[Health-related quality of life among people with intellectual disabilities in Spain].
To measure health-related quality-of-life (HRQL) among people with intellectual disabilities in the province of Salamanca, Spain. A population-based, cross-sectional descriptive study. The SF-36 Health Survey, adapted and validated for the Spanish population, was selected and administered to 265 people with intellectual disabilities in the province of Salamanca, Spain. Personal interviews were also conducted with the participants in the presence of their parents, tutors, or close family. Eight quality-of-life scales were explored: general health, physical functioning, role-physical, bodily pain, role-emotional, social functioning, vitality, and mental health, based on questions on sociodemographic and lifestyle variables, health services utilization, support needs, and health status and HRQL. Of the 265 people studied, 69.8% were men and 30.2% were women (median age: 35 years; minimum: 16; maximum: 72). The highest number of points pertained to role-physical and physical functioning (more than 85 points), and the lowest, to general health and vitality (less than 70 points). No significant differences were found between men and women for any of the eight components. The independent variables, age, family income, level of education, and support needs showed the greatest number of independent associations with the general health, physical functioning, and social functioning components. Of the participants, 41.5% indicated that they felt their health was good. The study participants perceived their HRQL to be good, especially on the role-physical and physical functioning scales. Additional studies should be designed to evaluate HRQL in people with different degrees of intellectual disability to further contribute to intervention efforts and health and social programs designed specifically for this population group and to evaluate the interventions and program already underway.


Psychological problems in children with burns--parents' reports on the Strengths and Difficulties Questionnaire.
Burns may have a devastating effect on psychological health among children, although previous studies report difficulties as well as positive findings. The aims were to describe the rate of psychological problems in children with burns using a standardised instrument and to explore statistical predictors of these problems. Parents (n=94) of children aged 3-18 years who sustained burns 0.3-9.0 years previously answered the Strengths and Difficulties Questionnaire (SDQ) covering Emotional symptoms, Conduct problems, Hyperactivity/Inattention, Peer relationship problems, Prosocial behaviour, and a Total difficulties score. Questions regarding parental psychological health and family situation were also included. The results for three of the SDQ subscales were close to the norm (10%) regarding the rate of cases where clinical problems were indicated, while the rate of cases indicated for Conduct, Peer problems and Total difficulties was 18-20%. Statistical predictors of the SDQ subscales were mainly parents' psychological symptoms, father's education, and changes in living arrangements. Visible scars were relevant for the Total difficulties score and Hyperactivity/Inattention. In summary, a slightly larger proportion of children with burns had psychological problems than is the case among children in general, and family variables exerted the most influence on parental reports of children's psychological problems.


Natural hybrids of S. cerevisiae x S. kudriavzevii share alleles with European wild populations of Saccharomyces kudriavzevii.
Saccharomyces kudriavzevii, a yeast species described from a pair of strains isolated from decayed leaves in Japan, has recently been isolated from oak barks in Portugal. Some data suggest that these European S. kudriavzevii populations could be closely related to the S. kudriavzevii genetic background present in natural hybrids isolated from wines and beers in different regions of Europe. However, a more exhaustive study of European S. kudriavzevii natural populations is necessary to confirm this observation. In this study, new S. kudriavzevii isolates were recovered from oak trees in different areas in Spain, and identified and characterized according to their molecular and physiological features. The restriction analysis of 35 nuclear genes amplified by PCR demonstrated that all Spanish S. kudriavzevii isolates exhibit three gene alleles different from those present in the Japanese S. kudriavzevii type strain, but identical to the alleles previously reported for natural S. cerevisiaexS. kudriavzevii hybrids. These results clearly support the hypothesis of a European origin for these natural hybrids.


Ketamine Administration by Special Operations Medical Personnel During Training Mishaps.
Opioids can have adverse effects on casualties in hemorrhagic shock. In 2014, the Committee on Tactical Combat Casualty Care (CoTCCC) recommended the use of ketamine at the point of injury (POI). Despite these recommendations the adherence is moderate at best. Poor use may stem from a lack of access to use ketamine during training. The United States Special Operations Command (USSOCOM) is often in a unique position, they maintain narcotics for use during all training events and operations. The goal of this work is to demonstrate that ketamine is safe and effective in both training and operational environments. This was a retrospective, observational performance improvement project within United States Special Operations Command and Air Combat Command that included the US Army's 75th Ranger Regiment, 160th Special Operations Aviation Regiment, and US Air Force Pararescue. Descriptive statistics were used to calculate the doses per administration to include the interquartile range (IQR), standard deviation (SD) and the range of likely doses using a 95% confidence interval (CI). A Wilcoxon signed-rank test was used to compare the mean pre-ketamine pain scores to the mean post-ketamine on a 0-to-10 pain scale. From July 2010 to October 2017, there was a total of 34 patients; all were male. A total of 22 (64.7%) received intravenous ketamine and 12 (35.3%) received intramuscular ketamine and 8 (23.5%) received intranasal ketamine. The mean number of ketamine doses via all routes administered to patients was 1.88 (SD 1.094) and the mean total dose of all ketamine administration was 90.29mg (95% CI, 70.09-110.49). The mean initial dose of all ketamine administration was 47.35mg (95% CI, 38.52-56.18). The median preketamine pain scale for casualties was noted to be 8.0 (IQR 3) and the median post-ketamine pain scale was 0.0 (IQR 3). Ketamine appears to be safe and effective for use during military training accidents. Military units should consider allowing their medics to carry and use as needed.


Store-operated Ca2+ entry regulates Ca2+-activated chloride channels and eccrine sweat gland function.
Eccrine sweat glands are essential for sweating and thermoregulation in humans. Loss-of-function mutations in the Ca2+ release-activated Ca2+ (CRAC) channel genes ORAI1 and STIM1 abolish store-operated Ca2+ entry (SOCE), and patients with these CRAC channel mutations suffer from anhidrosis and hyperthermia at high ambient temperatures. Here we have shown that CRAC channel-deficient patients and mice with ectodermal tissue-specific deletion of Orai1 (Orai1K14Cre) or Stim1 and Stim2 (Stim1/2K14Cre) failed to sweat despite normal sweat gland development. SOCE was absent in agonist-stimulated sweat glands from Orai1K14Cre and Stim1/2K14Cre mice and human sweat gland cells lacking ORAI1 or STIM1 expression. In Orai1K14Cre mice, abolishment of SOCE was associated with impaired chloride secretion by primary murine sweat glands. In human sweat gland cells, SOCE mediated by ORAI1 was necessary for agonist-induced chloride secretion and activation of the Ca2+-activated chloride channel (CaCC) anoctamin 1 (ANO1, also known as TMEM16A). By contrast, expression of TMEM16A, the water channel aquaporin 5 (AQP5), and other regulators of sweat gland function was normal in the absence of SOCE. Our findings demonstrate that Ca2+ influx via store-operated CRAC channels is essential for CaCC activation, chloride secretion, and sweat production in humans and mice.


Comparative phylogenomics and evolution of the Brucellae reveal a path to virulence.
Brucella species include important zoonotic pathogens that have a substantial impact on both agriculture and human health throughout the world. Brucellae are thought of as "stealth pathogens" that escape recognition by the host innate immune response, modulate the acquired immune response, and evade intracellular destruction. We analyzed the genome sequences of members of the family Brucellaceae to assess its evolutionary history from likely free-living soil-based progenitors into highly successful intracellular pathogens. Phylogenetic analysis split the genus into two groups: recently identified and early-dividing "atypical" strains and a highly conserved "classical" core clade containing the major pathogenic species. Lateral gene transfer events brought unique genomic regions into Brucella that differentiated them from Ochrobactrum and allowed the stepwise acquisition of virulence factors that include a type IV secretion system, a perosamine-based O antigen, and systems for sequestering metal ions that are absent in progenitors. Subsequent radiation within the core Brucella resulted in lineages that appear to have evolved within their preferred mammalian hosts, restricting their virulence to become stealth pathogens capable of causing long-term chronic infections.


Dynamics of leukemia stem-like cell extinction in acute promyelocytic leukemia.
Many tumors are believed to be maintained by a small number of cancer stem-like cells, where cure is thought to require eradication of this cell population. In this study, we investigated the dynamics of acute promyelocytic leukemia (APL) before and during therapy with regard to disease initiation, progression, and therapeutic response. This investigation used a mathematical model of hematopoiesis and a dataset derived from the North American Intergroup Study INT0129. The known phenotypic constraints of APL could be explained by a combination of differentiation blockade of PML-RARα-positive cells and suppression of normal hematopoiesis. All-trans retinoic acid (ATRA) neutralizes the differentiation block and decreases the proliferation rate of leukemic stem cells in vivo. Prolonged ATRA treatment after chemotherapy can cure patients with APL by eliminating the stem-like cell population over the course of approximately one year. To our knowledge, this study offers the first estimate of the average duration of therapy that is required to eliminate stem-like cancer cells from a human tumor, with the potential for the refinement of treatment strategies to better manage human malignancy.


Where is VALDO? VAscular Lesions Detection and segmentatiOn challenge at MICCAI 2021.
Imaging markers of cerebral small vessel disease provide valuable information on brain health, but their manual assessment is time-consuming and hampered by substantial intra- and interrater variability. Automated rating may benefit biomedical research, as well as clinical assessment, but diagnostic reliability of existing algorithms is unknown. Here, we present the results of the VAscular Lesions DetectiOn and Segmentation (Where is VALDO?) challenge that was run as a satellite event at the international conference on Medical Image Computing and Computer Aided Intervention (MICCAI) 2021. This challenge aimed to promote the development of methods for automated detection and segmentation of small and sparse imaging markers of cerebral small vessel disease, namely enlarged perivascular spaces (EPVS) (Task 1), cerebral microbleeds (Task 2) and lacunes of presumed vascular origin (Task 3) while leveraging weak and noisy labels. Overall, 12 teams participated in the challenge proposing solutions for one or more tasks (4 for Task 1-EPVS, 9 for Task 2-Microbleeds and 6 for Task 3-Lacunes). Multi-cohort data was used in both training and evaluation. Results showed a large variability in performance both across teams and across tasks, with promising results notably for Task 1-EPVS and Task 2-Microbleeds and not practically useful results yet for Task 3-Lacunes. It also highlighted the performance inconsistency across cases that may deter use at an individual level, while still proving useful at a population level.


Food and therapeutic product interactions - a therapeutic perspective.
Foods and therapeutic products are both used for well defined purposes. In simple terms food provides energy for sustenance, while therapeutic products are taken for managing ailments (1). However, over the years roles of foods have changed considerably. Now, food no longer is seen as simply the provider of energy, but it is expected to provide physiological benefits for good health and productive lifestyles. Well managed combination of foods and therapeutic products plays important role in the prevention and treatment of many diseases, including a number of chronic diseases such as cancer, diabetes, hypertension, obesity. Most often food is combined with medicine to enhance the benefits of medicine - an additive and/or synergistic effect: food-therapeutic product synergism. At the most basic level, food is a complex mixture of chemicals with many functional groups; hence, they not only confer positive effects, but may also make negative contributions. The later effect is of major concerns among the health practitioners and regulatory officials.


Accurate Quantification of Disease Markers in Human Serum Using Iron Oxide Nanoparticle-linked Immunosorbent Assay.
Accurate and reliable quantification of biomarkers in the blood is essential in disease screening and diagnosis. Here we describe an iron oxide nanoparticle (IONP)-linked immunosorbent assay (ILISA) for detecting biomolecules in human serum. Sandwich ILISA was optimized for the detection of four important serological markers, IgA, IgG, IgM, and C-reactive protein (CRP), and assessed with normal sera, simulated disease-state sera and the serum samples from patients infected with West Nile virus (WNV) or human herpes virus (HHV). Our study shows that using the detection assay formulated with 18.8 nm wüstite nanocrystals, ILISA can achieve sub-picomolar detection sensitivity, and all four markers can be accurately quantified over a large dynamic range. In addition, ILISA is not susceptible to variations in operating procedures and shows better linearity and higher stability compared with ELISA, which facilitates its integration into detection methods suitable for point of care. Our results demonstrate that ILISA is a simple and versatile nanoplatform for highly sensitive and reliable detection of serological biomarkers in biomedical research and clinical applications.


Piloting a nurse-led ultrasound cannulation scheme.
Intravenous therapy has evolved to form a fundamental cornerstone of modern health care, but there are significant groups of patients in whom obtaining peripheral venous access is a difficult and drawn out process. An ultrasound guided peripheral venous access service could potentially stop multiple 'blind' attempts, and subsequent damage. A pilot scheme to look at nurse-led ultrasound cannulation was established, and its early results are presented in this article. In addition, a one-operator technique of peripheral ultrasound guided cannulation is described. A total of 28 different patients were referred on 34 occasions for ultrasound guided peripheral cannulation. A total of 33 cannulae were inserted with an overall success rate of 97%. An average of 6.4 attempts at cannulation were undertaken prior to referral and an average of 1.3 attempts were needed to place a cannula under ultrasound guidance. Sixty-nine percent of the cannulae were inserted into the veins of the anterior forearm and 12% into the basilic veins. Overall, 2D ultrasound guided peripheral cannulation is a reliable technique for obtaining vascular access on any adult patients who have already undergone multiple cannulation attempts or in those who it is thought cannulation may be difficult.


Bayesian statistical analysis of circadian oscillations in fibroblasts.
Precise determination of a noisy biological oscillator's period from limited experimental data can be challenging. The common practice is to calculate a single number (a point estimate) for the period of a particular time course. Uncertainty is inherent in any statistical estimator applied to noisy data, so our confidence in such point estimates depends on the quality and quantity of the data. Ideally, a period estimation method should both produce an accurate point estimate of the period and measure the uncertainty in that point estimate. A variety of period estimation methods are known, but few assess the uncertainty of the estimates, and a measure of uncertainty is rarely reported in the experimental literature. We compare the accuracy of point estimates using six common methods, only one of which can also produce uncertainty measures. We then illustrate the advantages of a new Bayesian method for estimating period, which outperforms the other six methods in accuracy of point estimates for simulated data and also provides a measure of uncertainty. We apply this method to analyze circadian oscillations of gene expression in individual mouse fibroblast cells and compute the number of cells and sampling duration required to reduce the uncertainty in period estimates to a desired level. This analysis indicates that, due to the stochastic variability of noisy intracellular oscillators, achieving a narrow margin of error can require an impractically large number of cells. In addition, we use a hierarchical model to determine the distribution of intrinsic cell periods, thereby separating the variability due to stochastic gene expression within each cell from the variability in period across the population of cells.


Renal expression of IGF I in hypersomatotropic states.
We examined insulin-like growth factor I (IGF I) gene expression in kidney in two models of hypersomatotropism, rats implanted with GH3 pituitary tumors, and rats administered exogenous growth hormone (GH). Both GH3 tumor-bearing rats and rats administered GH gained weight more rapidly than control animals, and had kidneys that were larger than those of controls. Tumor-bearing rats had increased levels of circulating IGF I. Glomeruli from tumor-implanted rats were sclerotic. Immunostainable IGF I was increased in medullary collecting ducts from tumor-bearing and GH-injected rats compared with kidneys from control animals. Levels of IGF I mRNA in kidneys of rats implanted with GH3 tumors and GH-injected rats were elevated compared with levels in kidneys from controls. Our findings demonstrate enhanced renal IGF I gene expression in hypersomatotropism. Stimulation of renal IGF I synthesis by GH could be causative of changes in renal function and renal size that occur in states of GH excess such as acromegaly.


The effects of scattering and mirror reflectivity on the performance of a ruby laser.
The output energy expected from a conventional ruby laser generator with plane parallel mirrors is calculated for a range of excitation energies, pulse lengths, mirror reflectivities and absorption, scattering and reflection losses. A linear dependence of output energy on excitation energy is expected only for a vanishingly small pulse length. The effects of localized losses such as those from reflections at the ends of the crystal are similar to scattering losses distributed through the crystal. The output mirror reflectivity giving maximum output energy falls as the excitation energy and scattering increase but is typically 50-60%. The reduction in output caused by scattering is less for lower reflectivities. The angular distribution of light scattered from the ruby when lasing is measured by varying the resonator length to assess the scattering. The predictions of output energy are in good agreement with experiment for all the excitation energies, introduced scattering losses, and mirror reflectivities tri d, except that above 70% reflectivity the prediction is up to 60% low. Possible reasons for this discrepancy are discussed. It was also found experimentally that the resonances between the ends of the ruby are suppressed when lasing, probably due to the optical inhomogeneities produced by the refractive index changes associated with the population changes during a laser spike. The output energy is thus reduced when the ends are not aligned in the resonator. These dynamic inhomogeneities are thought to override any static inhomogeneities already present in the crystal and are a major source of resonator loss.


Robustness of antenna-coupled distributed bolometers.
This Letter shows the effect of the geometrical and material properties of lead lines and connections on the robustness and reliability of optical antennas working as distributed bolometers. We analyze the operational limits of the biasing voltage using a mutiphysics finite element method. We demonstrate that, after evaluating the effect of the electromagnetic irradiance falling on the device, biasing voltage is the main limiting factor to maintain operative titanium optical antennas. Results have been experimentally verified by finding the biasing values needed to destroy optical antennas working as distributed bolometers. Structural damage has been identified from scanning electron microscopy images.


Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors.
GSK-3beta is a regulatory serine/threonine kinase with a plethora of cellular targets. Consequently, selective small molecule inhibitors of GSK-3beta may have a variety of therapeutic uses including the treatment of neurodegenerative diseases, type II diabetes and cancer. In order to characterize the active site of GSK-3beta, we determined crystal structures of unphosphorylated GSK-3beta in complex with selective and non-selective ATP-mimetic inhibitors. Analysis of the inhibitors' interactions with GSK-3beta in the structures reveals how the enzyme can accommodate a number of diverse molecular scaffolds. In addition, a conserved water molecule near Thr138 is identified that can serve a functional role in inhibitor binding. Finally, a comparison of the interactions made by selective and non-selective inhibitors highlights residues on the edge of the ATP binding-site that can be used to obtain inhibitor selectivity. Information gained from these structures provides a promising route for the design of second-generation GSK-3beta inhibitors.


Effectiveness of Palivizumab in High-risk Infants and Children: A Propensity Score Weighted Regression Analysis.
Infants with premature birth ≤35 weeks gestational age, chronic lung disease of prematurity and congenital heart disease are at an increased risk for lower respiratory tract infections and hospitalization from respiratory syncytial virus (RSV), which has been shown in randomized trials to be prevented by palivizumab. However, palivizumab effectiveness (PE) has not been studied in a large clinical setting. A multicenter study among high-risk US and Canadian children younger than 24 months hospitalized with lower respiratory tract infection and whose nasopharyngeal aspirates were tested for human metapneumovirus (HMPV) and RSV were the subjects of the trial. We conducted a test-negative case-control study in these subjects to determine PE. We used an inverse propensity score weighted (IPSW) multiple logistic regression model to adjust PE. Palivizumab was used in 434 (51%) of 849 eligible children. RSV was identified in 403 (47%) children. The unadjusted PE was 43% [95% confidence interval (CI), 34%-51%)]. After IPSW adjustment, the adjusted PE was 58% (95% CI, 43%-69%). Palivizumab prevented intensive care unit admissions (PE, 62%; 95% CI, 35%-78%). PE for 29-35 weeks gestational age and ≤6 months of chronologic age without chronic lung disease of prematurity or congenital heart disease was 74% (95% CI, 56%-85%). Using a test-negative case-control design with RSV molecular detection, palivizumab is shown to prevent RSV hospitalizations and intensive care unit admissions in high-risk infants.


Blood culture contamination in Tanzania, Malawi, and the United States: a microbiological tale of three cities.
We conducted retrospective, comparative analyses of contamination rates for cultures of blood obtained in the emergency rooms of Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania; Lilongwe Central Hospital (LCH) in central Malawi; and the Duke University Medical Center (DUMC) in the United States. None of the emergency room patients had indwelling intravascular devices at the time that the blood samples for cultures were obtained. In addition, we reviewed the contamination rates for a cohort of patients already hospitalized in the DUMC inpatient medical service, most of whom had indwelling intravascular devices. The bloodstream infection rates among the patients at MNH (n=513) and LCH (n=486) were similar (approximately 28%); the contamination rates at the two hospitals were 1.3% (7/513) and 0.8% (4/486), respectively. Of 54 microorganisms isolated from cultures of blood collected in the DUMC emergency room, 26 (48%) were identified as skin contaminants. Cultures of blood collected in the DUMC emergency room were significantly more likely to yield growth of contaminants than the cultures of blood collected in the emergency rooms at MNH and LCH combined (26/332 versus 11/1,003; P<0.0001) or collected in the DUMC inpatient medical service (26/332 versus 7/283; P<0.01). For the MNH and LCH blood cultures, lower contamination rates were observed when skin was disinfected with isopropyl alcohol plus tincture of iodine rather than isopropyl alcohol plus povidone-iodine. In conclusion, blood culture contamination was minimized in sub-Saharan African hospitals with substantially limited resources through scrupulous attention to aseptic skin cleansing and improved venipuncture techniques. Application of these principles when blood samples for culture are obtained in U.S. hospital emergency rooms should help mitigate blood culture contamination rates and the unnecessary microbiology workup of skin contaminants.


First Report of Sirosporium celtidis Causing a Foliar Disease of European Hackberry in Spain.
Hackberry (Celtis australis L.) is widely used for reforestation and as shade tree in parks and roadside plantings in southern Europe (4). In autumn 2011, a foliar disease was observed affecting several trees planted in a garden area located in Alzira (Valencia province, eastern Spain). Symptoms appeared on lower leaf surfaces as reddish to dark brown velvety irregular spots, later becoming grayish brown on the upper surface. Most of the infected trees were prematurely defoliated. Spots on lower leaf surfaces were covered by mycelium, conidiophores, and conidia. Fungal isolates were recovered directly from the structures present on the lesions and by surface-disinfecting small fragments of symptomatic leaf tissue in 0.5% NaOCl, double-rinsing the sections in sterile water, and plating the sections onto potato dextrose agar (PDA) amended with 0.5 g of streptomycin sulfate per liter. Single conidium cultures made onto PDA were maintained for 2 months at 25°C in darkness for morphological examination. Conidia were thick walled, dark reddish brown, often markedly curved or coiled, cylindrical to obclavate, smooth, wrinkled, or verrucose, typically multicellular, 2 to 40 transversely septate and occasionally with 1 to 3 longitudinal or oblique septa that were often constricted, 20 to 96 (44.9) × 6 to 9 (7.1) μm, with an inconspicuous scar at the base. Morphological characters corresponded to the description of Sirosporium celtidis (Biv. ex Spreng) M. B. Ellis published in 1963 (3). The internal transcribed spacer (ITS) region of the rDNA was amplified with the primers ITS1 and ITS4 from DNA extracted from the isolate AL1, and sequenced (GenBank Accession No. JX397963). The sequence was identical to that obtained from an isolate of S. celtidis from the Centraalbureau voor Schimmelcultures, Utrecht, The Netherlands (CBS 289.50). Pathogenicity tests were conducted on five 2-year-old hackberry trees by spraying onto the upper and lower leaf surfaces a conidial suspension of S. celtidis (approximately 50 ml/plant, 106 conidia/ml of water). Five control plants were sprayed with sterile water. Plants were covered with clear plastic bags and incubated in a growth chamber for 72 h at 25°C with a 12-h photoperiod. First leaf spots were visible on inoculated plants after 7 days, but symptoms were not observed on control plants. The fungus was reisolated from leaf lesions on inoculated plants, confirming Koch's postulates. S. celtidis was first described in Sicily in 1815 (3) and has been recorded on various hackberry species in Mediterranean countries and the USA (1,2). To our knowledge, this is the first report of the disease in Spain. The economic and ecological significance of the pathogen in natural ecosystems in Spain remains to be determined but it could certainly become a serious problem for nurseries and urban plantings. References: (1) S.O. Cacciola. 2000. Plant Dis. 84, 492. (2) D. H. Linder. 1931. Ann. Mo. Bot. Garden 18, 31. (3) M. B. Ellis. 1963. Mycological Papers, No. 87. Commonw. Mycol. Inst. Kew, England. (4) S. Pauleit et al., Urban For. Urban Green. 1:83, 2002.


The ocean lifeguard drowning prevention paradigm: how and where do lifeguards intervene in the drowning process?
Drowning is a global health problem that can be addressed with multiple strategies including utilisation of lifeguards in recreational swim areas. However, few studies have described lifeguard prevention activities. We conducted a retrospective analysis using lifeguard activity data collected in real time with a Computer-Aided-Dispatch (CAD) system to characterise the nature of lifeguard primary and secondary drowning prevention at a popular ocean beach in California. Preventative actions constituted the majority (232 065/423 071; 54.8%) of lifeguard activities, while rescues represented 1.9%. Most preventative actions and rescues occurred during summer months, weekends and afternoons. Statistically significant geographical clusters of preventative actions were identified all over the beach, while rescue clusters were primarily restricted to two sites. Using the most reliable and valid collection system to date, these data show spatial and temporal patterns for ocean lifeguard provision of primary prevention as well as secondary drowning prevention (rescue).


Identification of the most common problems by patients with ankylosing spondylitis using the international classification of functioning, disability and health.
The International Classification of Functioning, Disability and Health (ICF) aims to classify functioning and health by a number of categories divided over 3 components: body functions and body structures, participation and activities, and environmental factors. We identified the common health problems of patients with ankylosing spondylitis (AS) based on the ICF from the perspective of the patient. During structured interviews with the extended ICF checklist, trained assessors collected data from 111 patients with AS. ICF categories identified by more than 5% of the patients as at least mildly impaired or restricted were selected. Categories identified by less than 5% were removed. Additional impairments/restrictions reported by more than 5% of the patients, after the structured interviews and not yet included in the checklist, were added. One hundred nineteen (72%) out of 165 categories of the extended ICF checklist were identified to be at least mildly impaired or restricted. Within each of the 4 components of the ICF, at least one-third of the categories were impaired or restricted for more than 50% of the patients. Thirty-nine (33%) categories were related to movement and mobility. Within the component "environmental factors" the categories "support of immediate family" and "health professionals" were the most important facilitators, "climate" was the most important barrier. Eight impairments were additionally mentioned as relevant. These were hierarchically lower levels of ICF categories previously included and they were added. One hundred twenty-seven ICF categories represent the comprehensive classification of functioning in AS from the patients' perspective. The results underscore the need to address the 4 ICF components when classifying functioning and to emphasize that functioning implies more than physical functioning.


Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation.
Endurance training induces a partial fast-to-slow muscle phenotype transformation and mitochondrial biogenesis but no growth. In contrast, resistance training mainly stimulates muscle protein synthesis resulting in hypertrophy. The aim of this study was to identify signaling events that may mediate the specific adaptations to these types of exercise. Isolated rat muscles were electrically stimulated with either high frequency (HFS; 6x10 repetitions of 3 s-bursts at 100 Hz to mimic resistance training) or low frequency (LFS; 3 h at 10 Hz to mimic endurance training). HFS significantly increased myofibrillar and sarcoplasmic protein synthesis 3 h after stimulation 5.3- and 2.7-fold, respectively. LFS had no significant effect on protein synthesis 3 h after stimulation but increased UCP3 mRNA 11.7-fold, whereas HFS had no significant effect on UCP3 mRNA. Only LFS increased AMPK phosphorylation significantly at Thr172 by approximately 2-fold and increased PGC-1alpha protein to 1.3 times of control. LFS had no effect on PKB phosphorylation but reduced TSC2 phosphorylation at Thr1462 and deactivated translational regulators. In contrast, HFS acutely increased phosphorylation of PKB at Ser473 5.3-fold and the phosphorylation of TSC2, mTOR, GSK-3beta at PKB-sensitive sites. HFS also caused a prolonged activation of the translational regulators p70 S6k, 4E-BP1, eIF-2B, and eEF2. These data suggest that a specific signaling response to LFS is a specific activation of the AMPK-PGC-1alpha signaling pathway which may explain some endurance training adaptations. HFS selectively activates the PKB-TSC2-mTOR cascade causing a prolonged activation of translational regulators, which is consistent with increased protein synthesis and muscle growth. We term this behavior the "AMPK-PKB switch." We hypothesize that the AMPK-PKB switch is a mechanism that partially mediates specific adaptations to endurance and resistance training, respectively.


Family structure, parent-child conversation time and substance use among Chinese adolescents.
The family plays a vital role in shaping adolescent behaviours. The present study investigated the associations between family structure and substance use among Hong Kong Chinese adolescents. A total of 32,961 Form 1 to 5 (grade 7-12 in the US) Hong Kong students participated in the Youth Smoking Survey in 2003-4. An anonymous questionnaire was used to obtain information about family structure, daily duration of parent-child conversation, smoking, alcohol drinking and drug use. Logistic regression was used to calculate the adjusted odds ratios (OR) for each substance use by family structure. Adjusting for sex, age, type of housing, parental smoking and school, adolescents from non-intact families were significantly more likely to be current smokers (OR = 1.62), weekly drinkers (OR = 1.72) and ever drug users (OR = 1.72), with significant linear increases in ORs from maternal, paternal to no-parent families compared with intact families. Furthermore, current smoking (OR = 1.41) and weekly drinking (OR = 1.46) were significantly more common among adolescents from paternal than maternal families. After adjusting for parent-child conversation time, the ORs for non-intact families remained significant compared with intact families, but the paternal-maternal differences were no longer significant. Non-intact families were associated with substance use among Hong Kong Chinese adolescents. The apparently stronger associations with substance use in paternal than maternal families were probably mediated by the poorer communication with the father.


Hexagonal Ti2B2 monolayer: a promising anode material offering high rate capability for Li-ion and Na-ion batteries.
Combining the first-principles density functional method and crystal structure prediction techniques, we report a series of hexagonal two-dimensional transition metal borides including Sc2B2, Ti2B2, V2B2, Cr2B2, Y2B2, Zr2B2, and Mo2B2. Their dynamic and thermal stabilities are testified by phonon and molecular dynamics simulations. We investigate the potential of the two-dimensional Ti2B2 monolayer as an anode material for Li-ion and Na-ion batteries. The Ti2B2 monolayer possesses high theoretical specific capacities of 456 and 342 mA h g-1 for Li and Na, respectively. The very high Li/Na diffusivity with an ultralow energy barrier of 0.017/0.008 eV indicates an excellent charge-discharge capability. In addition, good electronic conductivity during the whole lithiation process is found by electronic structure calculations. The very small change in volume after the adsorption of one, two, and three layers of Li and Na ions indicates that the Ti2B2 monolayer is robust. These results highlight the suitability of Ti2B2 monolayer as well as the other two-dimensional transition metal borides as excellent anode materials for both Li-ion and Na-ion batteries.


Developing a vocabulary and ontology for modeling insect natural history data: example data, use cases, and competency questions.
Insects are possibly the most taxonomically and ecologically diverse class of multicellular organisms on Earth. Consequently, they provide nearly unlimited opportunities to develop and test ecological and evolutionary hypotheses. Currently, however, large-scale studies of insect ecology, behavior, and trait evolution are impeded by the difficulty in obtaining and analyzing data derived from natural history observations of insects. These data are typically highly heterogeneous and widely scattered among many sources, which makes developing robust information systems to aggregate and disseminate them a significant challenge. As a step towards this goal, we report initial results of a new effort to develop a standardized vocabulary and ontology for insect natural history data. In particular, we describe a new database of representative insect natural history data derived from multiple sources (but focused on data from specimens in biological collections), an analysis of the abstract conceptual areas required for a comprehensive ontology of insect natural history data, and a database of use cases and competency questions to guide the development of data systems for insect natural history data. We also discuss data modeling and technology-related challenges that must be overcome to implement robust integration of insect natural history data.


Inflammatory mechanisms of idiopathic epiretinal membrane formation.
The pathogenesis of idiopathic epiretinal membranes (iERMs), a common pathology found in retina clinics, still eludes researchers to date. Ultrastructural studies of iERMs in the past have failed to identify the cells of origin due to the striking morphologic changes of cells involved via transdifferentiation. Thus, immunohistochemical techniques that stain for the cytostructural components of cells have confirmed the importance of glial cells and hyalocytes in iERM formation. The cellular constituents of iERMs are thought to consist of glial cells, fibroblasts, hyalocytes, etc. that, in concert with cytokines and growth factors present in the vitreous, lead to iERM formation. Recently, research has focused on the role of the posterior hyaloid in iERM formation and contraction, particularly the process of anomalous PVD as it relates to iERM formation. Recent advances in proteomics techniques have also elucidated the growth factors and cytokines involved in iERM formation, most notably nerve growth factor, glial cell line-derived growth factor, and transforming growth factor β1.


Kefir treatment ameliorates dextran sulfate sodium-induced colitis in rats.
To investigate the preventive effect of kefir on colitis induced with dextran sulfate sodium (DSS) in rats. Twenty-four male Wistar-albino rats were randomized into four groups: normal control, kefir-control, colitis, and kefir-colitis groups. Rats in the normal and kefir-control groups were administered tap water as drinking water for 14 d. Rats in the colitis and kefir-colitis groups were administered a 3% DSS solution as drinking water for 8-14 d to induce colitis. Rats in the kefir-control and kefir-colitis groups were administered 5 mL kefir once a day for 14 d while rats in the normal control and colitis group were administered an identical volume of the placebo (skim milk) using an orogastric feeding tube. Clinical colitis was evaluated with reference to the disease activity index (DAI), based on daily weight loss, stool consistency, and presence of bleeding in feces. Rats were sacrificed on the 15(th) day, blood specimens were collected, and colon tissues were rapidly removed. Levels of myeloperoxidase (MPO), tumor necrosis factor (TNF)-α, interleukin (IL)-10, malondialdehyde, and inducible nitric oxide synthase (iNOS) were measured in colon tissue. The DAI was lower in the kefir-colitis group than in the colitis group (on the 3(rd) and 5(th) days of colitis induction; P < 0.01). The DAI was also significantly higher in the colitis group between days 2 and 6 of colitis induction when compared to the normal control and kefir-control groups. The DAI was statistically higher only on the 6(th) day in the kefir-colitis group when compared to that in the normal control groups. Increased colon weight and decreased colon length were observed in colitis-induced rats. Mean colon length in the colitis group was significantly shorter than that of the kefir-control group. Kefir treatment significantly decreased histologic colitis scores (P < 0.05). MPO activity in the colitis group was significantly higher than in the kefir-control group (P < 0.05). Kefir treatment significantly reduced the DSS colitis-induced TNF-α increase (P < 0.01). No statistically significant differences were observed among groups for IL-10 and MDA levels. Colon tissue iNOS levels in the colitis group were significantly higher than those in the control and kefir-colitis groups (P < 0.05). Kefir reduces the clinical DAI and histologic colitis scores in a DSS-induced colitis model, possibly via reduction of MPO, TNF-α, and iNOS levels.


Use of lenalidomide in the management of relapsed or refractory multiple myeloma: expert recommendations in Korea.
Multiple myeloma (MM) is the third most common hematologic malignancy in Korea. Historically, the incidence of MM in Korea has been lower than that in Western populations, although there is growing evidence that the incidence of MM in Asian populations, including Korea, is increasing rapidly. Despite advances in the management of MM, patients will ultimately relapse or become refractory to their current treatment, and alternative therapeutic options are required in the relapsed/refractory setting. In Korea, although lenalidomide/dexamethasone is indicated for the treatment of relapsed or refractory MM (RRMM) in patients who have received at least one prior therapy, lenalidomide is reimbursable specifically only in patients with RRMM who have failed bortezomib-based treatment. Based on evidence from pivotal multinational clinical trials as well as recent studies in Asia, including Korea, lenalidomide/dexamethasone is an effective treatment option for patients with RRMM, regardless of age or disease status. Adverse events associated with lenalidomide/dexamethasone, including hematologic toxicity, venous thromboembolism, fatigue, rash, infection, and muscle cramps, are largely predictable and preventable/manageable with appropriate patient monitoring and/or the use of standard supportive medication and dose adjustment/interruption. Lenalidomide/dexamethasone provides an optimal response when used at first relapse, and treatment should be continued long term until disease progression. With appropriate modification of the lenalidomide starting dose, lenalidomide/dexamethasone is effective in patients with renal impairment and/or cytopenia. This review presents updated evidence from the published clinical literature and provides recommendations from an expert panel of Korean physicians regarding the use of lenalidomide/dexamethasone in patients with RRMM.


Epithelial transformation of the corneal endothelium in forceps birth-injury-associated keratopathy.
Using light and electron microscopy, we studied four keratectomy specimens obtained by penetrating keratoplasty from four patients (ages 33-54 years; mean age: 43 years old) who had clinical evidence of Descemet's folds and bullous keratopathy after ruptures in Descemet's membrane after forceps injury at birth. Histopathologically, three patients showed the typical features of forceps birth injury: Descemet's membrane at the margin of the rupture was folded and assumed a scroll-shape configuration. The fourth patient showed clusters of proliferated endothelial cells at the site of two ruptures, and from one site of the ruptures, these cells invaded into Descemet's membrane, forming a new basement membrane. Transmission electron microscopy revealed that these proliferated cells were epithelial-like cells characterized by desmosomal junctions, basal lamina, numerous microvilli, and 8-nm cytoplasmic filaments. The epithelial transformation of the corneal endothelium was identified in cases of posterior polymorphous dystrophy and assumed to be specific for this entity. The findings in our fourth patient represent the first documentation of epithelial-like cells on the posterior corneal surface in forceps birth-injury-associated keratopathy. Our results suggest that epithelial transformation may be a nonspecific reaction of the young cornea to various stimuli.


Genome analyses of an aggressive and invasive lineage of the Irish potato famine pathogen.
Pest and pathogen losses jeopardise global food security and ever since the 19(th) century Irish famine, potato late blight has exemplified this threat. The causal oomycete pathogen, Phytophthora infestans, undergoes major population shifts in agricultural systems via the successive emergence and migration of asexual lineages. The phenotypic and genotypic bases of these selective sweeps are largely unknown but management strategies need to adapt to reflect the changing pathogen population. Here, we used molecular markers to document the emergence of a lineage, termed 13_A2, in the European P. infestans population, and its rapid displacement of other lineages to exceed 75% of the pathogen population across Great Britain in less than three years. We show that isolates of the 13_A2 lineage are among the most aggressive on cultivated potatoes, outcompete other aggressive lineages in the field, and overcome previously effective forms of plant host resistance. Genome analyses of a 13_A2 isolate revealed extensive genetic and expression polymorphisms particularly in effector genes. Copy number variations, gene gains and losses, amino-acid replacements and changes in expression patterns of disease effector genes within the 13_A2 isolate likely contribute to enhanced virulence and aggressiveness to drive this population displacement. Importantly, 13_A2 isolates carry intact and in planta induced Avrblb1, Avrblb2 and Avrvnt1 effector genes that trigger resistance in potato lines carrying the corresponding R immune receptor genes Rpi-blb1, Rpi-blb2, and Rpi-vnt1.1. These findings point towards a strategy for deploying genetic resistance to mitigate the impact of the 13_A2 lineage and illustrate how pathogen population monitoring, combined with genome analysis, informs the management of devastating disease epidemics.


Evaluation of transversus abdominis plane block for renal transplant recipients - A meta-analysis and trial sequential analysis of published studies.
Patients undergoing renal transplant (RT) have altered drug/opioid pharmacokinetics. Transversus abdominis plane (TAP) block in renal transplant recipients has been recently evaluated for analgesic and opioid-sparing potential by many trials. The studies comparing TAP-block to conventional analgesic regimens for RT were searched. Comparisons were made for total opioids consumed (as morphine-equivalents) during the first postoperative 24-h (primary objective), intraoperative, and immediate-postoperative period. Pain scores and postoperative nausea-vomiting (PONV) were also evaluated. Trial sequential analysis (TSA) was used to quantify the strength of analysis. Ten-trials with 258 and 237 patients in control and TAP-block group, respectively, were included. TAP-block decreased the 24-h (reported in 9-trials) opioid consumption by 14.61 ± 4.34 mg (reduction by 42.7%, random-effects, P < 0.001, I2 = 97.82%). Sample size of the present analysis (472) was well past the required "information-size" variable (396) as per the TSA for a power of 85%. Intraoperative opioid consumption also decreased by 2.06 ± 0.63 mg (reduction of 27.8%) (random effects, P < 0.001, I2 = 98.84%). Pain scores with TAP-block were significantly lower in both early and delayed postoperative phase. Odds ratio for PONV without TAP block was 1.99 ± 1.05 (Fixed-effects, P = 0.04, I2 = 0%). Publication bias was likely (Egger's test, X-intercept=7.89, P < 0.05). TAP-block significantly lowers the intraoperative and cumulative postoperative 24-h opioid consumption in RT recipients. Persistent and better pain control is achieved when TAP-Block is used. Benefits of TAP block extend beyond the analgesic actions alone as it also decreases the 24-h incidence of postoperative nausea vomiting as well. The technique of the block needs standardization for RT recipients.


Molecular evolution of the tprC, D, I, K, G, and J genes in the pathogenic genus Treponema.
We investigated the evolution of 6 genes from the Treponema pallidum repeat (tpr) gene family, which encode potential virulence factors and are assumed to have evolved through gene duplication and gene conversion events. The 6 loci (tprC, D, G, J, I, and K) were sequenced and analyzed in several members of the genus Treponema, including the 3 subspecies of human T. pallidum (T. pallidum subsp. pallidum, pertenue, and endemicum), Treponema paraluiscuniculi (rabbit syphilis), and the unclassified Fribourg-Blanc (simian) isolate. Phylogenetic methods, recombination analysis, and measures of nucleotide diversity were used to investigate the evolutionary history of the tpr genes. Numerous instances of gene conversion were detected by all 3 methods including both homogenizing gene conversion that involved the entire length of the sequence as well as site-specific conversions that affected smaller regions. We determined the relative age and directionality of the gene conversion events whenever possible. Our data are also relevant to a discussion of the evolution of the treponemes themselves. Higher levels of variation exist between the human subspecies than within them, supporting the classification of the human treponemes into 3 subspecies. In contrast to published theories, the divergence and diversity of T. pallidum subsp. pertenue relative to the other subspecies does not support a much older origin of yaws at the emergence of modern human, nor is the level of divergence seen in T. pallidum subsp. pallidum consistent with a very recent (< 500 years) origin of this subspecies. In general, our results demonstrate that intragenomic recombination has played a significant role in the evolution of the studied tpr genes and emphasize that efforts to infer evolutionary history of the treponemes can be complicated if past recombination events are not recognized.


Ecological Model to Predict Potential Habitats of Oncomelania hupensis, the Intermediate Host of Schistosoma japonicum in the Mountainous Regions, China.
Schistosomiasis japonica is a parasitic disease that remains endemic in seven provinces in the People's Republic of China (P.R. China). One of the most important measures in the process of schistosomiasis elimination in P.R. China is control of Oncomelania hupensis, the unique intermediate host snail of Schistosoma japonicum. Compared with plains/swamp and lake regions, the hilly/mountainous regions of schistosomiasis endemic areas are more complicated, which makes the snail survey difficult to conduct precisely and efficiently. There is a pressing call to identify the snail habitats of mountainous regions in an efficient and cost-effective manner. Twelve out of 56 administrative villages distributed with O. hupensis in Eryuan, Yunnan Province, were randomly selected to set up the ecological model. Thirty out of the rest of 78 villages (villages selected for building model were excluded from the villages for validation) in Eryuan and 30 out of 89 villages in Midu, Yunnan Province were selected via a chessboard method for model validation, respectively. Nine-year-average Normalized Difference Vegetation Index (NDVI) and Land Surface Temperature (LST) as well as Digital Elevation Model (DEM) covering Eryuan and Midu were extracted from MODIS and ASTER satellite images, respectively. Slope, elevation and the distance from every village to its nearest stream were derived from DEM. Suitable survival environment conditions for snails were defined by comparing historical snail presence data and remote sensing derived images. According to the suitable conditions for snails, environment factors, i.e. NDVI, LST, elevation, slope and the distance from every village to its nearest stream, were integrated into an ecological niche model to predict O. hupensis potential habitats in Eryuan and Midu. The evaluation of the model was assessed by comparing the model prediction and field investigation. Then, the consistency rate of model validation was calculated in Eryuan and Midu Counties, respectively. The final ecological niche model for potential O. hupensis habitats prediction comprised the following environmental factors, namely: NDVI (≥ 0.446), LST (≥ 22.70°C), elevation (≤ 2,300 m), slope (≤ 11°) and the distance to nearest stream (≤ 1,000 m). The potential O. hupensis habitats in Eryuan distributed in the Lancang River basin and O. hupensis in Midu shows a trend of clustering in the north and spotty distribution in the south. The consistency rates of the ecological niche model in Eryuan and Midu were 76.67% and 83.33%, respectively. The ecological niche model integrated with NDVI, LST, elevation, slope and distance from every village to its nearest stream adequately predicted the snail habitats in the mountainous regions.


Effects of temperature, salinity and composition of the dinoflagellate assemblage on the growth of Gambierdiscus carpenteri isolated from the Great Barrier Reef.
Increases in reported incidence of ciguatera fish poisoning (hereafter ciguatera) have been linked to warmer sea temperatures that are known to trigger coral bleaching events. The drivers that trigger blooms of ciguatera-causing dinoflagellates on the Great Barrier Reef (GBR) are poorly understood. This study investigated the effects of increased temperatures and lowered salinities, often associated with environmental disturbance events, on the population growth of two strains of the potentially ciguatera-causing dinoflagellate, Gambierdiscus carpenteri (NQAIF116 and NQAIF380). Both strains were isolated from the central GBR with NQAIF116 being an inshore strain and NQAIF380 an isolate from a stable environment of a large coral reef aquarium exhibit in ReefHQ, Townsville, Australia. Species of Gambierdiscus are often found as part of a mixed assemblage of benthic toxic dinoflagellates on macroalgal substrates. The effect of assemblage structure of dinoflagellates on the growth of Gambierdiscus populations has, however, not been explored. The study, therefore investigated the growth of G. carpenteri within mixed assemblages of benthic dinoflagellates. Population growth was monitored over a period of 28days under three salinities (16, 26 and 36) and three temperature (24, 28 and 34°C) conditions in a fully crossed experimental design. Temperature and salinity had a significant effect on population growth. Strain NQAIF380 exhibited significantly higher growth at 28°C compared to strain NQAIF116, which had highest growth at 24°C. When strain NQAIF116 was co-cultured with the benthic dinoflagellates, Prorocentrum lima and Ostreopsis sp., inhibitory effects on population growth were observed at a salinity of 36. In contrast, growth stimulation of G. carpenteri (strain NQAIF116) was observed at a salinity of 26 and particularly at 16 when co-cultured with Ostreopsis-dominated assemblages. Range expansion of ciguatera-causing dinoflagellates could lead to higher frequency of reported ciguatera illness in populated temperate Australian regions, outside the tropical range of the GBR. Therefore, the findings on salinity and temperature tolerance of two strains of G. carpenteri indicates potential adaptability to different local environmental conditions. These are baseline data for future investigations into the potential southward range expansion of ciguatera-causing dinoflagellates originating from the GBR.


Clinical Outcomes of Patients with Diabetes Who Exhibit Upper-Quartile Insulin Antibody Responses After Treatment with LY2963016 or Lantus® Insulin Glargine.
We compared insulin antibody response (IAR) profiles in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D) who received LY2963016 insulin glargine (LY IGlar) or Lantus® insulin glargine (IGlar) and evaluated the potential relationship between higher IARs and clinical and safety outcomes with a focus on patients who exhibited antibody responses in the upper quartile. Data from ELEMENT-1 (52-week open-label in T1D) and ELEMENT-2 (24-week, double-blind study in T2D) were analyzed. Maximum postbaseline IAR levels and proportions of patients in the upper quartile of maximum antibody percent binding (UQMAPB; patients with maximum postbaseline percent binding in the highest 25% of maximum values observed) were compared for differential treatment effects on clinical efficacy outcomes and incidence of adverse events. Continuous outcomes were analyzed by analysis of covariance. Categorical data were analyzed by the Cochran-Mantel-Haenszel or Breslow-Day test. In both studies (N = 532 evaluable patients with T1D; N = 730 with T2D), no statistically significant differences between LY IGlar and IGlar were observed for maximum antibody percent binding (MAPB) levels or for proportions of patients in the respective UQMAPB. No statistically significant differential treatment effects were observed in the relationship between MAPB and clinical efficacy and safety outcomes. Maximum postbaseline IAR levels and the proportion of patients with high IAR levels were similar for LY IGlar and IGlar. High antibody levels did not affect clinical outcomes. These results add further evidence supporting similar IARs of LY IGlar and IGlar. Eli Lilly and Company and Boehringer-Ingelheim.


Metabolic acidosis is a potent stimulus for cellular inorganic phosphate generation in uraemia.
1. During metabolic acidosis, significant fluxes of inorganic phosphate (Pi) may occur from cellular to extracellular fluid. In this study Pi was measured in erythrocytes of uraemic patients before and after haemodialysis and was related to their plasma pH (acidosis), plasma Pi (hyperphosphataemia) and cellular organic phosphate concentrations. 2. Before dialysis, the ratio of cellular to extracellular Pi concentration correlated inversely with plasma pH, increasing 2.5-fold as pH fell from 7.4 to 7.2. 3. An increase in cellular Pi similar to that seen in the patients was observed within 90 min of adding acid to normal erythrocytes in vitro. 4. The total Pi content of the cell suspension increased 25% on decreasing plasma pH from 7.4 to 7.2, largely as a result of generation of Pi from 2,3-bisphosphoglycerate in the cells. This was accompanied by net efflux of Pi into plasma. 5. In addition, the increase in the steady-state cellular Pi concentration on adding a constant extracellular Pi load was 50% greater at pH 7.2 than at 7.4, implying that alterations in the regulation of the transmembrane Pi gradient also contribute to the rise in cellular Pi observed at low pH. 6. At normal plasma Pi concentration (1 mM), glycolytic flux (lactate production) was inhibited by 20% when pH was lowered from 7.4 to 7.2. However, this inhibition was blocked when cellular Pi was increased by adding Pi to the plasma in vitro. 7. Metabolic acidosis is therefore a potent stimulus for Pi generation in erythrocytes, and this Pi may serve to stimulate glycolysis which is normally inhibited by low pH.


Alternate injections coupled with flow-gated capillary electrophoresis for rapid and accurate quantitative analysis of urine samples.
Capillary electrophoresis (CE) is a powerful separation technique with advantages over HPLC in terms of separation efficiency, speed, and cost. However, CE suffers in poor reproducibility in quantitative chemical analysis, which is one of major drawbacks preventing its widespread use in routine analytical laboratories. Here we report a novel strategy to enhance the quantitative capability of flow-gated CE. The platform integrated dual flow branches to respectively supply a sample and its standard additions that were then alternately injected into a single capillary for rapid separations (typically 20-90 s). A micro-fabricated switch was used to enable the alternate injections. It was assumed that the analytical system maintained constant conditions during neighboring injections that served as external self-standards for quantitation. This strategy was expected to reduce uncertainties caused by the fluctuation in capillary conditions and the drift of detection systems. Experimental results demonstrated that the dual-branch flow-gated CE coupled with alternate injections significantly improved the reproducibility with respect to peak height ratios under deliberate variations in injection volumes, separation voltages, optical focusing, and laser power; and thus the interday precision was ensured. To demonstrate its applicability, cyanide and amino acids in human urine were quantified rapidly with the one-point standard addition method after fluorogenic derivatization with naphthalene-2,3-dicarboxaldehyde (NDA), and the measurement accuracy was validated by determining the recovery of standard cyanide added to a urinary matrix. This strategy would be valuable to enable the quantitative capability of flow-gated CE in the measurements of a broad range of analytes, especially those lacking suited internal standards.


Precision of regional wall motion estimates from ultra-low-dose cardiac CT using SQUEEZ.
Resting regional wall motion abnormality (RWMA) has significant prognostic value beyond the findings of computed tomography (CT) coronary angiography. Stretch quantification of endocardial engraved zones (SQUEEZ) has been proposed as a measure of regional cardiac function. The purpose of the work reported here was to determine the effect of lowering the radiation dose on the precision of automatic SQUEEZ assessments of RWMA. Chronic myocardial infarction was created by a 2-h occlusion of the left anterior descending coronary artery in 10 swine (heart rates 80-100, ejection fraction 25-57%). CT was performed 5-11 months post infarct using first-pass contrast enhanced segmented cardiac function scans on a 320-detector row scanner at 80 kVp/500 mA. Images were reconstructed at end diastole and end systole with both filtered back projection and using the "standard" adaptive iterative dose reduction (AIDR) algorithm. For each acquisition, 9 lower dose acquisitions were created. End systolic myocardial function maps were calculated using SQUEEZ for all noise levels and contrast-to-noise ratio (CNR) between the left ventricle blood and myocardium was calculated as a measure of image quality. For acquisitions with CNR > 4, SQUEEZ could be estimated with a precision of ± 0.04 (p < 0.001) or 5.7% of its dynamic range. The difference between SQUEEZ values calculated from AIDR and FBP images was not statistically significant. Regional wall motion abnormality can be quantified with good precision from low dose acquisitions, using SQUEEZ, as long as the blood-myocardium CNR stays above 4.


Protective Effects of Diallyl Sulfide on Ovalbumin-Induced Pulmonary Inflammation of Allergic Asthma Mice by MicroRNA-144, -34a, and -34b/c-Modulated Nrf2 Activation.
Allergic airway disorder is characterized by an increase in the level of reactive oxygen species (ROS). The induction of inflammation and hyperresponsiveness by an allergen was ameliorated by antioxidants in vivo. This study investigated the protective effects and underlying mechanism of diallyl sulfide (DAS) on ovalbumin (OVA)-induced allergic asthma of BALB/c mice. The animals were intraperitoneally sensitized by inhaling OVA to induce chronic airway inflammation. By administering DAS, a decrease of the infiltrated inflammatory cell counts and the levels of IL-4 and IL-10 in bronchoalveolar lavage fluid as well as the OVA-specific immunoglobulin E levels in sera were observed. DAS also effectively inhibited OVA-induced inflammatory cell infiltration and mucus hypersecretion in lung tissue. Several OVA-induced inflammatory factors (ROS, 8-hydroxy-2'-deoxyguanosine, 8-iso-prostaglandin F2α, and NF-κB) were inhibited by DAS. In addition, DAS increased OVA inhalation-reduced levels of Nrf2 activation by regulating microRNA-144, -34a and -34b/c. Together, the pathogenesis of OVA-induced asthma is highly associated with oxidative stress, and DAS may be an effective supplement to alleviate this disease.


Longitudinal change in memory performance as a strong endophenotype for Alzheimer's disease.
Although large-scale genome-wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. We conducted a cross-ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non-Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene-level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD-related traits, neuropsychiatric traits, and autoimmune traits. We discovered several novel loci, genes, and genetic correlations associated with late-life memory performance and decline. Late-life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late-life memory. We identified four novel genes associated with late-life memory. Late-life memory shares genetic architecture with psychiatric/autoimmune traits.


Retention of moisture-tolerant fluoride-releasing sealant and amorphous calcium phosphate-containing sealant in 6-9-year-old children: A randomized controlled trial.
Pits and fissures of teeth have been recognized as the most susceptible areas for initiation of caries. The ability of the resin sealant to thoroughly fill pits, fissures, and/or morphological defects and remain completely intact and bonded to enamel surface is the primary basis for its caries prevention. The present study evaluated and compared the retention rates and development of caries in permanent molars of children sealed with amorphous calcium phosphate-containing (Aegis™) and moisture-tolerant fluoride-releasing (Embrace WetBond™) sealant over a period of 1 year. This was a double-blind, split-mouth, randomized controlled trial among children aged 6-9 years. Sixty-eight permanent mandibular first molars in 34 children were randomly assigned to be sealed with Aegis™ or Embrace Wetbond™ sealant. The follow-up examinations were conducted at 3, 6, and 12 months for evaluating the retention and development of caries. SPSS version 16.0 was used for the analysis. Within-group comparison of retention and development of caries at 3, 6, and 12 months was evaluated using the Friedman's test. The final sample was 32 children with 64 teeth. At 12 months, 23 of 32 (72%) sealants were completely retained in Aegis™, whereas 21 of 32 (65.6%) were retained in Embrace Wetbond™ group. There was no significant difference in the retention rates of Aegis™ and Embrace Wetbond™ sealants at 12 months (P > 0.05). Aegis™ was superior to Embrace Wetbond™ sealant as Aegis™ exhibited higher retention and lower caries scores.


Parents' experiences of what comforts them when their child is suffering from cancer.
The aim of the study was to describe parents' narratives concerning what they find comforting when they have a child suffering from cancer. Interviews were conducted with 9 parents--8 mothers and 1 father--of children aged 3 to 9 years who were admitted to a pediatric oncology ward and had undergone their first treatment. The findings showed that the parents derived comfort from being close to their child, perceiving the child's strength, feeling at home in the ward, being a family and being at home, and receiving support from their social network. Comfort experienced in communion with the child and others became important and helped the parents build a new normality perceived as being at home in life despite all their difficulties. Within the frame of communion, the parents seemed to experience moments of hope for their child's recovery and survival.


Practical methods for compensating for missed treatment days in radiotherapy, with particular reference to head and neck schedules.
Unscheduled interruption of a radiotherapy treatment can lead to significant loss in local tumour control, particularly in tumours that repopulate rapidly. General guidelines for dealing with such treatment gaps have been issued by the Royal College of Radiologists and more specific advice on the use of compensation methods has been published previously [Hendry et al., Clin Oncol 1996;8:297-307; Slevin et al., Radiother Oncol 1992;24:215-220]. This article further elaborates on the practical application of these methods. It sets out the main considerations arising in the especially critical case of head and neck treatments and simple calculations are used to illustrate the approaches which may be adapted for particular situations. Radiobiological parameter values are suggested for use in the calculations, but these may require modification in the light of further research in this important area.


Gradient-based 2-D/3-D rigid registration of fluoroscopic X-ray to CT.
We present a gradient-based method for rigid registration of a patient preoperative computed tomography (CT) to its intraoperative situation with a few fluoroscopic X-ray images obtained with a tracked C-arm. The method is noninvasive, anatomy-based, requires simple user interaction, and includes validation. It is generic and easily customizable for a variety of routine clinical uses in orthopaedic surgery. Gradient-based registration consists of three steps: 1) initial pose estimation; 2) coarse geometry-based registration on bone contours, and; 3) fine gradient projection registration (GPR) on edge pixels. It optimizes speed, accuracy, and robustness. Its novelty resides in using volume gradients to eliminate outliers and foreign objects in the fluoroscopic X-ray images, in speeding up computation, and in achieving higher accuracy. It overcomes the drawbacks of intensity-based methods, which are slow and have a limited convergence range, and of geometry-based methods, which depend on the image segmentation quality. Our simulated, in vitro, and cadaver experiments on a human pelvis CT, dry vertebra, dry femur, fresh lamb hip, and human pelvis under realistic conditions show a mean 0.5-1.7 mm (0.5-2.6 mm maximum) target registration accuracy.


Blood glucose test strips: options to reduce usage.
Recent evidence suggests that, despite widespread use, self-monitoring of blood glucose levels has little clinical benefit in many patients with diabetes. The impact of more focused public-payer policies for the use of blood glucose test strips may be substantial. We conducted a cross-sectional analysis of annual prescription claims for test strips between 1997 and 2008 for patients in Ontario aged 65 and older with diabetes. Patients were stratified into 1 of 4 hierarchical groups according to the most intensive glucose-lowering treatment received during each calendar year. Test strip use was calculated annually for each group over the study period, and the effects of 5 hypothetical policy scenarios of more selective test strip use were assessed. Test strip use increased by almost 250% from 1997 to 2008, with 52.6% (n = 263,513) of included patients receiving a prescription during 2008. Almost half of these patients were at low risk for drug-induced hypoglycemia. In 2008, over 117 million test strips were dispensed in Ontario; however, more focused policy scenarios could have reduced this number by between 9.5 million and 74.5 million test strips. Many people who self-monitor their blood glucose are at relatively low risk for drug-induced hypoglycemia. The economic benefits associated with more selective testing could be redirected to more effective interventions for patients with diabetes.


Profiling of Small Molecules by Chemical Proteomics.
Chemical proteomics provides a powerful means to gain systems-level insight into the mode of action of small molecules and/or natural products. In contrast to high-throughput screening efforts which only interrogate selected subproteomes such as kinases and often only consider individual domains, the methodology presented herein allows for the determination of the molecular targets of small molecules or drugs in a more relevant physiological setting. As such, the compound of interest is exposed to the entire variety of cellular proteins considering all naturally occurring posttranslational modifications and activation states. Samples prepared according to the procedures described in this protocol are compatible with lysates from cultured cell lines, primary cells, or samples from biopsies. In combination with state-of-the-art mass spectrometry techniques this approach grants access to a comprehensive view of small molecule-target protein interactions.


The landscape for women leaders in dental education, research, and practice.
Following early limitations on women becoming educated in and practicing dentistry, the proportion of women enrolled in dental schools around the world has increased dramatically over the past decades. Dental schools have undergone a transformation from male dominance to almost equal numbers in the United States and female predominance in other countries including the United Kingdom. However, this change in student gender distribution has not been matched among academic leaders. Data from across the globe indicate a clear disproportion in favor of males in leadership positions in dentistry-and the more senior the position, the greater the imbalance. This article reviews the evolving changes in gender distribution across the landscape of dental education, research, and practice and some initiatives to address the gender imbalance in leadership. Such initiatives can help to ensure that, in the future, the profession benefits from the spectrum of influences brought to bear by the leadership of both women and men.


Angiotensin II induces phosphorylation of the thiazide-sensitive sodium chloride cotransporter independent of aldosterone.
We studied here the independent roles of angiotensin II and aldosterone in regulating the sodium chloride cotransporter (NCC) of the distal convoluted tubule. We adrenalectomized three experimental and one control group of rats. Following surgery, the experimental groups were treated with either a high physiological dose of aldosterone, a non-pressor, or a pressor dose of angiotensin II for 8 days. Aldosterone and both doses of angiotensin II lowered sodium excretion and significantly increased the abundance of NCC in the plasma membrane compared with the control. Only the pressor dose of angiotensin II caused hypertension. Thiazides inhibited the sodium retention induced by the angiotensin II non-pressor dose. Both aldosterone and the non-pressor dose of angiotensin II significantly increased phosphorylation of NCC at threonine-53 and also increased the intracellular abundance of STE20/SPS1-related, proline alanine-rich kinase (SPAK). No differences were found in other modulators of NCC activity such as oxidative stress responsive protein type 1 or with-no-lysine kinase 4. Thus, our in vivo study shows that aldosterone and angiotensin II independently increase the abundance and phosphorylation of NCC in the setting of adrenalectomy; effects are likely mediated by SPAK. These results may explain, in part, the hormonal control of renal sodium excretion and the pathophysiology of several forms of hypertension.


Ex vivo model unravelling cell distribution effect in hydrogels for cartilage repair.
The implantation of chondrocyte-laden hydrogels is a promising cartilage repair strategy. Chondrocytes can be spatially positioned in hydrogels and thus in defects, while current clinical cell therapies introduce chondrocytes in the defect depth. The main aim of this study was to evaluate the effect of spatial chondrocyte distribution on the reparative process. To reduce animal experiments, an ex vivo osteochondral plug model was used and evaluated. The role of the delivered and endogenous cells in the repair process was investigated. Full thickness cartilage defects were created in equine osteochondral plugs. Defects were filled with (A) chondrocytes at the bottom of the defect, covered with a cell-free hydrogel, (B) chondrocytes homogeneously encapsulated in a hydrogel, and (C, D) combinations of A and B with different cell densities. Plugs were cultured for up to 57 days, after which the cartilage and repair tissues were characterized and compared to baseline samples. Additionally, at day 21, the origin of cells in the repair tissue was evaluated. Best outcomes were obtained with conditions C and D, which resulted in well-integrated cartilage-like tissue that completely filled the defect, regardless of the initial cell density. A critical role of the spatial chondrocyte distribution in the repair process was observed. Moreover, the osteochondral plugs stimulated cartilage formation in the hydrogels when cultured in the defects. The resulting repair tissue originated from the delivered cells. These findings confirm the potential of the osteochondral plug model for the optimization of the composition of cartilage implants and for studying repair mechanisms.


Natural history of the cavernous angioma.
The incidence and natural history of the cavernous angioma have remained unclear in part because of the difficulty of diagnosing and following this lesion prior to surgical excision. The introduction of magnetic resonance (MR) imaging has improved the sensitivity and specificity of diagnosing and following this vascular malformation. Seventy-six lesions with an MR appearance typical of a presumed cavernous angioma were discovered in 66 patients among 14,035 consecutive MR images performed at the Cleveland Clinic between 1984 and 1989. Follow-up studies in 86% of the cases over a mean period of 26 months provided 143 lesion-years of clinical survey of this condition. The most frequent presenting features were seizure, focal neurological deficit, and headache. While most lesions exhibited evidence of occult bleeding on MR imaging, there was overt hemorrhage in seven of the 57 symptomatic patients and only one overt hemorrhage occurred during the follow-up interval. The annualized bleeding rate was 0.7%. Analysis of the hemorrhage group revealed a significantly greater risk of overt hemorrhage in females. Pathological confirmation of cavernous angioma was obtained in all 14 surgical cases. This information assists in rational therapeutic planning and prognosis in patients with MR images showing lesions suggestive of cavernous angioma.


Integrating electronic health record information to support integrated care: practical application of ontologies to improve the accuracy of diabetes disease registers.
Information in Electronic Health Records (EHRs) are being promoted for use in clinical decision support, patient registers, measurement and improvement of integration and quality of care, and translational research. To do this EHR-derived data product creators need to logically integrate patient data with information and knowledge from diverse sources and contexts. To examine the accuracy of an ontological multi-attribute approach to create a Type 2 Diabetes Mellitus (T2DM) register to support integrated care. Guided by Australian best practice guidelines, the T2DM diagnosis and management ontology was conceptualized, contextualized and validated by clinicians; it was then specified, formalized and implemented. The algorithm was standardized against the domain ontology in SNOMED CT-AU. Accuracy of the implementation was measured in 4 datasets of varying sizes (927-12,057 patients) and an integrated dataset (23,793 patients). Results were cross-checked with sensitivity and specificity calculated with 95% confidence intervals. Incrementally integrating Reason for Visit (RFV), medication (Rx), and pathology in the algorithm identified nearly100% of T2DM cases. Incrementally integrating the four datasets improved accuracy; controlling for sample size, data incompleteness and duplicates. Manual validation confirmed the accuracy of the algorithm. Integrating multiple data elements within an EHR using ontology-based case-finding algorithms can improve the accuracy of the diagnosis and compensate for suboptimal data quality, and hence creating a dataset that is more fit-for-purpose. This clinical and pragmatic application of ontologies to EHR data improves the integration of data and the potential for better use of data to improve the quality of care.


Safe Passage: Improving the Transition of Care Between Triage and Labor and Delivery.
The multifaceted nature of the transition of care from the triage unit to labor and delivery has historically led to confusion, delays, and errors in care. This study evaluated the effect of standardization of roles and communication on improving this transition. A multidisciplinary team was assembled to define and standardize roles of team members. A huddle safety board was created as a visual aid to promote closed-loop communication during an admission bedside huddle. The primary metrics collected were duration of time from the admission decision in the triage unit to when the admission huddle was completed on labor and delivery, duration of time from the admission decision in the triage unit to initiation of the plan of care and documented completion of the admission huddle. There was a 66-minute reduction in time from the admission decision to the huddle completion between the preintervention and postintervention periods. There was a 93-minute reduction in the time from the admission decision to when the plan of care was initiated between the preintervention and post-intervention periods. The weekly huddle compliance rate improved from 48% to 84% by the postintervention period. The implementation of standardized roles and processes facilitating closed-loop communication decreases delays in communication and initiation of care in pregnant women transferred from the triage unit to labor and delivery.


Conceivable difference in the anti-inflammatory mechanisms of lipocortins 1 and 5.
Human recombinant lipocortins (LCT) 1 and 5 have been expressed in a yeast secretion vector and purified by ion exchange chromatography. The action of the proteins has been investigated in two models of experimental acute inflammation in the rat: carrageenin induced paw oedema and zymosan induced pleurisy. The effects of the proteins on PGE(2) release in vitro by rat macrophages stimulated with zymosan and on rat neutrophil chemotaxis induced by FMLP have also been assessed. LCT-1 significantly inhibited both paw swelling in carrageenin oedema and leukocyte migration in zymosan pleurisy. Moreover it showed a dose dependent, inhibitory effect on PGE(2) release. Neutrophil chemotaxis was only weakly affected by LCT-1. Conversely LCT-5 did not reduce carrageenin oedema and slightly inhibited PGE(2) release, but showed profound, dose dependent inhibitory activity on leukocyte migration in zymosan pleurisy and on neutrophil chemotaxis. These data suggest that LCT-1 acts mainly by interfering with arachidonic acid metabolism via the inhibition of phospholipase A(2). The anti-inflammatory activity of LCT-5, at variance with LCT-1, may be due to a direct effect on cell motility in addition to the interference with arachidonic acid metabolism.


A comparative study of the antacid effect of raw spinach juice and spinach extract in an artificial stomach model.
BackgroundSpinacia oleracea known as spinach is a green-leafy vegetable consumed by people across the globe. It is reported to possess potent medicinal properties by virtue of its numerous antioxidant phytoconstituents, together termed as the natural antioxidant mixture (NAO). The present study compares the antacid effect of raw spinach juice with an antioxidant-rich methanolic extract of spinach (NAOE) in an artificial stomach model. MethodsThe pH of NAOE at various concentrations (50, 100 and 200 mg/mL) and its neutralizing effect on artificial gastric acid was determined and compared with that of raw spinach juice, water, the active control sodium bicarbonate (SB) and a marketed antacid preparation ENO. A modified model of Vatier's artificial stomach was used to determine the duration of consistent neutralization of artificial gastric acid for the test compounds. The neutralizing capacity of test compounds was determined in vitro using the classical titration method of Fordtran. Results NAOE (50, 100 and 200 mg/mL), spinach juice, SB and ENO showed significantly better acid-neutralizing effect, consistent duration of neutralization and higher antacid capacity when compared with water. Highest antacid activity was demonstrated by ENO and SB followed by spinach juice and NAOE200. Spinach juice exhibited an effect comparable to NAOE (200 mg/mL). ConclusionsThus, it may be concluded that spinach displays significant antacid activity be it in the raw juice form or as an extract in methanol.


[Standards, options and recommendations for the management of prostate cancer: therapeutic decision criteria].
The "Standards, Options and Recommendations" (SOR) collaborative project was initiated in 1993 by the Federation of the French Cancer Centres (FNCLCC), with the 20 French Regional Cancer Centres, several French public university and general hospitals, as well as private clinics and medical specialty societies. Its main objective is the development of serviceable clinical practice guidelines in order to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review, followed by critical appraisal by a multidisciplinary group of experts. Draft guidelines are produced, then validated by specialists in cancer care delivery. Produce clinical practice guidelines for prostate cancer patients related to therapeutic main decision criteria, using the methodology developed by the Standards, Options and Recommendations project. The FNCLCC and the French Urology Society (AFU) set-up a multidisciplinary group of experts which reviewed the available evidence. Following the selection of pertinent articles, synthesis of the results, and production of the draft SOR, the document was validated by independent reviewers. The main recommendations are: 1) Specific survival with a minimum of 15 years follow-up, is required to assess the impact of a treatment for localised prostate cancer. 2) Ten-year metastatic-free survival is a good endpoint for assessing treatment efficacy for local cancer. 3) Complete remission is defined as undetectable PSA concentration (< 0.1 mug.L- 1). 4) Progression after radical prostactectomy, external-beam radiotherapy or brachytherapy is defined as an increase PSA concentration, measured in three successive determinations, at monthly intervals. 5) Clinical stage, Gleason score and pretherapeutic PSA concentration are the prognostic factors for locoregional involvement and therefore treatment response, which should be used as an aid for therapeutic decision-making.


Enzymatic Adaptation of Podospora anserina to Different Plant Biomass Provides Leads to Optimized Commercial Enzyme Cocktails.
As a late colonizer of herbivore dung, Podospora anserina has evolved an enzymatic machinery to degrade the more recalcitrant fraction of plant biomass, suggesting a great potential for biotechnology applications. The authors investigated its transcriptome during growth on two industrial feedstocks, soybean hulls (SBH) and corn stover (CS). Initially, CS and SBH results in the expression of hemicellulolytic and amylolytic genes, respectively, while at later time points a more diverse gene set is induced, especially for SBH. Substrate adaptation is also observed for carbon catabolism. Overall, SBH resulted in a larger diversity of expressed genes, confirming previous proteomics studies. The results not only provide an in depth view on the transcriptomic adaptation of P. anserina to substrate composition, but also point out strategies to improve saccharification of plant biomass at the industrial level.


Post-injury pain and behaviour: a control theory perspective.
Injuries of various types occur commonly in the lives of humans and other animals and lead to a pattern of persistent pain and recuperative behaviour that allows safe and effective recovery. In this Perspective, we propose a control-theoretic framework to explain the adaptive processes in the brain that drive physiological post-injury behaviour. We set out an evolutionary and ethological view on how animals respond to injury, illustrating how the behavioural state associated with persistent pain and recuperation may be just as important as phasic pain in ensuring survival. Adopting a normative approach, we suggest that the brain implements a continuous optimal inference of the current state of injury from diverse sensory and physiological signals. This drives the various effector control mechanisms of behavioural homeostasis, which span the modulation of ongoing motivation and perception to drive rest and hyper-protective behaviours. However, an inherent problem with this is that these protective behaviours may partially obscure information about whether injury has resolved. Such information restriction may seed a tendency to aberrantly or persistently infer injury, and may thus promote the transition to pathological chronic pain states.


DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1.
Disrupted-In-Schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, because of the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1, proximal to the NDEL1 binding site, affect the interaction between DISC1 and NDEL1.


Evolution of intrahost HIV-1 genetic diversity during chronic infection.
HIV-1 is one of the fastest evolving entities known. Given that census population sizes of HIV-1 within individuals are much greater than the inverse mutation rate, every possible single point mutation in the viral genome occurs each generation. This enormous capability to generate genetic variation allows for escape from immune surveillance and antiviral therapy. However, compared to this potential, populations of HIV-1 within individuals exhibit little genetic variation. This discrepancy between the known mutation rate of HIV-1 and the average level of genetic variation in the env gene observed in vivo is reflected in comparisons of the actual numbers of productively infected cells, estimated as 10(7), and the effective population size, estimated as 10(3). Using approximate Bayesian computation, we evaluated several hypotheses based on a variety of selective and demographic processes to explain the low effective population size of HIV-1. Of the models we examined, the metapopulation model, in which HIV-1 evolves within an individual as a large collection of small subpopulations subject to frequent migration, extinction, and recolonization, was most consistent with the observed levels of genetic variation and the average frequencies of those variants. The metapopulation model links previous studies of viral dynamics and population genetics.


Persistent productive Epstein-Barr virus replication in normal epithelial cells in vivo.
Productive Epstein-Barr virus (EBV) replication characterizes hairy leukoplakia, an oral epithelial lesion typically occurring in individuals infected with human immunodeficiency virus (HIV). Serial tongue biopsy specimens were obtained from HIV-infected subjects before, during, and after valacyclovir treatment. EBV replication was detected by Southern hybridization to linear terminal EBV genome fragments, reverse-transcriptase polymerase chain reaction amplification of EBV replicative gene transcripts, immunohistochemical detection of EBV replicative protein, and in situ hybridization to EBV DNA. EBV replication was detected in both hairy leukoplakia and normal tongue tissues. Valacyclovir treatment completely abrogated EBV replication in vivo, resulting in resolution of hairy leukoplakia when it was present. EBV replication returned in normal tongue epithelial cells after valacyclovir treatment. These data suggest that normal oral epithelium supports persistent EBV infection in individuals infected with HIV and that productive EBV replication is necessary but not sufficient for the pathogenesis of oral hairy leukoplakia.


Supportive care in severe and very severe aplastic anemia.
Optimal management of aplastic anemia (AA) is not confined to immediate diagnosis, early decision making and timely initiation of major treatment strategies (immunosuppression or SCT) but also involves supportive treatment as a crucial part of patient care. Patients are threatened by complications of cytopenia. Here, we summarize current recommendations for prevention and early treatment of fungal, bacterial and viral infections, transfusion strategy and iron chelation and assess the evidence basis. In fact, many recommendations for patients with AA are not based on randomized studies in AA itself, but they are deduced from other conditions with similar severity of cytopenia. Prevention and treatment of complications like hemorrhage, bacterial and fungal infections and of secondary events like alloimmunization to blood products and iron overload have a significant impact on the prognosis of AA patients and need to be carefully observed in daily practice. More controlled studies on supportive care should be performed in this rare disease.


Effects of mastectomy on shoulder and spinal kinematics during bilateral upper-limb movement.
Shoulder movement impairment is a commonly reported consequence of surgery for breast cancer. The aim of this study was to determine whether shoulder girdle kinematics, including those of the scapula, spine, and upper limb, in women who have undergone a unilateral mastectomy for breast cancer are different from those demonstrated by an age-matched control group. An observational study using 3-dimensional kinematic analysis was performed. Women who had a unilateral mastectomy on their dominant-arm side (n=29, mean [+/-SD] age=62.4+/-8.9 years) or nondominant-arm side (n=24, mean [+/-SD] age=59.8+/-9.9 years), as well as a control group of age-matched women without upper-limb, shoulder, or spinal problems (n=22, mean [+/-SD] age=58.1+/-11.5 years), were measured while performing bilateral arm movements in the sagittal, scapular, and coronal planes. All of the women were free of shoulder pain at the time of testing. Data were collected from the glenohumeral joint, the scapulothoracic articulation, and the spine (upper and lower thoracic and lumbar regions) using an electromagnetic tracking system. Women following mastectomy displayed altered patterns of scapular rotation compared with controls in all planes of movement. In particular, the scapula on the mastectomy side rotated upward to a markedly greater extent than that on the nonmastectomy side, and women following mastectomy displayed greater scapular excursion than controls. The findings suggest that altered motor patterns of the scapula are associated with mastectomy on the same side. Whether these changes are harmful or not is unclear. Investigation of interventions designed to restore normal scapulohumeral relationships on the affected side following unilateral mastectomy for breast cancer is warranted.