Factors associated with sleep-wake disturbances in child and adult survivors of pediatric brain tumors: a review.
To identify factors associated with sleep-wake disturbances in pediatric and adult survivors (aged older than 18 years) of pediatric brain tumors. A computerized literature search was completed using MEDLINE, CINAHL, CancerLit, Dissertation Abstracts International, and PsycINFO. The search and a personal communication with one author discovered 25 English-language research articles and case reports describing sleep-wake patterns in brain tumor survivors from 1966-2008. Disease- and treatment-related factors from direct injury to the hypothalamus results in irregular melatonin secretion and low hypocretin levels. This contributes to decreased daytime alertness, which remains the most reported sleep-wake disturbance in brain tumor survivors. Patients with craniopharyngiomas, radiation dose more than 3,500 cGy, and younger age at time of treatment experienced more severe sleep dysfunction. Patients with brain tumors experience a disruption of sleep-wake patterns associated with major dysfunction in the hypothalamic-pituitary axis, affecting both Process S (homeostasis) and Process C (circadian) from the Two-Process Model of Sleep Regulation. Various demographic-, disease-, and treatment-related variables are involved in driving the onset of sleep disturbances. Interventions are needed to improve daytime function and decrease the effect of sleep disturbances on quality of life. Current sleep literature has identified patterns of sleep disturbances in cross-sectional studies of brain tumor survivors. Rigorous longitudinal designs are needed for future studies to detect onset patterns and trajectory of sleep-wake disorders. Intervention studies are needed to impact excessive daytime sleepiness, irregular sleeping and waking patterns, and other identified sleep-wake disorders.


Two-color two-dimensional Fourier transform electronic spectroscopy with a pulse-shaper.
We report two-color two-dimensional Fourier transform electronic spectroscopy obtained using an acousto-optic pulse-shaper in a pump-probe geometry. The two-color setup will facilitate the study of energy transfer between electronic transitions that are widely separated in energy. We demonstrate the method at visible wavelengths on the laser dye LDS750 in acetonitrile. We discuss phase-cycling and polarization schemes to optimize the signal-to-noise ratio in the pump-probe geometry. We also demonstrate that phase-cycling can be used to separate rephasing and nonrephasing signal components.


Production of the antifungal compound pyrrolnitrin is quorum sensing-regulated in members of the Burkholderia cepacia complex.
Members of the genus Burkholderia are known for their ability to suppress soil-borne fungal pathogens by the production of various antibiotic compounds. In this study we investigated the role of N-acylhomoserine lactone (AHL)-dependent quorum sensing (QS) in the expression of antifungal traits. Using a quorum quenching approach, that is, by heterologous expression of the Bacillus sp. AiiA lactonase, we show that expression of antifungal activities is AHL-dependent in the large majority of the investigated strains belonging to various Burkholderia species. We demonstrate that in certain strains of Burkholderia ambifaria, Burkholderia pyrrocinia and Burkholderia lata, one of the QS-regulated antifungal agents is pyrrolnitrin (prn), a common broad-spectrum antibiotic that is also produced by some Pseudomonas and Serratia species. To investigate the underlying molecular mechanisms of AHL-dependent prn production in better detail, we inactivated the AHL synthase cepI as well as cepR, which encodes the cognate AHL receptor protein, in B. lata 383. Both QS mutants no longer produced prn as assessed by gas chromatography-mass spectrometry analysis and as a consequence were unable to inhibit growth of Rhizoctonia solani. Using fusions of the lacZ gene to the promoter of the prnABCD operon, which directs the synthesis of prn, we demonstrate that expression of prn is positively regulated by CepR at the level of transcription.


Assessment of patient perceptions of genomic testing to inform pharmacogenomic implementation.
Pharmacogenomics seeks to improve prescribing by reducing drug inefficacy/toxicity. However, views of patients during pharmacogenomic-guided care are largely unknown. We sought to understand the attitudes and perceptions of patients in an institutional implementation project and hypothesized that views would differ on the basis of experience with pharmacogenomic-guided care. Two focus groups were conducted - one group included patients who had previously been subjected to broad pharmacogenomic genotyping with results available to physicians (pharmacogenomic group), whereas the other had not been offered genotyping (traditional care). Five domains were explored: (i) experiences with medications/side effects, (ii) understanding of pharmacogenomics, (iii) impact of pharmacogenomics on relationships with healthcare professionals, (iv) scenarios involving pharmacogenomic-guided prescribing, and (v) responses to pharmacogenomic education materials. Nine pharmacogenomic and 13 traditional care participants were included. Participants in both groups agreed that pharmacogenomics could inform prescribing and help identify problem prescriptions, but expressed concerns over insurance coverage and employment discrimination. Both groups diverged on who should be permitted to access pharmacogenomic results, with some preferring access only for providers with a longstanding relationship, whereas others argued for open access. Notably, traditional care participants showed greater skepticism about how results might be used. Case scenarios and tested educational materials elicited strong desires on the part of patients for physicians to engage participants when considering pharmacogenomic-based prescribing and to utilize shared decision-making. Participants experiencing pharmacogenomic-guided care were more receptive toward pharmacogenomic information being used than traditional care participants. As key stakeholders in implementation, addressing patients' concerns will be important to successfully facilitate clinical dissemination.


Developing a test collection for biomedical word sense disambiguation.
Ambiguity, the phenomenon that a word has more than one sense, poses difficulties for many current Natural Language Processing (NLP) systems. Algorithms that assist in the resolution of these ambiguities, i.e. which make unambiguous a word, or more generally, a text string, will boost performance of these systems. To test such techniques in the biomedical language domain, we have developed a Word Sense Disambiguation (WSD) test collection that comprises 5,000 unambiguous instances for 50 ambiguous UMLS Metathesaurus strings.


Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination.
Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.


Single-dose intravenous iron for iron deficiency: a new paradigm.
Iron-deficiency anemia is the most common hematologic problem in the world. Although oral iron is often viewed as front-line therapy, extensive published evidence has accumulated that IV iron is superior, in both efficacy and safety, to oral iron in many clinical situations and should be introduced much sooner in the treatment paradigm of iron-deficient patients. In this chapter, we will review the formulations of IV iron that allow total complete replacement doses in 1 or 2 sessions including practical tips for administration. We realize safety concerns abound and therefore will analyze evidence based overstated concerns regarding serious adverse events highlighting unnecessary interventions for minor, self-limiting infusion reactions, which infrequently occur with intravenous iron administration. Recent data for the use of IV iron in a variety of clinic situations will be reviewed including women with heavy uterine bleeding, pregnancy, bariatric surgery, inflammatory bowel disease, and restless legs syndrome. Briefly discussed is the new frontier of IV iron's use in the prevention of acute (high altitude) mountain sickness. It is clear that in many clinical situations IV iron is a new and improved standard of care offering advantages over oral iron in efficacy, toxicity, and convenience to patients and health care providers.


The role of BMP signaling in outgrowth and patterning of the Xenopus tail bud.
Tail bud formation in Xenopus depends on interaction between a dorsal domain (dorsal roof) expressing lunatic fringe and Notch, and a ventral domain (posterior wall) expressing the Notch ligand Delta. Ectopic expression of an activated form of Notch, Notch ICD, by means of an animal cap graft into the posterior neural plate, results in the formation of an ectopic tail-like structure containing a neural tube and fin. However, somites are never formed in these tails. Here, we show that BMP signaling is activated in the posterior wall of the tail bud and is involved in the formation of tail somites from this region. Grafts into the posterior neural plate, in which BMP signaling is activated, will form tail-like outgrowths. Unlike the Notch ICD tails, the BMP tails contain well-organized somites as well as neural tube and fin, with the graft contributing to both somites and neural tube. Through a variety of epistasis-type experiments, we show that the most likely model involves a requirement for BMP signaling upstream of Notch activation, resulting in formation of the secondary neural tube, as well as a Notch-independent pathway leading to the formation of tail somites from the posterior wall.


Safety and functional outcome of thrombolysis in dissection-related ischemic stroke: a meta-analysis of individual patient data.
The safety and efficacy of thrombolysis in cervical artery dissection (CAD) are controversial. The aim of this meta-analysis was to pool all individual patient data and provide a valid estimate of safety and outcome of thrombolysis in CAD. We performed a systematic literature search on intravenous and intra-arterial thrombolysis in CAD. We calculated the rates of pooled symptomatic intracranial hemorrhage and mortality and indirectly compared them with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. We applied multivariate regression models to identify predictors of excellent (modified Rankin Scale=0 to 1) and favorable (modified Rankin Scale=0 to 2) outcome. We obtained individual patient data of 180 patients from 14 retrospective series and 22 case reports. Patients were predominantly female (68%), with a mean±SD age of 46±11 years. Most patients presented with severe stroke (median National Institutes of Health Stroke Scale score=16). Treatment was intravenous thrombolysis in 67% and intra-arterial thrombolysis in 33%. Median follow-up was 3 months. The pooled symptomatic intracranial hemorrhage rate was 3.1% (95% CI, 1.3 to 7.2). Overall mortality was 8.1% (95% CI, 4.9 to 13.2), and 41.0% (95% CI, 31.4 to 51.4) had an excellent outcome. Stroke severity was a strong predictor of outcome. Overlapping confidence intervals of end points indicated no relevant differences with matched controls from the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register. Safety and outcome of thrombolysis in patients with CAD-related stroke appear similar to those for stroke from all causes. Based on our findings, thrombolysis should not be withheld in patients with CAD.


Frequent BRAF gain in low-grade diffuse gliomas with 1p/19q loss.
Chromosomal 7q34 duplication and BRAF-KIAA1549 fusion is a characteristic genetic alteration in pilocytic astrocytomas. 7q34 gain appears to be common in diffuse astrocytomas, but its significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low-grade diffuse gliomas, including 55 diffuse astrocytomas, 18 oligoastrocytomas and 50 oligodendrogliomas. Quantitative polymerase chain reaction (PCR) revealed BRAF gain in 17/50 (34%) oligodendrogliomas, a significantly higher frequency than in diffuse astrocytomas (7/55; 13%; P = 0.0112). BRAF gain was common in low-grade diffuse gliomas with 1p/19q loss (39%) and those lacking any of the genetic alterations analyzed (31%), but was rare in those with TP53 mutations (2%). Logistic regression analysis showed a significant positive association between 1p/19q loss and BRAF gain (P = 0.0032) and a significant negative association between TP53 mutations and BRAF gain (P = 0.0042). Fluorescence in situ hybridization (FISH) analysis of 26 low-grade diffuse gliomas with BRAF gain additionally revealed BRAF-KIAA1549 fusion in one oligodendroglioma. Sequencing of cDNA in 17 low-grade diffuse gliomas showed BRAF-KIAA1549 fusion in another oligodendroglioma. A BRAF(V600E) mutation was also detected in one oligodendroglioma, and a BRAF(A598V) in one diffuse astrocytoma. These results suggest that low-grade diffuse gliomas with 1p/19q loss have frequent BRAF gains, and a small fraction of oligodendrogliomas may show BRAF-KIAA1549 fusion.


Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
The HER2 gene, which encodes the growth factor receptor HER2, is amplified and HER2 is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. We evaluated the efficacy and safety of trastuzumab, a recombinant monoclonal antibody against HER2, in women with metastatic breast cancer that overexpressed HER2. We randomly assigned 234 patients to receive standard chemotherapy alone and 235 patients to receive standard chemotherapy plus trastuzumab. Patients who had not previously received adjuvant (postoperative) therapy with an anthracycline were treated with doxorubicin (or epirubicin in the case of 36 women) and cyclophosphamide alone (138 women) or with trastuzumab (143 women). Patients who had previously received adjuvant anthracycline were treated with paclitaxel alone (96 women) or paclitaxel with trastuzumab (92 women). The addition of trastuzumab to chemotherapy was associated with a longer time to disease progression (median, 7.4 vs. 4.6 months; P<0.001), a higher rate of objective response (50 percent vs. 32 percent, P<0.001), a longer duration of response (median, 9.1 vs. 6.1 months; P<0.001), a lower rate of death at 1 year (22 percent vs. 33 percent, P=0.008), longer survival (median survival, 25.1 vs. 20.3 months; P=0.01), and a 20 percent reduction in the risk of death. The most important adverse event was cardiac dysfunction of New York Heart Association class III or IV, which occurred in 27 percent of the group given an anthracycline, cyclophosphamide, and trastuzumab; 8 percent of the group given an anthracycline and cyclophosphamide alone; 13 percent of the group given paclitaxel and trastuzumab; and 1 percent of the group given paclitaxel alone. Although the cardiotoxicity was potentially severe and, in some cases, life-threatening, the symptoms generally improved with standard medical management. Trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2.


Temperature sensitivity on growth and/or replication of H1N1, H1N2 and H3N2 influenza A viruses isolated from pigs and birds in mammalian cells.
Influenza A viruses have been isolated from a wide range of animal species, aquatic birds being the reservoir for their genetic diversity. Avian influenza viruses can be transmitted to humans, directly or indirectly through an intermediate host like pig. This study aimed to define in vitro conditions that could prove useful to evaluate the potential of influenza viruses to adapt to a different host. Growth of H1N1, H1N2 and H3N2 influenza viruses belonging to different lineages isolated from birds or pigs prior to 2005 was tested on MDCK or NPTr cell lines in the presence or absence of exogenous trypsin. Virus multiplication was compared at 33, 37 and 40 degrees C, the infection site temperatures in human, swine and avian hosts, respectively. Temperature sensitivity of PB2-, NP- and M-RNA replication was also tested by quantitative real-time PCR. Multiplication of avian viruses was cold-sensitive, whatever cell type. By contrast, temperature sensitivity of swine viruses was found to depend on the virus and the host cell: for an H1N1 swine isolate from 1982, multiplication was cold-sensitive on NPTr cells and undetectable at 40 degrees C. From genetic analyses, it appears that temperature sensitivity could involve other residues than PB2 residue 627 and could affect other steps of the replication cycle than replication.


HPA Axis Gene Expression and DNA Methylation Profiles in Rats Exposed to Early Life Stress, Adult Voluntary Ethanol Drinking and Single Housing.
The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation. Concluding, single housing is a confounding factor to be considered in voluntary ethanol drinking paradigms. ELS and ethanol drinking in adulthood exert independent effects on hypothalamic and pituitary related genes, however, in a manner dependent on the control group used.


A systematic review of telestroke.
The use of 2-way audiovisual (AV) technology for delivery of acute stroke evaluation and management, termed "telestroke," is supported by a rapidly growing literature base. A systematic review that provides a comprehensive, easily digestible overview of telestroke science and practice is lacking. To conduct a systematic review of the published literature on telemedical consultation for the purposes of providing acute stroke evaluation and management. The Ovid Medline, Embase, PsychINFO, CINAHL, PubMed, and Cochrane databases were searched with numerous keywords relevant to telestroke from January 1996 through July 2012. Studies were included if the title or abstract expressed use of 2-way AV communication for acute stroke evaluation and management. Each article was classified using a novel scoring rubric to assess the level of Functionality, Application, Technology, and Evaluative stage (FATE). The search yielded 1405 potentially eligible articles, which were independently reviewed by 2 investigators. There were 344 unique studies that met eligibility criteria and underwent full-text review. Ultimately, 145 unique studies underwent FATE assessment and scoring. Most telestroke studies evaluated functionality in the context of acute stroke assessment of adults in emergency departments. Nearly half of all published articles on telestroke were narrative reviews. After exclusion of these reviews, the median FATE score for telestroke primary data was 4. Telestroke technology is now part of mainstream clinical stroke practice in North America and internationally. Telestroke reliability, validity, efficacy, safety, clinical, and cost-effectiveness studies reflect maturity in the field, and new post-implementation studies in the pre-hospital setting present welcome and sophisticated advancements in the field.


Learning strategies during clerkships and their effects on clinical performance.
Previous research revealed relationships between learning strategies and knowledge acquisition. During clerkships, however, students' focus widens beyond mere knowledge acquisition as they further develop overall competence. This shift in focus can influence learning strategy use. We explored which learning strategies were used during clerkships and their relationship to clinical performance. Participants were 113 (78%) clerks at the university hospital or one of six affiliated hospitals. Learning strategies were assessed using the 'Approaches to Learning at Work Questionnaire' (deep, surface-rational and surface-disorganised learning). Clinical performance was calculated by taking the mean of clinical assessment marks. The relationship between learning strategies and clinical performance was explored using regression analysis. Most students (89%) did not clearly prefer a single learning strategy. No relationship was found between learning strategies and clinical performance. Since overall competence comprises integration of knowledge, skills and professional behaviour, we assume that students without a clear preference use more than one learning strategy. Finding no relationship between learning strategies and clinical performance reflects the complexity of clinical learning. Depending on circumstances it may be important to obtain relevant information quickly (surface-rational) or understand material thoroughly (deep). In future research we will examine when and why students use different learning strategies.


The anatomy of an OPTI: Part 2. The CORE system. Ohio Osteopathic Hospital Association. Ohio Association of Osteopathic Medical Directors. Ohio Osteopathic Association.
In July 1995, the American Osteopathic Association (AOA) Board of Trustees passed new regulations regarding the accreditation of osteopathic graduate medical education (GME) by establishing the Osteopathic Postdoctoral Training Institutions (OPTI) system. This system must be phased in by July 1999. The principal changes resulting from the OPTI system include establishing requirements for college cosponsorship of GME programs and for the number of residency programs, interns, and residents to be trained by the OPTI. In essence, OPTI is an osteopathic acronym for consortium. Each OPTI must include at least one college of osteopathic medicine (COM) and one AOA-accredited hospital. The OPTIs will be subject to interval AOA inspections and will be required to demonstrate a governing system, mission statement, organizational structure, and the presence of faculty development programs. The first article in this two-part series, published in the October JAOA, provided a general blueprint for OPTI building and presented both positive and negative issues germane to the formation of OPTIs. Part 2 reinforces the considerations outlined in Part 1 by describing the formation of a large OPTI--the Ohio University College of Osteopathic Medicine (OU-COM) Centers of Osteopathic Regional Education (CORE) system. Key features are described, including the mission statement, organizational structure, committee system, governance, GME programs, operations, and budget.


Depicted serving size: cereal packaging pictures exaggerate serving sizes and promote overserving.
Extensive work has focused on the effects of nutrition label information on consumer behavior on the one hand, and on the effects of packaging graphics on the other hand. However, little work has examined how serving suggestion depictions - graphics relating to serving size - influence the quantity consumers serve themselves. The current work examines the prevalence of exaggerated serving size depictions on product packaging (study 1) and its effects on food serving in the context of cereal (study 2). Study 1 was an observational field survey of cereal packaging. Study 2 was a mixed experimental cross-sectional design conducted at a U.S. university, with 51 student participants. Study 1 coded 158 US breakfast cereals and compared the serving sizes depicted on the front of the box with the suggested serving size stated on the nutrition facts panel. Study 2 measured the amount of cereal poured from exaggerated or accurate serving size depictions. Study 1 compared average servings via t-tests. Study 2 used a mixed model with cereal type as the repeated measure and a compound symmetry covariance matrix. Study 1 demonstrated that portion size depictions on the front of 158 cereal boxes were 65.84% larger (221 vs. 134 calories) than the recommended portions on nutrition facts panels of those cereals. Study 2 showed that boxes that depicted exaggerated serving sizes led people to pour 20% more cereal compared to pouring from modified boxes that depicted a single-size portion of cereal matching suggested serving size. This was 45% over the suggested serving size. Biases in depicted serving size depicted on cereal packaging are prevalent in the marketplace. Such biases may lead to overserving, which may consequently lead to overeating. Companies should depict the recommended serving sizes, or otherwise indicate that the depicted portion represents an exaggerated serving size.


The geography of happiness: connecting twitter sentiment and expression, demographics, and objective characteristics of place.
We conduct a detailed investigation of correlations between real-time expressions of individuals made across the United States and a wide range of emotional, geographic, demographic, and health characteristics. We do so by combining (1) a massive, geo-tagged data set comprising over 80 million words generated in 2011 on the social network service Twitter and (2) annually-surveyed characteristics of all 50 states and close to 400 urban populations. Among many results, we generate taxonomies of states and cities based on their similarities in word use; estimate the happiness levels of states and cities; correlate highly-resolved demographic characteristics with happiness levels; and connect word choice and message length with urban characteristics such as education levels and obesity rates. Our results show how social media may potentially be used to estimate real-time levels and changes in population-scale measures such as obesity rates.


Liver Transplantation Trends and Outcomes for Hereditary Hemorrhagic Telangiectasia in the United States.
Liver arteriovenous malformations (AVM) in hereditary hemorrhagic telangiectasia (HHT) can necessitate liver transplantation. There is limited data on HHT patients undergoing liver transplantation (LT) in the United States. Two sources of data were used: (1) Scientific Registry of Transplant Recipients (SRTR) database (1998-2016) (2) Single center liver transplant database (Mayo Clinic Rochester, MN). The aims of this study were (1) to determine trends in LT for HHT-related liver involvement in the United States using the SRTR database; (2) to identify clinical characteristics, indications, and outcomes for LT in HHT. Thirty-nine HHT patients were listed for LT in the SRTR database from 1998-2016 to 1998-2001 (n = 1); 2002-2005 (n = 4); 2006-2010 (n = 10), and 2011-2016 (n = 24). Twenty-four underwent LT at a median age of 47.5 years (interquartile range, 37.0-58.5 years). Median calculated MELD score at time of LT was 8.0 (interquartile range, 7.0-9.5), and 75% received an exception MELD score. Two status-1 patients died during transplant surgery. Nineteen (86%) patients were alive after a median post-LT follow-up of 48 months, whereas 2 patients were lost to follow-up. Five of the aforementioned HHT patients underwent LT at Mayo Clinic, 4 with high output cardiac failure, and 1 with biliary ischemia. All 5 were alive at the time of last follow-up with good graft function and resolution of heart failure. Outcomes after LT for HHT patients are excellent with 86% survival after a median follow-up of 48 months and resolution of heart failure. LT listing for HHT has increased in substantially in more recent eras.


The mitochondrial division inhibitor Mdivi-1 rescues mammalian neurons from anesthetic-induced cytotoxicity.
Concerns have risen regarding the potential side effects of clinical exposure of the pediatric population to inhalational anesthetics, and how they might impact cognitive, learning, and memory functions. However, neither the mechanisms of anesthetic cytotoxicity, nor potential protective strategies, have yet been fully explored. In this study, we examined whether two of the most commonly used inhalational anesthetics, sevoflurane and desflurane, affect neuronal viability and synaptic network assembly between cultured rat cortical neurons. Primary rat cortical neuron cultures were exposed to equipotent sevoflurane or desflurane for 1 hour. Neuron viability, synaptic protein expression, mitochondrial morphology, and neurite growth were assayed with immunostaining and confocal microscopy techniques. The effects of anesthetics on the functional development of neural networks were evaluated with whole-cell patch clamp recordings of spontaneous synaptic currents. Our results demonstrate that an acute exposure to sevoflurane and desflurane inhibits the development of neurite processes, impacts the mitochondria, and compromises synaptic proteins - concomitant with a reduction in synaptic function in mature networks. Interestingly, pretreatment of neurons with a mitochondrial division inhibitor (Mdivi-1) not only protected mitochondria integrity but also played a protective role against anesthetic-induced structural and functional neurotoxicity. We show that Mdivi-1 likely plays a protective role against certain harmful effects of general anesthetics on primary rat neuronal cultures. In addition, Mdivi-1 alone plays a direct role in enhancing growth and modulating synaptic activity. This study highlights the importance of further study into possible protective agents against anesthetic neurotoxicity.


Underlying mechanisms of the synergistic role of Li2MnO3 and LiNi1/3Co1/3Mn1/3O2 in high-Mn, Li-rich oxides.
For large-scale energy storage applications requiring high energy density, the development of Li-rich oxides with enhanced cyclic stabilities during high-voltage operations and large specific capacities is required. In this regard, high-Mn, Li-rich oxides (HMLOs; xLi2MnO3 (1 - x)LiNi1/3Co1/3Mn1/3O2 at x > 0.5) warrant an in-depth study because of their good cyclic performance at high operating voltages and potentially large specific capacities. Here, to understand the synergistic effects and enhanced cyclic stability of HMLOs, mechanically blended HMLO (m-HMLO) and chemically bonded HMLO (c-HMLO) were prepared and investigated. c-HMLO exhibits relatively high reaction voltages, large specific capacities, and enhanced cyclic stabilities (∼99%) at a high operating voltage (∼4.8 V vs. Li/Li(+)) compared with m-HMLO. First-principles calculations with electronic structure analysis were performed using an atomic model developed by Rietveld refinement using as-synthesised c-HMLO. The redox mechanisms of Ni, Co, and Mn ions were determined via the partial density of states of the ground states predicted using the cluster expansion method, which elucidates that LiNi1/3Co1/3Mn1/3O2 stabilises the transition metal (TM) layer of Li2MnO3 and separates Li delithiation potentials in Li2MnO3 in the HMLO. Kinetic analyses including electronic structures revealed that the interlayer migration of TMs from the TM layer to the Li layer depends on the crystal field stabilisation. Thus, TMs with reduced character in the tetrahedral sites than the octahedral sites owing to the effects of crystal field stabilisation, such as Ni ions, in HMLOs would face a higher interlayer migration barrier, impeding phase transformation into spinel phases. Furthermore, Cu ions could constitute a doping source for HMLOs to improve the material's cyclic stability through this mechanism. These characteristics may be widely applied to explain experimental phenomena and improve the properties of cathode materials for Li-ion batteries.


Australian children's perceptions of discretionary foods.
Energy-dense nutrient poor foods and drinks, often referred to as discretionary choices, can contribute a significant amount of energy, fat, sodium and sugar to the diet if consumed in large quantities. Currently many Australian children are consuming a diet that is characterised by large quantities of discretionary items. We undertook a qualitative study to gain a descriptive account of preadolescent children's attitudes and perceptions towards health and nutrition. A series of 6 focus groups and 14 individual semi-structured interviews were conducted with thirty-eight children aged 11-12 years, across three state government schools in a socially disadvantaged region of metropolitan South Australia. The naturalistic manner of qualitative inquiry led to several unintended yet highly pertinent emergent themes, including children's perceptions and practices surrounding discretionary food consumption. Our results indicate that while Australian guidelines recommend that discretionary foods are consumed 'only sometimes and in small amounts', children generally held a different belief with respect to what constituted 'sometimes'. Many children identified that discretionary foods should be consumed in moderation to maintain a balanced diet, yet reported consuming these foods frequently. Self-reported discretionary food consumption was grounded in socially constructed experiences valued by the children, who made situational attributions to foods and legitimised discretionary food consumption in certain contexts, for example during the weekend. Overall, there is variability between children's opinions about the acceptable frequency of consumption of discretionary foods compared with national guidelines.


Sequence analysis and functional characterization of the promoter of the Picea glauca Cinnamyl Alcohol Dehydrogenase gene in transgenic white spruce plants.
The enzyme Cinnamyl Alcohol Dehydrogenase (CAD) catalyses the last step of lignin monomer synthesis, and is considered as a molecular marker of cell wall lignification in different plants species. Here, we report the isolation and analysis of 5' flanking genomic DNA regions upstream to the CAD gene, from two conifers, i.e. white spruce (Picea glauca (Moench) Voss) and loblolly pine (Pinus taeda L.). Sequence comparisons with available CAD gene promoters from angiosperms highlighted the conservation of cis-elements matching MYB, WRKY and bHLH binding sites. Functional characterization of the P. glauca CAD promoter used P. glauca seedlings stably transformed with a DNA fragment of 1,163 base pairs (PgCAD) fused to the beta-glucuronidase (GUS) gene. Histochemical observations of different vegetative organs of the transgenic trees showed that this sequence was sufficient to drive GUS expression in lignifying tissues, and more specifically in differentiating xylem cells. Quantitative RT-PCR experiments also indicated that the native CAD gene was preferentially expressed in differentiating xylem both in stems and roots. In addition, GUS expression driven by the PgCAD promoter was wound-inducible which was consistent with the accumulation of CAD mRNA in response to jasmonate application and mechanical wounding. The spruce CAD promoter represents a valuable tool for research and biotechnology applications related to xylem and wood.


Issues in performing a network meta-analysis.
The example of the analysis of a collection of trials in diabetes consisting of a sparsely connected network of 10 treatments is used to make some points about approaches to analysis. In particular various graphical and tabular presentations, both of the network and of the results are provided and the connection to the literature of incomplete blocks is made. It is clear from this example that is inappropriate to treat the main effect of trial as random and the implications of this for analysis are discussed. It is also argued that the generalisation from a classic random-effect meta-analysis to one applied to a network usually involves strong assumptions about the variance components involved. Despite this, it is concluded that such an analysis can be a useful way of exploring a set of trials.


The relationship between RTS,S vaccine-induced antibodies, CD4⁺ T cell responses and protection against Plasmodium falciparum infection.
Vaccination with the pre-erythrocytic malaria vaccine RTS,S induces high levels of antibodies and CD4(+) T cells specific for the circumsporozoite protein (CSP). Using a biologically-motivated mathematical model of sporozoite infection fitted to data from malaria-naive adults vaccinated with RTS,S and subjected to experimental P. falciparum challenge, we characterised the relationship between antibodies, CD4(+) T cell responses and protection from infection. Both anti-CSP antibody titres and CSP-specific CD4(+) T cells were identified as immunological surrogates of protection, with RTS,S induced anti-CSP antibodies estimated to prevent 32% (95% confidence interval (CI) 24%-41%) of infections. The addition of RTS,S-induced CSP-specific CD4(+) T cells was estimated to increase vaccine efficacy against infection to 40% (95% CI, 34%-48%). This protective efficacy is estimated to result from a 96.1% (95% CI, 93.4%-97.8%) reduction in the liver-to-blood parasite inoculum, indicating that in volunteers who developed P. falciparum infection, a small number of parasites (often the progeny of a single surviving sporozoite) are responsible for breakthrough blood-stage infections.


Chronic subdural hematomas treated by burr hole trepanation and a subperiostal drainage system.
Most symptomatic chronic subdural hematomas are treated by subdural drainage. However, a subperiostal (i.e., extracranial) passive closed-drainage system in combination with double burr hole trepanation is used at our institution. Therefore, we wanted to analyze our results and compare them with the alternate treatment strategies reported in the current literature. In a retrospective single-center study, we analyzed the data of all patients undergoing double burr hole trepanation with a subperiostal passive closed-drainage system. Data analysis included general patient data, complications, postoperative seizure rate, and outcome. One hundred forty-seven patients underwent surgery for 183 symptomatic chronic subdural hematomas. The perioperative mortality rate was 3.4%. Hematoma persistence or recurrence occurred in 13.1% of the cases. The postoperative seizure rate was 6.6%, and the infection rate was 1.6%, including 3 cases of superficial wound infection and 1 case with deep infection. The reintervention rate was 9.3%, including trepanation in 8.2% of the patients and craniotomy in 1.1%. The overall complication rate was 10.9%. Double burr hole trepanation combined with a subperiostal passive closed-drainage system is a technically easy, highly effective, safe, and cost-efficient treatment strategy for symptomatic chronic subdural hematomas. The absence of a drain in direct contact with the hematoma capsule may moderate the risk of postoperative seizure and limit the secondary spread of infection to intracranial compartments.


Epidemiology and risk of invasive fungal infections in systemic lupus erythematosus: a nationwide population-based cohort study.
Infections are a leading cause of mortality in patients with systemic lupus erythematosus (SLE). Among various infections, invasive fungal infections (IFIs) have a particularly high mortality rate; however, studies examining IFIs in patients with SLE are limited. Patients diagnosed as having SLE between 1997 and 2012 were enrolled from Taiwan's National Health Insurance Research Database along with age- and sex-matched non-SLE controls at a ratio of 1:10. IFIs were identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes and validated by the prescriptions of systemic antifungal agents. The incidence rate (IR), incidence rate ratio (IRR), and all-cause mortality rate of IFIs and its subtypes were analyzed. A Cox multivariate regression model with time-dependent covariates was applied to analyze independent risk factors for IFIs. A total of 24,541 patients with SLE and 245,410 non-SLE controls were included. We observed 445 IFI episodes in the SLE cohort, with an all-cause mortality rate of 26.7%. Candida spp. (52.8%) was the most common pathogen, followed by Cryptococcus spp. (18.2%) and Aspergillus spp. (18.2%). The IR of IFIs in the SLE cohort was 20.83 per 10,000 person-years, with an IRR of 11.1 [95% confidence interval (CI): 9.8-12.6] relative to the non-SLE controls. Juvenile patients with SLE aged ⩽18 years had the highest IRR of 47.2 (95% CI: 26.9-86.8). Intravenous steroid therapy administered within 60 days (hazard ratio: 29.11, 95% CI: 23.30-36.37) was the most critical risk factor for overall IFIs and each of the three major fungal pathogens. Distinct risk factors were found among different IFI subtypes. Patients with SLE had a higher risk of IFIs, especially juvenile patients. Intravenous steroid therapy is the most critical risk factor for IFIs. This study provides crucial information for the risk stratification of IFIs in SLE. Patients with systemic lupus erythematosus and physicians treating this patient group should be aware of the risk of invasive fungal infections.Invasive fungal infections (IFIs) are a severe complication with a high mortality rate among patients with systemic lupus erythematosus (SLE); however, studies on this topic are scant. We performed a nationwide population-based study in Taiwan to estimate the incidence and mortality of and risk factors for IFIs. We found an incidence rate of 20.83 per 10,000 person-years for IFIs, with a mortality rate of 26.7%. Juvenile patients aged ⩽18 years had the highest relative risk of IFIs. Although candidiasis was the most common IFI, cryptococcosis and aspergillosis should be concerned in juvenile patients as well. Intravenous steroid therapy was the most critical risk factor for all IFIs, and different immunosuppressive agents posed different risks in patients for acquiring certain fungal pathogens.Our findings provide pivotal epidemiological information and indicate risk factors for IFIs in patients with SLE. Age and exposure to specific immunosuppressants and steroids might help predict the risk of IFIs. Because the manifestation of these infections is sometimes indistinguishable from a lupus flare, physicians should be aware of this fatal complication, especially when patients are not responsive to immunosuppressive therapy. Early recognition, implication of diagnostic tools, and empirical antimicrobial agents can be the key to treating patients with IFIs. Additional studies are required to develop a risk management program for patients with SLE.


Embryonic stem cells overexpressing Pitx2c engraft in infarcted myocardium and improve cardiac function.
This study investigated the effects on cardiomyocyte differentiation of embryonic stem cells by the overexpression of the transcription factor, Pitx2c, and examined the effects of transplantation of these differentiated cells on cardiac function in a mouse model of myocardial infarction. Pitx2c overexpressing embryonic stem cells were characterized for cardiac differentiation by immunocytochemistry, RNA analysis, and electrophysiology. Differentiated cells were transplanted by directed injection into the infarcted murine myocardium and functional measurements of blood pressure, contractility, and relaxation were performed. Histochemistry and FISH analysis performed on these mice confirmed the engraftment and cardiac nature of the transplanted cells. Pitx2c overexpressing embryonic stem cells robustly differentiated into spontaneously contracting cells which acquired cardiac protein markers and exhibited action potentials resembling that of cardiomyocytes. These cells could also be synchronized to an external pacemaker. Significant improvements (P < 0.01) in blood pressure (56%), contractility (57%), and relaxation (59%) were observed in infarcted mice with transplants of these differentiated cells but not in mice which were transplanted with control cells. The Pitx2c overexpressing cells secrete paracrine factors which when adsorbed onto a heparinated gel and injected into the infarcted myocardium produce a comparable and significant (P < 0.01) functional recovery. Pitx2c overexpression is a valuable method for producing cardiomyocytes from embryonic stem cells, and transplantation of these cardiomyocytes into infracted myocardium restores cardiac function through multiple mechanisms.


Sex differences in cannabinoid pharmacology: a reflection of differences in the endocannabinoid system?
Marijuana is the most widely used illicit drug in the U.S., and marijuana use by women is on the rise. Women have been found to be more susceptible to the development of cannabinoid abuse and dependence, have more severe withdrawal symptoms, and are more likely to relapse than men. The majority of research in humans suggests that women are more likely to be affected by cannabinoids than men, with reports of enhanced and decreased performance on various tasks. In rodents, females are more sensitive than males to effects of cannabinoids on tests of antinociception, motor activity, and reinforcing efficacy. Studies on effects of cannabinoid exposure during adolescence in both humans and rodents suggest that female adolescents are more likely than male adolescents to be deleteriously affected by cannabinoids. Sex differences in response to cannabinoids appear to be due to activational and perhaps organizational effects of gonadal hormones, with estradiol identified as the hormone that contributes most to the sexually dimorphic effects of cannabinoids in adults. Many, but not all sexually dimorphic effects of exogenous cannabinoids can be attributed to a sexually dimorphic endocannabinoid system in rodents, although the same has not yet been established firmly for humans. A greater understanding of the mechanisms underlying sexually dimorphic effects of cannabinoids will facilitate development of sex-specific approaches to treat marijuana dependence and to use cannabinoid-based medications therapeutically.


Non-oxidative hair dye products on the European market: What do they contain?
Hair dyeing is very common and may cause allergic contact dermatitis. Oxidative (often termed permanent or semi-permanent) hair dye products have constituted the focus of market surveys and toxicological risk assessments, while non-oxidative (semi-permanent, temporary or direct) products have not been assessed. To identify the hair dye substances presently used in non-oxidative hair dye products in Europe. Ingredient label data on eligible products in 5 European countries were collected, and 289 different non-oxidative hair dye products were included in this study. Up to 9 hair dye substances were present in each product. Sixty-eight individual hair dye substances were identified on the 289 product labels, and their occurrence ranged from 0.3% to 34%. There were differences concerning substances used and their number per product between products of different consistency and colour. The hair dye substances in non-oxidative hair dye products are different from those in oxidative hair dye products, and are currently not covered by patch test series. The toxicological and skin-sensitizing profile of the substances in non-oxidative hair dye products, as well as their concentrations, should be further investigated.


Utilisation of fatty acid and triacylglycerol by rat macrophages: the effect of endotoxin.
Plasma very-low-density lipoprotein (VLDL) concentrations are increased during sepsis/endotoxaemia and VLDL may be substrates for the activated immune system. Lipid substrate utilisation by quiescent and activated macrophages was therefore examined. Rat R2 macrophages were incubated with oleate or rat VLDL, with or without lipopolysaccharide (LPS) stimulation. The metabolic fate of the lipids was examined. Macrophages utilised both oleate and (control) VLDL-triacylglycerol (TAG) to a similar extent. Most was deposited as cellular lipid; about 10% of oleate was oxidised compared to 25% of cVLDL-TAG. LPS significantly increased oleate oxidation and its deposition as cellular lipid (mostly as TAG) at 48hrs but abolished both oxidation and storage of VLDL-TAG. VLDL produced during endotoxaemia (eVLDL) was assimilated by the unstimulated macrophage to a greater extent than oleate or cVLDL-TAG and selectively stored as cellular lipids (no oxidation); LPS decreased eVLDL utilisation. VLDL-TAG utilisation was decreased by the lipoprotein lipase (LPL) inhibitor terahydrolipstatin. LPL activity was greater in oleate than in VLDL incubations, but was increased by incubation with eVLDL. LPS had no effect (oleate, cVLDL) or increased (eVLDL) LPL activity. VLDL represented an efficient substrate for the macrophage. However under conditions of sepsis/endotoxaemia eVLDL utilisation was limited and directed away from oxidation, suggesting that the increased plasma TAG (eVLDL) concentrations resulting from sepsis is not a respiratory fuel for the macrophage but may supply cellular lipid.


Somatostatin in renal physiology and autosomal dominant polycystic kidney disease.
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation, leading to growth in kidney volume and renal function decline. Although therapies have emerged, there is still an important unmet need for slowing the rate of disease progression in ADPKD. High intracellular levels of adenosine 3',5'-cyclic monophosphate (cAMP) are involved in cell proliferation and fluid secretion, resulting in cyst formation. Somatostatin (SST), a hormone that is involved in many cell processes, has the ability to inhibit intracellular cAMP production. However, SST itself has limited therapeutic potential since it is rapidly eliminated in vivo. Therefore analogues have been synthesized, which have a longer half-life and may be promising agents in the treatment of ADPKD. This review provides an overview of the complex physiological effects of SST, in particular renal, and the potential therapeutic role of SST analogues in ADPKD.


Incidence and characteristics of fall-related emergency department visits.
Unintentional falls are the leading cause of injury and the second most common cause of unintentional injury deaths in the United States, and place a great burden on EDs. In this study, the objective was to describe the incidence and characteristics of ED visits associated with unintentional falls in the United States. The authors performed a secondary analysis on data from the National Center for Health Statistics' National Hospital Ambulatory Medical Care Survey for 1992-1994. An ED visit was defined as fall-related if an ICD-9-CM cause of injury code was reported as E880.0-886.9 or E888. There were an estimated 7,946,000 fall-related ED visits per year, corresponding to an annual rate of 3.1 per 100 persons (95% CI=2.8 to 3.4). Children under 5 years of age comprised the largest proportion of visits (14%). Among those visits coded with respect to place of occurrence, the rate of visits associated with falls occurring at home (1.7/100; 95% CI=1.6 to 1.9) was significantly higher than that associated with falls occurring in all other locations combined (1.1/100; 95% CI=1.0 to 1.2). The mean injury severity score increased significantly with the age of the patient. Fall-related ED visits resulted in an estimated 860,000 hospitalizations, 62% of which involved individuals aged 65 years and older. An estimated $2.45 billion per year was paid for fall-related ED visits. Government sources paid all or part of 41% of visits. This study reports nationally representative data describing the incidence and characteristics of fall-related ED visits. These data expand what is known about the epidemiology of falls and help to define the burden that fall injuries place on EDs in the United States. The results of this study could serve as a benchmark to evaluate the effectiveness of future fall prevention efforts.


Interim outcomes of dorsal skin graft bulbar urethroplasty.
We update our interim results of bulbar urethroplasty using a skin graft placed on the dorsal urethral surface. A total of 45 patients with an average age of 45 years underwent dorsal onlay skin graft urethroplasty between January 1994 and December 2000. Of the patients 23 had undergone an average of 2.6 prior endoscopic procedures (range 1 to 14). Preoperative evaluation include clinical history, physical examination, retrograde and voiding urethrography, and ultrasonography. In all patients the bulbar urethra was opened along its dorsal surface, the graft was sutured, splayed and quilted to the corpora cavernosa, and the urethra was rotated to cover the graft. In all patients was used penile skin as substitution material. Mean graft length was 4.7 cm (range 2.5 to 11). Three weeks after surgery voiding cystourethrography was performed. Average followup was 71 months (range 41 to 110). Clinical outcome was considered a failure when postoperative instrumentation was needed, including dilation. Of 45 cases 33 (73%) were classified as successful and 12 (27%) were failures. The 12 failures were treated with internal urethrotomy (1), end-to-end-anastomosis (1), skin graft urethroplasty (2) and 2-stage urethroplasty (6). Six of the 12 initial failures had a satisfactory final outcome. The remaining 6 patients refused further surgical procedures and received a definitive perineal urethrostomy. Penile skin grafts used as a dorsal onlay for bulbar urethral reconstruction in a homogeneous series of patients showed a tendency to deteriorate with time. Longer followup is required to compare penile skin with buccal mucosa as substitute materials for bulbar urethral reconstruction.


Pediatric neuraxial blockade.
Regional anesthetic techniques for children have recently enjoyed a justified resurgence in popularity. Intraoperative blockade of the neuraxis, whether by the spinal or epidural route, provides excellent analgesia with minimal physiologic alteration and, with an indwelling catheter, can provide continuous pain relief for many days postoperatively. As a supplement to general anesthesia, local anesthetic blockade of the neuraxis decreases the total amount of general anesthetic required for surgery, hastens emergence, and allows for a better postoperative experience by providing a pain-free emergence from general anesthesia. Although some practitioners contend that a regional block on an already anesthetized child adds to the risk of the general anesthetic itself, in experienced hands the risks are negligible and the benefits dramatic. In this review of caudal and lumbar epidural and subarachnoid blockade in infants and children, anatomy, physiologic alterations, and pharmacology pertinent to the three types of neuraxial blockade are described, with the aim of providing the practicing anesthesiologist with the foundation needed to perform these blocks with relative confidence.


Caffeine-Induced Effects on Human Skeletal Muscle Contraction Time and Maximal Displacement Measured by Tensiomyography.
Studies on muscle activation time in sport after caffeine supplementation confirmed the effectiveness of caffeine. The novel approach was to determine whether a dose of 9 mg/kg/ body mass (b.m.) of caffeine affects the changes of contraction time and the displacement of electrically stimulated muscle (gastrocnemius medialis) in professional athletes who regularly consume products rich in caffeine and do not comply with the caffeine discontinuation period requirements. The study included 40 professional male handball players (age = 23.13 ± 3.51, b.m. = 93.51 ± 15.70 kg, height 191 ± 7.72, BMI = 25.89 ± 3.10). The analysis showed that in the experimental group the values of examined parameters were significantly reduced (p ≤ 0.001) (contraction time: before = 20.60 ± 2.58 ms/ after = 18.43 ± 3.05 ms; maximal displacement: before = 2.32 ± 0.80 mm/after = 1.69 ± 0.51 mm). No significant changes were found in the placebo group. The main achievement of this research was to demonstrate that caffeine at a dose of 9 mg/kg in professional athletes who regularly consume products rich in caffeine has a direct positive effect on the mechanical activity of skeletal muscle stimulated by an electric pulse.


CD8+ cytotoxic lymphocyte responses against cytomegalovirus after liver transplantation: correlation with time from transplant to receipt of tacrolimus.
The effects of the immunocompromised state after liver transplantation on the frequency of cytomegalovirus-specific cytotoxic T lymphocytes (CTL) were investigated in 93 patients by using HLA class I tetrameric complexes corresponding to HLA-A*0201, HLA-B*0702, HLA-B*0801, and HLA-B*3501 refolded with peptides from the ppUL83 matrix protein. ppUL83 CTL frequencies were suppressed during the first 6 months after transplantation. Patients with >1 HLA-restricted response detected had high correlation among ppUL83 CD8(+) CTL frequencies restricted by different HLA haplotypes (Spearman's rho=.67; P<.0001). There was an inverse correlation among levels of the calcineurin inhibitor, tacrolimus, and ppUL83 CD8(+) CTL frequencies (r=-.31; P=.005), which is consistent with the presence of a large proportion (70%) of activated (CD38(+)) ppUL83 CD8(+) CTL within the population of HLA class I tetramer-positive cells.


Food: The Main Course to Wellness and Illness in Patients With Irritable Bowel Syndrome.
Food sits at the intersection between gastrointestinal (GI) physiology and symptoms in patients with the irritable bowel syndrome (IBS). It is now clear that the majority of IBS sufferers associate eating a meal with their GI and non-GI symptoms. This is hardly surprising when one considers that food can affect a variety of physiologic factors (motility, visceral sensation, brain-gut interactions, microbiome, permeability, immune activation, and neuro-endocrine function) relevant to the pathogenesis of IBS. In recent years, clinical research has increasingly focused on diet as a treatment for IBS. There is a relative paucity of data from rigorous, randomized, controlled trials for any dietary intervention in IBS patients. Currently, the largest body of literature has addressed the efficacy of dietary restriction of fermentable oligo, di, monosaccharides, and polyols (FODMAPs). In the future, dietary treatments for IBS will move beyond the current focus on elimination to embrace supplementation with "functional" foods.


Coalescent: an open-source and scalable framework for exact calculations in coalescent theory.
Currently, there is no open-source, cross-platform and scalable framework for coalescent analysis in population genetics. There is no scalable GUI based user application either. Such a framework and application would not only drive the creation of more complex and realistic models but also make them truly accessible. As a first attempt, we built a framework and user application for the domain of exact calculations in coalescent analysis. The framework provides an API with the concepts of model, data, statistic, phylogeny, gene tree and recursion. Infinite-alleles and infinite-sites models are considered. It defines pluggable computations such as counting and listing all the ancestral configurations and genealogies and computing the exact probability of data. It can visualize a gene tree, trace and visualize the internals of the recursion algorithm for further improvement and attach dynamically a number of output processors. The user application defines jobs in a plug-in like manner so that they can be activated, deactivated, installed or uninstalled on demand. Multiple jobs can be run and their inputs edited. Job inputs are persisted across restarts and running jobs can be cancelled where applicable. Coalescent theory plays an increasingly important role in analysing molecular population genetic data. Models involved are mathematically difficult and computationally challenging. An open-source, scalable framework that lets users immediately take advantage of the progress made by others will enable exploration of yet more difficult and realistic models. As models become more complex and mathematically less tractable, the need for an integrated computational approach is obvious. Object oriented designs, though has upfront costs, are practical now and can provide such an integrated approach.


Hypothalamic Paraventricular and Arcuate Nuclei Contribute to Elevated Sympathetic Nerve Activity in Pregnant Rats: Roles of Neuropeptide Y and α-Melanocyte-Stimulating Hormone.
Pregnancy increases sympathetic nerve activity (SNA), but the mechanisms are unknown. Here, we investigated the contributions of the hypothalamic paraventricular and arcuate nuclei in α-chloralose-anesthetized pregnant and nonpregnant rats. Baseline arterial pressure (AP) was lower, and heart rate (HR), lumbar sympathetic activity, and splanchnic SNA were higher in pregnant rats compared with nonpregnant rats. Inhibition of the paraventricular nucleus via bilateral muscimol nanoinjections decreased AP and HR more in pregnant rats than in nonpregnant rats and decreased lumbar SNA only in pregnant rats. Similarly, after arcuate muscimol nanoninjections, the decreases in AP, HR, and lumbar, renal, and splanchnic sympathetic nerve activities were greater in pregnant rats than in nonpregnant rats. Major arcuate neuronal groups that project to the paraventricular nucleus express inhibitory neuropeptide Y (NPY) and excitatory α-melanocyte-stimulating hormone. Inhibition of paraventricular melanocortin 3/4 receptors with SHU9119 also decreased AP, HR, and lumbar SNA in pregnant rats but not in nonpregnant rats. Conversely, paraventricular nucleus NPY expression was reduced in pregnant animals, and although blockade of paraventricular NPY Y1 receptors increased AP, HR, and lumbar sympathetic activity in nonpregnant rats, it had no effects in pregnant rats. Yet, the sympathoinhibitory, depressor, and bradycardic effects of paraventricular NPY nanoinjections were similar between groups. In conclusion, the paraventricular and arcuate nuclei contribute to increased basal SNA during pregnancy, likely due in part to decreased tonic NPY inhibition and increased tonic α-melanocyte-stimulating hormone excitation of presympathetic neurons in the paraventricular nucleus.


Identification and remediation of biases in the activity of RNA ligases in small-RNA deep sequencing.
Deep sequencing of small RNAs (sRNA-seq) is now the gold standard for small RNA profiling and discovery. Biases in sRNA-seq have been reported, but their etiology remains unidentified. Through a comprehensive series of sRNA-seq experiments, we establish that the predominant cause of the bias is the RNA ligases. We further demonstrate that RNA ligases have strong sequence-specific biases which distort the small RNA profiles considerably. We have devised a pooled adapter strategy to overcome this bias, and validated the method through data derived from microarray and qPCR. In light of our findings, published small RNA profiles, as well as barcoding strategies using adapter-end modifications, may need to be revisited. Importantly, by providing a wide spectrum of substrate for the ligase, the pooled-adapter strategy developed here provides a means to overcome issues of bias, and generate more accurate small RNA profiles.


Application of the BioMek 2000 Laboratory Automation Workstation and the DNA IQ System to the extraction of forensic casework samples.
Robotic systems are commonly utilized for the extraction of database samples. However, the application of robotic extraction to forensic casework samples is a more daunting task. Such a system must be versatile enough to accommodate a wide range of samples that may contain greatly varying amounts of DNA, but it must also pose no more risk of contamination than the manual DNA extraction methods. This study demonstrates that the BioMek 2000 Laboratory Automation Workstation, used in combination with the DNA IQ System, is versatile enough to accommodate the wide range of samples typically encountered by a crime laboratory. The use of a silica coated paramagnetic resin, as with the DNA IQ System, facilitates the adaptation of an open well, hands off, robotic system to the extraction of casework samples since no filtration or centrifugation steps are needed. Moreover, the DNA remains tightly coupled to the silica coated paramagnetic resin for the entire process until the elution step. A short pre-extraction incubation step is necessary prior to loading samples onto the robot and it is at this step that most modifications are made to accommodate the different sample types and substrates commonly encountered with forensic evidentiary samples. Sexual assault (mixed stain) samples, cigarette butts, blood stains, buccal swabs, and various tissue samples were successfully extracted with the BioMek 2000 Laboratory Automation Workstation and the DNA IQ System, with no evidence of contamination throughout the extensive validation studies reported here.


Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35.
To determine whether an ultrasensitive assay can permit quantification of changes in circulating cardiac troponin (Tn) in the setting of stress test-induced myocardial ischaemia. Blood samples were obtained before, immediately after, and 2 and 4 h after stress testing with nuclear perfusion imaging in 120 patients. Troponin was measured using commercial assays as well as with a novel, ultrasensitive cardiac TnI assay with a limit of detection of 0.2 pg/mL. Using the ultrasensitive assay, TnI was detectable in all patients before stress testing (median 4.4 pg/mL, interquartile range 3.1-8.6 pg/mL). By 4 h, troponin levels were unchanged in patients without ischaemia, whereas circulating levels had increased by a median of 1.4 pg/mL (24% increase) in patients with mild ischaemia (P = 0.002) and by 2.1 pg/mL (40% increase) in patients with moderate-to-severe ischaemia (P = 0.0006). In contrast, changes in troponin levels across patients in different ischaemic categories were indistinguishable using commercial troponin assays. When added to clinical factors, a >1.3 pg/mL increase in TnI using the ultrasensitive assay was an independent predictor of ischaemia (odds ratio 3.54, P = 0.007). Transient stress test-induced myocardial ischaemia is associated with a quantifiable increase in circulating troponin that is detectable with a novel, ultrasensitive TnI assay.


Measuring the subjective: revisiting the psychometric properties of three rating scales that assess the acute effects of hallucinogens.
In the present study we explored the psychometric properties of three widely used questionnaires to assess the subjective effects of hallucinogens: the Hallucinogen Rating Scale (HRS), the Mystical Experience Questionnaire (MEQ), and the Addiction Research Center Inventory (ARCI). These three questionnaires were administered to a sample of 158 subjects (100 men) after taking ayahuasca, a hallucinogen whose main active component is N,N-dimethyltryptamine (DMT). A confirmatory factorial study was conducted to check the adjustment of previous data obtained via theoretical proposals. When this was not possible, we used an exploratory factor analysis without restrictions, based on tetrachoric and polychoric matrices and correlations. Our results sparsely match the theoretical proposals of the authors, perhaps because previous studies have not always employed psychometric methods appropriate to the data obtained. However, these data should be considered preliminary, pending larger samples to confirm or reject the proposed structures obtained. It is crucial that instruments of sufficiently precise measurement are utilized to make sense of the information obtained in the study of the subjective effects of psychedelic drugs. Copyright © 2016 John Wiley & Sons, Ltd.


Efficacy of holmium laser enucleation of the prostate (HoLEP) in men with bladder outlet obstruction (BOO) and non-neurogenic bladder dysfunction.
We aimed to compare the short-term outcomes of men who had urodynamic evidence of detrusor underactivity (DU) or detrusor overactivity (DO) of a non-neurogenic etiology as well as bladder outlet obstruction (BOO) and who underwent Holmium Laser Enucleation of the prostate (HoLEP). A database of 322 patients who underwent HoLEP between 2010 and 2014 was analyzed. Patients were classified into three groups according to the results of a preoperative urodynamic study. Preoperative parameters such as International Prostate Symptom Score (IPSS), Quality of Life (QoL) index, IPSS grade, uroflowmetry were compared with postoperative parameters measured at 6 months. There were 138 patients with BOO-only and 89 patients with BOO and detrusor dysfunction including 56 with DO and 33 with DU. The degree of improvement in IPSS-total (BOO: 10.7, DO: 8.3, DU: 7.0; p = 0.023) was greater in the BOO-only group than in the DU group. There were more patients whose IPSS grade improved in the BOO-only group (71%) than in the detrusor dysfunction group (DO: 53.6% and DU: 45.5%). Postoperative IPSS-voiding (4.5 vs 7.0), and Qmax (18 vs 13.7) in the BOO-only group were significantly better than those in the DU group. Additionally, postoperative IPSS-storage (4.7 vs 6.7), and IPSS-total (9.1 vs 12.3) in the BOO-only group were significantly better than in the DO group (all p < 0.05). In conclusion, early surgical management for men with severe LUTS and associated BPH before secondary degeneration occurs may be beneficial for preserving detrusor function and yield better treatment outcomes.


Reconfigurable hardware-software codesign methodology for protein identification.
In this paper we propose an on-the-fly reconfigurable hardware-software codesign based reconfigurable solution for real-time protein identification. Reconfigurable string matching is performed in the disciplines of protein identification and biomarkers discovery. With the generation of plethora of sequenced data and number of biomarkers for several diseases, it is becoming necessary to have an accelerated processing and on-the-fly reconfigurable system design methodology to bring flexibility to its usage in the medical science community without the need of changing the entire hardware every time with the advent of new biomarker or protein. The proteome database of human at UniProtKB (Proteome ID up000005640) comprising of 42132 canonical and isoform proteins with variable database-size are used for testing the proposed design and the performance of the proposed system has been found to compare favorably with the state-of-the-art approaches with the additional advantage of real-time reconfigurability.


Emerging approaches for treatment of schizophrenia: modulation of cholinergic signaling.
Currently available therapeutic agents for treatment of schizophrenia target signaling by monoaminergic neurotransmitters; however, these treatments do not adequately treat the range of symptoms observed in patients. While these therapies treat the positive symptoms, they do not have efficacy in treating the negative symptoms and cognitive deficits that are associated with the disease. Evidence suggests that molecules that modulate signaling by the neurotransmitter acetylcholine (ACh) could provide a more comprehensive treatment of schizophrenia than currently prescribed antipsychotics. Molecules that broadly increase ACh-signaling have been demonstrated to have efficacy in treating numerous symptom clusters in schizophrenia patients. Unfortunately, these compounds induce adverse effects via activation of peripheral receptors that limit their clinical utility. One proposed strategy for retaining the efficacy of cholinergic treatments, without the adverse effects, is to target specific cholinergic receptor subtypes in the brain. Several cholinergic receptors are able to modulate brain circuits that are dysregulated in schizophrenia patients including receptors belonging to both the muscarinic family (i.e., M1, M4, and M5), and the nicotinic family (i.e., α7, α4β2). Recently, great strides have been made in developing small molecules with high specificity for these receptors, and several of these novel molecules have robust efficacy in several preclinical models predictive of both anti-psychotic and pro-cognitive effectiveness. Promising studies suggest that targeting M1 and α7 may be beneficial for pro-cognitive effects, while molecules that target M4 may be ideally suited to address the positive symptoms. Since these receptor subtypes are distinct from those responsible for the adverse effects observed with non-selective cholinergic treatments, there is hope that molecules targeting these receptors could provide novel therapeutics. Further research is needed to examine the utility of such compounds as therapeutics that could be used either alone, or in combination with existing medications, to better treat schizophrenia.


PAX4 has the potential to function as a tumor suppressor in human melanoma.
We hypothesize that dysregulated expression levels of the developmental regulatory genes in the adult body result in tumor development and malignant progression. PAX genes discovered as human orthologous genes of Drosophila 'paired' encode transcription factors, which control the expression of target genes to go on along the program of development. In this study, we first quantified expression of 9 PAX genes in human nevus pigmentosus tissues, melanoma tissues and melanoma cell lines by the real-time reverse transcription-PCR method. As a result, we found that the expression levels of PAX4 and PAX9 were extremely low in melanoma tissues and cell lines compared to nevus pigmentosus tissues. We then established melanoma cells overexpressing PAX4 and examined roles of PAX4 in cell growth. PAX4-overexpression reduced in vitro cell growth of human melanoma C8161 and MeWo cells. BrdU-uptake assay and cell cycle analysis by flow cytometry indicated that the retardation of cell proliferation by PAX4-overexpression was due to decreased DNA synthesis and cell cycle arrest at the G0/G1 phase. Furthermore, treatment of C8161 and MeWo cells with 5-azacytidine, a DNA demethylating agent, induced the expression of PAX4, suggesting that DNA methylation repressed the PAX4 gene expression in human melanoma. These results suggest that PAX4 functions as a potent tumor suppressor.


Soil iron and aluminium concentrations and feet hygiene as possible predictors of Podoconiosis occurrence in Kenya.
Podoconiosis (mossy foot) is a neglected non-filarial elephantiasis considered to be caused by predisposition to cumulative contact of uncovered feet to irritative red clay soil of volcanic origins in the tropical regions. Data from structured observational studies on occurrence of Podoconiosis and related factors are not available in Kenya. To establish the occurrence and aspects associated with Podoconiosis, a cross-sectional survey was implemented in an area located within 30 km from the foot of volcanic Mount Longonot in the Great Rift Valley in Kenya. Five villages and 385 households were selected using multistage and systematic random sampling procedures respectively during the survey. Podoconiosis was determined by triangulating (1) the clinical diagnosis, (2) molecular assaying of sputum samples to rule out Wuchereria bancrofti microfilaria and (3) determining the concentration of six elements and properties in the soil known to be associated with Podoconiosis. A structured questionnaire was used to identify possible risk factors. Univariable and multivariable Poisson regression analyses were carried out to determine factors associated with Podoconiosis. Thirteen participants were clinically positive for Podoconiosis giving an overall prevalence of 3.4%. The prevalence ranged between 0% and 18.8% across the five villages. Molecular assay for W. bancrofti test turned negative in the 13 samples. The following factors were positively associated with the Podoconiosis prevalence (P<0.1) in the univariable analyses: (i) age, (ii) gender, (iii) education level, (iv) frequency of washing legs, (v) frequency of wearing shoes, (vi) soil pH, and (vii) village. Unexpectedly, the concentration of soil minerals previously thought to be associated with Podoconiosis was found to be negatively associated with the Podoconiosis prevalence (P<0.1). In the multivariable analyses, only frequency of wearing shoes and village turned out significant (P≤0.05). By modeling the different soil mineral concentrations and pH while adjusting for the variable frequency of wearing shoes, only iron concentration was significant and in the negative dimension (P≤0.05). However, controlling for Iron, Aluminum concentrations turned significant. This study has pointed to a hitherto unreported occurrence of Podoconiosis cases and has contributed to the baseline knowledge on the occurrence of Podoconiosis in Kenya. Consistent with many studies, wearing shoes remain an important risk factor for the occurrence of the disease. However, our findings are inconsistent with some of the hitherto postulations that associate Podoconiosis prevalence with certain minerals in the soil in other regions in Africa. These findings provide new beginnings for the cross-disciplinary research of Podoconiosis in environmental health, socio-ecology and ecological niche and geo-spatial modeling and prediction.


Production and Characterisation of Stabilised PV-3 Virus-like Particles Using Pichia pastoris.
Following the success of global vaccination programmes using the live-attenuated oral and inactivated poliovirus vaccines (OPV and IPV), wild poliovirus (PV) is now only endemic in Afghanistan and Pakistan. However, the continued use of these vaccines poses potential risks to the eradication of PV. The production of recombinant PV virus-like particles (VLPs), which lack the viral genome offer great potential as next-generation vaccines for the post-polio world. We have previously reported production of PV VLPs using Pichia pastoris, however, these VLPs were in the non-native conformation (C Ag), which would not produce effective protection against PV. Here, we build on this work and show that it is possible to produce wt PV-3 and thermally stabilised PV-3 (referred to as PV-3 SC8) VLPs in the native conformation (D Ag) using Pichia pastoris. We show that the PV-3 SC8 VLPs provide a much-improved D:C antigen ratio as compared to wt PV-3, whilst exhibiting greater thermostability than the current IPV vaccine. Finally, we determine the cryo-EM structure of the yeast-derived PV-3 SC8 VLPs and compare this to previously published PV-3 D Ag structures, highlighting the similarities between these recombinantly expressed VLPs and the infectious virus, further emphasising their potential as a next-generation vaccine candidate for PV.


Prosthetic complications in mandibular metal-resin implant-fixed complete dental prostheses: a 5- to 9-year analysis.
The purpose of this study was to investigate the prosthetic complications of patients with a maxillary complete removable dental prosthesis opposing a mandibular metal-resin implant fixed complete dental prosthesis. This study is a retrospective analysis of an ongoing prospective study. Dental records from 46 patients treated with a maxillary complete removable dental prosthesis and a mandibular metal-resin implant-fixed complete dental prosthesis were reviewed for 15 different prosthetic complications. The average recall time was 7.9 years. The percentage of patients exhibiting each complication and corresponding 95% confidence intervals was calculated. Logistic regression analysis determined the effect of recall period, age, and gender on each of the following major complications: tooth fracture, complete denture relines, screw complications, and tooth replacement. The recall period was divided into 3 parts: < or = 2 years, 2 to 5 years, and more than 5 years. Statistical significance was exhibited for complete denture relines, posterior tooth replacement, and screw complications. No abutment or framework fractures were recorded for any of the time intervals. The most common complications were prosthetic tooth fracture, tooth wear, maxillary hard relines, and screw complications. Patients were 1.06 times more likely to require a heat-processed hard reline with each year increase of age. After 2 to 5 years and > 5 years, patients were 3.7 times and 8.5 times more likely to require a hard reline than at < or = 2 years. Patients were 52.5 times more likely to need posterior tooth replacement at > 5 years than at < or = 2 years, and 7.7 times more likely to encounter a screw complication at > 5 years than at < or = 2 years.


Windowed correlation: a suitable tool for providing dynamic fMRI-based functional connectivity neurofeedback on task difficulty.
The goal of neurofeedback training is to provide participants with relevant information on their ongoing brain processes in order to enable them to change these processes in a meaningful way. Under the assumption of an intrinsic brain-behavior link, neurofeedback can be a tool to guide a participant towards a desired behavioral state, such as a healthier state in the case of patients. Current research in clinical neuroscience regarding the most robust indicators of pathological brain processes in psychiatric and neurological disorders indicates that fMRI-based functional connectivity measures may be among the most important biomarkers of disease. The present study therefore investigated the general potential of providing fMRI neurofeedback based on functional correlations, computed from short-window time course data at the level of single task periods. The ability to detect subtle changes in task performance with block-wise functional connectivity measures was evaluated based on imaging data from healthy participants performing a simple motor task, which was systematically varied along two task dimensions representing two different aspects of task difficulty. The results demonstrate that fMRI-based functional connectivity measures may provide a better indicator for an increase in overall (motor) task difficulty than activation level-based measures. Windowed functional correlations thus seem to provide relevant and unique information regarding ongoing brain processes, which is not captured equally well by standard activation level-based neurofeedback measures. Functional connectivity markers, therefore, may indeed provide a valuable tool to enhance and monitor learning within an fMRI neurofeedback setup.


Sleep disturbances in psoriasis.
Psoriasis negatively impacts sleep, but the factors that cause this sleep disturbance are not well characterized. To assess sleep quality in subjects with psoriasis. 35 outpatients diagnosed with chronic plaque psoriasis affecting at least 10 percent BSA and 44 controls completed the Pittsburgh Sleep Quality Index, Patient Health Questionnaire, Itch Severity Scale, Insomnia Severity Index, and Epworth Sleepiness Scale. For multiple testing, alpha was set at 0.008. Adjusting for age, BMI, and gender, patients with psoriasis had 4.3 times the odds to score in a higher insomnia category (OR 95% CI: 1.7, 11.2; p=0.01), a trend toward experiencing "poor sleep" (p=0.04), and no difference in odds to be "sleepy" (p=0.83). Patients with psoriasis had greater itch than those without psoriasis (mean ISS 8.5 vs. 2.0; p<0.0001). When adjusting for age, BMI, gender, and depression, those with psoriasis were not more likely to experience poor sleep quality (p=0.25), nor to score in a higher insomnia category (p=0.20) or be more "sleepy" (p=0.53). Patients with psoriasis suffer from sleep disturbances and pruritus more than those without psoriasis. Although sleep disturbances are more prevalent, this may be secondary to depression rather than related to a direct effect of psoriasis.


Treatment outcomes in black and white children with cancer: results from the SEER database and St Jude Children's Research Hospital, 1992 through 2007.
Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome between black and white pediatric patients. In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007. Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period. With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.


An analysis of human motion detection systems use during elder exercise routines.
Human motion analysis provides motion pattern and body pose estimations. This study integrates computer-vision techniques and explores a markerless human motion analysis system. Using human-computer interaction (HCI) methods and goals, researchers use a computer interface to provide feedback about range of motion to users. A total of 35 adults aged 65 and older perform three exercises in a public gym while human motion capture methods are used. Following exercises, participants are shown processed human motion images captured during exercises on a customized interface. Standardized questionnaires are used to elicit responses from users during interactions with the interface. A matrix of HCI goals (effectiveness, efficiency, and user satisfaction) and emerging themes are used to describe interactions. Sixteen users state the interface would be useful, but not necessarily for safety purposes. Users want better image quality, when expectations are matched satisfaction increases, and unclear meaning of motion measures decreases satisfaction.


Protection elicited by a replication-defective adenovirus vector expressing the tick-borne encephalitis virus non-structural glycoprotein NS1.
Tick-borne encephalitis virus (TBEV) encodes a conserved, immunogenic, non-structural protein NS1 that is glycosylated and secreted from infected cells in an oligomeric form. An adenovirus recombinant, RAd51, expressing high levels of TBEV NS1 has previously been demonstrated to protect mice against a lethal challenge with TBEV. We show here that BALB/c mice infected with TBEV experienced a transient viraemia between days 3 to 5 post-inoculation that was detectable prior to the encephalitic phase of infection. Mice vaccinated with RAd51 were protected against both the viraemic and encephalitic infections associated with the TBEV challenge. Protection was demonstrated to be due to NS1 synthesized de novo from RAd51 in the vaccinated mice. Since TBEV NS1 is expressed on the cell surface, antibody-dependent complement-mediated cytolysis (CMC) of infected cells was considered as a possible mechanism of protection. Vaccination with the recombinant adenovirus proved to be effective in a mouse strain carrying a genetic deletion in the complement receptor C5. CMC is therefore not an essential component of the observed protective immune response.


Pertussis requiring intensive care.
To describe children with pertussis who require intensive care. An audit in Auckland, New Zealand, of pertussis admissions to the national paediatric intensive care unit (PICU) from 1991 to 2003. 72 children, 97% of whom were <12 months old. The annual number of cases increased with time (p = 0.04). Forty patients (56%) were coughing for less than 8 days before admission. Apnoea or paroxysmal cough was present in 33 (83%) of these children. Thirty five (49%) received assisted ventilation. Four died. 19% were readmitted to PICU. Those readmitted presented with more atypical disease and had a shorter first admission but longer total PICU admission (9 vs 5 days, p = 0.009). Of the 58 children from Auckland, nine either died (three) or had subsequent respiratory or neurodevelopmental problems (six). There was an increased risk (relative risk, 95% CI) of death or disability associated with having a co-morbidity (RR = 5.56, 1.50 to 8.15), an elevated lymphocyte count (RR = 5.75, 1.54 to 13.65), presenting with seizures/encephalopathy (4.87, 1.18 to 8.34) or shock (6.50, 1.89 to 8.94), having a PIM score of 1% or more (RR = 6.20, 1.22 to 21.72), any abnormal neurological signs (RR = 9.65, 3.32 to 15.23) or being readmitted to PICU (RR = 4.63, 1.44 to 8.82). Apnoea and paroxysmal cough are key symptoms of pertussis in those with shorter cough duration. Death or disability are frequent. Clinical factors define children at increased risk of these poor outcomes. Early discharge from PICU is associated with an increased risk of readmission and poor outcome.


The relationship of malignant melanoma, basal and squamous skin cancers to indoor and outdoor work.
An analysis of occupational incidence data for malignant melanomas and squamous-and basal-self carcinomas of the skin in England and Wales from 1970 to 1975 is reported. The occupational pattern for melanomas of the trunk and limbs differed markedly from the pattern for melanomas of the head, face and neck. Office work was associated with a large excess of melanomas of the trunk and limbs. In contrast, outdoor work was associated with an excess of melanomas of the head, face and neck; and was also associated with an excess of squamous-and basal-cell carcinomas of the skin. This suggests that prolonged occupational exposure to sunlight is an important cause of squamous-and basal-cell carcinomas and of melanomas of the head, face and neck, but not of melanomas on other parts of the body. The high rate of lesions on the trunk and limbs in office workers may reflect their sunbathing or other recreational habits; but it contrasts clearly with other indoor work, where there is a generally low rate of all forms of skin cancer.


Monte Carlo simulations and atomic calculations for Auger processes in biomedical nanotheranostics.
We present numerical simulations of X-ray emission and absorption in a biological environment for which we have modified the general-purpose computer code Geant4. The underlying mechanism rests on the use of heavy nanoparticles delivered to specific sites, such as cancerous tumors, and treated with monoenergetic X-rays at resonant atomic and molecular transitions. X-ray irradiation of high-Z atoms results in Auger decays of photon emission and electron ejections creating multiple electron vacancies. These vacancies may be filled either be radiative decays from higher electronic shells or by excitations from the K-shell at resonant energies by an external X-ray source, as described in an accompanying paper by Pradhan et al. in this volume. Our Monte Carlo models assume normal body material embedded with a layer of gold nanoparticles. The simulation results presented in this paper demonstrate that resonant excitations via Kalpha, Kbeta, etc., transitions result in a considerable enhancement in localized X-ray energy deposition at the layer with gold nanoparticles, compared with nonresonant processes and energies. The present results could be applicable to in vivo therapy and diagnostics (theranostics) of cancerous tumors using high-Z nanoparticles and monochromatic X-ray sources according to the resonant theranostics (RT) methodology.


Radiobiologically based assessments of the net costs of fractionated focal radiotherapy.
To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time.


The Hepatic Protection Effects of Hepassocin in Hyperglycemic Crisis.
High glucose generates reactive oxygen species (ROS) and contributes to glucotoxicity in hepatocytes, and hyperglycemia causes structural and functional damage to the liver. However, only a mild hepatic dysfunction was observed in subjects with hyperglycemic crisis, implying a factor exists to exert a hepatic protective effect. Hepassocin is a hepatokine that modulates the proliferation and metabolism of hepatocytes and also exerts protective activity in liver injury. However, its role in hyperglycemic crisis-induced hepatic dysfunction remains unknown. To investigate the possible hepatic protection effects of hepassocin in hyperglycemic crisis. Plasma hepassocin concentrations and routine biochemistry were measured in 21 patients with hyperglycemic crisis before and after standard treatments. The effects of hepassocin on hepatic functions were evaluated in streptozotocin-induced hyperglycemic mice (STZ mice). HepG2 cells were used to clarify the possible mechanisms regulating hepassocin expression. Plasma hepassocin concentrations decreased significantly in subjects with hyperglycemic crisis after standard treatment accompanied by improved hepatic functions. Correction of hyperglycemia in STZ mice also decreased the hepatic hepassocin expression. Injection of recombinant hepassocin improved hepatic functions and histologic changes and increased the expression of antioxidative stress proteins, including superoxide dismutase 1 (SOD1). In HepG2 cells, high glucose increased hepassocin expression through signal transducer and activator of transcription 3 and hepatocyte nuclear factor-related pathways. We also demonstrated that hepassocin increased SOD1 expression through an extracellular signal-regulated kinase 1/2 nuclear factor erythroid-2-related factor 2 pathway, decreasing ethyl acetate-induced ROS production and improving cell viability. Increased hepassocin secretion in hyperglycemic crisis might offset the deleterious effects of hyperglycemia on hepatocytes.