Direct effects of HIV-1 Tat on excitability and survival of primary dorsal root ganglion neurons: possible contribution to HIV-1-associated pain.
The vast majority of people living with human immunodeficiency virus type 1 (HIV-1) have pain syndrome, which has a significant impact on their quality of life. The underlying causes of HIV-1-associated pain are not likely attributable to direct viral infection of the nervous system due to the lack of evidence of neuronal infection by HIV-1. However, HIV-1 proteins are possibly involved as they have been implicated in neuronal damage and death. The current study assesses the direct effects of HIV-1 Tat, one of potent neurotoxic viral proteins released from HIV-1-infected cells, on the excitability and survival of rat primary dorsal root ganglion (DRG) neurons. We demonstrated that HIV-1 Tat triggered rapid and sustained enhancement of the excitability of small-diameter rat primary DRG neurons, which was accompanied by marked reductions in the rheobase and resting membrane potential (RMP), and an increase in the resistance at threshold (R(Th)). Such Tat-induced DRG hyperexcitability may be a consequence of the inhibition of cyclin-dependent kinase 5 (Cdk5) activity. Tat rapidly inhibited Cdk5 kinase activity and mRNA production, and roscovitine, a well-known Cdk5 inhibitor, induced a very similar pattern of DRG hyperexcitability. Indeed, pre-application of Tat prevented roscovitine from having additional effects on the RMP and action potentials (APs) of DRGs. However, Tat-mediated actions on the rheobase and R(Th) were accelerated by roscovitine. These results suggest that Tat-mediated changes in DRG excitability are partly facilitated by Cdk5 inhibition. In addition, Cdk5 is most abundant in DRG neurons and participates in the regulation of pain signaling. We also demonstrated that HIV-1 Tat markedly induced apoptosis of primary DRG neurons after exposure for longer than 48 h. Together, this work indicates that HIV-1 proteins are capable of producing pain signaling through direct actions on excitability and survival of sensory neurons.


The Influence of New Technologies on the Visual Attention of CSIs Performing a Crime Scene Investigation.
Currently, a series of promising new tools are under development that will enable crime scene investigators (CSIs) to analyze traces in situ during the crime scene investigation or enable them to detect blood and provide information on the age of blood. An experiment is conducted with thirty CSIs investigating a violent robbery at a mock crime scene to study the influence of such technologies on the perception and interpretation of traces during the first phase of the investigation. Results show that in their search for traces, CSIs are not directed by the availability of technologies, which is a reassuring finding. Qualitative findings suggest that CSIs are generally more focused on analyzing perpetrator traces than on reconstructing the event. A focus on perpetrator traces might become a risk when other crime-related traces are overlooked, and when analyzed traces are in fact not crime-related and in consequence lead to the identification of innocent suspects.


Mitochondrial and cytosolic branched-chain amino acid transaminases from yeast, homologs of the myc oncogene-regulated Eca39 protein.
We have isolated a high copy suppressor of a temperature-sensitive mutation in ATM1, which codes for an ABC transporter of Saccharomyces cerevisiae mitochondria. The suppressor, termed BAT1, encodes a protein of 393 amino acid residues with an NH2-terminal extension that directs Bat1p to the mitochondrial matrix. A highly homologous protein, Bat2p, of 376 amino acid residues was found in the cytosol. Both Bat proteins show striking similarity to the mammalian protein Eca39, which is one of the few known targets of the myc oncogene. Deletion of a single BAT gene did not impair growth of yeast cells. In contrast, deletion of both genes resulted in an auxotrophy for branched-chain amino acids (Ile, Leu, and Val) and in a severe growth reduction on glucose-containing media, even after supply of these amino acids. Mitochondria and cytosol isolated from bat1 and bat2 deletion mutants, respectively, contained largely reduced activities for the conversion of branched-chain 2-ketoacids to their corresponding amino acids. Thus, the Bat proteins represent the first known isoforms of yeast branched-chain amino acid transaminases. The severe growth defect of the double deletion mutant observed even in the presence of branched-chain amino acids suggests that the Bat proteins, in addition to the supply of these amino acids, perform another important function in the cell.


Oxygen sensing: getting pumped by sterols.
Oxygen plays a pivotal role in the maintenance of life for all eukaryotes, with the exception of strict anaerobes. Eukaryotes have developed mechanisms to sense and respond to decreased oxygen levels. How eukaryotes sense oxygen is still not fully understood. What is (or are) the oxygen sensor(s)? This question has vital physiological and pathophysiological implications, because all living aerobic organisms have adaptive mechanisms to maintain oxygen homeostasis. A recent report describes a novel eukaryotic oxygen-sensing mechanism in the fission yeast Schizosaccharomyces pombe, involving the depletion of sterols as a trigger to induce gene expression in response to decreased oxygen levels. It is not yet clear whether this mechanism is involved in the mammalian response to hypoxia, possibly in conjunction with activation of one or both of the hypoxia-inducible factor (HIF-1 or HIF-2) transcription factors.


The Association Between Kidney Disease and Diabetes Remission in Bariatric Surgery Patients With Type 2 Diabetes.
The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Prospective observational study. 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Remission of diabetes at 5 years post-bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes.


Predictive suppression of cortical excitability and its deficit in schizophrenia.
Recent neuroscience advances suggest that when interacting with our environment, along with previous experience, we use contextual cues and regularities to form predictions that guide our perceptions and actions. The goal of such active "predictive sensing" is to selectively enhance the processing and representation of behaviorally relevant information in an efficient manner. Since a hallmark of schizophrenia is impaired information selection, we tested whether this deficiency stems from dysfunctional predictive sensing by measuring the degree to which neuronal activity predicts relevant events. In healthy subjects, we established that these mechanisms are engaged in an effort-dependent manner and that, based on a correspondence between human scalp and intracranial nonhuman primate recordings, their main role is a predictive suppression of excitability in task-irrelevant regions. In contrast, schizophrenia patients displayed a reduced alignment of neuronal activity to attended stimuli, which correlated with their behavioral performance deficits and clinical symptoms. These results support the relevance of predictive sensing for normal and aberrant brain function, and highlight the importance of neuronal mechanisms that mold internal ongoing neuronal activity to model key features of the external environment.


High dispersal ability inhibits speciation in a continental radiation of passerine birds.
Dispersal can stimulate speciation by facilitating geographical expansion across barriers or inhibit speciation by maintaining gene flow among populations. Therefore, the relationship between dispersal ability and speciation rates can be positive or negative. Furthermore, an 'intermediate dispersal' model that combines positive and negative effects predicts a unimodal relationship between dispersal and diversification. Because both dispersal ability and speciation rates are difficult to quantify, empirical evidence for the relationship between dispersal and diversification remains scarce. Using a surrogate for flight performance and a species-level DNA-based phylogeny of a large South American bird radiation (the Furnariidae), we found that lineages with higher dispersal ability experienced lower speciation rates. We propose that the degree of fragmentation or permeability of the geographical setting together with the intermediate dispersal model are crucial in reconciling previous, often contradictory findings regarding the relationship between dispersal and diversification.


Spatial and temporal analysis of human infection with avian influenza A(H7N9) virus in China, 2013.
Descriptive and geographic information system methods were used to depict the spatial and temporal characteristics of the outbreak of human infection with a novel avian influenza A(H7N9) virus in mainland China, the peak of which appeared between 28 March and 18 April 2013. As of 31 May 2013, there was a total of 131 reported human infections in China, with a cumulative mortality of 29% (38/131). The outbreak affected 10 provinces, with 106 of the cases being concentrated in the eastern coastal provinces of Zhejiang, Shanghai and Jiangsu. Statistically significant spatial clustering of cumulative human cases was identified by the Cuzick–Edwards' k-nearest neighbour method. Three spatio-temporal clusters of cases were detected by space–time scan analysis. The principal cluster covered 18 counties in Zhejiang during 3 to 18 April (relative risk (RR): 26.39;p<0.0001), while two secondary clusters in March and April covered 21 counties along the provincial boundary between Shanghai and Jiangsu (RR: 6.35;p<0.0001) and two counties in Jiangsu (RR: 72.48;p=0.0025). The peak of the outbreak was in the eastern coastal provinces of Zhejiang, Shanghai and Jiangsu that was characterised by statistically significant spatio-temporal aggregation, with a particularly high incidence in March and April 2013.


Gene expression signatures in tree shrew sclera in response to three myopiagenic conditions.
We compared gene expression signatures in tree shrew sclera produced by three different visual conditions that all produce ocular elongation and myopia: minus-lens wear, form deprivation, and dark treatment. Six groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye-opening (days of visual experience [DVE]), two minus-lens groups wore a monocular -5 diopter (D) lens for 2 days (ML-2) or 4 days (ML-4); two form-deprivation groups wore a monocular translucent diffuser for 2 days (FD-2) or 4 days (FD-4). A dark-treatment (DK) group was placed in continuous darkness for 11 days after experiencing a light/dark environment until 17 DVE. A normal colony-reared group was examined at 28 DVE. Quantitative PCR was used to measure the relative differences in mRNA levels for 55 candidate genes in the sclera that were selected, either because they showed differential expression changes in previous ML studies or because a whole-transcriptome analysis suggested they would change during myopia development. The treated eyes in all groups responded with a significant myopic shift, indicating that the myopia was actively progressing. In the ML-2 group, 27 genes were significantly downregulated in the treated eyes, relative to control eyes. In the treated eyes of the FD-2 group, 16 of the same genes also were significantly downregulated and one was upregulated. The two gene expression patterns were significantly correlated (r(2) = 0.90, P < 0.001). After 4 days of treatment, 31 genes were significantly downregulated in the treated eyes of the ML-4 group and three were upregulated. Twenty-nine of the same genes (26 down- and 3 up-regulated) and six additional genes (all downregulated) were significantly affected in the FD-4 group. The response patterns were highly correlated (r(2) = 0.95, P < 0.001). When the DK group (mean of right and left eyes) was compared to the control eyes of the ML-4 group, the direction and magnitude of the gene expression patterns were similar to those of the ML-4 (r(2) = 0.82, P < 0.001, excluding PENK). Similar patterns also were found when the treated eyes of the ML-4, FD-4, and DK groups were compared to the age-matched normal eyes. The very similar gene expression signatures produced in the sclera by the three different myopiagenic visual conditions at different time points suggests that there is a "scleral remodeling signature" in this mammal, closely related to primates. The scleral genes examined did not distinguish between the specific visual stimuli that initiate the signaling cascade that results in axial elongation and myopia.


Agreement between central venous and arterial blood gas measurements in the intensive care unit.
Venous blood gas (VBG) analysis is a safer procedure than arterial blood gas (ABG) analysis and may be an alternative for determining acid-base status. The objective of this study was to examine the agreement between ABG and central VBG samples for all commonly used parameters in a medical intensive care unit (ICU) population. We performed a single-center, prospective trial to assess the agreement between arterial and central VBG measurements in a medical ICU. Adult patients who were admitted to the ICU and required both a central venous line and an arterial line were enrolled. When an ABG was performed, a central venous sample was obtained to examine the agreement among the pH, Pco(2), and bicarbonate. Data comparing central and peripheral VBG values were also obtained. The mean arterial minus venous difference for pH, Pco(2), and bicarbonate was 0.027, -3.8, and -0.80, respectively. Bland-Altman plots for agreement of pH, Pco(2), and bicarbonate showed 95% limits of agreement of -0.028 to 0.081, -12.3 to 4.8, and -4.0 to 2.4, respectively. Regression equations were derived to predict arterial values from venous values as follows: Arterial pH = -0.307 + 1.05 x venous pH, arterial Pco(2) = 0.805 + 0.936 x venous Pco(2), and arterial bicarbonate = 0.513 + 0.945 x venous bicarbonate. The mean central minus peripheral differences for pH, Pco(2), and bicarbonate were not clinically important. Peripheral or central venous pH, Pco(2), and bicarbonate can replace their arterial equivalents in many clinical contexts encountered in the ICU.


Evaluating the psychometric properties of an e-based version of the 39-item Parkinson's Disease Questionnaire.
The 39-item Parkinson's Disease Questionnaire (PDQ-39) is the most thoroughly validated and extensively used self-report measure for the assessment of health-related quality of life in people with Parkinson's (PwP). Given the extent of its use and increasing emphasis on electronic data capture, an e-based version of the PDQ-39, the ePDQ, has recently been developed. The aim of this short report is to present some key reliability and validity data that confirm the psychometric quality of the ePDQ. Participants were emailed a unique link to an online survey incorporating the ePDQ and demographic questions. A total of 118 PwP fully completed the survey. Floor and ceiling effects were calculated to ensure responses were not biased to extreme values. Consequently, score reliability was assessed by item-total correlations with a range from 0.34 to 0.90. Cronbach's alpha was calculated at between 0.64 and 0.95 for the eight domains of the ePDQ. Construct validity was assessed by comparing domain scores in relation to disease duration and gender, with hypothesised differences being largely confirmed. Construct validity was further assessed following a higher order factor analysis which confirmed the appropriateness of calculating a summary index score. Subsequently, significant, but moderate correlations were calculated between the ePDQ summary index score and disease duration and age at diagnosis. Results indicate that the ePDQ largely mirrors the properties of its parent instrument, the PDQ-39, in terms of reliability and validity. Potential users can therefore incorporate the ePDQ into computer-based data capture systems with confidence.


Occupational Exposure to Trichloramine and Trihalomethanes in Swedish Indoor Swimming Pools: Evaluation of Personal and Stationary Monitoring.
Chlorination is a method commonly used to keep indoor swimming pool water free from pathogens. However, chlorination of swimming pools produces several potentially hazardous by-products as the chlorine reacts with nitrogen containing organic matter. Up till now, exposure assessments in indoor swimming pools have relied on stationary measurements at the poolside, used as a proxy for personal exposure. However, measurements at fixed locations are known to differ from personal exposure. Eight public swimming pool facilities in four Swedish cities were included in this survey. Personal and stationary sampling was performed during day or evening shift. Samplers were placed at different fixed positions around the pool facilities, at ~1.5 m above the floor level and 0-1 m from the poolside. In total, 52 personal and 110 stationary samples of trichloramine and 51 personal and 109 stationary samples of trihalomethanes, were collected. The average concentration of trichloramine for personal sampling was 71 µg m(-3), ranging from 1 to 240 µg m(-3) and for stationary samples 179 µg m(-3), ranging from 1 to 640 µg m(-3). The air concentrations of chloroform were well below the occupational exposure limit (OEL). For the linear regression analysis and prediction of personal exposure to trichloramine from stationary sampling, only data from personal that spent >50% of their workday in the pool area were included. The linear regression analysis showed a correlation coefficient (r2) of 0.693 and a significant regression coefficient β of 0.621; (95% CI = 0.329-0.912, P = 0.001). The trichloramine exposure levels determined in this study were well below the recommended air concentration level of 500 µg m(-3); a WHO reference value based on stationary sampling. Our regression data suggest a relation between personal exposure and area sampling of 1:2, implying an OEL of 250 µg m(-3) based on personal sampling.


A new flavor-coated sachet bait for delivering oral rabies vaccine to raccoons and coyotes.
Research was conducted during 1996-2000 to develop baits for delivering an oral rabies vaccine to raccoons (Procyon lotor) and coyotes (Canis latrans). A bait was sought that: (1) was attractive to the target species, (2) could be distributed by aircraft, (3) was as effective (or more so) than the currently used fish meal polymer bait, and (4) could be produced in large numbers by automated procedures and could be purchased by user groups at substantially lower cost. Ten field trials were conducted to document raccoons' bait flavor preferences, evaluate a new vaccine sachet bait coated with various attractants, and determine if the sachet bait would effectively deliver Raboral V-RG oral rabies vaccine (Merial Limited, Athens, Georgia, USA) to this species. Raccoons preferred fish and crustacean-based flavors over those derived from plant materials. Raccoon visits to tracking stations, frequency of bait removals, and percent of sachets discarded by this species that were emptied of placebo vaccine indicated efficacy of the new bait was equal or superior to the currently used fish meal polymer bait. A field trial conducted in fall 1998 compared aerially distributed vaccine-laden sachet and polymer baits and showed there was no difference between the percent of raccoons from the test and reference areas subsequently found positive for rabies antibody. Four bait trials to determine coyote response to sachet baits were conducted in 1997-98. The propensity for canids to gulp or bolt smaller food items is well known. Thus, a first trial involved offering fish-flavored sachet baits of different sizes to 30 captive coyotes to determine if smaller size baits were more frequently swallowed intact. Two field trials were also conducted in fall 1997 to determine if free-ranging coyotes discriminated among sachet baits coated with different attractants. Finally, Raboral V-RG-laden poultry-flavored sachet baits were aerially dropped and the percent of seropositive coyotes was compared with coyotes from surrounding areas where fish meal polymer vaccine baits had been distributed. Captive coyotes did not swallow sachet baits intact, regardless of size. Bait preference field trials indicated that coyotes preferred poultry, cheese/beef tallow, and fish-flavored sachet baits and that such baits were taken at the same rate as polymer baits. A sample of coyotes from the area baited with vaccine-laden sachet baits had a markedly higher (P = 0.01) seropositivity rate than coyotes from areas where vaccine was distributed in polymer baits. Sachet bait production could be facilitated by automated technology and sachet baits used either as an alternative vaccine delivery device or in combination with the fish meal polymer bait.


Whole-Brain Network Connectivity Underlying the Human Speech Articulation as Emerged Integrating Direct Electric Stimulation, Resting State fMRI and Tractography.
Production of fluent speech in humans is based on a precise and coordinated articulation of sounds. A speech articulation network (SAN) has been observed in multiple brain studies typically using either neuroimaging or direct electrical stimulation (DES), thus giving limited knowledge about the whole brain structural and functional organization of this network. In this study, seven right-handed patients underwent awake surgery resection of low-grade gliomas (4) and cavernous angiomas. We combined pre-surgical resting state fMRI (rs-fMRI) and diffusion MRI together with speech arrest sites obtained intra-operatively with DES to address the following goals: (i) determine the cortical areas contributing to the intrinsic functional SAN using the speech arrest sites as functional seeds for rs-fMRI; (ii) evaluate the relative contribution of gray matter terminations from the two major language dorsal stream bundles, the superior longitudinal fasciculus (SLF III) and the arcuate fasciculus (AF); and (iii) evaluate the possible pre-surgical prediction of SAN with rs-fMRI. In all these right-handed patients the intrinsic functional SAN included frontal, inferior parietal, temporal, and insular regions symmetrically and bilaterally distributed across the two hemispheres regardless of the side (four right) of speech arrest evocation. The SLF III provided a much higher density of terminations in the cortical regions of SAN in respect to AF. Pre-surgical rs-fMRI data demonstrated moderate ability to predict the SAN. The set of functional and structural data provided in this multimodal study characterized, at a whole-brain level, a distributed and bi-hemispherical network subserving speech articulation.


First principles studies of the effect of ostwald ripening on carbon nanotube chirality distributions.
The effect of Ostwald ripening of metal particles attached to carbon nanotubes has been studied using density functional theory. It has been confirmed that Ostwald ripening may be responsible for the termination of growth of carbon nanotube forests. It was seen that the Ostwald ripening of metal particles attached to carbon nanotubes is governed by a critical factor that depends on both the cluster size and the carbon nanotube chirality. For example, clusters attached to armchair and zigzag nanotubes of similar diameters will have different critical factors although the exact behavior may depend on which molecules are present in the surrounding medium. The critical factor was also observed to have a critical point with the effect that clusters with a narrow size distribution close to the critical point may experience a narrowing rather than a widening of the size distribution, as is the case for free clusters.


Evaluation of sodium alginate for bone marrow cell tissue engineering.
Sodium alginate has applications as a material for the encapsulation and immobilisation of a variety of cell types for immunoisolatory and biochemical processing applications. It forms a biodegradable gel when crosslinked with calcium ions and it has been exploited in cartilage tissue engineering since chondrocytes do not dedifferentiate when immobilised in it. Despite its attractive properties of degradability, ease of processing and cell immobilisation, there is little work demonstrating the efficacy of alginate gel as a substrate for cell proliferation, except when RGD is modified. In this study we investigated the ability of rat bone marrow cells to proliferate and differentiate on alginates of differing composition and purity. The mechanical properties of the gels were investigated. It was found that high purity and high G-type alginate retained 27% of its initial strength after 12 days in culture and that comparable levels of proliferation were observed on this material and tissue culture plastic. Depending on composition, calcium crosslinked alginate can act as a substrate for rat marrow cell proliferation and has potential for use as 3D degradable scaffold.


WestREN: a description of an Irish academic general practice research network.
Primary care research networks have been established internationally since the 1960s to enable diverse practitioners to engage in and develop research and education and implement research evidence.The newly established Western Research and Education Network (WestREN) is one such network consisting of a collaboration between the Discipline of General Practice at NUI Galway and 71 West of Ireland general practices. In September 2009 all member practices were issued with a questionnaire with two objectives: to describe the structure and characteristics of the member practices and to compare the results to the national profile of Irish general practice. A postal survey was used followed by one written and one email reminder. A response rate of 73% (52/71) was achieved after two reminders.Half of practices were in a rural location, one quarter located in an urban setting and another quarter in a mixed location.Ninety-four per cent of general practitioners practice from purpose-built or adapted premises with under 6% of practices being attached to the general practitioner's residence. Over 96% of general practitioners use appointment systems with 58% using appointment only.All practices surveyed were computerised, with 80% describing their practices as 'fully computerised'. Almost 60% of general practitioners are coding chronic diagnoses with 20% coding individual consultations. Twenty-five per cent of general practitioners were single-handed with the majority of practices having at least two general practitioners, and a mean number of general practitioners of 2.4. Ninety-two per cent of practices employed a practice nurse with 30% employing more than one nurse.Compared to the national profile, WestREN practices appear somewhat larger, and more likely to be purpose-built and in rural areas. National trends apparent between 1982 and 1992, such as increasing computerisation and practice nurse availability, appear to be continuing. WestREN is a new university-affiliated general practice research network in Ireland. Survey of its initial membership confirms WestREN practices to be broadly representative of the national profile and has provided us with valuable information on the current and changing structure of Irish general practice.


T cells or active Epstein-Barr virus infection in the development of lymphoproliferative disease in human B cell-injected severe combined immunodeficient mice.
Severe combined immunodeficient (SCID) mice develop Epstein-Barr virus (EBV) containing human lymphoproliferative disease (LPD) tumors when reconstituted with human peripheral blood leukocytes (PBLs) from EBV-seropositive donors, but LPD tumors do not develop in the presence of immunosuppressive agents, such as cyclosporine A or corticosteroids. Therefore, LPD development in SCID mice was used as a model to explore the relationship among B cells, T cells, and EBV in vivo. SCID mice were engrafted with PBLs isolated by leukapheresis from a single EBV-seropositive donor. Purified populations of CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) were isolated and engrafted into SCID mice. SCID mice engrafted with purified CD3+ lymphocytes (T cells) or CD19+ lymphocytes (B cells) did not develop LPD. In contrast, mice engrafted with purified B cells developed LPD if they were co-engrafted with purified T cells or if they were inoculated with infectious EBV. This study confirms the requirement of T cells or active EBV infection in the development of LPD in animals engrafted with B cells latently infected with EBV. A greater understanding of the cellular and viral interactions leading to transformation and malignancy may allow the development of specific interventional therapies for malignancies in the immunosuppressed host.


Genome-wide association study of equine herpesvirus type 1-induced myeloencephalopathy identifies a significant single nucleotide polymorphism in a platelet-related gene.
Equine herpesvirus type 1 (EHV-1)-induced myeloencephalopathy (EHM) is a neurologic disease of horses that represents one outcome of infection. The neurologic form of disease occurs in a subset of infected horses when virus-induced endothelial cell damage triggers vasculitis and subsequent ischemic insult to the central nervous system. EHM causes considerable animal suffering and economic loss for the horse industry. Virus polymorphisms have been previously associated with disease outcome but cannot fully explain why only some horses develop EHM. This study investigated the role of host genetics in EHM. DNA samples were collected from 129 horses infected with EHV-1 (61 that developed EHM and 68 in which disease resolved without the development of neurologic signs) during natural outbreaks or experimental infections. A genome-wide association study (GWAS) was performed to investigate host genetic variations associated with EHM. Genotyping was performed using the Illumina SNP50 and SNP70 arrays and a custom Sequenom array. Mixed linear model (MLM) analysis using a recessive model identified one marker that surpassed the threshold for genome-wide significance (P<0.001) after Bonferroni correction. The marker (BIEC2_946397) is in an intron of the tetraspanin 9 (TSPAN9) gene, which is expressed in endothelial cells and platelets. The GWAS identified a region in the horse genome that is associated with EHM in the sample population and thus warrants further exploration. Understanding the contribution of host genetic variation to the development of EHM will enhance our knowledge of disease pathophysiology, and lead to improved strategies for treating individual cases and managing outbreaks.


Changes in the legal environment and enforcement of firearm transfer laws in Pennsylvania and Maryland.
The effectiveness of laws depends on circumstances affecting their enforcement. To assess such circumstances for comprehensive background check (CBC) and straw purchase laws for firearm sales, we examined prosecutions for CBC and straw purchase violations in Pennsylvania and CBC violations in Maryland. We generated pre-post variables and conducted t-tests to assess differences in the mean number of prosecutions filed following changes to the legal environments. The annual number of prosecutions for straw purchase violations increased significantly in Pennsylvania following the passage of a law that strengthened penalties for these violations (difference in means = +1310.86, P=0.003). The annual number of prosecutions for CBC violations decreased significantly in Maryland following a court decision that narrowed the definition of a firearm transfer making enforcement more difficult (difference in means = -20.52, P=0.026). Our findings suggest enforcement is likely influenced by the penalties associated with violating these laws and the interpretation of the language of the laws.


Exposure to multiple metals from groundwater-a global crisis: geology, climate change, health effects, testing, and mitigation.
This paper presents an overview of the global extent of naturally occurring toxic metals in groundwater. Adverse health effects attributed to the toxic metals most commonly found in groundwater are reviewed, as well as chemical, biochemical, and physiological interactions between these metals. Synergistic and antagonistic effects that have been reported between the toxic metals found in groundwater and the dietary trace elements are highlighted, and common behavioural, cultural, and dietary practices that are likely to significantly modify health risks due to use of metal-contaminated groundwater are reviewed. Methods for analytical testing of samples containing multiple metals are discussed, with special attention to analytical interferences between metals and reagents. An overview is presented of approaches to providing safe water when groundwater contains multiple metallic toxins.


Coronary vascular and myocardial responses to carotid body stimulation in the dog.
Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.


Voltage and e-liquid composition affect nicotine deposition within the oral cavity and carbonyl formation.
The diversity of e-liquids along with higher powered e-cigarette nicotine delivery devices are increasing. This study evaluated the effect of voltage and e-liquid composition on particle size, nicotine deposition in a human oral-trachea cast model and generation of carbonyls. Nineteen e-liquids were evaluated for 30 common chemicals by gas chromatography-mass spectrometry (GC-MS). E-cigarette aerosols containing nicotine (1.2%) were generated at 4 and 5 volts for assessment of particle size distribution using Aerodynamic Particle Sizer (APS), Fast Mobility Particle Size (FMPS) and an In-Tox cascade impactor and nicotine deposition by GC-MS. Carbonyl formation in aerosols was assessed by liquid chromatography tandem triple-quad mass spectrometry. Total chemical burden ranged from 0.35 to 14.6 mg/mL with ethyl maltol present in all e-liquids. Increasing voltage was associated with an increase in median size of aerosol particles and the deposition of nicotine in the oral cast. Two e-liquids caused a 2.5-fold to 5-fold increase in nicotine deposition independent of particle size and voltage. Increasing voltage caused an increase in formaldehyde, acetaldehyde and acrolein in the presence and absence of nicotine. Most striking, aerosols from several e-liquids significantly increased levels of acetaldehyde and acrolein compared with unflavoured. Increasing voltage and composition of e-liquid can increase the exposure of the oral pharynx and bronchial airways to carbonyls that can react with DNA to generate adducts, induce oxidative stress, inflammation and cell death. The elevated nicotine and carbonyls readily enter the circulation where they can also cause cardiovascular stress. The growing popularity of higher voltage e-cigarette delivery devices will likely further elevate health risks from chronic exposure to these complex aerosols.


Hendra virus and horse owners--risk perception and management.
Hendra virus is a highly pathogenic novel paramyxovirus causing sporadic fatal infection in horses and humans in Australia. Species of fruit-bats (genus Pteropus), commonly known as flying-foxes, are the natural host of the virus. We undertook a survey of horse owners in the states of Queensland and New South Wales, Australia to assess the level of adoption of recommended risk management strategies and to identify impediments to adoption. Survey questionnaires were completed by 1431 respondents from the target states, and from a spectrum of industry sectors. Hendra virus knowledge varied with sector, but was generally limited, with only 13% of respondents rating their level of knowledge as high or very high. The majority of respondents (63%) had seen their state's Hendra virus information for horse owners, and a similar proportion found the information useful. Fifty-six percent of respondents thought it moderately, very or extremely likely that a Hendra virus case could occur in their area, yet only 37% said they would consider Hendra virus if their horse was sick. Only 13% of respondents stabled their horses overnight, although another 24% said it would be easy or very easy to do so, but hadn't done so. Only 13% and 15% of respondents respectively had horse feed bins and water points under solid cover. Responses varied significantly with state, likely reflecting different Hendra virus history. The survey identified inconsistent awareness and/or adoption of available knowledge, confusion in relation to Hendra virus risk perception, with both over-and under-estimation of true risk, and lag in the uptake of recommended risk minimisation strategies, even when these were readily implementable. However, we also identified frustration and potential alienation by horse owners who found the recommended strategies impractical, onerous and prohibitively expensive. The insights gained from this survey have broader application to other complex risk-management scenarios.


Spatial turnover in the global avifauna.
Despite its wide implications for many ecological issues, the global pattern of spatial turnover in the occurrence of species has been little studied, unlike the global pattern of species richness. Here, using a database on the breeding distributions of birds, we present the first global maps of variation in spatial turnover for an entire taxonomic class, a pattern that has to date remained largely a matter of conjecture, based on theoretical expectations and extrapolation of inconsistent patterns from different biogeographic realms. We use these maps to test four predictions from niche theory as to the form that this variation should take, namely that turnover should increase with species richness, towards lower latitudes, and with the steepness of environmental gradients and that variation in turnover is determined principally by rare (restricted) species. Contrary to prediction, we show that turnover is high both in areas of extremely low and high species richness, does not increase strongly towards the tropics, and is related both to average environmental conditions and spatial variation in those conditions. These results are closely associated with a further important and novel finding, namely that global patterns of spatial turnover are driven principally by widespread species rather than the restricted ones. This complements recent demonstrations that spatial patterns of species richness are also driven principally by widespread species, and thus provides an important contribution towards a unified model of how terrestrial biodiversity varies both within and between the Earth's major land masses.


New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.


Cardiac natriuretic peptides for diagnosis of covert atrial fibrillation after acute ischaemic stroke: a meta-analysis of diagnostic accuracy studies.
Detection of atrial fibrillation (AF) after acute ischaemic stroke is pivotal for the timely initiation of anticoagulation to prevent recurrence. Besides heart rhythm monitoring, various blood biomarkers have been suggested as complimentary diagnostic tools for AF. We aimed to summarise data on the performance of cardiac natriuretic peptides for the diagnosis of covert AF after acute ischaemic stroke and to assess their potential clinical utility. We searched PubMed and Embase for prospective studies reporting the performance of B-type natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) for the diagnosis of covert AF after acute ischaemic stroke. Summary diagnostic performance measures were pooled using bivariate meta-analysis with a random-effect model. We included six studies focusing on BNP (n=1930) and three studies focusing on NT-proBNP (n=623). BNP had a sensitivity of 0.83 (95% CI 0.64 to 0.93), a specificity of 0.74 (0.67 to 0.81), a positive likelihood ratio of 3.2 (2.6 to 4.0) and a negative likelihood ratio of 0.23 (0.11 to 0.49). NT-proBNP had a sensitivity of 0.91 (0.65 to 0.98), a specificity of 0.77 (0.52 to 0.91), a positive likelihood ratio of 3.9 (1.8 to 8.7) and a negative likelihood ratio of 0.12 (0.03 to 0.48). Considering a pretest probability of 20%, BNP and NT-proBNP had post-test probabilities of 45% and 50%. NT-proBNP has a better performance than BNP for the diagnosis of covert AF after acute ischaemic stroke. Both biomarkers have low post-test probabilities and may not be used as a stand-alone decision-making tool for the diagnosis of covert AF in patients with acute ischaemic stroke. However, they may be useful for a screening strategy aiming to select patients for long-term monitoring of the heart rhythm.


Sequential treatment of mood and anxiety disorders.
Administration of treatments in a sequential order is a common practice in clinical medicine, but has received insufficient attention in psychiatry. The aim of this review was to survey the literature concerned with a sequential use of pharmacotherapy and psychotherapy in mood and anxiety disturbances. A review of the clinical trials in which treatment components were used in a sequential order (i.e., pharmacotherapy followed by psychotherapy, psychotherapy followed by pharmacotherapy, one drug treatment following another, or one psychotherapeutic technique following another) was performed. Studies were identified by using MEDLINE (English language articles published from 1967 to March 2005; keywords: sequential treatment, drugs and psychotherapy, combined treatment related to depressive disorder, bipolar disorder, depression, mania, anxiety disorders, panic disorder, social phobia, obsessive-compulsive disorder, generalized anxiety disorder, and posttraumatic stress disorder) and a manual search of the literature and Index Medicus for the years 1960 to 2005. In unipolar recurrent depression, the sequential use of pharmacotherapy was found to reduce relapse rate. In bipolar disorder, the use of psychotherapeutic strategies in patients who were already undergoing treatment with mood stabilizers was also found to yield clinical benefits. In anxiety disorders, the sequential use of pharmacotherapy and psychotherapy was not found to improve long-term outcome. The sequential treatment of mood and anxiety disorders does not fall within the realm of maintenance strategies. It is an intensive, 2-stage approach, which is based on the fact that one course of treatment with a specific treatment (whether pharmacotherapy or psychotherapy) is unlikely to entail solution to the complex array of symptoms of patients with mood and anxiety disorders. The sequential model introduces a conceptual shift in current assessment methods.


Parotid gland dose in intensity-modulated radiotherapy for head and neck cancer: is what you plan what you get?
To quantify the differences between planned and delivered parotid gland and target doses, and to assess the benefits of daily bone alignment for head and neck cancer patients treated with intensity-modulated radiotherapy (IMRT). Eleven head and neck cancer patients received two CT scans per week with an in-room CT scanner over the course of their radiotherapy. The clinical IMRT plans, designed with 3-mm to 4-mm planning margins, were recalculated on the repeat CT images. The plans were aligned using the actual treatment isocenter marked with radiopaque markers (BB) and bone alignment to the cervical vertebrae to simulate image-guided setup. In-house deformable image registration software was used to map daily dose distributions to the original treatment plan and to calculate a cumulative delivered dose distribution for each patient. Using conventional BB alignment led to increases in the parotid gland mean dose above the planned dose by 5 to 7 Gy in 45% of the patients (median, 3.0 Gy ipsilateral, p = 0.026; median, 1.0 Gy contralateral, p = 0.016). Use of bone alignment led to reductions relative to BB alignment in 91% of patients (median, 2 Gy; range, 0.3-8.3 Gy; 15 of 22 parotids improved). However, the parotid dose from bone alignment was still greater than planned (median, 1.0 Gy, p = 0.007). Neither approach affected tumor dose coverage. With conventional BB alignment, the parotid gland mean dose was significantly increased above the planned mean dose. Using daily bone alignment reduced the parotid dose compared with BB alignment in almost all patients. A 3- to 4-mm planning margin was adequate for tumor dose coverage.


A profile of the online dissemination of national influenza surveillance data.
Influenza surveillance systems provide important and timely information to health service providers on trends in the circulation of influenza virus and other upper respiratory tract infections. Online dissemination of surveillance data is useful for risk communication to health care professionals, the media and the general public. We reviewed national influenza surveillance websites from around the world to describe the main features of surveillance data dissemination. We searched for national influenza surveillance websites for every country and reviewed the resulting sites where available during the period from November 2008 through February 2009. Literature about influenza surveillance was searched at MEDLINE for relevant hyperlinks to related websites. Non-English websites were translated into English using human translators or Google language tools. A total of 70 national influenza surveillance websites were identified. The percentage of developing countries with surveillance websites was lower than that of developed countries (22% versus 57% respectively). Most of the websites (74%) were in English or provided an English version. The most common surveillance methods included influenza-like illness consultation rates in primary care settings (89%) and laboratory surveillance (44%). Most websites (70%) provided data within a static report format and 66% of the websites provided data with at least weekly resolution. Appropriate dissemination of surveillance data is important to maximize the utility of collected data. There may be room for improvement in the style and content of the dissemination of influenza data to health care professionals and the general public.


A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry's disease and mucopolysaccharidosis type 1.
To determine the clinical effectiveness and cost-effectiveness of the administration of intravenous enzyme replacement therapy (ERT) to symptomatic patients for the prevention of long-term damage and symptoms in Fabry's disease and in mucopolysaccharidosis type 1 (MPS1). Electronic databases from inception up to mid-2004. Contact with clinical experts. Relevant studies were identified and assessed using recommended quality criteria. The results suggested beneficial effects of ERT for Fabry's disease on measures of pain, cardiovascular function and some end-points reflecting neurosensory function. Renal function appeared to be stabilised by ERT. At present there are no utility-related health-related quality of life data on which to assess the relative health gain of ERT in MPS1. In order to be able to demonstrate the full extent of health gain from treatment, it was necessary to review the natural history of untreated patients in each disease in order to try to estimate the health loss prevented. The published information for Fabry's disease tallied with descriptions of a multi-system, life-threatening disorder particularly involving kidney, heart and brain with individual patients exhibiting many manifestations. The fragmentary information reviewed in 16 studies relevant to the natural history of MPS1 did not generate a coherent picture of disease progression and could provide little added value to published narrative reviews. For Fabry's disease, the mean cost per patient (50 kg) treated is around pounds sterling 85,000 per annum in England and Wales. The cost per patient varies considerably by dose. No published evidence reporting an economic evaluation of ERT for Fabry's disease was identified by this review. A dynamic decision model was constructed based on a birth cohort of male patients who are followed up until death. Owing to lack of information reported in the literature, many assumptions had to be applied. The key assumptions were that ERT returns patients to full health and a normal life expectancy. As far as possible, all assumptions favoured rather than detracted from the value of ERT. ERT was assumed to restore patients to full health in the base case. The estimated incremental cost-effectiveness ratio (ICER) in the base case was pounds sterling 252,000 per QALY (agalsidase beta). Univariate sensitivity analysis around the key assumptions produced ICERs ranging from pounds sterling 602,000 to pounds sterling 241,000. The base case unit cost of ERT was taken as pounds sterling 65.1/mg based on the cost of agalsidase beta. The unit cost would have had to be reduced to pounds sterling 9 to obtain an ICER of pounds sterling 30,000 per QALY. For MPS1, the mean cost per child patient (20 kg) treated is approximately pounds sterling 95,000 and an adult (70 kg) around pounds sterling 335,000 per annum in England and Wales. The cost per patient varies considerably by dose. There is no published evidence reporting an economic evaluation of ERT for MPS1 and no study was identified that reported the quality of life of MPS1 patients within a utility format. Furthermore, no or minimal information of the severity and rate of change of clinical manifestations of disease or the impact of ERT on these factors was identified. Information on the effect of ERT on mortality is also lacking owing to the relatively short time that the treatment has been available. Given this lack of data, it was not possible to develop a cost-effectiveness model of ERT treatment for MPS1 as the model would consist almost completely of assumptions based on no published evidence, leading to an incremental cost per QALY result that would be meaningless. Although ERT for treating the 'average' patient with Fabry's disease exceeds the normal upper threshold for cost-effectiveness seen in NHS policy decisions by over sixfold, and the value for MPS1 is likely to be of a similar order of magnitude, clinicians and the manufacturers argue that, as the disease is classified as an orphan disease under European Union legislation, it has special status, and the NHS has no option but to provide ERT. More information is required before the generalisability of the findings can be determined. Although data from the UK have been used wherever possible, this was very thin indeed. Nonetheless, even large errors in assumptions made will not reduce the ICER to anywhere near the upper level of treatments usually considered cost-effective. In order to overcome limited evidence on the natural history of the disease and the clinical effectiveness of the intervention, the establishment of disease-specific data registries is suggested to facilitate the process of technology assessment and improving patient care. These registries should attempt to include all affected patients in the UK, and collect longitudinal patient level data on clinically relevant problems, interventions received and quality of life in a utility format.


Limited contemporary gene flow and high self-replenishment drives peripheral isolation in an endemic coral reef fish.
Extensive ongoing degradation of coral reef habitats worldwide has lead to declines in abundance of coral reef fishes and local extinction of some species. Those most vulnerable are ecological specialists and endemic species. Determining connectivity between locations is vital to understanding recovery and long-term persistence of these species following local extinction. This study explored population connectivity in the ecologically-specialized endemic three-striped butterflyfish (Chaetodon tricinctus) using mt and msatDNA (nuclear microsatellites) to distinguish evolutionary versus contemporary gene flow, estimate self-replenishment and measure genetic diversity among locations at the remote Australian offshore coral reefs of Middleton Reef (MR), Elizabeth Reef (ER), Lord Howe Island (LHI), and Norfolk Island (NI). Mt and msatDNA suggested genetic differentiation of the most peripheral location (NI) from the remaining three locations (MR, ER, LHI). Despite high levels of mtDNA gene flow, there is limited msatDNA gene flow with evidence of high levels of self-replenishment (≥76%) at all four locations. Taken together, this suggests prolonged population recovery times following population declines. The peripheral population (NI) is most vulnerable to local extinction due to its relative isolation, extreme levels of self-replenishment (95%), and low contemporary abundance.


Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1.
Tissue inhibitor of metalloproteinases-3 (TIMP-3) plays a key role in regulating extracellular matrix turnover by inhibiting matrix metalloproteinases (MMPs), adamalysins (ADAMs), and adamalysins with thrombospondin motifs (ADAMTSs). We demonstrate that levels of this physiologically important inhibitor can be regulated post-translationally by endocytosis. TIMP-3 was endocytosed and degraded by a number of cell types including chondrocytes, fibroblasts, and monocytes, and we found that the endocytic receptor low density lipoprotein receptor-related protein-1 (LRP-1) plays a major role in TIMP-3 internalization. However, the cellular uptake of TIMP-3 significantly slowed down after 10 h due to shedding of LRP-1 from the cell surface and formation of soluble LRP-1 (sLRP-1)-TIMP-3 complexes. Addition of TIMP-3 to HTB94 human chondrosarcoma cells increased the release of sLRP-1 fragments of 500, 215, 160, and 110 kDa into the medium in a concentration-dependent manner, and all of these fragments were able to bind to TIMP-3. TIMP-3 bound to sLRP-1, which was resistant to endocytosis, retained its inhibitory activity against metalloproteinases. Extracellular levels of sLRP-1 can thus increase the half-life of TIMP-3 in the extracellular space, controlling the bioavailability of TIMP-3 to inhibit metalloproteinases.


Clinical Implication of Quantitative Flow Ratio After Percutaneous Coronary Intervention for 3-Vessel Disease.
The aim of this study was to investigate the impact of post-percutaneous coronary intervention (PCI) quantitative flow ratio (QFR) on clinical outcomes in patients with de novo 3-vessel disease (3VD) treated with contemporary PCI. The clinical impact of post-PCI QFR in patients treated with state-of-the-art PCI for de novo 3VD is undetermined. All vessels treated in the SYNTAX (SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery) II trial were retrospectively screened and analyzed for post-PCI QFR. The primary endpoint of this substudy was vessel-oriented composite endpoint (VOCE) at 2 years, defined as the composite of vessel-related cardiac death, vessel-related myocardial infarction, and target vessel revascularization. The receiver-operating characteristic curve was used to calculate the optimal cutoff value of post-PCI QFR for predicting 2-year VOCE. All the analyzable vessels were stratified on the basis of the optimal cutoff value. A total of 968 vessels treated with PCI were screened. Post-PCI QFR was analyzable in 771 (79.6%) vessels. A total of 52 (6.7%) VOCEs occurred at 2 years. The mean value of post-PCI QFR was 0.91 ± 0.07. The diagnostic performance of post-PCI QFR to predict 2-year VOCE was moderate (area under the curve: 0.702; 95% confidence interval: 0.633 to 0.772), with the optimal cutoff value of post-PCI QFR for predicting 2-year VOCE 0.91 (sensitivity 0.652, specificity 0.635). The incidence of 2-year VOCE in the vessels with post-PCI QFR <0.91 (n = 284) was significantly higher compared with vessels with post-PCI QFR ≥0.91 (n = 487) (12.0% vs. 3.7%; hazard ratio: 3.37; 95% confidence interval: 1.91 to 5.97; p < 0.001). A higher post-PCI QFR value is associated with improved vessel-related clinical outcomes in state-of-the art PCI practice for de novo 3VD. Achieving a post-PCI QFR value ≥0.91 in all treated vessels should be a target when treating de novo 3VD. These findings require confirmation in future prospective trials.


A prospective randomised study of a rotary powered device (OnControl) for bone marrow aspiration and biopsy.
Bone marrow aspiration and biopsy is an invasive procedure associated with morbidity and mortality risk. We compared a powered bone marrow aspiration and biopsy device to the traditional method by relatively assessing pain scores, procedure times, biopsy capture rates, quality of material retrieved, and safety and operator satisfaction. Two large academic medical centres participated in this trial. Patients were randomised to have procedures carried out using the powered system or the manual technique. A visual analogue scale pain score was recorded immediately following skin puncture and once again at the end of the procedure for each patient. Procedure time was measured from skin puncture to core specimen acquisition. Pathologic assessment of 30 randomised samples was carried out. Operator satisfaction with devices was measured on a scale of 0-10, with 10 as the highest rating. Five operators from two sites enrolled 50 patients (powered, n=25; manual, n=25). Groups were evenly matched, with no significant differences in the means for age, weight and height. The powered system was superior to the manual system with respect to patient perceived pain from needle insertion (2.6±2.0 vs 4.1±2.5, p=0.022) and procedural time (100.0±72.8 s vs 224.1±79.0 s, p<0.001). Overall pain scores at the end of both procedures were comparable (3.2±2.2 vs 3.8±3.0, p=0.438). No complications were observed in either arm of the study. Blinded pathologic analysis of the specimens retrieved revealed that cores obtained using the powered system were longer and wider than those obtained using the manual technique (25.4±12.3 mm² vs 11.9±5.6 mm², p=0.001). For marrow aspiration, no difference was seen between groups for clot/particle spicules or smear spicules. Operator assessment favoured the use of the powered device. Results of this trial suggest that the use of a powered bone marrow biopsy device significantly reduces needle insertion pain and procedural time when compared to a manual technique. The superior size and overall quality of core specimens retrieved by the powered device provides more material for pathologic evaluation, thereby increasing diagnostic yield and reducing the need for repeat procedures.


Awareness of the risks of HIV infection by Zimbabwean urban and rural high school attendees.
The purpose of this report was to investigate the awareness by high school attendees of risky behaviour likely to lead to sexually transmitted infections (STIs) including HIV/AIDS and to assess their preparedness to prevent or obviate the consequences. Cross sectional study. A small town located 100 km south of the Zimbabwean capital, Harare and in communal and commercial farming areas within a 50 km radius of the town. With the permission of school authorities, a group of second year medical students from the University of Zimbabwe on rural attachment administered an anonymous questionnaire to teenagers attending four high schools in the study area. Specific questions to determine whether the teenagers were sexually active and if they used any protection during sex were incorporated into a general and environmental health questionnaire. A total of 241 teenagers, 153 boys and 89 girls from all four schools completed the questionnaire. The percentages of sexually active boys (48%) and girls (49%) were similar. The majority had heterosexual preferences, 4.6% boys were homosexual. Half (50%) of the 16 year old pupils were sexually active. There were more urban than rural school attendees who reported personal knowledge of someone with HIV or AIDS. Condom use was low. We found that half of the 16 to 19 year old students were sexually active. Rural school attendees were more likely to be sexually active and less likely to practice safe sex. We conclude that the risk of sexually transmitted diseases (including HIV) amongst these teenagers is significant and recommend that, there is a need to design a group targeted awareness programme in order to obviate sexually transmitted diseases including HIV.


Implementing a free school-based fruit and vegetable programme: barriers and facilitators experienced by pupils, teachers and produce suppliers in the Boost study.
Multi-component interventions which combine educational and environmental strategies appear to be most effective in increasing fruit and vegetable (FV) intake in adolescents. However, multi-component interventions are complex to implement and often poorly implemented. Identification of barriers and facilitators for implementation is warranted to improve future interventions.This study aimed to explore implementation of two intervention components which addressed availability and accessibility of FV in the multi-component, school-based Boost study which targeted FV intake among Danish 13-year-olds and to identify barriers and facilitators for implementation among pupils, teachers and FV suppliers. We conducted focus group interviews with 111 13-year-olds and 13 teachers, completed class observations at six schools, and conducted telephone interviews with all involved FV suppliers. Interviews were transcribed, coded and analysed using qualitative analytical procedures. FV suppliers affected the implementation of the FV programme at schools and thereby pupils' intake through their timing of delivery and through the quality, quantity and variety of the delivered FV. Teachers influenced the accessibility and appearance of FV by deciding if and when the pupils could eat FV and whether FV were cut up. Different aspects of time acted as barriers for teachers' implementation of the FV programme: time spent on having a FV break during lessons, time needed to prepare FV and time spent on pupils' misbehaviour and not being able to handle getting FV. Teacher timing of cutting up and serving FV could turn into a barrier for pupils FV intake due to enzymatic browning. The appearance of FV was important for pupils' intake, especially for girls. FV that did not appeal to the pupils e.g. had turned brown after being cut up were thrown around as a part of a game by the pupils, especially boys. Girls appreciated the social dimension of eating FV together to a larger extent than boys. Limited time and pupils' misbehaviour were barriers for teachers' implementation. Establishing FV delivery to schools as a new routine challenged FV suppliers' implementation. Food aesthetics were important for most pupils' FV intake while the social dimension of eating FV together seemed more important to girls than boys. Current Controlled Trials ISRCTN11666034.


Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults.
Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids. Participants from the GLACIER Study (Nmax = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms; replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (ΔTC) and triglycerides (ΔTG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; Nmax = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N ∼ 190 000) and functional annotation for the top ranking variants. In total, 956 variants were associated (P < 0.01) with either ΔTC or ΔTG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with ΔTG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 × 10-8), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 × 10-6). The rs7412 variant at APOE was associated with ΔTC in GLACIER (P < 1.7 × 10-6). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with ΔTC and for ΔTG, respectively (P < 10-3). Of these, a variant at CAPN3 (P = 1.2 × 10-4), multiple variants at HPR (Pmin = 1.5 × 10-6) and a variant at SIX5 (P = 1.9 × 10-4) showed evidence for association with CAD. We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.


Urachal anomalies in children: a single center experience.
The objective of this study is to define optimal diagnosis and treatment strategies for patients with urachal anomalies in the pediatric age group. The medical records of 21 children who had undergone surgery for urachal anomalies at Severance Hospital, Yonsei University College of Medicine from January 1990 to April 2005 were reviewed. The subjects included 14 males and 7 females (M:F 2:1). The four types of urachal anomalies confirmed were a urachal cyst in 10 patients (47.6%), a patent urachus in 6 (28.6%), a urachal sinus in 4 (19.0%) and a urachal diverticulum in 1 (4.8%) patient. The most common presenting complaint was umbilical discharge (n = 10, 40.0%), followed by abdominal mass (n = 9, 36.0%). Urachal anomalies were diagnosed by ultrasonography in 18 patients, and 7 of them were additionally examined by computed tomography. The remaining patients were diagnosed solely by surgical exploration. Excision was performed in all patients and was supplemented by partial cystectomy in three. Umbilical discharge was the most common clinical manifestation in our patients, suggesting that ultrasonography should be performed in patients with umbilical discharge to differentiate urachal anomalies. We found the most common anomaly to be the urachal cyst, and all patients were successfully treated by surgical excision.


Snow cover trend and hydrological characteristics of the Astore River basin (Western Himalayas) and its comparison to the Hunza basin (Karakoram region).
A large proportion of Pakistan's irrigation water supply is taken from the Upper Indus River Basin (UIB) in the Himalaya-Karakoram-Hindukush range. More than half of the annual flow in the UIB is contributed by five of its snow and glacier-fed sub-basins including the Astore (Western Himalaya - south latitude of the UIB) and Hunza (Central Karakoram - north latitude of the UIB) River basins. Studying the snow cover, its spatio-temporal change and the hydrological response of these sub-basins is important so as to better manage water resources. This paper compares new data from the Astore River basin (mean catchment elevation, 4100 m above sea level; m asl afterwards), obtained using MODIS satellite snow cover images, with data from a previously-studied high-altitude basin, the Hunza (mean catchment elevation, 4650 m asl). The hydrological regime of this sub-catchment was analyzed using the hydrological and climate data available at different altitudes from the basin area. The results suggest that the UIB is a region undergoing a stable or slightly increasing trend of snow cover in the southern (Western Himalayas) and northern (Central Karakoram) parts. Discharge from the UIB is a combination of snow and glacier melt with rainfall-runoff at southern part, but snow and glacier melt are dominant at the northern part of the catchment. Similar snow cover trends (stable or slightly increasing) but different river flow trends (increasing in Astore and decreasing in Hunza) suggest a sub-catchment level study of the UIB to understand thoroughly its hydrological behavior for better flood forecasting and water resources management.


Directed calcium chloride coalescence method for preparation of silver nanocubes.
Controlling the size, shape, and structure of metal nanoparticles is very important because of the strong correlation between these parameters and their resulting optical, electrical, and catalytic properties. This paper describes a directed calcium chloride coalescence method, based upon incubating a silver colloid with an aqueous solution of CaCl(2), for preparation of silver nanocubes with a particle size of 270 to 950 nm. The method avoids the use of nonvolatile surfactants and polymers, which may be adsorbed onto the silver nanocubes and interfere with their possible applications in catalysis and analytical devices based on surface-enhanced Raman scattering (SERS) spectroscopy. The nanocubes show good SERS activity in the presence of adsorbed 4-mercaptobenzoic acid (4-MBA) with excitation at 632.8 nm, and the enhancement factor reaches approximately 7 x 10(5). The nanocubes are produced in a simple and cost-effective way, and they are expected to play an important role in the development of SERS-based analytical devices. The method may represent a novel route for preparation of metal nanocubes, which is a subject of intense interest.


Detection of potentially novel bacterial components of the human skin microbiota using culture-independent molecular profiling.
Although the micro-organisms forming the cutaneous microbiota are considered to play important roles in the modification and prevention of skin diseases, a comprehensive analysis of their composition has not yet been carried out because of difficulties in determining yet-to-be-cultured micro-organisms in the samples. Swab-scrubbed forehead skin samples of five healthy volunteers were analysed by profiling 16S rRNA genes, as well as by conventional culture methods, to provide a profile of the cutaneous microbiota that included yet-to-be-cultured bacteria from normal human skin. Cluster analyses of the 16S rRNA gene sequences indicated a marked increase in diversity compared with that derived from the culture methods. Nineteen previously recognized species and 13 novel phylotypes were obtained from the analysis of 416 clones. In addition to well-known bacteria such as Staphylococcus epidermidis and Propionibacterium acnes, phylotype A, the 16S rRNA gene of which is 97 % similar to that of Methylophilus methylotrophus, was detected in three of the five samples, in one of which it was the predominant clone. Culture-independent genetic profiling of 16S rRNA genes for detecting human cutaneous microbiota has allowed us to detect potentially novel components of the cutaneous microbiota in humans.


Psychometric and behavioral measures of central auditory function: the relationship between dichotic listening and digit span tasks.
We hypothesized that the Digit Span (DS) subtest and component tasks (Wechsler, 1991) would show strong relationships with a dichotic listening test (Musiek, 1983). In two sets of archival clinical data (N = 74 and N = 51) we demonstrated that: (a) individuals with central auditory deficits had lower DS scores, F(1, 72) = 7.34, p = .008; eta2 = .09; and (b) left-ear dichotic deficits impacted forward span, F(2, 48) = 8.45, p = .001. Right-ear dichotic listening performance also accounted for significant variance in digit forward span (R2 = 0.17, p = .003). While limited in scope, the studies conclude that forward but not reverse span performance is strongly related to dichotic listening, and can serve as a marker for possible central auditory deficits.


Bichromatic optical switch of diffractive light from a BCT photonic crystal based on an azo component-doped HPDLC.
This study demonstrates all optical switches between the four diffractive light levels of a body-centered tetragonal photonic crystal. The sample is based on holographic polymer-dispersed liquid crystals that are fabricated using a two-beam interference with multiple exposures. The switching mechanism bases on the effective index modulation of the PC that contains a liquid crystal/azo-dye mixture could be controlled by two pumping laser beams. The switching time between the blue-laser-pumped and the blue-and-green-laser-pumped levels is fast. The study also discusses the switching time of the various levels.


Temporomandibular disorders in Turkish children with mixed and primary dentition: prevalence of signs and symptoms.
The prevalence of signs and symptoms related to TM (temporomandibular) disorders was examined in 40 children with primary dentition and in 40 children with mixed dentition. The purpose of this study was to evaluate the relationship between dentition and TM disorders in the examined population. Maximum mouth opening was also evaluated. Clinical examination was done by one investigator. A questionnaire was used in combination with the clinical examination. The results showed that there was an increase in signs and symptoms from the primary to the mixed dentition group, but only the joint sounds were found significantly different between the two groups. There was no statistically significant difference in maximum mouth opening capacity between the groups.


Micro-Spec: an ultracompact, high-sensitivity spectrometer for far-infrared and submillimeter astronomy.
High-performance, integrated spectrometers operating in the far-infrared and submillimeter ranges promise to be powerful tools for the exploration of the epochs of reionization and initial galaxy formation. These devices, using high-efficiency superconducting transmission lines, can achieve the performance of a meter-scale grating spectrometer in an instrument implemented on a 4 inch silicon wafer. Such a device, when combined with a cryogenic telescope in space, provides an enabling capability for studies of the early universe. Here, the optical design process for Micro-Spec (μ-Spec) is presented, with particular attention given to its two-dimensional diffractive region, where the light of different wavelengths is focused on the different detectors. The method is based on the stigmatization and minimization of the light path function in this bounded region, which results in an optimized geometrical configuration. A point design with an efficiency of ~90% has been developed for initial demonstration and can serve as the basis for future instruments. Design variations on this implementation are also discussed, which can lead to lower efficiencies due to diffractive losses in the multimode region.


A 2021 taxonomy update for the family Smacoviridae.
The family Smacoviridae (order Cremevirales, class Arfiviricetes, phylum Cressdnaviricota) is comprised of viruses with small circular single-stranded DNA genomes of ~2.3-3 kb in length that have primarily been identified in fecal sample of various animals. Smacovirus genomes carry two genes in ambisense orientation encoding a capsid protein and a rolling-circle replication initiation protein, respectively. We have revised the taxonomy of the family by assigning 138 new genomic sequences deposited in GenBank to already established taxa as well as 41 new species and six new genera. Furthermore, we have adopted binomial species nomenclature, conforming to the "Genus + freeform epithet" format for all 84 species from 12 genera. The updated Smacoviridae taxonomy presented in this article has been ratified by the International Committee on Taxonomy of Viruses (ICTV).


Comprehensive Survey of miRNA-mRNA Interactions Reveals That Ccr7 and Cd247 (CD3 zeta) are Posttranscriptionally Controlled in Pancreas Infiltrating T Lymphocytes of Non-Obese Diabetic (NOD) Mice.
In autoimmune type 1 diabetes mellitus (T1D), auto-reactive clones of CD4+ and CD8+ T lymphocytes in the periphery evolve into pancreas-infiltrating T lymphocytes (PILs), which destroy insulin-producing beta-cells through inflammatory insulitis. Previously, we demonstrated that, during the development of T1D in non-obese diabetic (NOD) mice, a set of immune/inflammatory reactivity genes were differentially expressed in T lymphocytes. However, the posttranscriptional control involving miRNA interactions that occur during the evolution of thymocytes into PILs remains unknown. In this study, we postulated that miRNAs are differentially expressed during this period and that these miRNAs can interact with mRNAs involved in auto-reactivity during the progression of insulitis. To test this hypothesis, we used NOD mice to perform, for the first time, a comprehensive survey of miRNA and mRNA expression as thymocytes mature into peripheral CD3+ T lymphocytes and, subsequently, into PILs. Reconstruction of miRNA-mRNA interaction networks for target prediction revealed the participation of a large set of miRNAs that regulate mRNA targets related to apoptosis, cell adhesion, cellular regulation, cellular component organization, cellular processes, development and the immune system, among others. The interactions between miR-202-3p and the Ccr7 chemokine receptor mRNA or Cd247 (Cd3 zeta chain) mRNA found in PILs are highlighted because these interactions can contribute to a better understanding of how the lack of immune homeostasis and the emergence of autoimmunity (e.g., T1D) can be associated with the decreased activity of Ccr7 or Cd247, as previously observed in NOD mice. We demonstrate that these mRNAs are controlled at the posttranscriptional level in PILs.


Quality of life, level of functioning, and its relationship with mental and physical disorders in the elderly: results from the MentDis_ICF65+ study.
An ageing population worldwide needs to investigate quality of life (QoL) and level of functioning (LoF) in the elderly and its associated variables. We aimed to study the relationship between Quality of Life (QoL) and Level of Functioning (LoF) in an elderly population in Europe. As part of the Ment_Dis65+ European Project, 3142 community-dwelling adults aged 65-84 years in six countries were assessed by using the adaptation for the elderly of the Composite International Diagnostic Interview (CIDI65+) to provide psychiatric diagnosis according to the International Classification of Diseases (10th edition) (ICD-10 Classification of Mental and Behavioural Disorders). Socio-demographic and clinical interviews, and two self-report tools, the World Health Organization QoL assessment (WHO QoL BREF), to assess QoL, and the WHO Disability Assessment Schedule -II (WHODAS-II), to assess LoF, were also administered. Most subjects reported good levels of QoL (56.6%) and self-rated health (62%), with no or mild disability (58.8%). There was a linear decrease of the QoL and the LoF by increase of age. Elderly with ICD-10 mental disorder (e.g. somatoform, affective and anxiety disorders) had poorer QoL and lower LoF. There were a number of predictors of lower levels of QoL and disability, including both socio-demographic variables (e.g. male gender, increase in age, poor financial situation, retirement, reduced number of close significant others), ICD-10 psychiatric diagnosis (mainly anxiety, somatoform disorders) and presence of medical disorders (mainly heart and respiratory diseases). The study indicates that QoL and LoF were quite acceptable in European elderly people. A series of variables, including psychiatric and somatic disorders, as well as socio-demographic factor influenced in a negative way both QoL and LoF. More specific links between mental health, social and health services dedicated to this segment of the population, should be implemented in order to provide better care for elderly people with conditions impacting their QoL and functioning.


A negative feedback regulatory loop associates the tyrosine kinase receptor ERBB2 and the transcription factor GATA4 in breast cancer cells.
Overexpression of the ERBB2 gene, linked to genomic and transcriptional amplifications, is a poor prognosis indicator in 25% to 30% of breast cancers. In contrast to some well-documented genomic amplifications, molecular mechanisms leading to ERBB2 transcriptional overexpression remain poorly characterized. Gene expression analyses of breast cancer have characterized distinct transcriptional signatures allowing a molecular classification of breast carcinoma. Coexpression of the ERBB2 and GATA4 genes was originally observed in tumors. Both genes are essential for cardiovascular development and GATA4 has been proposed to control the transcription of critical genes for the differentiation and the function of myocardium. We determined that ERBB2-targeted small interfering RNA repressed both ERBB2 and GATA4 genes, whereas GATA4-targeted small interfering RNA repressed GATA4 and activated ERBB2 transcription. Transfected GATA4-expressing construct repressed ERBB2 promoter. Phylogenetic foot printing revealed multiple putative GATA4 binding sites conserved in mammals within the ERBB2 promoter region. Chromatin immunoprecipitation showed that GATA4 binds specifically to several ERBB2 gene noncoding regions. Electrophoretic mobility shift assay revealed GATA4 binding to a well-conserved consensus motif. Site-directed mutagenesis confirmed the role of this new regulatory element for the activity of the ERBB2 gene enhancer. In agreement with a repressor role of GATA4 on ERBB2 gene expression balanced by ERBB2 activation of the GATA4 gene, a negative correlation between the relative levels of ERBB2 and GATA4 mRNA was observed in breast cancer cell lines and breast tumor samples. We propose that the negative feedback loop linking ERBB2 and GATA4 plays a role in the transcriptional dysregulation of ERBB2 gene expression in breast cancer.


Evaluating lifetime nitrogen use efficiency of dairy cattle: A modelling approach.
The increased nitrogen (N) use efficiency in cattle farming is proposed as a key action to improve N management and reduce the environmental impact of cattle farming systems. Most attention has been given to lactating cow nutrition, excluding the elements of fertility, disease, and the non-lactating animals within the herd. Therefore, the aim of the current study was to develop a herd-level simulation model incorporating these elements to assess dairy farm N use efficiency. We developed a cattle N use efficiency (CNE) model with six primary compartments: (i) heifer growth, (ii) heifer removal, (iii) pregnancy, (iv) cow removal, (v) disease and fertility, and (vi) milk production. The CNE model calculates N loss or gain for each compartment, and then calculates the lifetime N loss or gain taking into account the replacement rate (rep) and/or the corresponding number of lactations in a herd (Lact = 1/rep). Finally, three N use efficiencies were estimated: (i) ReplNE: replacement cattle N use efficiency, (ii) LactNE: lifetime N use efficiency for lactation, and (iii) LNE: lifetime N use efficiency. The sensitivity of the model to variation in farm- and animal-related input values was evaluated using Monte Carlo simulation. Values for a model dairy farm were used based on published data reflecting typical dairy farming practices in the United Kingdom. To assist reporting net values of main N outputs, a dairy herd of 100 lactating cows was modelled. Productive N outputs (1000s of kg) over the course of an animal's lifetime, partitioned into milk and meat, were dominated by milk production (89% of total N output). We estimated a mean ReplNE of 23.7%, affected most by the last stage of heifer growth. The Monte Carlo sensitivity analysis suggested that variation in time to first calving (T1stCal) might cause larger changes on ReplNE than variation in feed. The sensitivity analysis revealed a strong positive correlation between dietary oriented milk N use efficiency (MNE) and LactNE and LNE (r = 0.99 and 0.97 for LactNE and LNE, respectively). However, our study highlighted two other model variables that affected LNE. Variation in calving interval (CI; r = -0.15) and T1stCal (r = -0.15) may cause measurable reductions of overall LNE. The first is an indicator of lactating cattle fertility, and the second an indicator of replacement cattle growth and fertility efficiency. In conclusion, with the current study we provided a dairy cattle herd model that is sensitive in elements of diet, fertility and health. Lifetime N use efficiency of dairy cattle is dominated by MNE, but we detected specific non-diet related variables that affect ReplNE, LactNE and LNE.


Hematopoietic Cell Transplantation for Older Patients with MDS.
The incidence of myeloid malignancies, including myelodysplastic syndromes (MDS) increases with age. While several therapeutic modalities have been developed, for most of these patients the only treatment with curative potential is allogeneic hematopoietic cell transplantation (HCT). The development of reduced/low intensity transplant conditioning regimens allows to successfully transplant patients in their '60s and even '70s, although comorbidities may determine who does come to transplantation and who does not. Also, as many as half of the patients will develop graft versus host disease (GVHD), even with HLA matched donors, requiring therapy for extended periods of time, and GVHD and treatment with glucocorticoids is likely to impact the quality of life. Nevertheless, dependent upon disease stage at HCT, the presence of comorbidities and the regimen used, 30% to 50% of patients 60 years of age or older, may survive long-term cured of their disease. Future studies should focus on the incorporation of non-transplant modalities into the overall transplant approach, the prevention of GVHD, and the utilization of immunotherapy to reduce the incidence of relapse and GVHD and further improve overall transplant success.


Optimizing Postprandial Glucose Management in Adults With Insulin-Requiring Diabetes: Report and Recommendations.
Faster-acting insulins, new noninsulin drug classes, more flexible insulin-delivery systems, and improved continuous glucose monitoring devices offer unprecedented opportunities to improve postprandial glucose (PPG) management and overall care for adults with insulin-treated diabetes. These developments led the Endocrine Society to convene a working panel of diabetes experts in December 2018 to assess the current state of PPG management, identify innovative ways to improve self-management and quality of life, and align best practices to current and emerging treatment and monitoring options. Drawing on current research and collective clinical experience, we considered the following issues for the ∼200 million adults worldwide with type 1 and insulin-requiring type 2 diabetes: (i) the role of PPG management in reducing the risk of diabetes complications; (ii) barriers preventing effective PPG management; (iii) strategies to reduce PPG excursions and improve patient quality of life; and (iv) education and clinical tools to support endocrinologists in improving PPG management. We concluded that managing PPG to minimize or prevent diabetes-related complications will require elucidating fundamental questions about optimal ways to quantify and clinically assess the metabolic dysregulation and consequences of the abnormal postprandial state in diabetes and recommend research strategies to address these questions. We also identified practical strategies and tools that are already available to reduce barriers to effective PPG management, optimize use of new and emerging clinical tools, and improve patient self-management and quality of life.


Prelinguistic human infants and great apes show different communicative strategies in a triadic request situation.
In the present research, we investigate the communicative strategies of 20 month old human infants and great apes when requesting rewards from a human experimenter. Infants and apes both adapted their signals to the attentional state of the experimenter as well as to the location of the reward. Yet, while infants frequently positioned themselves in front of the experimenter and pointed towards a distant reward, apes either remained in the experimenter's line of sight and pointed towards him or moved out of sight and pointed towards the reward. Further, when pointing towards a reward that was placed at a distance from the experimenter, only the infants, and not the apes, took the experimenter's attentional state into account. These results demonstrate that prelinguistic human infants and nonhuman apes use different means when guiding others' attention to a location; indicating that differing cognitive mechanisms may underlie their pointing gestures.


Expression of Ku70 correlates with survival in carcinoma of the cervix.
Cervical carcinoma affects around 3400 women in the UK each year and advanced disease is routinely treated with radiation. As part of a programme to establish rapid and convenient methods of predicting tumour and patient responses to radiotherapy, we have examined the relationship between the pre-treatment expression of the Ku components of the DNA damage recognition complex DNA-PK and patient survival in cervical carcinoma. Using immunohistochemistry of formalin-fixed sections of tumour biopsies, antibodies to Ku70 and Ku80 stained identical regions of tumour and there was a high degree of correlation between the mean number of cells stained positive for the two components in 77 tumours (r = 0.82, P<0.001). In 53 tumours there was a borderline significant correlation between measurements of tumour radiosensitivity (surviving fraction at 2 gray: SF2) and Ku70 expression (r = 0.26, P = 0.057) and no correlation for Ku80 (r = 0.18, P = 0.19). However, all tumours with a low number of Ku70 or Ku80 positive cells were radiosensitive. Furthermore, using log-rank analysis there was significantly higher survival in the patients whose tumours had a low Ku70 expression (P = 0.046). This difference was also reflected with Ku80, but did not reach statistical significance (P = 0.087). The study suggests that lack of Ku protein leads to radiosensitivity in some tumours and that other factors are responsible for radiosensitive tumours with high Ku expression. It is likely that the most accurate prediction of treatment outcome will lie in assessing the expression of several proteins involved in the recognition and repair of DNA damage, one of which will be Ku.


Acoustothermal tweezer for droplet sorting in a disposable microfluidic chip.
Precise control over droplet position within a microchannel is fundamental to droplet microfluidic applications. This article proposes acoustothermal tweezer for the control of droplet position, which is based on thermocapillary droplet migration actuated by acoustothermal heating. The proposed system comprises an acoustothermal heater, which is composed of a slanted finger interdigital transducer patterned on a piezoelectric substrate and a thin PDMS membrane, and a PDMS microchannel. In the proposed system, droplets moving in a droplet microfluidic chip experience spatiotemporally varying thermal stimuli produced by acoustothermal heating and thus migrate laterally. In comparison to previous methods for droplet sorting, the acoustothermal tweezer offers significant advantages: first, the droplet position can be manipulated in two opposite directions, which enables bidirectional droplet sorting to one of three outlets downstream; second, precise control over the droplet position as well as improved droplet lateral displacement on the order of hundreds of micrometers can be achieved in a deterministic manner, thereby enabling multichannel droplet sorting; third, the PDMS microfluidic chip is disposable and thus can be easily replaced since it is attached to the substrate by reversible bonding, which allows the acoustothermal heater to be reused. Given these advantages, the proposed droplet sorting system is a promising droplet microfluidic lab-on-a-chip platform for tunable, on-demand droplet position control.


Factors influencing online health information seeking behaviour among patients in Kwahu West Municipal, Nkawkaw, Ghana.
Over the years, health care delivery and ways of accessing health information have transformed rapidly through the use of technology. The internet has played a key role in this advancement by serving as an important source of health information to people regardless of their location, language or condition. This cross sectional study was conducted in the Kwahu West Municipal to determine factors influencing online health information seeking behaviours among patients. Three hospitals in the municipality were purposively selected for the study. Outpatients attending these facilities were systematically selected and data was collected using structured interviewer administered questionnaire. The study findings revealed that internet usage rate among patients was 85.8%. However, only 35.7% of patients ever used the internet to access health information. Sex, education and average monthly income were significant factors associated with online health information seeking. The study also showed that, computer and internet experience factors increased the probability of using internet for health information. After adjusting for confounding factors; being employed, earning higher income and owning a computer were positive predictors of online health information seeking. It is important to explore other means of reducing the disparity in information access by improving skill and health literacy among the low social class who cannot afford internet ready devices. Health care providers should recognize that patients are seeking health information from the internet and should be prepared to assist and promote internet user skills among their patients.