbred cattle.


The Effects of Test Trial and Processing Level on Immediate and Delayed Retention.
The purpose of the present study was to investigate the effects of test trial and processing level on immediate and delayed retention. A 2 × 2 × 2 mixed ANOVAs was used with two between-subject factors of test trial (single test, repeated test) and processing level (shallow, deep), and one within-subject factor of final recall (immediate, delayed). Seventy-six college students were randomly assigned first to the single test (studied the stimulus words three times and took one free-recall test) and the repeated test trials (studied the stimulus words once and took three consecutive free-recall tests), and then to the shallow processing level (asked whether each stimulus word was presented in capital letter or in small letter) and the deep processing level (whether each stimulus word belonged to a particular category) to study forty stimulus words. The immediate test was administered five minutes after the trials, whereas the delayed test was administered one week later. Results showed that single test trial recalled more words than repeated test trial in immediate final free-recall test, participants in deep processing performed better than those in shallow processing in both immediate and delayed retention. However, the dominance of single test trial and deep processing did not happen in delayed retention. Additional study trials did not further enhance the delayed retention of words encoded in deep processing, but did enhance the delayed retention of words encoded in shallow processing.


[Dental caries experience in children at public and private schools from a city with fluoridated water].
The aim of this study was to verify the relationship between type of school as a measure of socioeconomic conditions and caries prevalence among preschoolers and schoolchildren in Rio Claro, São Paulo State, Brazil, a city with fluoridated water supply. The data were secondary, from a sample of 888 children 5 to 12 years old enrolled in private and public schools. Caries was measured by the dmft and DMFT indices as well as the Care index. Qui-square and Mann-Whitney tests were utilized with 5% significance. In 5-year-old children, mean dmft was 2.50, and 42.20% were caries-free. At age 12, mean DMFT was 2.70 and 28.90% were caries-free. Caries prevalence rates in public schoolchildren as compared to private were 74.50% and 61.20%, respectively (p < 0.0001), and the dmft and DMFT scores were the highest in public schoolchildren (p < 0.05). The Care Index was higher in private schoolchildren (71.20%) as compared to public (52.80%). Highest caries rates were found among public schoolchildren, so the variable type of school proved sensitive for discriminating different oral health conditions; however limitations need to be recognized, suggesting that other variables should be assessed.


Clinical usefulness of electronic drug-drug interaction checking in the care of cardiovascular surgery inpatients.
Drug-related problems (DRPs) are events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes. This study tested the applicability of clinical decision support software in identifying and managing DRPs among cardiovascular surgery inpatients. Two clinical pharmacologists attended ward rounds on a low-dependency cardiovascular surgery ward every 2 weeks over a 7-month period. Three hundred and three patients were assessed. On average, patients received 17 scheduled and 'as required' medicines. DRPs were identified 'manually' via assessment of electronic prescription charts and patient records and 'electronically' using clinical decision support software (Pharmavista). The numbers of alerts for optimizing medication safety generated by the two methods were compared. Manual checking identified 346 DRPs leading to 346 alerts in 201 patients (overall 1.1 alerts/patient). Relevant interactions accounted for 44% of DRPs detected by clinical pharmacologists. Clinical decision support software, which could only report interactions, however, generated 1,370 alerts (average 4.5 alerts/patient). Only 147 (11%) drug-drug interaction alerts were identical to those identified by manual checking; the remaining 89% were considered not clinically relevant. Compared to identification of DRPs by clinical pharmacologists, the clinical decision support software performed poorly due to over-alerting and inability to assess for problems not caused by drug-drug interactions.


A descriptive study comparing health attitudes of urban and rural oncology patients.
Rural patients have poor outcomes in cancer management. Previous studies have shown different health beliefs and values in rural populations with high levels of stoicism and fatalism, leading to later presentation and diagnosis, with subsequent poorer prognosis and survival. This study explores the relationship between urban or rural background and health attitudes of newly diagnosed oncology patients, attending one oncology unit in north Queensland, during a 5 month period. This study is a forerunner to a planned larger project to explore the research question: do oncology patients from rural backgrounds differ in their health attitudes and hope levels compared with those from urban backgrounds? The aim of this study was to determine the utility of the selected validated instruments, newly diagnosed patients' willingness and ability to complete the composite survey instrument, and to identify likely issues for inclusion and/or greater focus in the larger project. As pilot studies are also used to develop or refine research questions and hypotheses, this article also considers some research questions for the planned large scale study. Self-administered questionnaire survey of 47 patients newly referred to the Medical Oncology Department in The Townsville Cancer Centre. Scales used were: the EORTC QLQ-C30 to assess symptom burden and quality of life; the Duke UNS Functional Social Support Questionnaire to assess social support; the Herth Hope Index to assess hope; and the Multi-Dimensional Health Locus of Control to assess health beliefs. Data were collated and transformed according to the various scales' scoring manuals. Rurality was ascertained using the RRMA classification and patient self-assessment. Uni-variate analyses were conducted as small numbers precluded multi-variate analysis. Non-parametric Mann-Whitney U and Kruskal-Wallis tests were used where data were skewed, or categorical. Monte-Carlo estimations of p-values were generated. In all, 28 of 47 patients classified as rural, 27 were suitable for curative treatment, and 31 were male. Median age was 56 years. Some respondents (17%) identified as 'rural', although they had an urban residence, and vice versa. Health attitude scores were not affected by global health scores or by intent of treatment (palliative/curative). Males scored significantly higher for belief in chance. Rural patients scored significantly higher for internal belief and belief in chance. No statistically significant differences were evident between rural/urban patients by gender, nor social support scores. Hope levels were generally high with no significant difference between urban and rural patients, regardless of treatment intent. The study does reveal differences in health attitudes between urban and rural populations; however, there are several confounding factors which may contribute to this, especially gender. In this study women were under-represented. People with fatalistic beliefs (high belief in chance) tend to have poor initiative in health matters which may cause delay in seeking treatment, or poor compliance with treatment. Analysis is limited by small numbers of patients. This study is a pilot to a larger project to investigate health attitudes and decisions by oncology patients in northern Queensland. The questionnaire was well received by patients, but the need for a dedicated recruitment person was evident. There is a need to determine how patients identify in terms of rurality over and above their actual place of residence.


Effects of aqueous celery (Apium graveolens) extract on lipid parameters of rats fed a high fat diet.
The antihyperlipidemic property of aqueous celery extract was studied in rats. Two groups of Wistar rats were fed a high fat diet for eight weeks to induce hyperlipidemia. One group was supplemented with aqueous celery extract in the diet while the other group served as control. At the end of the experiment, a significant reduction was found in the serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations in the celery-treated rats. However, the concentration of hepatic TG was significantly higher in the celery-treated group than in the control group. Hepatic triacylglycerol lipase (HL) activity was found to be significantly lower in the celery-treated rats while the reverse was observed for the hepatic microsomal P450 content. Analysis of an ethereal extract of the aqueous extract of celery by thin layer chromatography (TLC) with two different solvent systems showed that the extract did not contain 3-n-butylphthalide (BuPh), a unique compound in celery that has previously been reported to have lipid-lowering action. Our study indicates that other active principle(s) could be responsible for the observed effects of aqueous celery extract on serum and hepatic lipid levels.


Post-SSRI Sexual Dysfunction: Clinical Characterization and Preliminary Assessment of Contributory Factors and Dose-Response Relationship.
Emerging evidence suggests that sexual dysfunction emerging during treatment with selective serotonin reuptake inhibitors (SSRIs) and/or serotonin-norepinephrine reuptake inhibitors (SNRIs) persists in some patients beyond drug discontinuation (post-SSRI sexual dysfunction [PSSD]). We sought to identify and characterize a series of such cases and explore possible explanatory factors and exposure-response relationship. Subjects who responded to an invitation in a forum dedicated to PSSD filled out a survey via online software. Case probability was defined according to the following 3 categories of increasing presumed likelihood of PSSD. Noncases did not meet the criteria for possible cases. Possible cases were subjects with normal pretreatment sexual function who first experienced sexual disturbances while using a single SSRI/SNRI, which did not resolve upon drug discontinuation for 1 month or longer as indicated by Arizona Sexual Experience Scale scores. High-probability cases were also younger than 50-year-olds; did not have confounding medical conditions, medications, or drug use; and had normal scores on the Hospital Anxiety and Depression Scale. Five hundred thirty-two (532) subjects completed the survey, among which 183 possible cases were identified, including 23 high-probability cases. Female sex, genital anesthesia, and depression predicted current sexual dysfunction severity, but dose/defined daily dose ratio and anxiety did not. Genital anesthesia did not correlate with depression or anxiety, but pleasureless orgasm was an independent predictor of both depression and case probability. Limitations of the study include retrospective design and selection and report biases that do not allow generalization or estimation of incidence. However, our findings add to previous reports and support the existence of PSSD, which may not be fully explained by alternative nonpharmacological factors related to sexual dysfunction, including depression and anxiety.


Neural network mechanism for the orientation behavior of sand scorpions towards prey.
Sand scorpions use their tactile sense organs on their legs to capture their prey. They are able to localize their prey by processing vibration signals generated by the prey movement. The central nervous system receives stimulus-locked neuron firings of the sense organs on their eight legs. It is believed that eight receptor neurons in the brain interact with each other with triad inhibitions and then a voting contribution of the receptor neurons is calculated to obtain the resource direction. This letter presents a neuronal model of the voting procedure to locate prey. The neural network consists of a sinusoidal array of neurons for the resource vector, and it has been tested on the orientation data of scorpions.


Nosocomial acquisition of Candida albicans: an epidemiologic study.
To evaluate the mechanism and risk factors associated with the nosocomial acquisition of Candida albicans, a 10-month prospective study was conducted in a 24-bed bone marrow transplant unit and an 8-bed medical intensive care unit of a university hospital. A total of 98 patients had samples taken on admission and during hospitalization for culture. Samples from hands of hospital personnel and environmental surfaces were also cultured. C. albicans was isolated from 52 patients, and each patient was matched with a control. Fourteen patients acquired C. albicans after admission to the study. Prior antibiotics and length of time spent in the unit were more common in patients with new acquisition of C. albicans than in controls (92% vs. 64% and 32.5 vs. 13.0 days, respectively). Restriction enzyme analysis revealed 32 strain types; 4 were common to 30 patients and 10 environmental surfaces. Identical strains of C. albicans from patients who were geographically and temporally associated suggests the exogenous nosocomial acquisition of C. albicans through indirect patient contact.


A systematic review of interventions used to treat catatonic symptoms in people with autistic spectrum disorders.
A systematic review was conducted to examine the efficacy of a range of treatments for autistic catatonia. The review identified 22 relevant papers, reporting a total of 28 cases including both adult and paediatric patients. Treatment methods included electroconvulsive therapy (ECT), medication, behavioural and sensory interventions. Quality assessment found the standard of the existing literature to be generally poor, with particular limitations in treatment description and outcome measurement. There is some limited evidence to support the use of ECT, high dose lorazepam and behavioural interventions for people with autistic catatonia. However, there is a need for controlled, high-quality trials. Reporting of side effects and adverse events should also be improved, in order to better evaluate the safety of these treatments.


Antimicrobial resistance and antibiotic stewardship programs in the ICU: insistence and persistence in the fight against resistance. A position statement from ESICM/ESCMID/WAAAR round table on multi-drug resistance.
Antimicrobial resistance (AMR) is a clear and present danger to patients in any intensive care unit (ICU) around the world. Whereas AMR may affect any patient in the hospital, patients in the ICU are particularly at risk of acquiring AMR infections due to the intensity of the treatment, use of invasive devices, increased risk of transmission and exposure to antibiotics. AMR is present in every ICU, although prevalence is geographically different and AMR pathogens encountered are variable. Intensive care and infectious disease specialists from the European Society of Intensive Care Medicine, European Society of Microbiology and Infectious Diseases and World Alliance Against Antimicrobial Resistance, united in the ANTARCTICA (Antimicrobial Resistance in Critical Care) coalition, call for increased awareness and action among health care professionals to reduce AMR development in critically ill patients, to improve treatment of AMR infections and to coordinate scientific research in this high-risk patient population. Close collaboration with other specialties, and combining these and other interventions in antibiotic stewardship programmes should be a priority in every ICU. Considerate antibiotic use and adopting strict infection control practices to halt AMR remains a responsibility shared by all healthcare workers, from physicians to maintenance personnel, from nurses to physiotherapists, from consultants to medical students. Together, we can reduce AMR in our ICUs and continue to treat our patients effectively.


Water oxidation intermediates on iridium oxide electrodes probed by in situ electrochemical SHINERS.
Shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) is applied to the study of a state-of-the-art water oxidation electrocatalyst, IrOx, during oxygen evolution. The excellent sensitivity allows for in situ detection of surface intermediate species during cyclic voltammetry. Features in the Raman spectrum are correlated with the redox behaviour of the electrode, demonstrating a way to study the mechanisms of electrocatalytic water splitting using equipment available in most laboratories.


Cerebral oxygenation and optimal vascular brain organization.
The cerebral vascular network has evolved in such a way so as to minimize transport time and energy expenditure. This is accomplished by a subtle combination of the optimal arrangement of arteries, arterioles and capillaries and the transport mechanisms of convection and diffusion. Elucidating the interaction between cerebral vascular architectonics and the latter physical mechanisms can catalyse progress in treating cerebral pathologies such as stroke, brain tumours, dementia and targeted drug delivery. Here, we show that brain microvascular organization is predicated on commensurate intracapillary oxygen convection and parenchymal diffusion times. Cross-species grey matter results for the rat, cat, rabbit and human reveal very good correlation between the cerebral capillary and tissue mean axial oxygen convective and diffusion time intervals. These findings agree with the constructal principle.


Neuronal oscillations and functional interactions between resting state networks.
Functional magnetic imaging (fMRI) studies showed that resting state activity in the healthy brain is organized into multiple large-scale networks encompassing distant regions. A key finding of resting state fMRI studies is the anti-correlation typically observed between the dorsal attention network (DAN) and the default mode network (DMN), which - during task performance - are activated and deactivated, respectively. Previous studies have suggested that alcohol administration modulates the balance of activation/deactivation in brain networks, as well as it induces significant changes in oscillatory activity measured by electroencephalography (EEG). However, our knowledge of alcohol-induced changes in band-limited EEG power and their potential link with the functional interactions between DAN and DMN is still very limited. Here we address this issue, examining the neuronal effects of alcohol administration during resting state by using simultaneous EEG-fMRI. Our findings show increased EEG power in the theta frequency band (4-8 Hz) after administration of alcohol compared to placebo, which was prominent over the frontal cortex. More interestingly, increased frontal tonic EEG activity in this band was associated with greater anti-correlation between the DAN and the frontal component of the DMN. Furthermore, EEG theta power and DAN-DMN anti-correlation were relatively greater in subjects who reported a feeling of euphoria after alcohol administration, which may result from a diminished inhibition exerted by the prefrontal cortex. Overall, our findings suggest that slow brain rhythms are responsible for dynamic functional interactions between brain networks. They also confirm the applicability and potential usefulness of EEG-fMRI for central nervous system drug research.


Validity of Postural Sway Assessment on the Biodex BioSway™ Compared With the NeuroCom Smart Equitest.
Current tools for sideline assessment of balance following a concussion may not be sufficiently sensitive to identify impairments, which may place athletes at risk for future injury. Quantitative field-expedient balance assessments are becoming increasingly accessible in sports medicine and may improve sensitivity to enable clinicians to more readily detect these subtle deficits. To determine the validity of the postural sway assessment on the Biodex BioSway™ compared with the gold standard NeuroCom Smart Equitest System. Cross-sectional cohort study. Clinical research laboratory. Forty-nine healthy adults (29 females: 24.34 [2.45] y, height 163.65 [7.57] cm, mass 63.64 [7.94] kg; 20 males: 26.00 [3.70] y, height 180.11 [7.16] cm, mass 82.97 [12.78] kg). The participants completed the modified clinical test of sensory interaction in balance on the Biodex BioSway™ with 2 additional conditions (head shake and firm surface; head shake and foam surface) and the Sensory Organization Test and Head Shake Sensory Organization Test on the NeuroCom Smart Equitest. Interclass correlation coefficient and Bland-Altman limits of agreement for Sway Index, equilibrium ratio, and area of 95% confidence ellipse. Fair-good reliability (interclass correlation coefficient = .48-.65) was demonstrated for the stance conditions with eyes open on a firm surface. The Head Shake Sensory Interaction and Balance Test condition on a firm surface resulted in fair reliability (interclass correlation coefficient = .50-.59). The authors observed large ranges for limits of agreement across outcome measures, indicating that the systems should not be used interchangeably. The authors observed fair reliability between BioSway™ and NeuroCom, with better agreement between systems with the assessment of postural sway on firm/static surfaces. However, the agreement of these systems may improve by incorporating methods that mitigate the floor effect in an athletic population (eg, including a head shake condition). BioSway™ may provide a surrogate field-expedient measurement tool.


Inter-observer variation in delineation of the heart and left anterior descending coronary artery in radiotherapy for breast cancer: a multi-centre study from Denmark and the UK.
To determine the extent of inter-observer variation in delineation of the heart and left anterior descending coronary artery (LADCA) and its impact on estimated doses. Nine observers from five centres delineated the heart and LADCA on fifteen patients receiving left breast radiotherapy. The delineations were carried out twice, first without guidelines and then with a set of common guidelines. For the heart, most spatial variation in delineation was near the base of the heart whereas for the LADCA most variation was in its length at the apex of the heart. Common guidelines reduced the spatial variation for the heart and the length of the LAD, but increased the variation in the anterior-posterior/right-left plane. The coefficients of variation (CV) in the estimated doses to the heart were: mean dose 7.5% without and 3.6% with guidelines, maximum dose 8.7% without and 4.0% with guidelines. The CVs in the estimated doses to the LADCA were: mean dose 27% without and 29% with guidelines, maximum dose 39% without and 31% with guidelines. For the heart, there was little inter-observer variation in the estimated dose, especially when guidelines were used. In contrast, for the LADCA there was substantial variation in the estimated dose, which was not reduced with guidelines.


The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation.
There is increasing interest in the potential role of the NTRK family of neurotrophin receptors in human neoplasia. These receptor protein tyrosine kinases (PTKs) are well-known mediators of neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in mesenchymal, hematopoietic, and epithelial malignancies. We recently identified a novel gene fusion involving one of the neurotrophin receptor genes, NTRK3, in the pediatric solid tumor, congenital fibrosarcoma. In these tumors (and subsequently demonstrated in several other human malignancies), a t(12;15)(p13;q25) rearrangement fuses the 3' portion of the ETV6 gene with exons encoding the PTK domain of NTRK3. The resulting ETV6-NTRK3 fusion protein functions as a chimeric PTK with potent transforming activity. However, previous studies failed to detect interactions between ETV6-NTRK3 and molecules known to link wild-type NTRK3 to its two major effector pathways, namely the Ras-Raf1-Mek1-Erk1/2 mitogenic pathway or the phosphatidylinositol 3'-kinase pathway leading to activation of the AKT survival factor. Therefore, it remains unknown whether ETV6-NTRK3 transformation involves altered NTRK3 signaling. We now report that ETV6-NTRK3 expression in NIH3T3 cells leads to constitutive activation of Mek1 and Akt, as well as to constitutively high expression of cyclin D1. ETV6-NTRK3-induced soft agar colony formation was almost completely abolished by inhibition of either the Ras-Raf1-Mek1-Erk1/2 or the phosphatidylinositol 3'-kinase-Akt pathway. Moreover, this inhibition dramatically reduced expression of cyclin D1. Our results indicate that ETV6-NTRK3 transformation involves a link between known NTRK3 signaling pathways and aberrant cell cycle progression and that Mek1 and Akt activation act synergistically to mediate these effects.


Biotransformation products of 3,4,4'-trichlorocarbanilide in rat, monkey, and man.
3,4,4'-Trichlorocarbanilide (TCC), uniformly labeled with 14C in the monochloro ring, was administered to rats, rhesus monkeys, and humans. Radioactive materials in the plasma and urine of all three species and in the bile of rats and monkeys were separated by high performance liquid chromatography. The chromatography showed great similarity between the monkey and the human. Principal metabolites common to all species were the sulfate and glucuronide conjugates of 2'-, 3'-, and 6-hydroxy-TCC. The rat also produced the glucuronide and sulfate conjugates of 2',6-dihydroxy-TCC. The major urinary excretion products found in humans and monkeys were the N- and N'-TCC glucuronides.


A "Schrodinger Cat" Superposition State of an Atom
A "Schrodinger cat"-like state of matter was generated at the single atom level. A trapped 9Be+ ion was laser-cooled to the zero-point energy and then prepared in a superposition of spatially separated coherent harmonic oscillator states. This state was created by application of a sequence of laser pulses, which entangles internal (electronic) and external (motional) states of the ion. The Schrodinger cat superposition was verified by detection of the quantum mechanical interference between the localized wave packets. This mesoscopic system may provide insight into the fuzzy boundary between the classical and quantum worlds by allowing controlled studies of quantum measurement and quantum decoherence.


Synaptic vesicle-like lipidome of human cytomegalovirus virions reveals a role for SNARE machinery in virion egress.
Human cytomegalovirus induces and requires fatty acid synthesis. This suggests an essential role for lipidome remodeling in viral replication. We used mass spectrometry to quantify glycerophospholipids in mock-infected and virus-infected fibroblasts, as well as in virions. Although the lipid composition of mock-infected and virus-infected fibroblasts was similar, virions were markedly different. The virion envelope contained twofold more phosphatidylethanolamines and threefold less phosphatidylserines than the host cell. This indicates that the virus buds from a membrane with a different lipid composition from the host cell as a whole. Compared with published datasets, the virion envelope showed the greatest similarity to the synaptic vesicle lipidome. Synaptosome-associated protein of 25 kDa (SNAP-25) is a component of the complex that mediates exocytosis of synaptic vesicles in neurons; and its homolog, SNAP-23, functions in exocytosis in many other cell types. Infection induced the relocation of SNAP-23 to the cytoplasmic viral assembly zone, and knockdown of SNAP-23 inhibited the production of virus. We propose that cytomegalovirus capsids acquire their envelope by budding into vesicles with a lipid composition similar to that of synaptic vesicles, which subsequently fuse with the plasma membrane to release virions from the cell.


The evolution of a series of behavioral traits is associated with autism-risk genes in cavefish.
An essential question in evolutionary biology is whether shifts in a set of polygenic behaviors share a genetic basis across species. Such a behavioral shift is seen in the cave-dwelling Mexican tetra, Astyanax mexicanus. Relative to surface-dwelling conspecifics, cavefish do not school (asocial), are hyperactive and sleepless, adhere to a particular vibration stimulus (imbalanced attention), behave repetitively, and show elevated stress hormone levels. Interestingly, these traits largely overlap with the core symptoms of human autism spectrum disorder (ASD), raising the possibility that these behavioral traits are underpinned by a similar set of genes (i.e. a repeatedly used suite of genes). Here, we explored whether modification of ASD-risk genes underlies cavefish evolution. Transcriptomic analyses revealed that > 58.5% of 3152 cavefish orthologs to ASD-risk genes are significantly up- or down-regulated in the same direction as genes in postmortem brains from ASD patients. Enrichment tests suggest that ASD-risk gene orthologs in A. mexicanus have experienced more positive selection than other genes across the genome. Notably, these positively selected cavefish ASD-risk genes are enriched for pathways involved in gut function, inflammatory diseases, and lipid/energy metabolism, similar to symptoms that frequently coexist in ASD patients. Lastly, ASD drugs mitigated cavefish's ASD-like behaviors, implying shared aspects of neural processing. Overall, our study indicates that ASD-risk genes and associated pathways (especially digestive, immune and metabolic pathways) may be repeatedly used for shifts in polygenic behaviors across evolutionary time.


Blunt traumatic occult pneumothorax: is observation safe?--results of a prospective, AAST multicenter study.
An occult pneumothorax (OPTX) is found incidentally in 2% to 10% of all blunt trauma patients. Indications for intervention remain controversial. We sought to determine which factors predicted failed observation in blunt trauma patients. A prospective, observational, multicenter study was undertaken to identify patients with OPTX. Successfully observed patients and patients who failed observation were compared. Multivariate logistic regression was used to identify predictors of failure of observation. OPTX size was calculated by measuring the largest air collection along a line perpendicular from the chest wall to the lung or mediastinum. Sixteen trauma centers identified 588 OPTXs in 569 blunt trauma patients. One hundred twenty-one patients (21%) underwent immediate tube thoracostomy and 448 (79%) were observed. Twenty-seven patients (6%) failed observation and required tube thoracostomy for OPTX progression, respiratory distress, or subsequent hemothorax. Fourteen percent (10 of 73) failed observation during positive pressure ventilation. Hospital and intensive care unit lengths of stay, and ventilator days were longer in the failed observation group. OPTX progression and respiratory distress were significant predictors of failed observation. Most patient deaths were from traumatic brain injury. Fifteen percentage of patients in the failed observation group developed complications. No patient who failed observation developed a tension PTX, or experienced adverse events by delaying tube thoracostomy. Most blunt trauma patients with OPTX can be carefully monitored without tube thoracostomy; however, OPTX progression and respiratory distress are independently associated with observation failure.


Frequent emergency department presentations among people who inject drugs: A record linkage study.
People who inject drugs (PWID) have been described as frequent users of health services such as emergency departments (EDs), however few studies have described demographic factors, patterns of substance use and previous health service use associated with frequent use of EDs in this population. Using a combination of self-reported data from a cohort of PWID and administrative ED data obtained through record linkage, we identified longitudinal factors associated with the use of ED services. Bivariate and multivariate analyses were conducted using negative binomial regression to identify exposures associated with both cumulative ED presentations, and logistic regression to identify exposures of frequent ED presentations (defined as three or more annual presentations). Among 612 PWID, over half (58%) presented to EDs at least once and over a third (36%) presented frequently between January 2008 and June 2013. Frequent and cumulative ED presentations were associated with reporting the main drug of choice as cannabis (AOR:1.42, 95%CI:1.07-1.89 and AIRR:2.96, 95%CI:1.44-6.07 respectively) or methamphetamine (AOR:1.62, 95%CI:1.17-2.2 and AIRR:2.42, 95%CI:1.08-5.46 respectively) compared to heroin, and past month use of mental health (AOR:1.42, 95%CI:1.08-1.85 and AIRR:3.32, 95%CI:1.69-6.53 respectively) and outpatient services (AOR:1.47, 95%CI: 1.00-2.16 and AIRR:0.95, 95%CI 1.52-10.28 respectively). PWID who are frequent users of EDs are likely to have complex health and substance use-related needs. EDs should actively refer people who present with cannabis and methamphetamine dependence to harm reduction services. Harm reduction services should ensure people referred from EDs are screened for co-occurring mental health conditions and receive adequate support.


A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance.
We previously reported the existence of a unique autosomal recessive syndrome consisting of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance mapping to chromosome 15q26. In this manuscript, we have used whole exome sequencing on two affected members of a consanguineous family with this condition and carried out detailed bioinformatics analysis to elucidate the causative mutation. Our analysis resulted in the identification of a homozygous p.N1060S missense mutation in a highly conserved residue in KIF7, a regulator of Hedgehog signaling that has been recently found to be causing Joubert syndrome, fetal hydrolethalus and acrocallosal syndromes. The phenotype in our patients partially overlaps with the phenotypes associated with those syndromes but they also exhibit some distinctive features including multiple epiphyseal dysplasia. We report the first missense homozygous disease-causing mutation in KIF7 and expand the clinical spectrum associated with mutations in this gene to include multiple epiphyseal dysplasia. The missense nature of the mutation might account for the unique presentation in our patients.


Hippocampal alpha 7 and alpha 4 beta 2 nicotinic receptors and working memory.
Nicotine and other nicotinic receptor agonists have been found in a variety of studies to improve memory, while nicotinic receptor blockade can impair memory. The critical neural mechanisms for nicotinic involvement with memory are still under investigation. Initial evidence supports the involvement of the ventral hippocampus. Lesions in this area block nicotine-induced memory improvement and mecamylamine-induced impairment. Local ventral hippocampal application of the nicotinic channel blocker mecamylamine impairs memory in the 8-arm radial maze. Both alpha 4 beta 2 and alpha 7 nicotinic receptors seem to be involved. Ventral hippocampal infusions of high doses of the alpha 4 beta 2 nicotinic antagonist dihydro-beta-erythrodine (DH beta E) and the alpha 7 nicotinic antagonist methyllycaconitine (MLA) impair memory performance on the 8-arm radial maze. However, high doses of these drugs may limit specificity and they cause preconvulsant effects, which in themselves may affect memory. The current study used the more challenging 16-arm radial maze to determine the effects of lower doses of these drugs on memory and to differentiate effects on working and reference memory. Adult female Sprague-Dawley rats were trained on a working and reference memory task in the 16-arm radial maze and then were implanted with bilateral chronic guide cannulae directed to the ventral hippocampus. After recovery from surgery, the rats received acute intrahippocampal infusions of dose combinations of DH beta E and MLA. In the first study, DH beta E (0 and 6.75 microg/side) and MLA (0, 6.75, 13.5 and 27 microg/side) were administered in a counter-balanced order. In the second study, lower doses of DH beta E (0, 1.6375, 3.275 and 6.75 microg/side) were administered alone or with MLA (0 and 6.75 microg/side) in a counter-balanced order. In the first study, DH beta E caused a significant increase in both working and reference memory errors. MLA at a dose of 27 microg/side caused a significant increase in working memory errors, but this dose had no significant effect on reference memory errors. Interestingly, no additive effects were seen with combined administration of DH beta E and MLA in this study, and at the doses used, no effects were seen on response latency. In the second study, lower doses of DH beta E did not cause a significant deficit in working memory performance. Co-administration of MLA with these subthreshold doses did precipitate a memory impairment. The current results confirm the specificity of the memory deficits caused by these drugs. These results support the involvement of alpha 4 beta 2 and alpha 7 nicotinic receptors in the ventral hippocampus as being critical for memory function.


Odin (ANKS1A) is a Src family kinase target in colorectal cancer cells.
Src family kinases (SFK) are implicated in the development of some colorectal cancers (CRC). One SFK member, Lck, is not detectable in normal colonic epithelium, but becomes aberrantly expressed in a subset of CRCs. Although SFK have been extensively studied in fibroblasts and different types of immune cells, their physical and functional targets in many epithelial cancers remain poorly characterised. 64 CRC cell lines were tested for expression of Lck. SW620 CRC cells, which express high levels of Lck and also contain high basal levels of tyrosine phosphorylated (pY) proteins, were then analysed to identify novel SFK targets. Since SH2 domains of SFK are known to often bind substrates after phosphorylation by the kinase domain, the LckSH2 was compared with 14 other SH2s for suitability as affinity chromatography reagent. Mass spectrometric analyses of LckSH2-purified pY proteins subsequently identified several proteins readily known as SFK kinase substrates, including cortactin, Tom1L1 (SRCASM), GIT1, vimentin and AFAP1L2 (XB130). Additional proteins previously reported as substrates of other tyrosine kinase were also detected, including the EGF and PDGF receptor target Odin. Odin was further analysed and found to contain substantially less pY upon inhibition of SFK activity in SW620 cells, indicating that it is a formerly unknown SFK target in CRC cells. Rapid identification of known and novel SFK targets in CRC cells is feasible with SH2 domain affinity chromatography. The elucidation of new SFK targets like Odin in epithelial cancer cells is expected to lead to novel insight into cancer cell signalling mechanisms and may also serve to indicate new biomarkers for monitoring tumor cell responses to drug treatments.


Determination of glyphosate in groundwater samples using an ultrasensitive immunoassay and confirmation by on-line solid-phase extraction followed by liquid chromatography coupled to tandem mass spectrometry.
Despite having been the focus of much attention from the scientific community during recent years, glyphosate is still a challenging compound from an analytical point of view because of its physicochemical properties: relatively low molecular weight, high polarity, high water solubility, low organic solvent solubility, amphoteric behaviour and ease to form metal complexes. Large efforts have been directed towards developing suitable, sensitive and robust methods for the routine analysis of this widely used herbicide. In the present work, a magnetic particle immunoassay (IA) has been evaluated for fast, reliable and accurate part-per-trillion monitoring of glyphosate in water matrixes, in combination with a new analytical method based on solid-phase extraction (SPE), followed by liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS), for the confirmatory analysis of positive samples. The magnetic particle IA has been applied to the analysis of about 140 samples of groundwater from Catalonia (NE Spain) collected during four sampling campaigns. Glyphosate was present above limit of quantification levels in 41% of the samples with concentrations as high as 2.5 μg/L and a mean concentration of 200 ng/L. Good agreement was obtained when comparing the results from IA and on-line SPE-LC-MS/MS analyses. In addition, no false negatives were obtained by the use of the rapid IA. This is one of the few works related to the analysis of glyphosate in real groundwater samples and the presented data confirm that, although it has low mobility in soils, glyphosate is capable of reaching groundwater.