Control of valence and conduction band energies in layered transition metal phosphates via surface functionalization.
Layered transition metal phosphates and phosphites (TMPs) are a class of materials composed of layers of 2D sheets bound together via van der Waals interactions and/or hydrogen bonds. Explored primarily for use in proton transfer, their unique chemical tunability also makes TMPs of interest for forming large-scale hybrid materials. Further, unlike many layered materials, TMPs can readily be solution exfoliated to form single 2D sheets or bilayers, making them exciting candidates for a variety of applications. However, the electronic properties of TMPs have largely been unstudied to date. In this work, we use first-principles computations to investigate the atomic and electronic structure of TMPs with a variety of stoichiometries. We demonstrate that there exists a strong linear relationship between the band gap and the ionic radius of the transition metal cation in these materials, and show that this relationship, which opens opportunities for engineering new compositions with a wide range of band gaps, arises from constraints imposed by the phosphorus-oxygen bond geometry. In addition, we find that the energies of the valence and conduction band edges can be systematically tuned over a range of ∼3 eV via modification of the functional group extending from the phosphorus. Based on the Hammett constant of this functional group, we identify a simple, predictive relationship for the ionization potential and electron affinity of layered TMPs. Our results thus provide guidelines for systematic design of TMP-derived functional materials, which may enable new approaches for optimizing charge transfer in electronics, photovoltaics, electrocatalysts, and other applications.


Distribution pattern of urine albumin creatinine ratio and the prevalence of high-normal levels in untreated asymptomatic non-diabetic hypertensive patients.
Even high-normal albuminuria is reportedly associated with cardiovascular events. We determined the urine albumin creatinine ratio (UACR) in spot urine samples and analyzed the UACR distribution and the prevalence of high-normal levels. The UACR was determined using immunoturbidimetry in 332 untreated asymptomatic non-diabetic Japanese patients with hypertension and in 69 control subjects. The microalbuminuria and macroalbuminuria levels were defined as a UCAR ≥30 and <300 µg/mg·creatinine and a UCAR ≥300 µg/mg·creatinine, respectively. The distribution patterns showed a highly skewed distribution for the lower levels, and a common logarithmic transformation produced a close fit to a Gaussian distribution with median, 25th and 75th percentile values of 22.6, 13.5 and 48.2 µg/mg·creatinine, respectively. When a high-normal UACR was set at >20 to <30 µg/mg·creatinine, 19.9% (66/332) of the hypertensive patients exhibited a high-normal UACR. Microalbuminuria and macroalbuminuria were observed in 36.1% (120/336) and 2.1% (7/332) of the patients, respectively. UACR was significantly correlated with the systolic and diastolic blood pressures and the pulse pressure. A stepwise multivariate analysis revealed that these pressures as well as age were independent factors that increased UACR. The UACR distribution exhibited a highly skewed pattern, with approximately 60% of untreated, non-diabetic hypertensive patients exhibiting a high-normal or larger UACR. Both hypertension and age are independent risk factors that increase the UACR. The present study indicated that a considerable percentage of patients require anti-hypertensive drugs with antiproteinuric effects at the start of treatment.


The complete genome sequence of Bacillus velezensis 9912D reveals its biocontrol mechanism as a novel commercial biological fungicide agent.
A Bacillus sp. 9912 mutant, 9912D, was approved as a new biological fungicide agent by the Ministry of Agriculture of the People's Republic of China in 2016 owing to its excellent inhibitory effect on various plant pathogens and being environment-friendly. Here, we present the genome of 9912D with a circular chromosome having 4436 coding DNA sequences (CDSs), and a circular plasmid encoding 59 CDSs. This strain was finally designated as Bacillus velezensis based on phylogenomic analyses. Genome analysis revealed a total of 19 candidate gene clusters involved in secondary metabolite biosynthesis, including potential new type II lantibiotics. The absence of fengycin biosynthetic gene cluster is noteworthy. Our data offer insights into the genetic, biological and physiological characteristics of this strain and aid in deeper understanding of its biocontrol mechanism.


Vaccination guidelines: a bridge between official requirements and the daily use of vaccines.
Vaccination guidelines are non-compulsory recommendations which assist the veterinary practitioner to use vaccines efficiently. They complement the official information contained in the shortened form of the summary of product characteristics that is included in the package insert of the product. The aim of this article is to clarify the role of guidelines and examine how they can improve the use of vaccines in practical conditions. The development of vaccination guidelines is explained. Several issues are discussed: primary vaccination schedule; interference with maternally derived antibodies; duration of immunity; vaccination and ageing. Three guidelines dealing with the vaccination of cats against upper respiratory tract disease are compared, as an example. In conclusion, vaccination guidelines are essential tools to assist veterinarians in good vaccination practices. They fill the gap that exists between the official recommendations included in the regulations and the licensing dossiers and the daily use of the vaccines.


"Bar-coding" primate chromosomes: molecular cytogenetic screening for the ancestral hominoid karyotype.
Two recently introduced multicolor FISH approaches, cross-species color banding (also termed Rx-FISH) and multiplex FISH using painting probes derived from somatic cell hybrids retaining fragments of human chromosomes, were applied in a comparative molecular cytogenetic study of higher primates. We analyzed these "chromosome bar code" patterns to obtain an overview of chromosomal rearrangements that occurred during higher primate evolution. The objective was to reconstruct the ancestral genome organization of hominoids using the macaque as outgroup species. Approximately 160 individual and discernible molecular cytogenetic markers were assigned in these species. Resulting comparative maps allowed us to identify numerous intra-chromosomal rearrangements, to discriminate them from previous contradicting chromosome banding interpretations and to propose an ancestral karyotype for hominoids. From 25 different chromosome forms in an ancestral karyotype for all hominoids of 2N=48 we propose 21. Probes for chromosomes 2p, 4, 9 and Y were not informative in the present experiments. The orangutan karyotype was very similar to the proposed ancestral organization and conserved 19 of the 21 ancestral forms; thus most chromosomes were already present in early hominoid evolution, while African apes and human show various derived changes.


Psychosocial approaches to pain management: an organizational framework.
Many different psychosocial treatments for pain have been described in the literature. All of these treatments have at least some evidence supporting their efficacy. However, each treatment is based on a theory or model that is most useful only for that particular intervention. An overarching model or framework that includes all of the factors hypothesized to play a role in the effects of these treatments would be useful for (1) understanding the similarities and differences between existing and future psychosocial pain treatments, (2) guiding the psychosocial evaluation of patients with chronic pain, and (3) giving clinicians greater flexibility for including psychosocial interventions that have proven efficacy, but that may not be explained by their preferred (but perhaps limited) model. This article proposes an initial version of such a framework, with the hope that it will increase our understanding of the role that psychosocial factors play in the experience of pain and its negative effects on functioning, and informs future research seeking to identify the common and specific factors associated with psychosocial pain treatments.


Normocyte-binding protein required for human erythrocyte invasion by the zoonotic malaria parasite Plasmodium knowlesi.
The dominant cause of malaria in Malaysia is now Plasmodium knowlesi, a zoonotic parasite of cynomolgus macaque monkeys found throughout South East Asia. Comparative genomic analysis of parasites adapted to in vitro growth in either cynomolgus or human RBCs identified a genomic deletion that includes the gene encoding normocyte-binding protein Xa (NBPXa) in parasites growing in cynomolgus RBCs but not in human RBCs. Experimental deletion of the NBPXa gene in parasites adapted to growth in human RBCs (which retain the ability to grow in cynomolgus RBCs) restricted them to cynomolgus RBCs, demonstrating that this gene is selectively required for parasite multiplication and growth in human RBCs. NBPXa-null parasites could bind to human RBCs, but invasion of these cells was severely impaired. Therefore, NBPXa is identified as a key mediator of P. knowlesi human infection and may be a target for vaccine development against this emerging pathogen.


Single Molecule Protein Detection with Attomolar Sensitivity Using Droplet Digital Enzyme-Linked Immunosorbent Assay.
Many proteins are present at low concentrations in biological samples, and therefore, techniques for ultrasensitive protein detection are necessary. To overcome challenges with sensitivity, the digital enzyme-linked immunosorbent assay (ELISA) was developed, which is 1000× more sensitive than conventional ELISA and allows sub-femtomolar protein detection. However, this sensitivity is still not sufficient to measure many proteins in various biological samples, thereby limiting our ability to detect and discover biomarkers. To overcome this limitation, we developed droplet digital ELISA (ddELISA), a simple approach for detecting low protein levels using digital ELISA and droplet microfluidics. ddELISA achieves maximal sensitivity by improving the sampling efficiency and counting more target molecules. ddELISA can detect proteins in the low attomolar range and is up to 25-fold more sensitive than digital ELISA using Single Molecule Arrays (Simoa), the current gold standard tool for ultrasensitive protein detection. Using ddELISA, we measured the LINE1/ORF1 protein, a potential cancer biomarker that has not been previously measured in serum. Additionally, due to the simplicity of our device design, ddELISA is promising for point-of-care applications. Thus, ddELISA will facilitate the discovery of biomarkers that have never been measured before for various clinical applications.


Separating fusion from rivalry.
Visual fusion is the process in which differing but compatible binocular information is transformed into a unified percept. Even though this is at the basis of binocular vision, the underlying neural processes are, as yet, poorly understood. In our study we therefore aimed to investigate neural correlates of visual fusion. To this end, we presented binocularly compatible, fusible (BF), and incompatible, rivaling (BR) stimuli, as well as an intermediate stimulus type containing both binocularly fusible and monocular, incompatible elements (BFR). Comparing BFR stimuli with BF and BR stimuli, respectively, we were able to disentangle brain responses associated with either visual fusion or rivalry. By means of functional magnetic resonance imaging, we measured brain responses to these stimulus classes in the visual cortex, and investigated them in detail at various retinal eccentricities. Compared with BF stimuli, the response to BFR stimuli was elevated in visual cortical areas V1 and V2, but not in V3 and V4 - implying that the response to monocular stimulus features decreased from V1 to V4. Compared to BR stimuli, the response to BFR stimuli decreased with increasing eccentricity, specifically within V3 and V4. Taken together, it seems that although the processing of exclusively monocular information decreases from V1 to V4, the processing of binocularly fused information increases from earlier to later visual areas. Our findings suggest the presence of an inhibitory neural mechanism which, depending on the presence of fusion, acts differently on the processing of monocular information.


Family functionality and burden of family caregivers of users with mental disorders.
to verify the difference of mean or median in the scores of family functionality and burden of family caregivers of people with mental disorders. cross-sectional study carried out in a Psychosocial Care Center with 61 family caregivers. Instruments were used for sociodemographic characterization, care process, Family Apgar Index and Family Burden Interview Schedule. Mean/median difference tests were adopted. women with mental disorders and the presence of children in the home decreased the median of the family Apgar score. Difficulty in the relationship between caregiver/user, nervousness/tension, physical aggression and agitation of patients increased the global average of subjective burden. nursing interventions to reduce burden and promote family functionality should prioritize caregivers of women with mental disorders, assist them in managing troublesome behaviors and raising awareness of family nucleus to co-responsibility for caring for sick people, especially in families with children who demand daily care.


Cardiovascular phenotypes predict clinical outcomes in sickle cell disease: An echocardiography-based cluster analysis.
This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.


Immune cell trafficking across the blood-brain barrier in the absence and presence of neuroinflammation.
To maintain the homeostatic environment required for proper function of CNS neurons the endothelial cells of CNS microvessels tightly regulate the movement of ions and molecules between the blood and the CNS. The unique properties of these blood vascular endothelial cells are termed blood-brain barrier (BBB) and extend to regulating immune cell trafficking into the immune privileged CNS during health and disease. In general, extravasation of circulating immune cells is a multi-step process regulated by the sequential interaction of adhesion and signalling molecules between the endothelial cells and the immune cells. Accounting for the unique barrier properties of CNS microvessels, immune cell migration across the BBB is distinct and characterized by several adaptations. Here we describe the mechanisms that regulate immune cell trafficking across the BBB during immune surveillance and neuroinflammation, with a focus on the current state-of-the-art in vitro and in vivo imaging observations.


Dubiofossils from a Mars-analogue subsurface palaeoenvironment: The limits of biogenicity criteria.
The search for a fossil record of Earth's deep biosphere, partly motivated by potential analogies with subsurface habitats on Mars, has uncovered numerous assemblages of inorganic microfilaments and tubules inside ancient pores and fractures. Although these enigmatic objects are morphologically similar to mineralized microorganisms (and some contain organic carbon), they also resemble some abiotic structures. Palaeobiologists have responded to this ambiguity by evaluating problematic filaments against checklists of "biogenicity criteria". Here, we describe material that tests the limits of this approach. We sampled Jurassic calcite veins formed through subseafloor serpentinization, a water-rock reaction that can fuel the deep biosphere and is known to have occurred widely on Mars. At two localities ~4 km apart, veins contained curving, branched microfilaments composed of Mg-silicate and Fe-oxide minerals. Using a wide range of analytical techniques including synchrotron X-ray microtomography and scanning transmission electron microscopy, we show that these features meet many published criteria for biogenicity and are comparable to fossilized cryptoendolithic fungi or bacteria. However, we argue that abiotic processes driven by serpentinization could account for the same set of lifelike features, and report a chemical garden experiment that supports this view. These filaments are, therefore, most objectively described as dubiofossils, a designation we here defend from criticism and recommend over alternative approaches, but which nevertheless signifies an impasse. Similar impasses can be anticipated in the future exploration of subsurface palaeo-habitats on Earth and Mars. To avoid them, further studies are required in biomimetic geochemical self-organization, microbial taphonomy and micro-analytical techniques, with a focus on subsurface habitats.


Apurinic/apyrimidinic endonuclease 1, p53, and thioredoxin are linked in control of aging in C. elegans.
Deletions in mitochondrial DNA (mtDNA) accumulate during aging. Expression of the Caenorhabditis elegans apurinic/apyrimidinic endonuclease 1 (APE1) ortholog exo-3, involved in DNA repair, is reduced by 45% (P < 0.05) during aging of C. elegans. Suppression of exo-3 by treatment with RNAi resulted in a threefold increase in mtDNA deletions (P < 0.05), twofold enhanced generation of reactive oxygen species (ROS) (P < 0.01), distortion of the structural integrity of the nervous system, reduction of head motility by 43% (P < 0.01) and whole animal motility by 38% (P < 0.05). Suppression of exo-3 significantly reduced life span: mean life span decreased from 18.5 +/- 0.4 to 15.4 +/- 0.1 days (P < 0.001) and maximum life span from 25.9 +/- 0.4 to 23.2 +/- 0.1 days (P = 0.001). Additional treatment of exo-3-suppressed animals with a mitochondrial uncoupler decreased ROS levels, reduced neuronal damage, and increased motility and life span. Additional suppression of the C. elegans p53 ortholog cep-1 in exo-3 RNAi-treated animals similarly decreased ROS levels, preserved neuronal integrity, and increased motility and life span. In wild-type animals, suppression of cep-1, involved in downregulation of exo-3, increased expression of exo-3 without a significant effect on ROS levels, preserved neuronal integrity, and increased motility and life span. Suppression of the C. elegans thioredoxin orthologs trx-1 and trx-2, involved in the redox chaperone activity of exo-3, overrides the protective effect of cep-1 RNAi treatment on neuronal integrity, neuronal function, mean and maximum life span. These results show that APE1/EXO-3, p53/CEP-1, and thioredoxin affect each other and that these interactions determine aging as well as neuronal structure and function.


Lung injury after cardiopulmonary bypass.
Pulmonary injury during cardiopulmonary bypass is common as patient factors (smoking, pain, pneumonia) and the effects of cardiopulmonary bypass combine to compromise lung function after cardiac surgery. Lung injury follows the propagation of an inflammatory response involving cytokines, complement, neutrophils, monocytes, activated endothelial cells and platelets. Neutrophils sequester in the lung in response to chemotactic agents and release injurious oxygen free radicals and specific enzymes resulting in widespread pulmonary injury. To alleviate this lung injury a number of possible interventions exist. Off pump surgery may reduce the degree of systemic inflammation but respiratory impairment still occurs and the clinical advantage is uncertain. The use of leukocyte filtration can attenuate the acute inflammatory response with encouraging though variable results. Aprotinin, Pentoxyfilline, Nitric oxide, Aspirin and other agents have shown benefits in lung function after cardiopulmonary bypass induced lung injury. Given the magnitude and diversity of the inflammatory response to cardiopulmonary bypass many possible interventions exist to attenuate lung injury resulting from extracorporeal circulation. Immediate clinical benefits are likely to result from successful amelioration of the processes involved.


A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings.
Alparslan C, Öncel EP, Akbay S, Alaygut D, Mutlubaş F, Tatlı M, Konrad M, Yavaşcan Ö, Kasap-Demir B. A novel homozygous W99G mutation in CLDN-16 gene causing familial hypomagnesemic hypercalciuric nephrocalcinosis in Turkish siblings. Turk J Pediatr 2018; 60: 76-80. Familial hypomagnesemic hypercalciuric nephrocalcinosis (FHHNC) (OMIM: 248250) is characterized by hypomagnesemia, hypercalciuria and nephrocalcinosis. FHHNC inevitably progresses to end-stage renal disease in decades. Mutations in CLDN-16 and CLDN-19 genes are associated with disrupted magnesium handling in the thick ascending limp of Henle`s loop. Patients with mutations in these genes share similar clinical features, and those with CLDN-19 gene mutations have ocular findings in addition. A 2-month-old boy, was admitted to our clinic with the complaints of upper respiratory tract infection. He was the first-born child of consanguineous parents. Laboratory findings revealed hypocalcemia and hypomagnesemia. Bilateral medullary nephrocalcinosis was detected on abdominal ultrasound. His ophthalmologic examination was unremarkable. With hypomagnesemia, hypercalciuria and nephrocalcinosis, the patient was considered to have FHHNC. Oral magnessium supplementation was initiated. Four years of follow-up has been completed uneventfully. When 6-days-old the brother of the case above was admitted with seizure. The patient was resistant to calcium and anticonvulsant drugs and the seizure activity could only be controlled after magnesium infusion. Biochemistry profile revealed hypocalcemia and hypomagnesemia. Urinary calcium extraction was 11 mg/kg/day. Medullary nephrocalcinosis was reported on renal ultrasound. His eye examination, echocardiography, transfontanel ultrasound and electroencephalography were normal. Due to the triad of hypomagnesemia, hypercalciuria and nephrocalcinosis, and the medical history of his elder brother, he was diagnosed with FHHNC. After correction of the electrolyte abnormalities, he was discharged from hospital and is currently being followed-up without any problem. In this manuscript, we shared our experience about a novel homozygous mutation (W99C) in CLDN-16 gene causing FHHNC in a couple of Turkish siblings.


A TCR-based Chimeric Antigen Receptor.
Effector T cells equipped with engineered antigen receptors specific for cancer targets have proven to be very efficient. Two methods have emerged: the Chimeric Antigen Receptors (CARs) and T-cell Receptor (TCR) redirection. Although very potent, CAR recognition is limited to membrane antigens which represent around 1% of the total proteins expressed, whereas TCRs have the advantage of targeting any peptide resulting from cellular protein degradation. However, TCRs depend on heavy signalling machinery only present in T cells which restricts the type of eligible therapeutic cells. Hence, an introduced therapeutic TCR will compete with the endogenous TCR for the signalling proteins and carries the potential risk of mixed dimer formation giving rise to a new TCR with unpredictable specificity. We have fused a soluble TCR construct to a CAR-signalling tail and named the final product TCR-CAR. We here show that, if expressed, the TCR-CAR conserved the specificity and the functionality of the original TCR. In addition, we demonstrate that TCR-CAR redirection was not restricted to T cells. Indeed, after transduction, the NK cell line NK-92 became TCR positive and reacted against pMHC target. This opens therapeutic avenues combing the killing efficiency of NK cells with the diversified target recognition of TCRs.


Automated identification of epidermal keratinocytes in reflectance confocal microscopy.
Keratinocytes in skin epidermis, which have bright cytoplasmic contrast and dark nuclear contrast in reflectance confocal microscopy (RCM), were modeled with a simple error function reflectance profile: erf( ). Forty-two example keratinocytes were identified as a training set which characterized the nuclear size a = 8.6±2.8 μm and reflectance gradient b = 3.6±2.1 μm at the nuclear∕cytoplasmic boundary. These mean a and b parameters were used to create a rotationally symmetric erf( ) mask that approximated the mean keratinocyte image. A computer vision algorithm used an erf( ) mask to scan RCM images, identifying the coordinates of keratinocytes. Applying the mask to the confocal data identified the positions of keratinocytes in the epidermis. This simple model may be used to noninvasively evaluate keratinocyte populations as a quantitative morphometric diagnostic in skin cancer detection and evaluation of dermatological cosmetics.


Transmural palliative care by means of teleconsultation: a window of opportunities and new restrictions.
Audio-visual teleconsultation is expected to help home-based palliative patients, hospital-based palliative care professionals, and family physicians to jointly design better, pro-active care. Consensual knowledge of the possibilities and limitations of teleconsultation in transmural palliative care is, however, largely lacking.This paper aims at describing elements of both the physical workplace and the cultural-social context of the palliative care practice, which are imperative for the use of teleconsultation technologies. A semi-structured expert meeting and qualitative, open interviews were deployed to explore professionals' assumptions and wishes, which are considered to contain latent presumptions about the practice's physical workplace and latent elements of the cultural-social context, regarding (1) the mediating potential of audio-visual teleconsultation, (2) how the audio-visual teleconsultations will affect medical practice, and (3) the design and usage of the teleconsultation technology. We used a qualitative analysis to investigate how palliative care professionals interpret the teleconsultation package in preparation. The analysis entailed open and axial coding techniques developed in a grounded theory approach. Respondents assume: 1. teleconsultation will hinder physical proximity, thereby compromising anamnesis and diagnosis of new or acutely ill patients as well as "real contact" with the person behind the patient; 2. teleconsultation will help patients becoming more of a pivotal figure in their own care trajectory; 3. they can use teleconsultation to keep a finger on the pulse; 4. teleconsultations have a healing effect of their own due to offered time and digital attention; 5. teleconsultation to open up an additional "gray" network outside the hierarchical structures of the established chain of transmural palliative care. This network could cause bypassing of caregivers and uncertainty about responsibilities; 6. teleconsultations lead to an extended flow of information which helps palliative care professionals to check the stories of patients and medical specialists. Professionals assume teleconsultation co-defines a new patient-professional relationship by extending hospital-based caregivers' perceptions of as well as attention for their patients. At the cost, however, of clinical and personal connectedness. Secondly, a hermeneutics is needed to carefully interpret teleconsultation images. Thirdly, teleconsultations transform caregiving cultures as formerly separated care domains collide, demanding a redefinition of roles and responsibilities.


Comparison of low and high dose ionising radiation using topological analysis of gene coexpression networks.
The growing use of imaging procedures in medicine has raised concerns about exposure to low-dose ionising radiation (LDIR). While the disastrous effects of high dose ionising radiation (HDIR) is well documented, the detrimental effects of LDIR is not well understood and has been a topic of much debate. Since little is known about the effects of LDIR, various kinds of wet-lab and computational analyses are required to advance knowledge in this domain. In this paper we carry out an "upside-down pyramid" form of systems biology analysis of microarray data. We characterised the global genomic response following 10 cGy (low dose) and 100 cGy (high dose) doses of X-ray ionising radiation at four time points by analysing the topology of gene coexpression networks. This study includes a rich experimental design and state-of-the-art computational systems biology methods of analysis to study the differences in the transcriptional response of skin cells exposed to low and high doses of radiation. Using this method we found important genes that have been linked to immune response, cell survival and apoptosis. Furthermore, we also were able to identify genes such as BRCA1, ABCA1, TNFRSF1B, MLLT11 that have been associated with various types of cancers. We were also able to detect many genes known to be associated with various medical conditions. Our method of applying network topological differences can aid in identifying the differences among similar (eg: radiation effect) yet very different biological conditions (eg: different dose and time) to generate testable hypotheses. This is the first study where a network level analysis was performed across two different radiation doses at various time points, thereby illustrating changes in the cellular response over time.


The local physicochemical environment conditions the proinflammatory response of endothelial cells and thus modulates leukocyte recruitment.
The locations at which vascular endothelial cells recruit leukocytes during physiological or pathological inflammatory responses are influenced by direct effects of local haemodynamics on leukocyte adhesion. However, the expression of genes by endothelial cells, and their ability to respond to inflammatory cytokines also depend on the flow forces to which they are exposed. In addition, cells of the underlying stroma can modify the phenotype and responsiveness of endothelial cells, and hence their ability to recruit leukocytes. Thus, endothelial cells are plastic in their responses, and we hypothesise that the pattern of recruitment of leukocytes to tissues is critically dependent on the variable modulation of the endothelium by the local physicochemical microenvironment.


Separate lateral hypothalamic pathways for extracellular and intracellular thirst.
Small lesions of the midlateral zone of the lateral hypothalamus in rats attentuated water intake elicted by the central microinjection angiotensin or by the peripheral injection of isoproterenol or renin without attenuating drinking to peripherally administered hypertonic saline. Lesions placed further lateral in the hypothalamus, which destroyed the medial aspects of the internal capsule and globus pallidus, produced a marked decrease in water intake induced by hypertonic saline. Abaltion of the ventromedial nucleus of the hypothalamus increased drinking elicited by angiotension, isoproterenol, or renin. These results suggest that extracellular and intracellular thirst stimuli are mediated by separate neural pathways at the level of the lateral hypothalamus.


Activation of human dendritic cells following infection with Mycobacterium tuberculosis.
Dendritic cells (DC) play an essential role in the initiation of primary T cell responses to foreign Ag. It is likely that these potent APC are critical in the initiation of immune responses to pathogens, such as bacteria or parasites. However, little is known about the interaction of these important APC with pathogens. To address this issue, the interaction of the bacterium Mycobacterium tuberculosis with human DC was studied. DC generated from human peripheral blood by short term culture in medium containing recombinant human cytokines granulocyte-macrophage-CSF and IL-4 were capable of phagocytosing M. tuberculosis. Infection of DC with live M. tuberculosis bacilli resulted in increased APC surface expression of the costimulatory molecules CD54, CD40, and B7.1, as well as MHC class I molecules. In addition, infected DC secreted elevated levels of inflammatory cytokines, including TNF-alpha, IL-1, and IL-12. M. tuberculosis-infected human monocytes also secreted inflammatory cytokines, but exhibited no enhancement of costimulatory or MHC class I molecule expression. These data indicate that infection with M. tuberculosis results in the direct activation and maturation of these DC. In vivo, such activation may facilitate migration to the lymph nodes, and enhance presentation of Ag to T cells, thereby facilitating the induction of the immune response against this pathogen.


Dextrose and morrhuate sodium injections (prolotherapy) for knee osteoarthritis: a prospective open-label trial.
This study determined whether injection with hypertonic dextrose and morrhuate sodium (prolotherapy) using a pragmatic, clinically determined injection schedule for knee osteoarthritis (KOA) results in improved knee pain, function, and stiffness compared to baseline status. This was a prospective three-arm uncontrolled study with 1-year follow-up. The setting was outpatient. The participants were 38 adults who had at least 3 months of symptomatic KOA and who were in the control groups of a prior prolotherapy randomized controlled trial (RCT) (Prior-Control), were ineligible for the RCT (Prior-Ineligible), or were eligible but declined the RCT (Prior-Declined). The injection sessions at occurred at 1, 5, and 9 weeks with as-needed treatment at weeks 13 and 17. Extra-articular injections of 15% dextrose and 5% morrhuate sodium were done at peri-articular tendon and ligament insertions. A single intra-articular injection of 6 mL 25% dextrose was performed through an inferomedial approach. The primary outcome measure was the validated Western Ontario McMaster University Osteoarthritis Index (WOMAC). The secondary outcome measure was the Knee Pain Scale and postprocedure opioid medication use and participant satisfaction. The Prior-Declined group reported the most severe baseline WOMAC score (p=0.02). Compared to baseline status, participants in the Prior-Control group reported a score change of 12.4±3.5 points (19.5%, p=0.002). Prior-Decline and Prior-Ineligible groups improved by 19.4±7.0 (42.9%, p=0.05) and 17.8±3.9 (28.4%, p=0.008) points, respectively; 55.6% of Prior-Control, 75% of Prior-Decline, and 50% of Prior-Ineligible participants reported score improvement in excess of the 12-point minimal clinical important difference on the WOMAC measure. Postprocedure opioid medication resulted in rapid diminution of prolotherapy injection pain. Satisfaction was high and there were no adverse events. Prolotherapy using dextrose and morrhuate sodium injections for participants with mild-to-severe KOA resulted in safe, significant, sustained improvement of WOMAC-based knee pain, function, and stiffness scores compared to baseline status.


In Silico Evaluation of Ibuprofen and Two Benzoylpropionic Acid Derivatives with Potential Anti-Inflammatory Activity.
Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.


A model for the computation and encoding of azimuthal information by the lateral superior olive.
A structural model is proposed for the processing of interaural intensity differences by the lateral superior olive. One fundamental assumption is that the incoming excitatory projections from the ipsilateral anteroventral cochlear nucleus innervate columns of LSO neurons serially according to threshold. A second fundamental assumption is that the inhibitory innervation from the ipsilateral medial nucleus of the trapezoid body is also serially arranged according to threshold but in the opposite direction along the LSO column. Using neurophysiological and neuroanatomical data for neuronal response curves, connectional patterns, and cell and synapse numbers, the model was formulated quantitatively and implemented for machine computation. Azimuthal location is encoded by the position along the LSO column where LSO cell firing first goes to zero. Accuracy of coding was tested for three different connectional schemes, for variations in neuronal parameters, and for cell and synapse death. Encoding is shown to be independent of absolute sound level and to vary linearly with interaural intensity difference.


Challenges and Considerations When Balancing the Risks of Contaminants with the Benefits of Fruits and Vegetables for Infants and Toddlers.
Fruits and vegetables are key to a healthy diet, particularly in children; however, parents may be concerned about contaminants found in fruits and vegetables. Making informed food choices for children requires understanding and balancing the risks of contaminant exposure with the importance of providing a healthy diet. The objective of this work is to identify fruits and vegetables commonly consumed by infants and toddlers; identify potential contaminants in fruits and vegetables; and outline considerations in assessing contaminant risks in food categories with a critical role in a healthy diet. Commonly consumed fruits and vegetables were obtained from the Feeding Infants & Toddlers Study (FITS 2016). The US Food and Drug Administration Total Diet Study was reviewed for contaminant occurrence, and multiple experts were consulted on considerations in assessing risk of certain contaminants. FITS data show eight fruits and nine vegetables account for over 80% of consumption in infants and toddlers. Several contaminants have been detected in fruits and vegetables. Questions to be addressed prior to establishing contaminant guidance were identified. Contaminant guidance for fruits and vegetables consumed by infants and toddlers raises several challenges. Expertise from multiple disciplines is required to find an approach that maximizes public health benefit.


Induction of the c-myc but not the cH-ras promoter by platinum compounds.
The recombinant plasmids p324, p330 and p323 carrying the aminoglycoside phosphotransferase (aph) gene and 5' flanking c-myc sequences linked to the reporter gene chloramphenicol acetyl-transferase (cat) were introduced into the mouse erythroleukaemic cell line F412B2TK- and stable transfectants resistant to geneticin G418 were obtained. The effects of cis-platin and two novel platinum compounds, D19466 (lobaplatin) and D17872, on c-myc promoter regions were studied using a large range of drug concentrations and correlated with cytotoxicity data. It was found that cis-platin and D19466 show a similar pattern of cytotoxicity and activation of c-myc promoter-driven cat gene expression with maximum effect (increased expression of 7.4- and 8.1-fold, respectively) at a concentration of 5 x 10(-5) M, while the less cytotoxic D17872 only slightly activates cat expression at the same concentration. However, when the F412B2TK- cell line was transfected with a plasmid carrying 5' flanking sequences of the c-Hras1 gene with promoter/enhancer function, linked to the cat reporter, no similar inductive effect was observed with any of the platinum drugs used. These data suggest that platinum compounds and possibly other DNA-damaging agents may specifically influence the expression of certain genes.


Polyethylene Glycol Camouflaged Earthworm Hemoglobin.
Nearly 21 million components of blood and whole blood and transfused annually in the United States, while on average only 13.6 million units of blood are donated. As the demand for Red Blood Cells (RBCs) continues to increase due to the aging population, this deficit will be more significant. Despite decades of research to develop hemoglobin (Hb) based oxygen (O2) carriers (HBOCs) as RBC substitutes, there are no products approved for clinical use. Lumbricus terrestris erythrocruorin (LtEc) is the large acellular O2 carrying protein complex found in the earthworm Lumbricus terrestris. LtEc is an extremely stable protein complex, resistant to autoxidation, and capable of transporting O2 to tissue when transfused into mammals. These characteristics render LtEc a promising candidate for the development of the next generation HBOCs. LtEc has a short half-life in circulation, limiting its application as a bridge over days, until blood became available. Conjugation with polyethylene glycol (PEG-LtEc) can extend LtEc circulation time. This study explores PEG-LtEc pharmacokinetics and pharmacodynamics. To study PEG-LtEc pharmacokinetics, hamsters instrumented with the dorsal window chamber were subjected to a 40% exchange transfusion with 10 g/dL PEG-LtEc or LtEc and followed for 48 hours. To study the vascular response of PEG-LtEc, hamsters instrumented with the dorsal window chamber received multiple infusions of 10 g/dL PEG-LtEc or LtEc solution to increase plasma LtEc concentration to 0.5, then 1.0, and 1.5 g/dL, while monitoring the animals' systemic and microcirculatory parameters. Results confirm that PEGylation of LtEc increases its circulation time, extending the half-life to 70 hours, 4 times longer than that of unPEGylated LtEc. However, PEGylation increased the rate of LtEc oxidation in vivo. Vascular analysis verified that PEG-LtEc showed the absence of microvascular vasoconstriction or systemic hypertension. The molecular size of PEG-LtEc did not change the colloid osmotic pressure or blood volume expansion capacity compared to LtEc, due to LtEc's already large molecular size. Taken together, these results further encourage the development of PEG-LtEc as an O2 carrying therapeutic.


Efficient coding of natural images with a population of noisy Linear-Nonlinear neurons.
Efficient coding provides a powerful principle for explaining early sensory coding. Most attempts to test this principle have been limited to linear, noiseless models, and when applied to natural images, have yielded oriented filters consistent with responses in primary visual cortex. Here we show that an efficient coding model that incorporates biologically realistic ingredients - input and output noise, nonlinear response functions, and a metabolic cost on the firing rate - predicts receptive fields and response nonlinearities similar to those observed in the retina. Specifically, we develop numerical methods for simultaneously learning the linear filters and response nonlinearities of a population of model neurons, so as to maximize information transmission subject to metabolic costs. When applied to an ensemble of natural images, the method yields filters that are center-surround and nonlinearities that are rectifying. The filters are organized into two populations, with On- and Off-centers, which independently tile the visual space. As observed in the primate retina, the Off-center neurons are more numerous and have filters with smaller spatial extent. In the absence of noise, our method reduces to a generalized version of independent components analysis, with an adapted nonlinear "contrast" function; in this case, the optimal filters are localized and oriented.


Idiotype vaccines for human B-cell malignancies.
After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.


Preserved cardiac mitochondrial function and reduced ischaemia/reperfusion injury afforded by chronic continuous hypoxia: role of opioid receptors.
Chronic continuous normobaric hypoxia (CNH) increases cardiac tolerance to acute ischaemia/reperfusion injury. The objective of this study was to find out whether the cardioprotective effect of CNH mediated by opioid receptors is associated with preservation of mitochondrial function. Rats were adapted to CNH (12% oxygen) for 3 weeks. Isolated perfused hearts were subjected to 45 min of global ischaemia and 30 min of reperfusion; subgroups were pretreated with non-selective opioid receptor antagonist naloxone (300 nmol/L) for 10 min. Cardiac contractile function, creatine kinase activity in coronary effluent, mitochondrial respiration rate, and calcium retention capacity were assessed. Adaptation to CNH decreased myocardial creatine kinase release during reperfusion and improved the post-ischaemic recovery of contractile function, mitochondrial state 3 and uncoupled respiration rates, and calcium retention capacity compared to the normoxic group. These protective effects were completely abolished by naloxone. The contractile recovery positively correlated with state 3 respiration and calcium retention capacity. The results suggest that the preserved mitochondrial function contributes to the protected cardiac phenotype afforded by adaptation to CNH and point to an important role of opioid receptor activation.


I-SceI-induced gene replacement at a natural locus in embryonic stem cells.
Gene targeting is a very powerful tool for studying mammalian development and physiology and for creating models of human diseases. In many instances, however, it is desirable to study different modifications of a target gene, but this is limited by the generally low frequency of homologous recombination in mammalian cells. We have developed a novel gene-targeting strategy in mouse embryonic stem cells that is based on the induction of endogenous gap repair processes at a defined location within the genome by induction of a double-strand break (DSB) in the gene to be mutated. This strategy was used to knock in an NH2-ezrin mutant in the villin gene, which encodes an actin-binding protein expressed in the brush border of the intestine and the kidney. To induce the DSB, an I-SceI yeast meganuclease restriction site was first introduced by gene targeting to the villin gene, followed by transient expression of I-SceI. The repair of the ensuing DSB was achieved with high efficiency (6 x 10[-6]) by a repair shuttle vector sharing only a 2.8-kb region of homology with the villin gene and no negative selection marker. Compared to conventional gene-targeting experiments at the villin locus, this represents a 100-fold stimulation of gene-targeting frequency, notwithstanding a much lower length of homology. This strategy will be very helpful in facilitating the targeted introduction of several types of mutations within a gene of interest.


Stevia Nonsweetener Fraction Displays an Insulinotropic Effect Involving Neurotransmission in Pancreatic Islets.
Stevia rebaudiana (Bert.) Bertoni besides being a source of noncaloric sweeteners is also an important source of bioactive molecules. Many plant extracts, mostly obtained with ethyl acetate solvent, are rich in polyphenol compounds that present insulinotropic effects. To investigate whether the nonsweetener fraction, which is rich in phenolic compounds isolated from Stevia rebaudiana with the solvent ethyl acetate (EAF), has an insulinotropic effect, including interference at the terminals of the autonomic nervous system of the pancreatic islets of rats. Pancreatic islets were isolated from Wistar rats and incubated with EAF and inhibitory or stimulatory substances of insulin secretion, including cholinergic and adrenergic agonists and antagonists. EAF potentiates glucose-stimulated insulin secretion (GSIS) only in the presence of high glucose and calcium-dependent concentrations. EAF increased muscarinic insulinotropic effects in pancreatic islets, interfering with the muscarinic receptor subfamily M3. Adrenergic inhibitory effects on GSIS were attenuated in the presence of EAF, which interfered with the adrenergic α2 receptor. Results suggest that EAF isolated from stevia leaves is a potential therapy for treating type 2 diabetes mellitus by stimulating insulin secretion only in high glucose concentrations, enhancing parasympathetic signal transduction and inhibiting sympathetic signal transduction in beta cells.


Thioxanthone hydroquinone-O,O'-diacetic acid: photoinitiator or photostabilizer?
A photoinitiator for free-radical polymerization based on a thioxanthone chromophore containing two acetic acid functions was synthesized and characterized. Photophysical studies such as fluorescence, phosphorescence, and laser flash photolysis in addition to photopolymerization of acrylates were performed to elucidate the radical generation mechanism involving intramolecular electron transfer from the triplet state followed by decarboxylation. We found that the position of the acetic acid substituent is critical for the photoreactivity. In most solvents and acrylic monomers, if the acetic acid functionality is at the 1-position, the singlet excited states are deactivated rapidly before electron transfer can occur, resulting in negligible photoreactivity. The excited-state deactivation probably involves intramolecular H-bonding deactivation. The intramolecular H-bonding is disrupted by solvents that support intermolecular H-bonding, such as DMF and DMSO, leading to efficient intramolecular photoreaction.


Cesarean Section, Formula Feeding, and Infant Antibiotic Exposure: Separate and Combined Impacts on Gut Microbial Changes in Later Infancy.
Established during infancy, our complex gut microbial community is shaped by medical interventions and societal preferences, such as cesarean section, formula feeding, and antibiotic use. We undertook this study to apply the significance analysis of microarrays (SAM) method to quantify changes in gut microbial composition during later infancy following the most common birth and postnatal exposures affecting infant gut microbial composition. Gut microbiota of 166 full-term infants in the Canadian Healthy Infant Longitudinal Development birth cohort were profiled using 16S high-throughput gene sequencing. Infants were placed into groups according to mutually exclusive combinations of birth mode (vaginal/cesarean birth), breastfeeding status (yes/no), and antibiotic use (yes/no) by 3 months of age. Based on repeated permutations of data and adjustment for the false discovery rate, the SAM statistic identified statistically significant changes in gut microbial abundance between 3 months and 1 year of age within each infant group. We observed well-known patterns of microbial phyla succession in later infancy (declining Proteobacteria; increasing Firmicutes and Bacteroidetes) following vaginal birth, breastfeeding, and no antibiotic exposure. Genus Lactobacillus, Roseburia, and Faecalibacterium species appeared in the top 10 increases to microbial abundance in these infants. Deviations from this pattern were evident among infants with other perinatal co-exposures; notably, the largest number of microbial species with unchanged abundance was seen in gut microbiota following early cessation of breastfeeding in infants. With and without antibiotic exposure, the absence of a breast milk diet by 3 months of age following vaginal birth yielded a higher proportion of unchanged abundance of Bacteroidaceae and Enterobacteriaceae in later infancy, and a higher ratio of unchanged Enterobacteriaceae to Alcaligenaceae microbiota. Gut microbiota of infants born vaginally and exclusively formula fed became less enriched with family Veillonellaceae and Clostridiaceae, showed unchanging levels of Ruminococcaceae, and exhibited a greater decline in the Rikenellaceae/Bacteroidaceae ratio compared to their breastfed, vaginally delivered counterparts. These changes were also evident in cesarean-delivered infants to a lesser extent. The clinical relevance of these trajectories of microbial change is that they culminate in taxon-specific abundances in the gut microbiota of later infancy, which we and others have observed to be associated with food sensitization.


Opioid substitution treatment and heroin dependent adolescents: reductions in heroin use and treatment retention over twelve months.
Opioid dependence is a major health concern across the world and does also occur in adolescents. While opioid substitution treatment (OST) has been thoroughly evaluated in adult populations, very few studies have examined its use in adolescents. There are concerns that OST is underutilised in adolescents with heroin dependence. We sought to measure changes in drug use among adolescents receiving OST and also to examine treatment attrition during the first 12 months of this treatment. We included all heroin dependent patients aged under 18.5 years commencing OST at one outpatient multidisciplinary adolescent addiction treatment service in Dublin, Ireland. Psycho-social needs were also addressed during treatment. Drug use was monitored by twice weekly urine drugs screens (UDS). Change in the proportion of UDS negative for heroin was examined using the Wilcoxon signed rank test. Attrition was explored via a Cox Regression multivariate analysis. OST was commenced by 120 patients (51% female and mean age 17.3 years). Among the 39 patients who persisted with OST until month 12, heroin abstinence was 21% (95% confidence interval [CI] = 9-36%) at month three and it was 46% (95% CI = 30-63%) at month 12. Heroin use declined significantly from baseline to month three (p < 0.001) and from month three to month 12 (p = 0.01). Use of other drugs did not change significantly. People using cocaine during month 12 were more likely to be also using heroin (p = 0.02). Unplanned exit occurred in 25% patients by 120 days. The independent predictors of attrition were having children, single parent family of origin, not being in an intimate relationship with another heroin user and evidence of cocaine use just before treatment entry. We found that heroin dependent adolescent patients achieved significant reductions in heroin use within three months of starting OST and this improved further after a year of treatment, about half being heroin abstinent at that stage. Patient drop out from treatment remains a challenge, as it is in adults. Cocaine use before and during treatment may be a negative prognostic factor.


Dissociation of long-term verbal memory and fronto-executive impairment in first-episode psychosis.
Verbal memory is frequently and severely affected in schizophrenia and has been implicated as a mediator of poor clinical outcome. Whereas encoding deficits are well demonstrated, it is unclear whether retention is impaired. This distinction is important because accelerated forgetting implies impaired consolidation attributable to medial temporal lobe (MTL) dysfunction whereas impaired encoding and retrieval implicates involvement of prefrontal cortex. We assessed a group of healthy volunteers (n=97) and pre-morbid IQ- and sex-matched first-episode psychosis patients (n=97), the majority of whom developed schizophrenia. We compared performance of verbal learning and recall with measures of visuospatial working memory, planning and attentional set-shifting, and also current IQ. All measures of performance, including verbal memory retention, a memory savings score that accounted for learning impairments, were significantly impaired in the schizophrenia group. The difference between groups for delayed recall remained even after the influence of learning and recall was accounted for. Factor analyses showed that, in patients, all variables except verbal memory retention loaded on a single factor, whereas in controls verbal memory and fronto-executive measures were separable. The results suggest that IQ, executive function and verbal learning deficits in schizophrenia may reflect a common abnormality of information processing in prefrontal cortex rather than specific impairments in different cognitive domains. Verbal memory retention impairments, however, may have a different aetiology.


Is cold or warm blood cardioplegia superior for myocardial protection?
A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether the use of warm or cold blood cardioplegia has superior myocardial protection. More than 192 papers were found using the reported search, of which 20 represented the best evidence to answer the clinical question. The authors, journal, date, country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. A good breadth of high-level evidence addressing this clinical dilemma is available, including a recent meta-analysis and multiple large randomized clinical trials. Yet despite this level of evidence, no clear significant clinical benefit has been demonstrated by warm or cold blood cardioplegia. This suggests that neither method is significantly superior and that both provide similar efficacy of myocardial protection. The meta-analysis, including 41 randomized control trials (5879 patients in total), concluded that although a lower cardiac enzyme release and improved postoperative cardiac index was demonstrated in the warm cardioplegia group, this benefit was not reflected in clinical outcomes, which were similar in both groups. This theme of benefit in biochemical markers, physiological metrics and non-fatal postoperative events in the warm cardioplegia group ran throughout the literature, in particular the 'Warm Heart investigators' who conducted a randomized trial of 1732 patients, demonstrated a reduction in postoperative low output syndrome (6.1 versus 9.3%, P = 0.01) in the warm cardioplegia group, but no significant drop in 30-day all-cause mortality (1.4 versus 2.5%, P = 0.12). However, their later follow-up indicates non-fatal postoperative events predict reduced late survival, independent of cardioplegia. A minority of studies suggested a benefit of cold cardioplegia over warm in particular patient subgroups: One group conducted a retrospective study of 520 patients who required prolonged aortic cross-clamp times, results demonstrated less myocardial damage and reduced postoperative cardiac mortality and morbidity in the cold group. The clinical bottom line is that warm and cold cardioplegia result in similar short-term mortality. However, large studies have shown that warm cardioplegia reduces adverse post-operative events; the significance of which is unclear.


Degradation of host sphingomyelin is essential for Leishmania virulence.
In eukaryotes, sphingolipids (SLs) are important membrane components and powerful signaling molecules. In Leishmania, the major group of SLs is inositol phosphorylceramide (IPC), which is common in yeast and Trypanosomatids but absent in mammals. In contrast, sphingomyelin is not synthesized by Leishmania but is abundant in mammals. In the promastigote stage in vitro, Leishmania use SL metabolism as a major pathway to produce ethanolamine (EtN), a metabolite essential for survival and differentiation from non-virulent procyclics to highly virulent metacyclics. To further probe SL metabolism, we identified a gene encoding a putative neutral sphingomyelinase (SMase) and/or IPC hydrolase (IPCase), designated ISCL (Inositol phosphoSphingolipid phospholipase C-Like). Despite the lack of sphingomyelin synthesis, L. major promastigotes exhibited a potent SMase activity which was abolished upon deletion of ISCL, and increased following over-expression by episomal complementation. ISCL-dependent activity with sphingomyelin was about 20 fold greater than that seen with IPC. Null mutants of ISCL (iscl(-)) showed modest accumulation of IPC, but grew and differentiated normally in vitro. Interestingly, iscl(-) mutants did not induce lesion pathology in the susceptible BALB/c mice, yet persisted indefinitely at low levels at the site of infection. Notably, the acute virulence of iscl(-) was completely restored by the expression of ISCL or heterologous mammalian or fungal SMases, but not by fungal proteins exhibiting only IPCase activity. Together, these findings strongly suggest that degradation of host-derived sphingomyelin plays a pivotal role in the proliferation of Leishmania in mammalian hosts and the manifestation of acute disease pathology.


Population divergence in venom bioactivities of elapid snake Pseudonaja textilis: role of procoagulant proteins in rapid rodent prey incapacitation.
This study looked at how toxic proteins in venoms of adult Australian eastern Brown snakes Pseudonaja textilis from South Australian and Queensland populations interact with physiological functions of the lab SD rat Rattus norvegicus. Circulatory collapse and incoagulable blood occurred instantly after injection of venom under the dorsal skin of anaesthetised and mechanically ventilated rats in an imitation of a P. textilis bite. Intravenous injection of purified P. textilis (Mackay, QLD) venom prothrombin activator proteins caused instant failure of circulation, testifying of high toxicity of these proteins and suggesting their role in rapid incapacitation of rodent prey. The hypothesis is further supported by circulatory collapse occurring instantly despite artificial respiration in envenomed rats and the finding of extremely high venom procoagulant potency in rat plasma. LC-MS and physiology assays revealed divergent venom composition and biological activity of South Australian (Barossa locality) and Queensland (Mackay locality) populations, which may be driven by selection for different prey. The Queensland venom of P. textilis was found to be more procoagulant and to exhibit predominately presynaptic neurotoxicity, while the South Australian venom contained diverse postsynaptic type II and III α-neurotoxins in addition to the presynaptic neurotoxins and caused significantly faster onset of neuromuscular blockade in the rat phrenic nerve-diaphragm preparation. LC-MS analysis found evidence of multiple coagulation factor X-like proteins in P. textilis venoms, including a match to P. textilis coagulation factor X isoform 2, previously known to be expressed only in the liver.


Validity and reliability of 6-a-side small-sided game locomotor performance in assessing physical fitness in football players.
In order to determine whether small-sided game (SSG) locomotor performance can serve as a fitness indicator, we (1) compared 6-a-side (6v6) SSG-intensity of players varying in fitness and skill, (2) examined the relationship of the 6v6-SSG and Yo-Yo IR2 and (3) assessed the reliability of the 6v6-SSG. Thirty-three professional senior, 30 professional youth, 62 amateur and 16 professional woman football players performed 4 × 7 min 6v6-SSGs recorded by a Local Position Measurement system. A substantial subgroup (N = 113) also performed the Yo-Yo IR2. Forty-seven amateur players performed two or three 6v6-SSGs. No differences in 6v6-SSG time-motion variables were found between professional senior and professional youth players. Amateurs showed lower values than professional seniors on almost all time-motion variables (ES = 0.59-1.19). Women displayed lower high-intensity time-motion variables than all other subgroups. Total distance run during 6v6-SSG was only moderately related to Yo-Yo IR2 distance (r = 0.45), but estimated metabolic power, high speed (>14.4 km · h(-1)), high acceleration (>2 m · s(-2)), high power (>20 W · kg(-1)) and very high (35 W · kg(-1)) power showed higher correlations (r = 0.59-0.70) with Yo-Yo IR2 distance. Intraclass correlation coefficient values were higher for total distance (0.84) than other time-motion variables (0.74‒0.78). Although total distance and metabolic power during 6v6-SSG showed good reproducibility (coefficient of variation (CV) < 5%), CV was higher (8-14%) for all high-intensity time-motion variables. It was therefore concluded that standardised SSG locomotor performance cannot serve used as a valid and reliable fitness indicator for individual players.


High acuity rural transport: findings from a qualitative investigation.
The High Acuity Response Team (HART) was introduced in British Columbia (BC), Canada, to fill a gap in transport for rural patients that was previously being met by nurses and physicians leaving their communities to escort patients in need of critical care. The HART team consists of a critical care registered nurse (CCRN) and registered respiratory therapist (RRT) and attends acute care patients in rural sites by either stabilizing them in their community or transporting them. HART services are deployed in partnership with provincial ambulance services, which provide vehicles and coordination of all requests in the province for patient transport. This article presents the qualitative findings from a research evaluation of the efficacy of the HART model, including staffing and inter-organizational functioning. Open-ended qualitative research interviewing was done with key stakeholders from 21 sites. Research participants included HART CCRNs, RRTs, administrative leads, as well as local emergency department (ED) physicians and nurses. Thematic analysis was done of the transcripts. A total of 107 interviews in 21 study sites were completed. Participants described characteristics of the model, perceptions of efficacy and areas for improvement. Rural sites reported a decrease in physician- and nurse-accompanied transports for high-acuity patients due to the HART team, but also noted challenges in delayed deployment, sometimes leading to adverse patient outcomes. The salient issues for the HART model were grounded in a somewhat artificial distinction between pre-hospital and interfacility transport for rural patients, which leads to a lack of service coordination and potentially avoidable delays. A beneficial systems change would be to move towards dedicated integration of high-acuity transport services into hospital organizational structures and community health services in rural areas.


Plasmodium falciparum: characterization of gene R45 encoding a trophozoite antigen containing a central block of six amino acid repeats.
We describe here an antigen, called R45, expressed by the young trophozoites of Plasmodium falciparum. This antigen contains a block of tandem repeats of six amino acids which are recognized by sera from humans living in endemic areas. The R45 gene is located on chromosome 3. It is present in all strains examined and shows limited size polymorphism. The C-terminal unique region of the protein shows a strong homology with the catalytic domain of the serine protein kinases. Interestingly, the central repeats contain a large number of putative phosphorylation sites. The implications of these features are discussed.


Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital.
To determine if hospitalized medical and surgical patients were placed inappropriately on symptom-triggered therapy (STT) for alcohol withdrawal syndrome (AWS) and if certain conditions were more likely to be associated with inappropriate STT use or adverse events. We randomly selected 124 (25%) of the 495 Mayo Clinic inpatients who received STT according to the Revised Clinical Institute for Withdrawal Assessment for Alcohol (CIWA-Ar) protocol in 2003 and assessed them for STT appropriateness, defined as having both intact verbal communication and recent alcohol use. Adverse events, including delirium tremens, seizures, or death, were correlated with CIWA-Ar appropriateness. Of the 124 randomly selected patients, only 60 (48%) met both inclusion criteria. Of the remaining 64 patients, 9 (14%) were drinkers but could not communicate, and 35 (55%) could communicate but had not been drinking. Twenty (31%) met neither criterion. Univariate analysis identified a significant association between inappropriate initiation and chronic heart failure, postoperative status (POS), liver disease (LD), nonmetastatic cancer, and chemical dependency consultation. On multivariate analysis, only LD (P equals .02) and POS (P equals .01) retained significance, with LD more and POS less likely to predict appropriateness. Seven of 11 patients who experienced adverse events had received STT according to the CIWA-Ar protocol (P equals .05). Univariate analysis identified a significant association between adverse events and a history of alcohol dependence or AWS. Multivariate analysis showed significance only for a history of alcohol dependence (P equals .049). Fewer than half of the randomly selected patients met both of the inclusion criteria for the CIWA-Ar instrument, leading us to conclude that more stringent evaluation is needed. Particularly postoperatively, alternative explanations for putative AWS should be sought. Health care professionals should more aggressively seek information on recent alcohol use from medical records, family members, and patients themselves.


Acid-base status of critically ill patients with acute renal failure: analysis based on Stewart-Figge methodology.
The aim of the present study is to understand the nature of acid-base disorders in critically ill patients with acute renal failure (ARF) using the biophysical principles described by Stewart and Figge. A retrospective controlled study was carried out in the intensive care unit of a tertiary hospital. Forty patients with ARF, 40 patients matched for Acute Physiology and Chronic Health Evaluation II score (matched control group), and 60 consecutive critically ill patients without ARF (intensive care unit control group) participated. The study involved the retrieval of biochemical data from computerized records, quantitative biophysical analysis using the Stewart-Figge methodology, and statistical comparison between the three groups. We measured serum sodium, potassium, magnesium, chloride, bicarbonate, phosphate, ionized calcium, albumin, lactate and arterial blood gases. Intensive care unit patients with ARF had a mild acidemia (mean pH 7.30 +/- 0.13) secondary to metabolic acidosis with a mean base excess of -7.5 +/- 7.2 mEq/l. However, one-half of these patients had a normal anion gap. Quantitative acid-base assessment (Stewart-Figge methodology) revealed unique multiple metabolic acid-base processes compared with controls, which contributed to the overall acidosis. The processes included the acidifying effect of high levels of unmeasured anions (13.4 +/- 5.5 mEq/l) and hyperphosphatemia (2.08 +/- 0.92 mEq/l), and the alkalinizing effect of hypoalbuminemia (22.6 +/- 6.3 g/l). The typical acid-base picture of ARF of critical illness is metabolic acidosis. This acidosis is the result of the balance between the acidifying effect of increased unmeasured anions and hyperphosphatemia and the lesser alkalinizing effect of hypoalbuminemia.


Molecular diagnosis of a previously unreported predator-prey association in coffee: Karnyothrips flavipes Jones (Thysanoptera: Phlaeothripidae) predation on the coffee berry borer.
The coffee berry borer, Hypothenemus hampei, is the most important pest of coffee throughout the world, causing losses estimated at US $500 million/year. The thrips Karnyothrips flavipes was observed for the first time feeding on immature stages of H. hampei in April 2008 from samples collected in the Kisii area of Western Kenya. Since the trophic interactions between H. hampei and K. flavipes are carried out entirely within the coffee berry, and because thrips feed by liquid ingestion, we used molecular gut-content analysis to confirm the potential role of K. flavipes as a predator of H. hampei in an organic coffee production system. Species-specific COI primers designed for H. hampei were shown to have a high degree of specificity for H. hampei DNA and did not produce any PCR product from DNA templates of the other insects associated with the coffee agroecosystems. In total, 3,327 K. flavipes emerged from 17,792 H. hampei-infested berries collected from the field between April and September 2008. Throughout the season, 8.3% of K. flavipes tested positive for H. hampei DNA, although at times this figure approached 50%. Prey availability was significantly correlated with prey consumption, thus indicating the potential impact on H. hampei populations.


STRUCTURAL ANALYSIS AND COMPREHENSIVE SURGICAL OUTCOMES OF THE SUTURELESS INTRASCLERAL FIXATION OF SECONDARY INTRAOCULAR LENSES IN HUMAN EYES.
To describe surgical outcomes and structural characteristics of intraocular lenses (IOLs) implanted with transconjunctival sutureless intrascleral (SIS) fixation in human eyes. Retrospective interventional surgical case series involving live and cadaveric human eyes. In this study, we investigated the surgical outcomes and structural anatomy of secondary IOLs implanted with the SIS technique in human eyes. All cases involving SIS IOL fixation performed at a single academic center from January 1, 2012, through July 30, 2016, were reviewed to describe the surgical technique, common indications, clinical outcomes, and the rate of common operative complications. To investigate the structure of SIS-fixated IOLs in vivo, slit-lamp biomicroscopy, ultrasound biomicroscopy, and intraoperative endoscopy were analyzed to describe anatomical outcomes. The primary anatomical outcomes were the optic pupillary centration and location of haptic externalization. Results were correlated with cadaveric human eyes that underwent the SIS-IOL technique. Cadaveric eyes were imaged and analyzed using high-resolution photography for centration, stress measurements at the haptic-optic junction, and qualitative descriptors of IOL optic and haptic position. A total of 122 consecutive patients who underwent IOL placement using SIS technique were included in the study with mean follow-up of 1.52 years (range, 0.4-4.5 years). The majority (75%) of patients received a new 3-piece IOL for primary aphakia or after IOL exchange. The other patients (25%) had a dislocated 3-piece IOL that was rescued using the SIS technique. Preoperative mean Snellen visual acuity was 20/633 (logarithm of the minimum angle of resolution = 1.501). At the final visit, the mean best-corrected visual acuity was 20/83 (logarithm of the minimum angle of resolution = 0.6243) and final mean spherical equivalent was -0.57 diopters. The most common complications were vitreous hemorrhage (22% of eyes), which resolved spontaneously in most cases, and cystoid macular edema. The rates of IOL dislocation, IOL decentration, haptic erosion, IOL tilting, iris capture, and endophthalmitis were low. Intraoperative endoscopy and ultrasound biomicroscopy demonstrated a securely fixated IOL and well-centered optic without iris or ciliary body touch. Structural study of cadaveric eyes confirmed IOL optic and haptic anatomy observed during live human surgery. The ab interno haptic insertion was the anterior pars plana, away from the iris, ciliary processes and ora serrata. The degree of haptic externalization was correlated with the degree of strain on the haptic-optic junction. The angle of the haptic-optic junction in SIS-fixated IOLs (33.97°) was not significantly different compared with overlaid native nonfixated IOL (32.93°) but increased slightly with degree of haptic tip externalization (36.26 and 39.16 for 2 and 3 mm haptic externalizations, respectively). In this comprehensive study, we demonstrate the surgical outcomes achieved with SIS fixation of IOLs. Surgical and postoperative complications do occur, albeit at a low rate, and can effectively be managed with excellent anatomical and visual outcomes. The structural and anatomical data in this study may help guide SIS placement and optimize long-term surgical results.


Cauda equina syndrome secondary to portal vein thrombosis: case report of favorable outcome with conservative treatment.
Epidural varicosis is a rare though well-known cause of cauda equina syndrome (CES). Although inferior vena cava (IVC) obstruction is the most common finding in such cases, portal vein hypertension can lead to epidural venous plexus engorgement by means of lumbar portocaval shunt activation.A 40-year-old woman presented with right-sided sciatica, which progressed to right foot drop and a 3-day history of vesical tenesmus and fecal retention. She was initially diagnosed with L4-5 lumbar disc protrusion. However, contrast-enhanced lumbar MRI scan showed the presence of epidural varices in the L3-S1 tract. Given the absence of vascular anomalies amenable to resection, etiological conservative treatment was addressed. Therefore, a complete diagnostic workup was performed and revealed deep vein thrombosis (DVT), pulmonary embolism, and portal vein thrombosis. Oral anticoagulant therapy was initiated and prompt resolution of CES was observed. To the authors' knowledge, this is the first report of CES secondary to epidural varicosis in the setting of acute portal vein thrombosis and extrahepatic portal vein obstruction (EHPVO). In cases of epidural varicosis, conservative etiological treatment is the most appropriate choice as CES may be the epiphenomenon of underlying systemic pathophysiological processes.


Computer literacy of physicians among the hospitals of Makkah region.
A confidential inquiry by the Directorate General of Health Affairs, Makkah region, Saudi Arabia, found physicians in different hospitals were reluctant to enter patients' related information in electronic medical record systems. One of the major issues raised was that they didn't have the required computer literacy. Our aim, therefore, was to conduct a survey to highlight the computer literacy among the physicians of Makkah region. This cross-sectional survey was performed from May to July 2009. A structured questionnaire of four A4 size paper was distributed among the physicians of the Makkah region working in seven different hospitals. The questionnaire contained questions on background knowledge of computers, i.e., (a) basic computer vocabulary knowledge (BCVK) (10 questions), (b) basic computer skills (BCS) (22 questions), (c) basic communication and internet skills (BCIS) (12 questions). Response rate of 368, i.e., 81.6% of sample size (n = 451) was attained. The maximum response came from King Abdul Aziz Hospital (Taif), i.e., 79%. Overall BCVK, BCS and BCIS were the highest among the physicians of Alnoor Specialist Hospital, i.e., 71.3%, 91.4%, 87.7%, respectively. All the hospitals had a satisfactory level of BCVK, but levels of BCS and BCIS were above satisfactory except King Abdul Aziz Hospital (Jeddah) that showed a satisfactory level in BCIS. Majority of the physicians had a good or an excellent level of computer background knowledge that gave a prediction toward the issues of their non-promising attitude and beliefs about electronic data entry.


Time-related patient data retrieval for the case studies from the pharmacogenomics research network.
There are lots of question-based data elements from the pharmacogenomics research network (PGRN) studies. Many data elements contain temporal information. To semantically represent these elements so that they can be machine processiable is a challenging problem for the following reasons: (1) the designers of these studies usually do not have the knowledge of any computer modeling and query languages, so that the original data elements usually are represented in spreadsheets in human languages; and (2) the time aspects in these data elements can be too complex to be represented faithfully in a machine-understandable way. In this paper, we introduce our efforts on representing these data elements using semantic web technologies. We have developed an ontology, CNTRO, for representing clinical events and their temporal relations in the web ontology language (OWL). Here we use CNTRO to represent the time aspects in the data elements. We have evaluated 720 time-related data elements from PGRN studies. We adapted and extended the knowledge representation requirements for EliXR-TIME to categorize our data elements. A CNTRO-based SPARQL query builder has been developed to customize users' own SPARQL queries for each knowledge representation requirement. The SPARQL query builder has been evaluated with a simulated EHR triple store to ensure its functionalities.


Cardiometabolic multimorbidity is associated with a worse Covid-19 prognosis than individual cardiometabolic risk factors: a multicentre retrospective study (CoViDiab II).
Cardiometabolic disorders may worsen Covid-19 outcomes. We investigated features and Covid-19 outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. We collected and compared data retrospectively from patients hospitalized for Covid-19 with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). Multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [ICU] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. Of 354 patients enrolled, those with diabetes (n = 81), compared with those without diabetes (n = 273), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (COPD), higher levels of inflammatory markers and a lower PaO2/FIO2 ratio. The risk of the primary composite outcome in the 277 patients who completed the study as of May 15th, 2020, was higher in those with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12-3.73, p = 0.020), hypertension (adjOR 2.31, 95%CI: 1.37-3.92, p = 0.002) and COPD (adjOR 2.67, 95%CI 1.23-5.80, p = 0.013). Patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions (adjOR 3.19 95%CI 1.61-6.34, p = 0.001). The risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors (adjOR 1.66, 0.90-3.06, adjp = 0.10). Patients with diabetes hospitalized for Covid-19 present with high-risk features. They are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions.


Artificial intelligence: A rapid case for advancement in the personalization of Gynaecology/Obstetric and Mental Health care.
To evaluate and holistically treat the mental health sequelae and potential psychiatric comorbidities associated with obstetric and gynaecological conditions, it is important to optimize patient care, ensure efficient use of limited resources and improve health-economic models. Artificial intelligence applications could assist in achieving the above. The World Health Organization and global healthcare systems have already recognized the use of artificial intelligence technologies to address 'system gaps' and automate some of the more cumbersome tasks to optimize clinical services and reduce health inequalities. Currently, both mental health and obstetric and gynaecological services independently use artificial intelligence applications. Thus, suitable solutions are shared between mental health and obstetric and gynaecological clinical practices, independent of one another. Although, to address complexities with some patients who may have often interchanging sequelae with mental health and obstetric and gynaecological illnesses, 'holistically' developed artificial intelligence applications could be useful. Therefore, we present a rapid review to understand the currently available artificial intelligence applications and research into multi-morbid conditions, including clinical trial-based validations. Most artificial intelligence applications are intrinsically data-driven tools, and their validation in healthcare can be challenging as they require large-scale clinical trials. Furthermore, most artificial intelligence applications use rate-limiting mock data sets, which restrict their applicability to a clinical population. Some researchers may fail to recognize the randomness in the data generating processes in clinical care from a statistical perspective with a potentially minimal representation of a population, limiting their applicability within a real-world setting. However, novel, innovative trial designs could pave the way to generate better data sets that are generalizable to the entire global population. A collaboration between artificial intelligence and statistical models could be developed and deployed with algorithmic and domain interpretability to achieve this. In addition, acquiring big data sets is vital to ensure these artificial intelligence applications provide the highest accuracy within a real-world setting, especially when used as part of a clinical diagnosis or treatment.


Characteristics of a long-term procedural skill in the monkey.
The purpose of this study was to characterize the nature and structure of procedural memory. We have previously studied the process of learning sequential behavioral procedures using monkeys. The monkey's task was to press five consecutive pairs of buttons (indicated by illumination) in the correct order for every pair, which he had to find by trial-and-error in a block of trials. The whole sequence was called a "hyperset"; each pair was called a "set". We first examined whether monkeys learned to perform a hyperset as a single sequence or learned the order of button-presses individually for each set. To answer this question, we generated hypersets that were the same as the hypersets that had been extensively learned except that the order of the sets was reversed. The performance of these "reversed hypersets" was much worse than the performance of the original learned hypersets and was similar to the performance of new hypersets, as regards both the number of errors and the performance time. The result suggests that monkeys learned a hyperset as a sequence. To examine whether the learned performance was specific to the hand used for practice, we had monkeys use the same hand throughout the long-term practice of each hyperset, and then tested the opposite hand. The performance using the opposite hand was worse than the performance using the trained hand, but was better than the performance for new hypersets. This indicates that the memory for the sequential procedure is only partially accessible to the hand that was not used for the practice.


Reliability of measuring sciatic and tibial nerve movement with diagnostic ultrasound during a neural mobilisation technique.
Diagnostic ultrasound provides a technique whereby real-time, in vivo analysis of peripheral nerve movement is possible. This study measured sciatic nerve movement during a "slider" neural mobilisation technique (ankle dorsiflexion/plantar flexion and cervical extension/flexion). Transverse and longitudinal movement was assessed from still ultrasound images and video sequences by using frame-by-frame cross-correlation software. Sciatic nerve movement was recorded in the transverse and longitudinal planes. For transverse movement, at the posterior midthigh (PMT) the mean value of lateral sciatic nerve movement was 3.54 mm (standard error of measurement [SEM] +/- 1.18 mm) compared with anterior-posterior/vertical (AP) movement of 1.61 mm (SEM +/- 0.78 mm). At the popliteal crease (PC) scanning location, lateral movement was 6.62 mm (SEM +/- 1.10 mm) compared with AP movement of 3.26 mm (SEM +/- 0.99 mm). Mean longitudinal sciatic nerve movement at the PMT was 3.47 mm (SEM +/- 0.79 mm; n = 27) compared with the PC of 5.22 mm (SEM +/- 0.05 mm; n = 3). The reliability of ultrasound measurement of transverse sciatic nerve movement was fair to excellent (Intraclass correlation coefficient [ICC] = 0.39-0.76) compared with excellent (ICC = 0.75) for analysis of longitudinal movement. Diagnostic ultrasound presents a reliable, noninvasive, real-time, in vivo method for analysis of sciatic nerve movement.


Explicit Time Deficit in Schizophrenia: Systematic Review and Meta-Analysis Indicate It Is Primary and Not Domain Specific.
Although timing deficits are a robust finding in schizophrenia (SZ), the notion of a genuine time perception disorder in SZ is still being debated because distortions in timing might depend on neuropsychological deficits that are characteristics of the illness. Here we used meta-analytic methods to summarize the evidence of timing deficits in SZ and moderator analyses to determine whether defective timing in SZ arises from nontemporal sources or from defective time perception. PubMed Services, PsycNET, and Scopus were searched through March 2015, and all references in articles were investigated to find other relevant studies. Studies were selected if they included subjects with a primary diagnosis of SZ compared to a healthy control (HC) group and if they reported behavioral measures of duration estimation (perceptual and motor explicit timing). Data from 24 studies published from 1956 to 2015, which comprised 747 SZ individuals and 808 HC, were included. Results indicate that SZ individuals are less accurate than HC in estimating time duration across a wide range of tasks. Subgroup analyses showed that the fundamental timing deficit in SZ is independent from the length of the to-be-timed duration (automatic and cognitively controlled timing) and from methods of stimuli estimation (perceptual and motor timing). Thus, time perception per se is disturbed in SZ (not just task-specific timing processes) and this perturbation is independent from more generalized cognitive impairments. Behavioral evidence of disturbed automatic timing should be more thoroughly investigated with the aim of defining it as a cognitive phenotype for more homogeneous diagnostic subgrouping.


Transcriptional regulator BPTF/FAC1 is essential for trophoblast differentiation during early mouse development.
The putative transcriptional regulator BPTF/FAC1 is expressed in embryonic and extraembryonic tissues of the early mouse conceptus. The extraembryonic trophoblast lineage in mammals is essential to form the fetal part of the placenta and hence for the growth and viability of the embryo in utero. Here, we describe a loss-of-function allele of the BPTF/FAC1 gene that causes embryonic lethality in the mouse. BPTF/FAC1-deficient embryos form apparently normal blastocysts that implant and develop epiblast, visceral endoderm, and extraembryonic ectoderm including trophoblast stem cells. Subsequent development of mutants, however, is arrested at the early gastrula stage (embryonic day 6.5), and virtually all null embryos die before midgestation. Most notably, the ectoplacental cone is drastically reduced or absent in mutants, which may cause the embryonic lethality. Development of the mutant epiblast is also affected, as the anterior visceral endoderm and the primitive streak do not form correctly, while brachyury-expressing mesodermal cells arise but are delayed. The mutant phenotype suggests that gastrulation is initiated, but no complete anteroposterior axis of the epiblast appears. We conclude that BPTF/FAC1 is essential in the extraembryonic lineage for correct development of the ectoplacental cone and fetomaternal interactions. In addition, BPTF/FAC1 may also play a role either directly or indirectly in anterior-posterior patterning of the epiblast.


Sugar, meat, and fat intake, and non-dietary risk factors for colon cancer incidence in Iowa women (United States).
To investigate the relation of dietary intakes of sucrose, meat, and fat, and anthropometric, lifestyle, hormonal, and reproductive factors to colon cancer incidence, data were analyzed from a prospective cohort study of 35,215 Iowa (United States) women, aged 55-69 years and without a history of cancer, who completed mailed dietary and other questionnaires in 1986. Through 1990, 212 incident cases of colon cancer were documented. Proportional hazards regression was used to adjust for age and other risk factors. Risk factors found to be associated significantly with colon cancer included: (i) sucrose-containing foods and beverages other than ice cream/milk; relative risks (RR) across the quintiles = 1.00, 1.73, 1.56, 1.54, and 2.00 (95% confidence intervals [CI] for quintiles two and five exclude 1.0); (ii) sucrose; RR across the quintiles = 1.00, 1.70, 1.81, 1.82, and 1.45 (CI for quintiles two through four exclude 1.0); (iii) height; RR = 1.23 for highest to lowest quintile (P for trend = 0.02); (iv) body mass index; RR = 1.41 for highest to lowest quintile (P for trend = 0.03); and (v) number of livebirths, RR = 1.59 for having had one to two livebirths and 1.80 for having had three or more livebirths compared with having had none (P for trend = 0.04). These data support hypotheses that sucrose intake or being tall or obese increases colon cancer risk; run contrary to the hypothesis that increased parity decreases risk; support previous findings of no association with demographic factors other than age, cigarette smoking, or use of oral contraceptives or estrogen replacement therapy; and raise questions regarding previous associations with meat, fat, protein, and physical activity.