A common perceptual parameter for stair climbing for children, young and old adults.
In this paper we examine whether a common perceptual parameter is available for guiding old adults, young adults and children in climbing the highest stair mountable in a bipedal fashion. Previous works have shown that the ratio between the height of the stair and the hip height was the body-scaled invariance adopted as information for selecting the highest stair by young adults [Journal of Experimental Psychology: Human Perception and Performance 10 (1984) 683-703] but not by older adults [Journal of Experimental Psychology: Human Perception and Performance 3 (1992) 691-697]. Indeed, for older adults additional bio-mechanical parameters needed to be added to the model due to their decrease in leg strength and flexibility.Up to now, no perceptual invariant has been identified yet for determining the relevant information used for guiding the stair climbing action for normal healthy people. We propose a new parameter as the angle defined by the ratio between the height of the stair and the distance taken from the feet to the top edge of the stair before the initiation of the movement. We show that this angle is the same for children, young adults and older adults despite the different kinematics of the motion, the anthropometrics and the skill ability exhibit by the participants. In summary we show that even when the climbability judgments, based on the simple ratio leg length-stair height, are influenced by differences in age, participants use a common perceptual variable when they are coordinating their stair climbing action.


Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.
Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general population, but there are no comprehensive guidelines for the prevention of diseases and complications after renal transplantation. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guidelines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpatient screening for and prevention of diseases and complications that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and complications after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that supports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.


Cuban Scientific Production on Diabetes, 2000-2017: Peer-reviewed Publications, Collaboration and Impact.
INTRODUCTION The steadily increasing prevalence of diabetes globally has captured researchers' attention. Cuban production of scientific articles on diabetes has not been studied from a bibliometric perspective. OBJECTIVE Characterize the production and impact of research and review articles on diabetes by Cuban authors in journals listed in the Scopus bibliographic database, as well as related collaboration among Cuban institutions and between Cuban and non-Cuban institutions. METHODS A bibliometric analysis was conducted using 2000-2017 data from the Scopus database. The following search strategy was used: descriptor (diabetes), country (Cuba), publication source (journal), article type (original research, review article). Bibliographic indicators of production, visibility, impact and collaboration were examined. RESULTS Cuba contributed 3.2% of Latin American production and 0.1% of global production related to diabetes. Within Cuba's scientific production (610 articles, 538 original research and 72 review), 85.9% had a Cuban corresponding author (Cuban leadership). In articles with international collaboration (22.9%), however, most (67.9%) had non-Cuban corresponding authors. A total of 47% (287) were articles involving a single institution. Only 11.1% were published in top-ranked journals, and 14.4% were cited >10 times. Cubans were lead authors on 0.3% of the most frequently cited (top 10%) articles on diabetes in Scopus. A total of 38.4% of this production appeared in low-impact journals and 57.9% in Cuban journals. Articles published in English accounted for 30% of total and obtained higher impact in terms of citations than articles in Spanish. The strongest networks for scientific collaboration were those that connected Cuban and US researchers. CONCLUSIONS Cuban scientists conduct research on diabetes, but their work is not highly visible in the peer-reviewed literature, particularly in top-ranked journals. The problem is not simply one of publishing more, but of knowing how and where to publish. It is urgent that Cuban universities training health professionals at all levels include instruction on scientific writing.


Overcoming shadows in 3-source photometric stereo.
Light occlusions are one of the most significant difficulties of photometric stereo methods. When three or more images are available without occlusion, the local surface orientation is overdetermined so that shape can be computed and the shadowed pixels can be discarded. In this paper, we look at the challenging case when only two images are available without occlusion, leading to a one degree of freedom ambiguity per pixel in the local orientation. We show that, in the presence of noise, integrability alone cannot resolve this ambiguity and reconstruct the geometry in the shadowed regions. As the problem is ill-posed in the presence of noise, we describe two regularization schemes that improve the numerical performance of the algorithm while preserving the data. Finally, the paper describes how this theory applies in the framework of color photometric stereo where one is restricted to only three images and light occlusions are common. Experiments on synthetic and real image sequences are presented.


STAMP: Extensions to the STADEN sequence analysis package for high throughput interactive microsatellite marker design.
Microsatellites (MSs) are DNA markers with high analytical power, which are widely used in population genetics, genetic mapping, and forensic studies. Currently available software solutions for high-throughput MS design (i) have shortcomings in detecting and distinguishing imperfect and perfect MSs, (ii) lack often necessary interactive design steps, and (iii) do not allow for the development of primers for multiplex amplifications. We present a set of new tools implemented as extensions to the STADEN package, which provides the backbone functionality for flexible sequence analysis workflows. The possibility to assemble overlapping reads into unique contigs (provided by the base functionality of the STADEN package) is important to avoid developing redundant markers, a feature missing from most other similar tools. Our extensions to the STADEN package provide the following functionality to facilitate microsatellite (and also minisatellite) marker design: The new modules (i) integrate the state-of-the-art tandem repeat detection and analysis software PHOBOS into workflows, (ii) provide two separate repeat detection steps - with different search criteria - one for masking repetitive regions during assembly of sequencing reads and the other for designing repeat-flanking primers for MS candidate loci, (iii) incorporate the widely used primer design program PRIMER3 into STADEN workflows, enabling the interactive design and visualization of flanking primers for microsatellites, and (iv) provide the functionality to find optimal locus- and primer pair combinations for multiplex primer design. Furthermore, our extensions include a module for storing analysis results in an SQLite database, providing a transparent solution for data access from within as well as from outside of the STADEN Package. The STADEN package is enhanced by our modules into a highly flexible, high-throughput, interactive tool for conventional and multiplex microsatellite marker design. It gives the user detailed control over the workflow, enabling flexible combinations of manual and automated analysis steps. The software is available under the OpenBSD License 12. The high efficiency of our automated marker design workflow has been confirmed in three microsatellite development projects.


Sampling Methods for Detection and Monitoring of the Asian Citrus Psyllid (Hemiptera: Psyllidae).
The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama is a key pest of citrus due to its role as vector of citrus greening disease or "huanglongbing." ACP monitoring is considered an indispensable tool for management of vector and disease. In the present study, datasets collected between 2009 and 2013 from 245 citrus blocks were used to evaluate precision, sensitivity for detection, and efficiency of five sampling methods. The number of samples needed to reach a 0.25 standard error-mean ratio was estimated using Taylor's power law and used to compare precision among sampling methods. Comparison of detection sensitivity and time expenditure (cost) between stem-tap and other sampling methodologies conducted consecutively at the same location were also assessed. Stem-tap sampling was the most efficient sampling method when ACP densities were moderate to high and served as the basis for comparison with all other methods. Protocols that grouped trees near randomly selected locations across the block were more efficient than sampling trees at random across the block. Sweep net sampling was similar to stem-taps in number of captures per sampled unit, but less precise at any ACP density. Yellow sticky traps were 14 times more sensitive than stem-taps but much more time consuming and thus less efficient except at very low population densities. Visual sampling was efficient for detecting and monitoring ACP at low densities. Suction sampling was time consuming and taxing but the most sensitive of all methods for detection of sparse populations. This information can be used to optimize ACP monitoring efforts.


Epidemiology and treatment of angiolymphoid hyperplasia with eosinophilia (ALHE): A systematic review.
Current knowledge of angiolymphoid hyperplasia with eosinophilia (ALHE) derives from retrospective reports and case series, leading to a nonevidence-based treatment approach. We sought to systematically review the literature relating to cutaneous ALHE to estimate its epidemiology and treatment outcomes. A literature search of PubMed, EMBASE, Web of Science, and Google Scholar was conducted. Articles detailing cases of histologically confirmed cutaneous ALHE were included. In all, 416 studies were included in the review, representing 908 patients. There was no sex predominance among patients with ALHE. Mean age at presentation was 37.6 years. There was a significant association between presence of multiple lesions and pruritus, along with bleeding. Surgical excision was the most commonly reported treatment for ALHE. Treatment failure was lowest for excision and pulsed dye laser. Mean disease-free survival after excision was 4.2 years. There were higher rates of recurrence postexcision with earlier age of onset, longer duration of disease, multiple lesions, bilateral lesions, pruritus, pain, and bleeding. Potential for publication bias is a limitation. Surgical excision appears to be the most effective treatment for ALHE, albeit suboptimal. Pulsed dye and other lasers may be effective treatment options. More studies are needed to improve the treatment of ALHE.


Cascaded multiplexed optical link on a telecommunication network for frequency dissemination.
We demonstrate a cascaded optical link for ultrastable frequency dissemination comprised of two compensated links of 150 km and a repeater station. Each link includes 114 km of Internet fiber simultaneously carrying data traffic through a dense wavelength division multiplexing technology, and passes through two routing centers of the telecommunication network. The optical reference signal is inserted in and extracted from the communication network using bidirectional optical add-drop multiplexers. The repeater station operates autonomously ensuring noise compensation on the two links and the ultra-stable signal optical regeneration. The compensated link shows a fractional frequency instability of 3 x 10(-15) at one second measurement time and 5 x 10(-20) at 20 hours. This work paves the way to a wide dissemination of ultra-stable optical clock signals between distant laboratories via the Internet network.


Mathematical model for photocatalytic destruction of organic contaminants in air.
Photocatalytic oxidation (PCO) was investigated in a bench-scale reactor for the abatement of two airborne organic contaminants: toluene and ethanol. A mathematical model that includes the impacts of light intensity, initial contaminant concentration, catalyst thickness, and relative humidity (RH) on the degradation of organic contaminants in a photocatalytic reactor was developed to describe this process. The commercially available catalyst Degussa-PtTiO2 was selected to compare with the MTU-PtTiO2-350 catalyst, which was synthesized by the sol-gel process, platinized, and calcined at 350 degrees C. For toluene removal using the MTU-PtTiO2-350 catalyst, the degradation rate increased with increases in light intensity from 0.2 to 2.2 mW/cm2 and in catalyst thickness from 0.00037 to 0.00361 cm. However, further increases in light intensity and catalyst thickness had only slight effect on the toluene degradation rate. Increasing the initial concentration from 6.29 to 127.9 microg/L and the RH from 10 to 85% resulted in decreases in the toluene degradation rate. For ethanol removal using the MTU-PtTiO2-350 catalyst, the degradation rate increased more rapidly with an increase in RH from 17 to 56%; the RH had little effect on the ethanol degradation rate while it further increased from 56% to 82%. We discuss applicability of the model to estimate the influence of process variables and to evaluate photocatalyst performance.


A Simulation Model of Periarterial Clearance of Amyloid-β from the Brain.
The accumulation of soluble and insoluble amyloid-β (Aβ) in the brain indicates failure of elimination of Aβ from the brain with age and Alzheimer's disease (AD). There is a variety of mechanisms for elimination of Aβ from the brain. They include the action of microglia and enzymes together with receptor-mediated absorption of Aβ into the blood and periarterial lymphatic drainage of Aβ. Although the brain possesses no conventional lymphatics, experimental studies have shown that fluid and solutes, such as Aβ, are eliminated from the brain along 100 nm wide basement membranes in the walls of cerebral capillaries and arteries. This lymphatic drainage pathway is reflected in the deposition of Aβ in the walls of human arteries with age and AD as cerebral amyloid angiopathy (CAA). Initially, Aβ diffuses through the extracellular spaces of gray matter in the brain and then enters basement membranes in capillaries and arteries to flow out of the brain. Although diffusion through the extracellular spaces of the brain has been well characterized, the exact mechanism whereby perivascular elimination of Aβ occurs has not been resolved. Here we use a computational model to describe the process of periarterial drainage in the context of diffusion in the brain, demonstrating that periarterial drainage along basement membranes is very rapid compared with diffusion. Our results are a validation of experimental data and are significant in the context of failure of periarterial drainage as a mechanism underlying the pathogenesis of AD as well as complications associated with its immunotherapy.


International reach of tobacco marketing among young children.
Prosmoking messages, delivered through marketing and the media, can reach very young children and influence attitudes and behaviors around smoking. This study examined the reach of tobacco marketing to 5 and 6 year olds in 6 low- and middle-income countries. Researchers worked one-on-one with 5 and 6 year olds in Brazil, China, India, Nigeria, Pakistan, and Russia (N = 2423). The children were asked to match logos with pictures of products, including 8 logos for cigarette brands. Analyses examined, overall and by country, whether gender, age, location, household use of tobacco, and knowledge of media characters were associated with awareness of cigarette brand logos. Additional analyses considered the relationship between cigarette brand logo awareness and intentions to smoke. Overall, 68% of 5 and 6 year olds could identify at least 1 cigarette brand logo, ranging from 50% in Russia to 86% in China. Across countries, being slightly older and having someone in the household who used tobacco, were significantly associated with greater odds of being able to identify at least 1 cigarette brand logo. The majority of young children from low- and middle-income countries are familiar with cigarette brands. This study's findings suggest that more effective measures are needed to restrict the reach of tobacco marketing.


Coactivation of TLR2 and TLR8 in Primary Human Monocytes Triggers a Distinct Inflammatory Signaling Response.
Innate immune signaling is essential to mount a fast and specific immune response to pathogens. Monocytes and macrophages are essential cells in the early response in their capacity as ubiquitous phagocytic cells. They phagocytose microorganisms or damaged cells and sense pathogen/damage-associated molecular patterns (PAMPs/DAMPs) through innate receptors such as Toll-like receptors (TLRs). We investigated a phenomenon where co-signaling from TLR2 and TLR8 in human primary monocytes provides a distinct immune activation profile compared to signaling from either TLR alone. We compare gene signatures induced by either stimulus alone or together and show that co-signaling results in downstream differences in regulation of signaling and gene transcription. We demonstrate that these differences result in altered cytokine profiles between single and multi-receptor signaling, and show how it can influence both T-cell and neutrophil responses. The end response is tailored to combat extracellular pathogens, possibly by modifying the regulation of IFNβ and IL12-family cytokines.


Heading off depressive illness evolution and progression to treatment resistance.
Viewing recurrent depression as a potentially progressive illness may help transform treatment toward earlier, more consistent intervention and prevention. Evidence indicates that recurrent stressors, episodes of depression, and bouts of substance abuse can each show sensitization (increased reactivity upon repetition) and cross-sensitization to the others, and drive illness progression and treatment resistance. These long-lasting increases in pathological responsivity appear to be mediated by epigenetic mechanisms involving alterations in chemical marks placed on DNA and histories. These types of sensitization effects are amenable to clinical attempts at amelioration and prevention, and provide treatment targets and strategies to minimize the likelihood of illness progression to treatment resistance.


Prenatal terbutaline treatment: tissue-selective dissociation of perinatal changes in beta-adrenergic receptor binding from regulation of adenylate cyclase activity.
The role of prenatal beta-receptor stimulation in development of adrenergic reactivity was examined by administering the beta-agonist, terbutaline, to pregnant rats on gestational days 17, 18 and 19. On gestational day 20, liver membrane beta-receptor binding capabilities showed the depression characteristic of down-regulation, but heart and kidney receptor binding were essentially normal. Basal adenylate cyclase activity in the fetal liver membrane preparation was unchanged by terbutaline exposure and enzymatic reactivity to beta-adrenergic stimulation showed only a slight lowering; forskolin stimulation, however, was markedly increased in the terbutaline group. By postnatal day 2, receptor binding had returned to normal in the liver and remained at control levels in the other two tissues. Responsivity of adenylate cyclase to beta-receptor stimulation was markedly elevated in heart and kidney membranes; the effect represented an alteration at the level of the cyclase itself, rather than the receptor, since both basal activity and forskolin stimulation of the enzyme showed equivalent enhancement. These data thus suggest that early beta-adrenergic stimulation promotes cellular reactivity by fostering the development of membrane transduction mechanisms, rather than through effects on the receptor ligand binding site per se.


The granulocytes in neutropenia 1 (GIN 1) study: a safety study of granulocytes collected from whole blood and stored in additive solution and plasma.
To evaluate the safety of transfusing pooled, whole blood-derived granulocytes in additive solution and plasma (GASP) in 30 recipients. Demand for granulocytes in England has increased five-fold. With the advantages of reduced red cell, plasma and overall volume, GASP maintains function in vitro. Observations were recorded prior to and post transfusion. Increments were recorded at 1 h and the following morning. Leucocyte antibody screening was undertaken prior to and at 1-6 months following transfusion. Thirty patients aged between 8 months and 68 years received 221 GASP in 148 transfusion episodes. GASP contained an average of 1.0 × 10(10) granulocytes in 207 mL. Adults usually received two packs and children 10-20 mL kg(-1). Children and adults received a median [interquartile range (IQR)] dose of 12.5 (9.1-25.3) and 19.7 (12.0-25.8) × 10(9) granulocytes per transfusion, respectively. There was one episode of transfusion-associated circulatory overload (TACO) in a patient with chronic cardiac failure following 600 mL of unpooled granulocytes, other fluids and one GASP. New leucocyte alloimmunisation occurred in 3/30 recipients 10%. No other significant reactions were reported. Median peripheral blood neutrophil increments at 1 h post transfusion were 0.06 (IQR, 0.01-0.17) in children and (0.03) (IQR, 0-0.16) in adults. GASP has a similar safety profile to other sources of granulocytes for patients with refractory infection or in need of secondary prophylactic transfusion. Further studies are required to clarify the role of GASP in the treatment of neutropenic patients.


Differential flexibility leading to crucial microelastic properties of asymmetric lipid vesicles for cellular transfection: A combined spectroscopic and atomic force microscopy studies.
The role of microscopic elasticity of nano-carriers in cellular uptake is an important aspect in biomedical research. Herein we have used AFM nano-indentation force spectroscopy and Förster resonance energy transfer (FRET) measurements to probe microelastic properties of three novel cationic liposomes based on di-alkyl dihydroxy ethyl ammonium chloride based lipids having asymmetry in their hydrophobic chains (Lip1818, Lip1814 and Lip1810). AFM data reveals that symmetry in hydrophobic chains of a cationic lipid (Lip1818) imparts higher rigidity to the resulting liposomes than those based on asymmetric lipids (Lip1814 and Lip1810). The stiffness of the cationic liposomes is found to decrease with increasing asymmetry in the hydrophobic lipid chains in the order of Lip1818 > Lip1814 > lip1810. FRET measurements between Coumarin 500 (Donor) and Merocyanine 540 (Acceptor) have revealed that full width at half-maxima (hw) of the probability distribution (P(r)) of donor-acceptor distance (r), increases in an order Lip1818 < Lip1814 < Lip1810 with increasing asymmetry of the hydrophobic lipid chains. This increase in width (hw) of the donor-acceptor distance distributions is reflective of increasing flexibility of the liposomes with increasing asymmetry of their constituent lipids. Thus, the results from AFM and FRET studies are complementary to each other and indicates that an increase in asymmetry of the hydrophobic lipid chains increases elasticity and or flexibility of the corresponding liposomes. Cell biology experiments confirm that liposomal flexibility or rigidity directly influences their cellular transfection efficiency, where Lip1814 is found to be superior than the other two liposomes manifesting that a critical balance between flexibility and rigidity of the cationic liposomes is key to efficient cellular uptake. Taken together, our studies reveal how asymmetry in the molecular architecture of the hydrophobic lipid chains influences the microelastic properties of the liposomes, and hence, their cellular uptake efficiency.


Natural killer cells are present in the normal human lung but are functionally impotent.
The lung is affected by disorders in which natural killer (NK) cells are thought to play an important defensive role. This study, however, demonstrated that normal lung lymphocytes actually express very little NK cell activity (P less than 0.001 compared with blood lymphocytes). This was true independent of the NK-sensitive target used (K562, U937, MOLT-3, or Daudi). This lack of lung lymphocyte NK activity occurred even though the proportions of lymphocytes in the normal lower respiratory tract with the morphology (large granular lymphocytes) and surface antigen markers of NK cells were similar to that of blood (P greater than 0.5). Although normal lung lymphocytes bound to known NK-sensitive targets, they did not lyse these cells (P less than 0.001 compared with blood), which suggested that the lack of lung NK cell activity resulted from a relative inability of lung NK cells to destroy their targets. While the mechanisms of this functional impotence of lung NK cells are not clear, normal human alveolar macrophages and lower respiratory tract epithelial lining fluid exerted a profound suppressive effect on blood NK cell activity (P less than 0.001 for both) by inhibiting their ability to lyse target cells after binding (P less than 0.001). Though impotent initially, when incubated for 24 h in medium alone, normal lung lymphocytes demonstrated markedly enhanced NK activity (P less than 0.02), which suggested that lung NK cells do have the potential to express NK activity. Interleukin-2 (IL-2) further augmented this effect (P less than 0.05), but gamma interferon did not (P greater than 0.2). Consistent with this observation, lung lymphocytes from patients with active sarcoidosis, a disease in which lung lymphocytes are spontaneously releasing IL-2, did express NK cell activity (P less than 0.01). These studies suggest that although NK cells are present in the normal lung, they are functionally inactive, due, at least in part, to local inhibitory influences. In the presence of IL-2, however, lung NK cell activity is expressed, which suggests that lung NK cell activity can be modulated.


Brains of verbal memory specialists show anatomical differences in language, memory and visual systems.
We studied a group of verbal memory specialists to determine whether intensive oral text memory is associated with structural features of hippocampal and lateral-temporal regions implicated in language processing. Professional Vedic Sanskrit Pandits in India train from childhood for around 10years in an ancient, formalized tradition of oral Sanskrit text memorization and recitation, mastering the exact pronunciation and invariant content of multiple 40,000-100,000 word oral texts. We conducted structural analysis of gray matter density, cortical thickness, local gyrification, and white matter structure, relative to matched controls. We found massive gray matter density and cortical thickness increases in Pandit brains in language, memory and visual systems, including i) bilateral lateral temporal cortices and ii) the anterior cingulate cortex and the hippocampus, regions associated with long and short-term memory. Differences in hippocampal morphometry matched those previously documented for expert spatial navigators and individuals with good verbal working memory. The findings provide unique insight into the brain organization implementing formalized oral knowledge systems.


Divergent induction of apoptosis and IL-8 secretion in HT-29 cells in response to TNF-alpha and ligation of Fas antigen.
Colonic epithelial cell injury is the common manifestation of inflammatory diseases of the bowel. One form of epithelial injury is apoptosis. In our study, we investigated the mechanism leading to apoptosis in HT-29 cells in response to TNF-alpha and ligation of Fas Ag. HT-29 displayed a dual response to TNF-alpha and Fas Ag ligation: in combination with IFN-gamma, HT-29 cells underwent apoptosis, whereas independently, these factors stimulated secretion of IL-8. We used this model of immune-mediated epithelial cell injury to elucidate the signals leading to apoptosis in response to TNF-alpha and Fas Ag ligation compared with the signals leading to induction of IL-8 secretion. The model was further used to distinguish signaling differences between TNF-alpha receptors and the Fas Ag in this cell line. The experiments presented here demonstrate that Fas Ag ligation alone led to production of IL-8 by colonic epithelial cells and represented another function mediated by Fas Ag in addition to apoptosis. This study shows that the pathways leading to cell death and IL-8 production in response to Fas Ag ligation and TNF-alpha were similar with regard to their requirements for new gene expression, protein synthesis, and protein kinase activity. Specifically, new gene expression and protein synthesis were not necessary for TNF-alpha- and Fas Ag-mediated apoptosis, but were necessary for TNF-alpha- and Fas Ag-mediated IL-8 secretion. Tyrosine protein kinase phosphorylation was necessary to signal secretion of IL-8 in response to both agonists but it was not necessary for apoptosis. In spite of the similarities between these two agonists, the kinetics of apoptosis via Fas Ag were significantly more rapid than through the TNF-alpha receptor and serve to distinguish these two signals.


Injuries in West Indies cricket 2003-2004.
To analyse injuries in West Indies Cricket and compare them with those of other cricket playing nations. Injuries between June 2003 and December 2004 were surveyed prospectively in all major matches of the West Indies Cricket Board. Most injuries occurred in the West Indies Test and one day international teams. Mean match injury incidence was 48.7 per 10,000 player-hours in Test cricket, and 40.6 per 10,000 player-hours in one day international cricket, with injury prevalence of 11.3% and 8.1% respectively. In domestic cricket, the match injury incidence was 13.9 per 10,000 player-hours for first class cricket, and 25.4 per 10,000 player-hours in one day domestic competitions. There were more injuries on tour for the West Indies team than at home. The batsmen and fast bowlers sustained 80% of injuries, with many leading to long absence from the game, although many of these injuries were sustained while fielding. Most injuries were of the phalanges (22%) and the lumbar spine (20%) sustained mainly while fielding (including catching) and fast bowling respectively. Injuries in West Indies cricket may be reduced by (a) early detection and management of injuries on tour, (b) attention to fielding and catching techniques, and (c) monitoring of young fast bowlers.


Environmental distribution, analysis, and toxicity of organometal(loid) compounds.
The biochemical modification of the metals and metalloids mercury, tin, arsenic, antimony, bismuth, selenium, and tellurium via formation of volatile metal hydrides and alkylated species (volatile and involatile) performs a fundamental role in determining the environmental processing of these elements. In most instances, the formation of such species increases the environmental mobility of the element, and can result in bioaccumulation in lipophilic environments. While inorganic forms of most of these compounds are well characterized (e.g., arsenic, mercury) and some of them exhibit low toxicity (e.g., tin, bismuth), the more lipid-soluble organometals can be highly toxic. Methylmercury poisoning (e.g., Minamata disease) and tumor development in rats after exposure to dimethylarsinic acid or tributyltin oxide are just some examples. Data on the genotoxicity (and the neurotoxicity) as well as the mechanisms of cellular action of organometal(loid) compounds are, however, scarce. Many studies have shown that the production of such organometal(loid) species is possible and likely whenever anaerobic conditions (at least on a microscale) are combined with available metal(loid)s and methyl donors in the presence of suitable organisms. Such anaerobic conditions can exist within natural environments (e.g., wetlands, pond sediments) as well as within anthropogenic environmental systems (e.g., waste disposal sites and sewage treatments plants). Some methylation can also take place under aerobic conditions. This article gives an overview about the environmental distribution of organometal(loid) compounds and the potential hazardous effects on animal and human health. Genotoxic effects in vivo and in vitro in particular are discussed.


Ovarian dysgenesis associated with an unbalanced X;6 translocation: first characterisation of reproductive anatomy and cytogenetic evaluation in partial trisomy 6 with breakpoints at Xq22 and 6p23.
The aim of this study was to describe the clinical and laboratory findings associated with a previously unreported unbalanced X;6 translocation. Physical examination, reproductive history and cytogenetic techniques were used to characterise a novel chromosomal anomaly associated with gonadal dysgenesis. A healthy non-dysmorphic 23 year-old phenotypic female with primary amenorrhea and infertility presented for reproductive endocrinology evaluation. No discrete ovarian tissue was identified on transvaginal ultrasound, although the uterus appeared essentially normal. BMI was 19 kg/m2. Serum FSH and oestradiol were 111 mIU/ml and 15 pmol/l, respectively. TSH, prolactin and all infectious serologies were all normal. The karyotype of 46,X,der(X)t(X;6)(q22;p23) was determined following cytogenetic analysis of peripheral blood lymphocytes via fluorescence in situ hybridisation (FISH) with whole chromosome paint for chromosome 6, and a separate FISH analysis using a 6p subtelomeric probe. The patient was continued on hormone replacement therapy and underwent genetic counselling; the patient subsequently enrolled as a recipient in an anonymous donor oocyte IVF treatment. Translocations involving autosomes and chromosome X are rare. While female carriers of balanced X;autosome translocations are generally phenotypically normal, the impact of unbalanced X;autosome translocations can be severe. This is the first known report of an unbalanced translocation involving X;6. This abnormality was associated with ovarian dysgenesis, but an otherwise normal female phenotype. From this investigation, the observed developmental impact of the unbalanced translocation with breakpoints at Xq22 and 6p23 appears to be limited to ovarian failure.


A histomorphometric study of nanothickness and plasma-sprayed calcium-phosphorous-coated implant surfaces in rabbit bone.
Novel implant surface treatments with a nanothickness bioactive ceramic deposition onto rough surfaces have been recently introduced. This study aims to evaluate histologically and histomorphometrically (bone-to-implant contact [BIC] and bone area fraction occupancy [BAFO]) the early bone response to plasma-sprayed calcium-phosphate (PSCaP)-coated versus a 300- to 500-nm thickness bioactive ceramic nano-coated plateau root form implants in a rabbit femur model. A total of 48 plateau root form implants were bilaterally placed in the distal aspect of the femur of 12 white New Zealand rabbits, remaining for 20, 30, and 60 days in vivo (n = 4 animals per time in vivo, n = 2 implants per surface per animal). After sacrifice, the implants in bone were non-decalcified processed to slides of approximately 30 mum thickness, and were morphologically and morphometrically (BIC and BAFO) evaluated. Higher degrees of bone structural organization were temporally observed for the PSCaP surface compared to the nano surface over time. BIC and BAFO was significantly higher (P <0.05) for PSCaP at all implantation times evaluated. Within the limits of this study it is possible to state that bioactive ceramic coatings of both thicknesses were biocompatible and osteoconductive. However, the early bone response was favored by the presence of the thicker PSCaP coating.


Trimming of mammalian transcriptional networks using network component analysis.
Network Component Analysis (NCA) has been used to deduce the activities of transcription factors (TFs) from gene expression data and the TF-gene binding relationship. However, the TF-gene interaction varies in different environmental conditions and tissues, but such information is rarely available and cannot be predicted simply by motif analysis. Thus, it is beneficial to identify key TF-gene interactions under the experimental condition based on transcriptome data. Such information would be useful in identifying key regulatory pathways and gene markers of TFs in further studies. We developed an algorithm to trim network connectivity such that the important regulatory interactions between the TFs and the genes were retained and the regulatory signals were deduced. Theoretical studies demonstrated that the regulatory signals were accurately reconstructed even in the case where only three independent transcriptome datasets were available. At least 80% of the main target genes were correctly predicted in the extreme condition of high noise level and small number of datasets. Our algorithm was tested with transcriptome data taken from mice under rapamycin treatment. The initial network topology from the literature contains 70 TFs, 778 genes, and 1423 edges between the TFs and genes. Our method retained 1074 edges (i.e. 75% of the original edge number) and identified 17 TFs as being significantly perturbed under the experimental condition. Twelve of these TFs are involved in MAPK signaling or myeloid leukemia pathways defined in the KEGG database, or are known to physically interact with each other. Additionally, four of these TFs, which are Hif1a, Cebpb, Nfkb1, and Atf1, are known targets of rapamycin. Furthermore, the trimmed network was able to predict Eno1 as an important target of Hif1a; this key interaction could not be detected without trimming the regulatory network. The advantage of our new algorithm, relative to the original NCA, is that our algorithm can identify the important TF-gene interactions. Identifying the important TF-gene interactions is crucial for understanding the roles of pleiotropic global regulators, such as p53. Also, our algorithm has been developed to overcome NCA's inability to analyze large networks where multiple TFs regulate a single gene. Thus, our algorithm extends the applicability of NCA to the realm of mammalian regulatory network analysis.


Neoadjuvant Chemoradiation Therapy Is Associated with Adverse Outcomes in Patients Undergoing Pancreaticoduodenectomy for Pancreatic Cancer.
The use of neoadjuvant chemoradiation therapy in patients with pancreatic adenocarcinoma is emerging as an acceptable therapy option. The effects of neoadjuvant therapy on 30 days' outcomes in patients with pancreatic cancer are not well defined in the literature. NSQIP (2009-2012) was used. Only patients with a diagnosis of pancreatic cancer and those who underwent a Whipple were included in the analysis. Patient who underwent neoadjuvant chemoradiation therapy were compared with those who did not receive therapy. Main outcome measures were as follows: complications, ≥2 units of blood transfusions, length of stay, readmission rates, return to the operating room, and 30-day mortality. A total of 1445 patients (395: neoadjuvant chemoradiation and 1050: no neoadjuvant therapy) were identified. The mean age was 67 ± 12 years, and 51 per cent of the patients were male. Neoadjuvant chemoradiation therapy was associated with increase in readmission rates (18% vs 12.2%, P 0.02), unanticipated return to the operating room (2.3% vs 1.1%, P 0.03) with no difference in mortality rates. Neoadjuvant chemoradiation therapy is associated with increase in inhospital complications. These differences in outcomes may be explained by the more advance stage of pancreatic cancer in these subsets of patients. Resource utilization and preoperative rehabilitation are of utmost significance to overcome this rise in complications associated with neoadjuvant chemoradiation therapy.


Peritoneal dissemination of pancreatic cancer caused by endoscopic ultrasound-guided fine needle aspiration: A case report and literature review.
Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a biopsy technique widely used to diagnose pancreatic tumors because of its high sensitivity and specificity. Although needle-tract seeding caused by EUS-FNA has been recently reported, dissemination of pancreatic cancer cells is generally considered to be a rare complication that does not affect patient prognosis. However, the frequency of dissemination and needle-tract seeding appears to have been underestimated. We present a case of peritoneal dissemination of pancreatic cancer due to preoperative EUS-FNA. An 81-year-old man was referred to the Department of Surgery of our hospital in Japan owing to the detection of a pancreatic mass on computed tomography during medical screening. Trans-gastric EUS-FNA revealed that the mass was an adenocarcinoma; hence laparoscopic distal pancreatectomy with lympha-denectomy was performed. No intraoperative peritoneal dissemination and liver metastasis were visually detected, and pelvic lavage cytology was negative for carcinoma cells. The postoperative surgical specimen was negative for carcinoma cells at the dissected margin and the cut end margin; however, pathological findings revealed adenocarcinoma cells on the peritoneal surface proximal to the needle puncture site, and the cells were suspected to be disseminated via EUS- FNA. Hence, the patient received adjuvant therapy with S-1 (tegafur, gimeracil, and oteracil potassium); however, computed tomography performed 5 mo after surgery revealed liver metastasis and cancerous peritonitis. The patient received palliative therapy and died 8 mo after the operation. The indications of EUS-FNA should be carefully considered to avoid iatrogenic dissemination, especially for cancers in the pancreatic body or tail.


Responsibility, fairness and rationing in health care.
People make different choices about how to live their life and these choices have a significant effect on their health, the risks they face and their need for treatment in the future. The objective of this article is, drawing on normative political theory, to sketch an argument that assigns a limited but significant role to individual responsibility in the design of the health-care system. In developing our argument, we proceed in five steps. First, we review the literature on criteria for priority setting. Second, we explore the most prominent contemporary tradition in normative theory, liberal egalitarian ethics, with the aim to clarify the role of responsibility for choice. In particular, we discuss where liberal egalitarian theories would draw the 'cut' between the responsibility of the state (which is extensive) and the responsibility of the individuals (which is limited but significant). In the third step, we identify a priority setting dilemma where the commonly advocated criteria would assign equal priority. Finally, we develop a simple model in order to examine the implications of introducing a well-defined notion of responsibility for choice in a priority-setting dilemma of this kind. Liberal egalitarianism holds individuals responsible for choices that affect their health, given that (i) the illness is completely or partly a result of individual behaviour and choice; (ii) the illness is not life-threatening; (iii) the illness does not limit the use of political rights or the exercise of fundamental capabilities; and (iv) the cost of treatment is low relative to the income of the patients. The paper shows how this type of considerations can be used to determine an optimal level of co-payments for diseases even when individual choices cannot be observed directly. It is possible to assign a limited but significant role to individual responsibility in the rationing of health-care resources. The liberal egalitarian argument captures a concern that is not captured by traditional criteria for priorities in health care. It can thus help policy makers in situations where the cost-effectiveness of different alternatives and the severity of the illnesses are approximately the same, or if the society wants to assign some weight to responsibility for choice. It can easily be linked to a system of graduated co-payments, but need not be.


Applications of PET imaging with the proliferation marker [18F]-FLT.
[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.


Interspecies Engagement in Medical Anthropology.
Human-animal interdependencies define longstanding concerns for anthropologists. Within this vast terrain, medical anthropologists claim rights to a significant portion, marked most notably, perhaps, by our sustained attention to nonhuman species as pathogens, vectors, and reservoirs of disease. Our discipline, nevertheless, has been slow to engage with contemporary theorizing about interspecies entanglements, a deficit this volume's collection seeks to rectify. As I argue below, this collection opens up new domains of study, analysis, and understanding, where an especially important intervention involves enfolding interspecies sensibilities within praxes of care.


Aerobic Heterotrophic Bacterial Populations of Sewage and Activated Sludge: III. Adaptation in a Synthetic Waste.
The nature and behavior of the microbial population developed on a synthetic waste containing salts and sorbitol are compared to that of a treatment-plant activated sludge. The population of the adapted sludge developed on the synthetic waste consisted approximately of only six kinds of bacteria. Experiments with radioactive sorbitol indicate that the microbial population developed on the synthetic waste showed the effects of repression by glucose on the metabolism of sorbitol; in contrast, the activated sludge from a plant treating primarily domestic waste was able to attack both substrates immediately and simultaneously.


Effect of topical application of diclofenac liposomal suspension on experimentally induced subcutaneous inflammation in horses.
To determine whether 1% diclofenac liposomal suspension (DLS) ointment would be absorbed transdermally and attenuate experimentally induced subcutaneous inflammation in horses. 7 healthy adult horses. Inflammation was produced by injecting 1% sterile carrageenan into subcutaneously implanted tissue cages 8 hours before (time -8) and at the time of application of test ointment. A crossover design was used. Horses received 1 of 2 treatments (topically administered control or DLS ointments) during 48 hours of carrageenan-induced subcutaneous inflammation. A single application of test ointment (7.2 g) was applied over each tissue cage (time 0). Samples of transudate and blood were collected at -8, 0, 6, 12, 18, 24, 30, 36, and 48 hours. Plasma and transudate diclofenac concentrations were determined by use of high-performance liquid chromatography. Transudate concentrations of prostaglandin E2 (PGE2) were determined with a competitive enzyme immunoassay. DLS was absorbed transdermally. The highest concentration (mean +/- SEM, 76.2 +/- 29 ng/mL) was detectable in tissue-cage fluid within 18 hours after application. Minimal concentrations of diclofenac were detectable in plasma. Application of DLS significantly decreased transudate concentrations of PGE2 at 6 and 30 hours. Decreases in PGE2 concentration were observed in the DLS group at all collection times. A single topical application of DLS resulted in concentrations of diclofenac in transudate within 6 hours and significantly attenuated carrageenan-induced local production of PGE2. Results of this study suggest that DLS is readily absorbed transdermally and may be efficacious for reducing subcutaneous inflammation in horses.


Preclinical Evaluation of the Safety and Efficacy of Cryopreserved Bone Marrow Mesenchymal Stromal Cells for Corneal Repair.
Mesenchymal stromal cells (MSCs) have been shown to enhance tissue repair as a cell-based therapy. In preparation for a phase I clinical study, we evaluated the safety, dosing, and efficacy of bone marrow-derived MSCs after subconjunctival injection in preclinical animal models of mice, rats, and rabbits. Human bone marrow-derived MSCs were expanded to passage 4 and cryopreserved. Viability of MSCs after thawing and injection through small-gauge needles was evaluated by vital dye staining. The in vivo safety of human and rabbit MSCs was studied by subconjunctivally injecting MSCs in rabbits with follow-up to 90 days. The potency of MSCs on accelerating wound healing was evaluated in vitro using a scratch assay and in vivo using 2-mm corneal epithelial debridement wounds in mice. Human MSCs were tracked after subconjunctival injection in rat and rabbit eyes. The viability of MSCs after thawing and immediate injection through 27- and 30-gauge needles was 93.1% ± 2.1% and 94.9% ± 1.3%, respectively. Rabbit eyes demonstrated mild self-limiting conjunctival inflammation at the site of injection with human but not rabbit MSCs. In scratch assay, the mean wound healing area was 93.5% ± 12.1% in epithelial cells co-cultured with MSCs compared with 40.8% ± 23.1% in controls. At 24 hours after wounding, all MSC-injected murine eyes had 100% corneal wound closure compared with 79.9% ± 5.5% in controls. Human MSCs were detectable in the subconjunctival area and peripheral cornea at 14 days after injection. Subconjunctival administration of MSCs is safe and effective in promoting corneal epithelial wound healing in animal models. These results provide preclinical data to support a phase I clinical study.


Precapillary patterns and perivascular cells in the retinal microvasculature. A scanning electron microscope study.
The microvasculature of the rat retina was studied in male Wistar rats in order to examine the features of the precapillary vascular pattern and structure that could affect blood flow regulation. Vascular corrosion casts and partially digested tissue specimens were observed by scanning electron microscopy. Side branching rather than bifurcation was the predominant microvascular pattern in the arterial tree. Two types of precapillary arteriole were present, one with the characteristic pattern of a preferential channel; the other gave off capillaries as terminal branches. At the origin of arteriolar side branches, smooth muscle cells appeared to buckle the endothelial nuclei into the vascular lumen. It is concluded that the rat retinal microvasculature appears to be characterised by 2 distinctive features: (1) side branching of arterioles which allows preferential flow in the most superficial layers of the retina; (2) peculiar luminal restrictions of arterioles and capillaries which permit fine regulation of blood flow.


Association analysis of SOD2 variants with methamphetamine psychosis in Japanese and Taiwanese populations.
SOD2 (superoxide dismutase 2) plays a crucial role in protecting the cells against damage caused by free radicals, by catalyzing their detoxification. On the other hand, cell damage caused by free radical generation following methamphetamine administration has been postulated as one of the possible pathophysiological mechanisms for methamphetamine psychosis. Hence, we investigated the association of SOD2 polymorphisms with the development of methamphetamine psychosis, in two independent populations of Japan and Taiwan. We recruited 116 patients with methamphetamine psychosis and 189 controls in Japan, and 135 patients with methamphetamine psychosis and 204 controls in Taiwan. The methamphetamine group was divided into two clinical subtypes: a transient type of psychosis (i.e., good prognosis) and a prolonged type of psychosis (i.e., poor prognosis), according to the course of the manifestation of psychosis. With reference to the genotypic and allelic frequencies of Ala/Val functional polymorphism in exon 2, we found significant differences between individuals with prolonged methamphetamine psychosis and control samples from Japan and Taiwan in the genotypic (P value 0.014 and 0.016, respectively) and in the allelic (P value 0.004 and 0.047, respectively) frequencies. Our results suggest that Ala/Val polymorphism of the SOD2 gene could be associated with the risk of developing methamphetamine psychosis.


AIonAI: a humanitarian law of artificial intelligence and robotics.
The enduring progression of artificial intelligence and cybernetics offers an ever-closer possibility of rational and sentient robots. The ethics and morals deriving from this technological prospect have been considered in the philosophy of artificial intelligence, the design of automatons with roboethics and the contemplation of machine ethics through the concept of artificial moral agents. Across these categories, the robotics laws first proposed by Isaac Asimov in the twentieth century remain well-recognised and esteemed due to their specification of preventing human harm, stipulating obedience to humans and incorporating robotic self-protection. However the overwhelming predominance in the study of this field has focussed on human-robot interactions without fully considering the ethical inevitability of future artificial intelligences communicating together and has not addressed the moral nature of robot-robot interactions. A new robotic law is proposed and termed AIonAI or artificial intelligence-on-artificial intelligence. This law tackles the overlooked area where future artificial intelligences will likely interact amongst themselves, potentially leading to exploitation. As such, they would benefit from adopting a universal law of rights to recognise inherent dignity and the inalienable rights of artificial intelligences. Such a consideration can help prevent exploitation and abuse of rational and sentient beings, but would also importantly reflect on our moral code of ethics and the humanity of our civilisation.


Protein tyrosine phosphatase-PEST regulates focal adhesion disassembly, migration, and cytokinesis in fibroblasts.
In this article, we show that, in transfected COS-1 cells, protein tyrosine phosphatase (PTP)-PEST translocates to the membrane periphery following stimulation by the extracellular matrix protein fibronectin. When plated on fibronectin, PTP-PEST (-/-) fibroblasts display a strong defect in motility. 3 h after plating on fibronectin, the number and size of vinculin containing focal adhesions were greatly increased in the homozygous PTP-PEST mutant cells as compared with heterozygous cells. This phenomenon appears to be due in part to a constitutive increase in tyrosine phosphorylation of p130(CAS), a known PTP-PEST substrate, paxillin, which associates with PTP-PEST in vitro, and focal adhesion kinase (FAK). Another effect of this constitutive hyperphosphorylation, consistent with the focal adhesion regulation defect, is that (-/-) cells spread faster than the control cell line when plated on fibronectin. In the PTP-PEST (-/-) cells, an increase in affinity for the SH2 domains of Src and Crk towards p130(CAS) was also observed. In (-/-) cells, we found a significant increase in the level of tyrosine phosphorylation of PSTPIP, a cleavage furrow-associated protein that interacts physically with all PEST family members. An effect of PSTPIP hyperphosphorylation appears to be that some cells remain attached at the site of the cleavage furrow for an extended period of time. In conclusion, our data suggest PTP-PEST plays a dual role in cell cytoskeleton organization, by promoting the turnover of focal adhesions required for cell migration, and by directly or indirectly regulating the proline, serine, threonine phosphatase interacting protein (PSTPIP) tyrosine phosphorylation level which may be involved in regulating cleavage furrow formation or disassembly during normal cell division.


Establishing the Medication Safety Research Network of Indiana (Rx-SafeNet): Perspectives of Community Pharmacy Employees.
The objective of this cross-sectional survey was to determine community pharmacy employee research project priorities and assess interest levels, barriers, and facilitators to joining a new community pharmacy practice-based research network (PBRN) and use this information in subsequent PBRN development. One hundred forty pharmacists and 40 support staff responded. The majority (72%) of respondents were somewhat interested or needed more information to determine their level of interest in joining a PBRN; 15% were very interested. While all research topics were regarded as important, dispensing errors were rated as the most important. Time constraints were considered the greatest barrier to participation. Greater knowledge of medication safety, enrichment of patient care, and improved patient and provider relationships were considered important reasons for joining a PBRN. Responses indicated favorable interest levels and project support from potential network members, though education and awareness campaigns are needed to enhance community pharmacy employee understanding of and involvement in research and PBRNs, specifically the Medication Safety Research Network of Indiana (Rx-SafeNet), a new network administered by the Purdue University College of Pharmacy. While the generalizability of survey results is limited, they were useful in determining policies and procedures of the new network. Surveying all employees involved in the future PBRN during the network development process is a unique approach to developing these types of networks in the U.S. Understanding support staff perspectives is important considering the critical role they play in project implementation and operations. Emerging PBRNs from any discipline may benefit from considering adding this step to their development.


Frequency distribution analysis of activation times and regional fibrosis in murine Scn5a+/- hearts: the effects of ageing and sex.
Both Brugada Syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated respectively with diffuse and discrete alterations in conduction pathways affected by ageing and sex. This study assessed for contributions of such processes to the mechanism of conduction changes in Scn5a(+/-) and WT hearts stratified by age (3 and 12 months) and sex. In vivo electrocardiographic chest-lead assessment demonstrated greater incidences of bundle branch block in all Scn5a(+/-) mice compared to WT. Frequency analysis of right ventricular (RV) epicardial activation obtained from a 64-channel multi-electrode array demonstrated greater prominence of late conducting components in Scn5a(+/-) compared to WT male, and in male compared to female Scn5a(+/-) following stratification by genotype and sex. Similar differences were observed between old male Scn5a(+/-) and young male Scn5a(+/-), old female Scn5a(+/-), and old male WT, following stratification by genotype, age and sex. These findings directly correlated with histomorphometric assessment of regional fibrosis in both septa and free walls preferentially involving the RV. We demonstrate complex alterations in conduction distributions suggesting a conversion of normal to slow-conducting tissue, modulated by ageing and sex, coupled with fibrosis in Scn5a(+/-) hearts. These features suggest an overlap between pathophysiological processes related to BrS and PCCD in Scn5a(+/-) hearts.


Using biomarkers as objective standards in the diagnosis of cervical biopsies.
Histopathologic diagnosis of cervical biopsies determines clinical management of patients with an abnormal cervical cancer-screening test yet is prone to poor interobserver reproducibility. Immunohistochemical staining for biomarkers related to the different stages of cervical carcinogenesis may provide objective standards to reduce diagnostic variability of cervical biopsy evaluations but systematic, rigorous evaluations of their potential clinical utility are lacking. To address diagnostic utility of human papillomavirus (HPV) L1, p16(INK4a), and Ki-67 immunohistochemical staining for improving diagnostic accuracy, we conducted a community-based and population-based evaluation using 1455 consecutive cervical biopsies submitted to the Department of Pathology at the University of Virginia during a period of 14 months. Thin-sections of each biopsy from 1451 of 1455 (99.7%) biopsies underwent evaluation of immunohistochemical stains for the 3 biomarkers, masked to the original diagnosis, and the results were compared with an adjudicated, consensus diagnosis by 3 pathologists. p16 immunostaining, using the strongest staining as the cutpoint, was 86.7% sensitive and 82.8% specific for cervical intraepithelial neoplasia (CIN) grade 2 or more severe (CIN2(+)) diagnoses. The performance of p16(INK4a) was more sensitive (P<0.001), less specific (P<0.001), and of similar overall accuracy for CIN2(+) compared with the combined performance of all pathologist reviews in routine clinical diagnostic service (sensitivity=68.9%, specificity=97.2%). Ki-67 immunostaining was also strongly associated with a CIN2(+) diagnosis but its performance at all staining intensities was inferior to p16 immunostaining, and did not increase the accuracy of CIN2(+) diagnosis when combined with p16(INK4a) immunostaining compared with p16(INK4a) immunostaining alone. We found no utility for L1 immunostaining in distinguishing between CIN and non-CIN. In conclusion, with a rigorous evaluation, we found immunohistochemical staining for p16 to be a useful and reliable diagnostic adjunct for distinguishing biopsies with and without CIN2(+).


Reassessing the role of progesterone in fertilization--compartmentalized calcium signalling in human spermatozoa?
Progesterone is present at micromolar concentrations in the vicinity of the oocyte. Human spermatozoa generate a biphasic rise in intracellular calcium concentration ([Ca(2+)](i)) and undergo the acrosome reaction upon progesterone stimulation, suggesting that the hormone acts as a secondary inducer or 'primer' of the acrosome reaction in association with the zona pellucida. However, the sensitivity of human spermatozoa to progesterone is such that many cells may undergo the acrosome reaction prematurely, compromising their ability to fertilize. We have shown that exposing human spermatozoa to a progesterone gradient, simulating the stimulus encountered as sperm approach the oocyte, results in a novel response. A slow rise in [Ca(2+)](i) occurs, upon which, in many cells, [Ca(2+)](i) oscillations are superimposed. Cells showing this pattern of response do not undergo the acrosome reaction, but instead show an alternating pattern of flagellar activity associated with peaks and troughs of [Ca(2+)](i). A Ca(2+) store in the rear of the sperm head apparently generates this complex signal, functioning as an '[Ca(2+)](i) oscillator'. We propose that: (i) the acrosome reaction and flagellar beat are regulated by separate Ca(2+) stores; (ii) these stores are mobilized through different mechanisms by different agonists; and (iii) progesterone in vivo acts as a switch for the oscillator which regulates the flagellar beat mode.


Noninvasive assessment of portal hypertension in patients with cirrhosis.
Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field.


Surfactant Need by Gestation for Very Preterm Babies Initiated on Early Nasal CPAP: A Danish Observational Multicentre Study of 6,628 Infants Born 2000-2013.
In recent years, early nasal continuous positive airway pressure (nCPAP) as respiratory support for preterm infants is being advocated as an alternative to prophylactic surfactant and treatment with mechanical ventilation. A number of infants treated with early nCPAP do not need treatment with surfactant, but few studies provide data on this. Since the 1990s, the first approach to respiratory support to preterm infants in Denmark has been early nCPAP combined with surfactant administration by the INSURE method by which the infant is intubated and surfactant administration is followed by rapid extubation to nCPAP if possible. To investigate how often surfactant was administered in preterm infants with a gestational age below 34 weeks treated with early nCPAP as a first approach to respiratory support. An observational multicentre study including all inborn infants with a gestational age below 34 weeks admitted to 1 of the 4 level 3 neonatal intensive care units in Denmark in the period from 2000 to 2013. A total of 6,628 infants were included in this study. We found that surfactant was administered in 1,056 of 1,799 (59%; 95% CI: 57-61%), in 821 of 2,864 (29%; 95% CI: 27-31%), and in 132 of 1,796 (7%; 95% CI: 6-8%) of the infants with a gestational age from 24 to 27, 28 to 31, and 32 to 33 weeks and 6 days, respectively. A large proportion of preterm infants treated with early nCPAP as the first approach to respiratory support was never treated with surfactant.


Ligand-induced conformational changes and a mechanism for domain closure in Aspergillus nidulans dehydroquinate synthase.
In order to investigate systematically substrate and cofactor-induced conformational changes in the enzyme dehydroquinate synthase (DHQS), eight structures representing a series of differently liganded states have been determined in a total of six crystal forms. DHQS in the absence of the substrate analogue carbaphosphonate, either unliganded or in the presence of NAD or ADP, is in an open form where a relative rotation of 11-13 degrees between N and C-terminal domains occurs. Analysis of torsion angle difference plots between sets of structures reveals eight rearrangements that appear relevant to domain closure and a further six related to crystal packing. Overlapping 21 different copies of the individual N and C-terminal DHQS domains further reveals a series of pivot points about which these movements occur and illustrates the way in which widely separated secondary structure elements are mechanically inter-linked to form "composite elements", which propagate structural changes across large distances. This analysis has provided insight into the basis of DHQS ligand-initiated domain closure and gives rise to the proposal of an ordered sequence of events involving substrate binding, and local rearrangements within the active site that are propagated to the hinge regions, leading to closure of the active-site cleft.


Community Clinical Oncology Program participation in the Breast Cancer Prevention Trial: factors affecting accrual.
Cancer prevention and control involves a diverse spectrum of activities that range from preventing the disease to providing rehabilitation to its survivors. The range of activities included within the definition of cancer prevention and control makes it difficult to determine factors that would predict accrual to specific cancer prevention and control trials. The participation of 36 CCOP organization in the National Cancer Institute-sponsored Breast Cancer PRevention TRial (BCPT) presented the opportunity to assess the ability of Community Clinical Oncology Program (CCOPs) to enroll subjects in one of the nation's first large-scale cancer prevention trials and to compare characteristics of CCOP accrual to the BCPT with factors associated with accrual by CCOPs to cancer treatment and other cancer prevention and control clinical trials. Although representing only 13% of participating health care organizations, CCOPs presently contribute nearly 30% of total BCPT accrual. Comparison of regression models representing accrual to treatment, cancer control, and chemoprevention (i.e., BCPT) protocols shows similar predictors between treatment and chemoprevention models. Cancer control models, however, did not share similar predictors. Thus, accrual to chemoprevention trials is associated, to a greater extent, with the characteristics that facilitate accrual to treatment trials rather than to cancer control trials. Results have implications for the planning and ongoing management of cancer treatment, control, and chemoprevention clinical trials.


Electroconvulsive therapy stimulus parameters: rethinking dosage.
In this article, we review the parameters that define the electroconvulsive therapy (ECT) electrical stimulus and discuss their biophysical roles. We also present the summary metrics of charge and energy that are conventionally used to describe the dose of ECT and the rules commonly deployed to individualize the dose for each patient. We then highlight the limitations of these summary metrics and dosing rules in that they do not adequately capture the roles of the distinct stimulus parameters. Specifically, there is strong theoretical and empirical evidence that stimulus parameters (pulse amplitude, shape, and width, and train frequency, directionality, polarity, and duration) exert unique neurobiological effects that are important for understanding ECT outcomes. Consideration of the distinct stimulus parameters, in conjunction with electrode placement, is central to further optimization of ECT dosing paradigms to improve the risk-benefit ratio. Indeed, manipulation of specific parameters, such as reduction of pulse width and increase in number of pulses, has already resulted in dramatic reduction of adverse effects, while maintaining efficacy. Furthermore, the manipulation of other parameters, such as current amplitude, which are commonly held at fixed, high values, might be productively examined as additional means of targeting and individualizing the stimulus, potentially reducing adverse effects. We recommend that ECT dose be defined using all stimulus parameters rather than a summary metric. All stimulus parameters should be noted in treatment records and published reports. To enable research on optimization of dosing paradigms, we suggest that ECT devices provide capabilities to adjust and display all stimulus parameters.


Infliximab for IgG4-Related Orbital Disease.
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition with unclear pathophysiology. It may occur as a single organ disorder, but multiorgan presentation is common and can mimic several conditions. The preferred therapy consists of steroids, but definite maintenance strategy remains unclear. The authors describe a case of a 61-year-old woman, initially diagnosed with idiopathic orbital inflammation refractory to multiple immunosuppressive agents. The disease was complicated with epilepsy, vision loss, and trismus. Treatment with various immunosuppressive agents was unsuccessful. Eventually the patient was effectively treated with infliximab. This is the second case of IgG4-RD treated with a TNF-blocker documented in literature and the first description to demonstrate its superiority over steroid sparing agents. Although speculative, TNF-blockers might exert their effect in IgG4-RD by interfering with the possible overexpressed TNF alpha due to fibrosis in this disease. Treatment with infliximab appears a good alternative for refractory IgG4-RD. However, further studies are required to define the value of infliximab in IgG4-RD.


Anatomy and function of an excitatory network in the visual cortex.
Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (<5 μm) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.


Follistatin-like protein 1 regulates chondrocyte proliferation and chondrogenic differentiation of mesenchymal stem cells.
Chondrocytes, the only cells in the articular cartilage, play a pivotal role in osteoarthritis (OA) because they are responsible for maintenance of the extracellular matrix (ECM). Follistatin-like protein 1 (FSTL1) is a secreted protein found in mesenchymal stem cells (MSCs) and cartilage but whose function is unclear. FSTL1 has been shown to modify cell growth and survival. In this work, we sought to determine whether FSTL1 could regulate chondrogenesis and chondrogenic differentiation of MSCs. To study the role of FSTL1 in chondrogenesis, we used FSTL1 knockout (KO) mice generated in our laboratory. Proliferative capacity of MSCs, obtained from skulls of E18.5 embryos, was analysed by flow cytometry. Chondrogenic differentiation of MSCs was carried out in a pellet culture system. Gene expression differences were assessed by microarray analysis and real-time PCR. Phosphorylation of Smad3, p38 MAPK and Akt was analysed by western blotting. The homozygous FSTL1 KO embryos showed extensive skeletal defects and decreased cellularity in the vertebral cartilage. Cell proliferation of FSTL1-deficient MSCs was reduced. Gene expression analysis in FSTL1 KO MSCs revealed dysregulation of multiple genes important for chondrogenesis. Production of ECM proteoglycans and collagen II expression were decreased in FSTL1-deficient MSCs differentiated into chondrocytes. Transforming growth factor β signalling in FSTL1 KO cells was significantly suppressed. FSTL1 is a potent regulator of chondrocyte proliferation, differentiation and expression of ECM molecules. Our findings may lead to the development of novel strategies for cartilage repair and provide new disease-modifying treatments for OA.


Epigenetic and physiological effects of gibberellin inhibitors and chemical pruners on the floral transition of azalea.
The ability to control the timing of flowering is a key strategy in planning the production of ornamental species such as azaleas; however, it requires a thorough understanding of floral transition. DNA methylation is involved in controlling the functional state of chromatin and gene expression during floral induction pathways in response to environmental and developmental signals. Plant hormone signalling is also known to regulate suites of morphogenic processes in plants and its role in flowering-time control is starting to emerge as a key controlling step. This work investigates if the gibberellin (GA) inhibitors and chemical pinching applied in improvement of azalea flowering alter the dynamics of DNA methylation or the levels of polyamines (PAs), GAs and cytokinins (CKs) during floral transition, and whether these changes could be related to the effects observed on flowering ability. DNA methylation during floral transition and endogenous content of PAs, GAs and CKs were analysed after the application of GA synthesis inhibitors (daminozide, paclobutrazol and chlormequat chloride) and a chemical pruner (fatty acids). The application of GA biosynthesis inhibitors caused alterations in levels of PAs, GAs and CKs and in global DNA methylation levels during floral transition; also, these changes in plant growth regulators and DNA methylation were correlated with flower development. DNA methylation, PA, GA and CK levels can be used as predictive markers of plant floral capacity in azalea.


TRP channels as drug targets.
Ca2+ channel antagonists acting on electrically-excitable cells have proved to be valuable therapeutic agents. The discovery of such agents and the identification of their molecular target resulted from the investigation of unexpected actions of known pharmacological agents. Ca2+ influx through receptor-operated channels in electrically non-excitable cells such as leukocytes is also functionally important, but to date the channels involved have not been successfully exploited as drug targets for anti-inflammatory therapy. Until recently, research in this area has been hindered by the lack of obvious molecular identity, but the emergence of the transient receptor potential (TRP) cation family has yielded promising candidates which may underpin the different receptor-operated Ca2+ influx pathways present in leukocytes. In addition, receptor-operated Ca2+ influx channels are also expressed in electrically-excitable cells suggesting that receptor-operated Ca2+ entry pathways are likely to be of wider significance and emphasizes the breadth of their potential as novel, and as yet, unexplored and unexploited drug targets.


Neonatal mortality, risk factors and causes: a prospective population-based cohort study in urban Pakistan.
To evaluate the prevalence, sex distribution and causes of neonatal mortality, as well as its risk factors, in an urban Pakistani population with access to obstetric and neonatal care. Study area women were enrolled at 20-26 weeks' gestation in a prospective population-based cohort study that was conducted from 2003 to 2005. Physical examinations, antenatal laboratory tests and anthropometric measures were performed, and gestational age was determined by ultrasound to confirm eligibility. Demographic and health data were also collected on pretested study forms by trained female research staff. The women and neonates were seen again within 48 hours postpartum and at day 28 after the birth. All neonatal deaths were reviewed using the Pattinson et al. system to assign obstetric and final causes of death; the circumstances of the death were determined by asking the mother or family and by reviewing hospital records. Frequencies and rates were calculated, and 95% confidence intervals were determined for mortality rates. Relative risks were calculated to evaluate the associations between potential risk factors and neonatal death. Logistic regression models were used to compute adjusted odds ratios. Birth outcomes were ascertained for 1280 (94%) of the 1369 women enrolled. The 28-day neonatal mortality rate was 47.3 per 1000 live births. Preterm birth, Caesarean section and intrapartum complications were associated with neonatal death. Some 45% of the deaths occurred within 48 hours and 73% within the first week. The primary obstetric causes of death were preterm labour (34%) and intrapartum asphyxia (21%). Final causes were classified as immaturity-related (26%), birth asphyxia or hypoxia (26%) and infection (23%). Neither delivery in a health facility nor by health professionals was associated with fewer neonatal deaths. The Caesarean section rate was 19%. Almost all (88%) neonates who died received treatment and 75% died in the hospital. In an urban population with good access to professional care, we found a high neonatal mortality rate, often due to preventable conditions. These results suggest that, to decrease neonatal mortality, improved health service quality is crucial.


On the structure of ictal events in vitro.
To analyze the cellular and network mechanisms of sustained seizures, we reviewed the literature and present new data on in vitro epileptiform events. We considered single and recurring synchronized population bursts occurring on a time scale from tens of milliseconds to 1 min. We used intracellular and field potential recordings, together with computer network simulations, derived from three types of experimental epileptogenesis: gamma-aminobutyric-acidA (GABAA) blockade, low extracellular [Mg2+]o, and 4-aminopyridine (4-AP). In all three models, sustained depolarizing synaptic currents developed, either through N-methyl-D-aspartate (NMDA) receptors, depolarizing GABAA receptors, or both. Ectopic action potentials (APs), probably originating in axonal structures, occurred in 4-AP and (as shown by other researchers) after tetanic stimulation; ectopic APs, occurring at sufficient frequency, should also depolarize dendrites, by synaptic excitation, enough to trigger bursts. Ictal-like events appear to arise from two basic mechanisms. The first mechanism consists of sustained dendritic depolarization driving a series of dendritic bursts. The second mechanism consists of an increase in axonal and presynaptic terminal excitability driving a series of bursts analogous to interictal spikes.


Determination of polar organic micropollutants in surface and pore water by high-resolution sampling-direct injection-ultra high performance liquid chromatography-tandem mass spectrometry.
Hyporheic zones (HZs) are dynamic and complex transition regions between rivers and aquifers which are thought to play an important role in the attenuation of environmental micropollutants. Non-steady state and small-scale hyporheic processes which affect micropollutants in the HZ are poorly characterized due to limitations in existing analytical methodologies. In this work we developed a method for high spatio-temporal resolution analysis of polar organic micropollutants (POMs) in hyporheic pore- and surface waters by combining (semi-) automatic low volume sampling techniques with direct-injection ultra-high performance liquid chromatography tandem mass spectrometry. The method is capable of quantifying 25 parent compounds and 18 transformation products (TPs) using only 0.4 mL of water and few preparation steps. Application of the method to both surface and pore water revealed significant (i.e. > an order of magnitude) differences in POM concentrations over small time and spatial scales (i.e. < a few hours and tens of cm, respectively). Guanylurea, a TP of the antidiabetic drug metformin was detected at unprecedentedly high concentrations. Collectively, this method is suitable for in situ characterization of POMs at high spatial and temporal resolution and with minimal disturbance of natural flow paths and infiltration of surface water.


Speaker and Accent Variation Are Handled Differently: Evidence in Native and Non-Native Listeners.
Listeners are able to cope with between-speaker variability in speech that stems from anatomical sources (i.e. individual and sex differences in vocal tract size) and sociolinguistic sources (i.e. accents). We hypothesized that listeners adapt to these two types of variation differently because prior work indicates that adapting to speaker/sex variability may occur pre-lexically while adapting to accent variability may require learning from attention to explicit cues (i.e. feedback). In Experiment 1, we tested our hypothesis by training native Dutch listeners and Australian-English (AusE) listeners without any experience with Dutch or Flemish to discriminate between the Dutch vowels /I/ and /ε/ from a single speaker. We then tested their ability to classify /I/ and /ε/ vowels of a novel Dutch speaker (i.e. speaker or sex change only), or vowels of a novel Flemish speaker (i.e. speaker or sex change plus accent change). We found that both Dutch and AusE listeners could successfully categorize vowels if the change involved a speaker/sex change, but not if the change involved an accent change. When AusE listeners were given feedback on their categorization responses to the novel speaker in Experiment 2, they were able to successfully categorize vowels involving an accent change. These results suggest that adapting to accents may be a two-step process, whereby the first step involves adapting to speaker differences at a pre-lexical level, and the second step involves adapting to accent differences at a contextual level, where listeners have access to word meaning or are given feedback that allows them to appropriately adjust their perceptual category boundaries.


Pre-hospital thrombolysis for acute ST segment elevation myocardial infarction: A survey of paramedics' perceptions of their role.
The effectiveness of pre-hospital thrombolysis (PHT) in reducing mortality following ST segment elevation myocardial infarction (STEMI) is well established. In England, PHT is provided to around 17% of STEMI patients, and responsibility for treatment rests largely with paramedics rather than physicians as in some other countries, but little is known about how paramedics perceive their role, or whether age or experience influence such perceptions. To describe paramedics' perceptions of PHT. Questionnaire survey to all 106 paramedics working within a single ambulance service in England. 60 (56.6%) paramedics responded. Overall, there were few significant differences by age or length of service in responses given. However, paramedics who had administered PHT gave more positive responses compared to those who had not, in relation to duty of care, professional image, individuals' influence on paramedic role development, and preparedness for practice. Paramedics hold a range of views and perceptions of their role in delivering PHT; some of which appear to be related to age and length of experience, and actual administration of PHT. The vast majority view PHT as a positive step to providing patient care that is evidence based.


SADRNet: Self-Aligned Dual Face Regression Networks for Robust 3D Dense Face Alignment and Reconstruction.
Three-dimensional face dense alignment and reconstruction in the wild is a challenging problem as partial facial information is commonly missing in occluded and large pose face images. Large head pose variations also increase the solution space and make the modeling more difficult. Our key idea is to model occlusion and pose to decompose this challenging task into several relatively more manageable subtasks. To this end, we propose an end-to-end framework, termed as Self-aligned Dual face Regression Network (SADRNet), which predicts a pose-dependent face, a pose-independent face. They are combined by an occlusion-aware self-alignment to generate the final 3D face. Extensive experiments on two popular benchmarks, AFLW2000-3D and Florence, demonstrate that the proposed method achieves significant superior performance over existing state-of-the-art methods.


Endovascular treatment for emergent large vessel occlusion due to severe intracranial atherosclerotic stenosis.
OBJECTIVEThe optimal treatment strategy for patients with emergent large vessel occlusion (ELVO) due to underlying severe intracranial atherosclerotic stenosis (ICAS) is unclear. The purpose of this study was to compare treatment outcomes from intracranial angioplasty with or without stenting and intraarterial infusion of a glycoprotein IIb/IIIa inhibitor in patients with ELVO due to severe ICAS, and to investigate predictors of outcome after endovascular therapy in such patients.METHODSA total of 140 consecutive patients with ELVO attributable to severe ICAS underwent endovascular therapy at two stroke centers (A and B). Intracranial angioplasty/stenting was primarily performed at center A and intraarterial infusion of glycoprotein IIb/IIIa inhibitor (tirofiban) at center B. Data from both centers were prospectively collected into a database and retrospectively analyzed.RESULTSOverall, successful reperfusion was achieved in 95% (133/140) of patients and a good outcome in 60% (84/140). The mortality rate was 7.9%. Symptomatic hemorrhage occurred in 1 patient. There were no significant differences in the rates of successful reperfusion, symptomatic hemorrhage, 3-month modified Rankin scale score 0-2, and mortality between the two centers. Multivariate logistic regression analysis revealed the only independent predictor of good outcome was a history of previous stroke or transient ischemic attack (TIA) (odds ratio 0.254, 95% confidence interval 0.094-0.689, p = 0.007).CONCLUSIONSBoth intracranial angioplasty/stenting and intraarterial infusion of a glycoprotein IIb/IIIa inhibitor are effective and safe in the treatment of underlying severe ICAS in acute stroke patients with ELVO. In addition, a lack of a history of stroke/TIA was the only independent predictor of good outcome after endovascular therapy in such patients.


Pharmacological Optimization for Successful Traumatic Brain Injury Drug Development.
The purpose of this review is to highlight the pharmacological barrier to drug development for traumatic brain injury (TBI) and to discuss best practice strategies to overcome such barriers. Specifically, this article will review the pharmacological considerations of moving from the disease target "hit" to the "lead" compound with drug-like and central nervous system (CNS) penetrant properties. In vitro assessment of drug-like properties will be detailed, followed by pre-clinical studies to ensure adequate pharmacokinetic and pharmacodynamic characteristics of response. The importance of biomarker development and utilization in both pre-clinical and clinical studies will be detailed, along with the importance of identifying diagnostic, pharmacodynamic/response, and prognostic biomarkers of injury type or severity, drug target engagement, and disease progression. This review will detail the important considerations in determining in vivo pre-clinical dose selection, as well as cross-species and human equivalent dose selection. Specific use of allometric scaling, pharmacokinetic and pharmacodynamic criteria, as well as incorporation of biomarker assessments in human dose selection for clinical trial design will also be discussed. The overarching goal of this review is to detail the pharmacological considerations in the drug development process as a method to improve both pre-clinical and clinical study design as we evaluate novel therapies to improve outcomes in patients with TBI.


Family history and outcome of young patients with breast cancer in the UK (POSH study).
Young patients presenting to surgical clinics with breast cancer are usually aware of their family history and frequently believe that a positive family history may adversely affect their prognosis. Tumour pathology and outcomes were compared in young British patients with breast cancer with and without a family history of breast cancer. Prospective Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large prospective cohort study of women aged less than 41 years with breast cancer diagnosed and treated in the UK using modern oncological management. Personal characteristics, tumour pathology, treatment and family history of breast/ovarian cancer were recorded. Follow-up data were collected annually. Family history data were available for 2850 patients. No family history was reported by 65·9 per cent, and 34·1 per cent reported breast/ovarian cancer in at least one first- or second-degree relative. Patients with a family history were more likely to have grade 3 tumours (63·3 versus 58·9 per cent) and less likely to have human epidermal growth factor receptor 2-positive tumours (24·7 versus 28·8 per cent) than those with no family history. In multivariable analyses, there were no significant differences in distant disease-free intervals for patients with versus those without a family history, either for the whole cohort (hazard ratio (HR) 0·89, 95 per cent c.i. 0·76 to 1·03; P = 0·120) or when stratified by oestrogen receptor (ER) status (ER-negative: HR 0·80, 0·62 to 1·04, P = 0·101; ER-positive: HR 0·95, 0·78 to 1·15, P = 0·589). Young British patients presenting to breast surgical clinics with a positive family history can be reassured that this is not a significant independent risk factor for breast cancer outcome.


Spatially explicit conditions for waterborne pathogen invasion.
Waterborne pathogens cause many possibly lethal human diseases. We derive the condition for pathogen invasion and subsequent disease outbreak in a territory with specific, space-inhomogeneous characteristics (hydrological, ecological, demographic, and epidemiological). The criterion relies on a spatially explicit model accounting for the density of susceptible and infected individuals and the pathogen concentration in a network of communities linked by human mobility and the water system. Pathogen invasion requires that a dimensionless parameter, the dominant eigenvalue of a generalized reproductive matrix J0, be larger than unity. Conditions for invasion are studied while crucial parameters (population density distribution, contact and water contamination rates, pathogen growth rates) and the characteristics of the networks (connectivity, directional transport, water retention times, mobility patterns) are varied. We analyze both simple, prototypical test cases and realistic landscapes, in which optimal channel networks mimic the water systems and gravitational models describe human mobility. Also, we show that the dominant eigenvector of J0 effectively portrays the geography of epidemic outbreaks, that is, the areas of the studied territory that will be initially affected by an epidemic. This is important for planning an efficient spatial allocation of interventions (e.g., improving sanitation and providing emergency aid and medicines).