Effects of Small-World Rewiring Probability and Noisy Synaptic Conductivity on Slow Waves: Cortical Network.
Physiological rhythms play a critical role in the functional development of living beings. Many biological functions are executed with an interaction of rhythms produced by internal characteristics of scores of cells. While synchronized oscillations may be associated with normal brain functions, anomalies in these oscillations may cause or relate the emergence of some neurological or neuropsychological pathologies. This study was designed to investigate the effects of topological structure and synaptic conductivity noise on the spatial synchronization and temporal rhythmicity of the waves generated by cells in the network. Because of holding the ability of clustering and randomizing with change of parameters, small-world (SW) network topology was chosen. The oscillatory activity of network was tried out by manipulating an insulated SW, cortical network model whose morphology is very close to real world. According to the obtained results, it was observed that at the optimal probabilistic rates of conductivity noise and rewiring of SW, powerful synchronized oscillatory small waves are generated in relation to the internal dynamics of cells, which are in line with the network's input. These two parameters were observed to be quite effective on the excitation-inhibition balance of the network. Accordingly, it may be suggested that the topological dynamics of SW and noisy synaptic conductivity may be associated with the normal and abnormal development of neurobiological structure.


A novel systematic approach for cancer treatment prognosis and its applications in oropharyngeal cancer with microRNA biomarkers.
Predicting early in treatment whether a tumor is likely to respond to treatment is one of the most difficult yet important tasks in providing personalized cancer care. Most oropharyngeal squamous cell carcinoma (OPSCC) patients receive standard cancer therapy. However, the treatment outcomes vary significantly and are difficult to predict. Multiple studies indicate that microRNAs (miRNAs) are promising cancer biomarkers for the prognosis of oropharyngeal cancer. The reliable and efficient use of miRNAs for patient stratification and treatment outcome prognosis is still a very challenging task, mainly due to the relatively high dimensionality of miRNAs compared to the small number of observation sets; the redundancy, irrelevancy and uncertainty in the large amount of miRNAs; and the imbalanced observation patient samples. In this study, a new machine learning-based prognosis model was proposed to stratify subsets of OPSCC patients with low and high risks for treatment failure. The model cascaded a two-stage prognostic biomarker selection method and an evidential K-nearest neighbors classifier to address the challenges and improve the accuracy of patient stratification. The model has been evaluated on miRNA expression profiling of 150 oropharyngeal tumors by use of overall survival and disease-specific survival as the end points of disease treatment outcomes, respectively. The proposed method showed superior performance compared to other advanced machine-learning methods in terms of common performance quantification metrics. The proposed prognosis model can be employed as a supporting tool to identify patients who are likely to fail standard therapy and potentially benefit from alternative targeted treatments. Availability and implementation: Code is available in https://github.com/shenghh2015/mRMR-BFT-outcome-prediction.


Transcytosis of HTLV-1 across a tight human epithelial barrier and infection of subepithelial dendritic cells.
Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis. In addition to blood transfusion and sexual transmission, HTLV-1 is transmitted mainly through prolonged breastfeeding, and such infection represents a major risk for the development of adult T-cell leukemia/lymphoma. Although HTLV-1-infected lymphocytes can be retrieved from maternal milk, the mechanisms of HTLV-1 transmission through the digestive tract remain unknown. In the present study, we assessed HTLV-1 transport across the epithelial barrier using an in vitro model. Our results show that the integrity of the epithelial barrier was maintained during coculture with HTLV-1-infected lymphocytes, because neither morphological nor functional alterations of the cell monolayer were observed. Enterocytes were not susceptible to HTLV-1 infection, but free infectious HTLV-1 virions could cross the epithelial barrier via a transcytosis mechanism. Such virions were able to infect productively human dendritic cells located beneath the epithelial barrier. Our data indicate that HTLV-1 crosses the tight epithelial barrier without disruption or infection of the epithelium to further infect target cells such as dendritic cells. The present study provides the first data pertaining to the mode of HTLV-1 transport across a tight epithelial barrier, as can occur during mother-to-child HTLV-1 transmission during breastfeeding.


Analysis of expressed sequence tags from the marine microalga Pseudochattonella farcimen (Dictyochophyceae).
Pseudochattonella farcimen (Eikrem, Edvardsen, et Throndsen) is a unicellular alga belonging to the Dictyochophyceae (Heterokonta). It forms recurring blooms in Scandinavian coastal waters, and has been associated to fish mortality. Here we report the sequencing and analysis of 10,368 expressed sequence tags (ESTs) corresponding to 8,149 unique gene models from this species. Compared to EST libraries from other heterokonts, P. farcimen contains a high number of genes with functions related to cell communication and signaling. We found several genes encoding proteins related to fatty acid metabolism, including eight fatty acid desaturases and two phospholipase A2 genes. Three desaturases are highly similar to Δ4-desaturases from haptophytes. P. farcimen also possesses three putative polyketide synthases (PKSs), belonging to two different families. Some of these genes may have been acquired via horizontal gene transfer by a common ancestor of brown algae and dictyochophytes, together with genes involved in mannitol metabolism, which are also present in P. farcimen. Our findings may explain the unusual fatty acid profile previously observed in P. farcimen, and are discussed from an evolutionary perspective and in relation to the ichthyotoxicity of this alga.


Effect of FOLFOX on minimal residual disease in Stage III colon cancer and risk of relapse.
25% of Stage III colon cancer patients relapse within 5 years due to minimal residual disease (MRD) not eliminated by surgery and chemotherapy. We hypothesise that sub-types of MRD, defined by circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) have different types and kinetics of relapse. One month of curative surgery and 1 month after completing six cycles of FOLFOX chemotherapy blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcino-embryonic antigen (CEA). Follow up was up to 5 years or disease progression defined as new images on CT scanning. Survival curves using Kaplan-Meier (KM) and Restricted Mean Survival Time (RMST) were calculated for three prognostic groups: CTC and mM negative, CTC negative mM positive, and CTC positive. 76 patients (39 men) participated, mean age 67 years, median follow-up 3.6 years. The response to chemotherapy was heterogeneous and MRD pre-treatment did not predict response to therapy. Of 21 patients MRD (-), 20 remained MRD negative and one patient became mM (+); of 21 patients mM (+), 10 became MRD (-), 8 remained the same and 3 became CTC (+); of the 34 CTC positive, 8 became MRD (-), 8 with only mM, and 18 remained positive.After chemotherapy, 38 patients were negative for CTC and mM, 17 were positive for only mM, and 21 for CTCs. For the whole cohort, the 5 year KM was 58%, the median survival was not reached. For the three prognostic groups, the KM 5-year survivals were 87%, 58%, and 4%, respectively, the median survival for patients MRD negative and mM only was not reached. RMST for the whole cohort was 3.6 years, for the three prognostic groups the RMST was 4.6 years, 4.0 years, and 1.5 years, respectively. Serum CEA was significantly higher pre-surgery in the CTC positive group. There were no significant differences with respect to age or sex between the three groups. MRD subtypes pre-chemotherapy did not predict treatment response. Post-chemotherapy MRD subtypes were associated with the pattern of failure and time to failure. MRD negative patients had an excellent prognosis with 87% disease-free survival at 5 years. Those with only mM had a similar outcome up to 2 years and then were at increasing risk of late failure. Patients who were CTC positive had a high risk of early failure. MRD subclassification may be useful to define the risk of relapse in Stage III colon cancer patients and warrants further studies with a larger number of patients.


First-principles study on thermodynamic stability of the hybrid interfacial structure of LiMn2O4 cathode and carbonate electrolyte in Li-ion batteries.
The solid electrolyte interphase (SEI) of Li-ion batteries (LIBs) has been extensively studied, with most research focused on the anode, because of its significant impact on the prolonged cycle life, initial capacity loss, and safety issues. Using first-principles density functional theory (DFT) calculations and ab initio molecular dynamics (AIMD) simulations with the Hubbard correction, we examine the thermodynamic structure prediction and electrochemical stability of a spinel LiMn2O4 cathode interfaced with a carbonate electrolyte. The electronic energy levels of frontier orbitals of the electrolyte and the work function of the cathode offer clear characterization of the interfacial reactions. Our results based on both DFT calculations and AIMD simulations propose that the proton transfer mechanism at the hybrid interface is essential for initiating the SEI layer formation on the LiMn2O4 surface. Our results can be useful for identifying design concepts in the development of stable and high capacity LIBs with optimized electrodes and high-performance electrolytes.


Prevention with tamoxifen or other hormones versus prophylactic surgery in BRCA1/2-positive women: a decision analysis.
Recent randomized controlled trials have shown that tamoxifen and raloxifene may prevent invasive breast cancer. This decision analysis study compares the outcomes of chemoprevention with tamoxifen, raloxifene, or oral contraceptives with the outcomes of prophylactic surgery among women with high-risk BRCA1/2 mutations. We used a simulated cohort of 30-year-old women who tested positive for BRCA1/2 mutations and constructed a Markov model with Monte Carlo simulations, incorporating cumulative breast and ovarian cancer incidence rates from the literature and survival figures from SEER data. We assumed that prophylactic surgery reduces ovarian cancer risk by 45% and breast cancer risk by 90%, that tamoxifen reduces invasive breast cancer risk by 49%, and that raloxifene has similar efficacy and safety in premenopausal and postmenopausal women. We used data obtained from high-risk women by a time trade-off questionnaire to calculate quality-adjusted life-years. We based our cost estimates for hospital and ambulatory care on Health Care Financing Administration payments, the SEER-HCFA database, and the Pharmacy Fundamental Reference. In our model, a 30-year-old BRCA1/2+ woman could prolong survival by 0.9 years (95% probability interval, 0.4-1.2 years) by having bilateral oophorectomy, 3.4 years (2.7-3.7 years) by having bilateral mastectomy, and 4.3 years (3.6-4.6 years) by having both procedures instead of surveillance alone. Chemoprevention with tamoxifen and raloxifene increased survival by 1.6 years (1.0-2.1 years) and 2.2 years (1.3-2.8 years), respectively. Chemoprevention yielded more quality-adjusted life-years than did prophylactic surgery, even when treatment was delayed to age 40 or 50 years. All these procedures were cost-effective or cost-saving compared with surveillance alone. Our model suggests that although surgery may yield more substantial survival and cost benefits, quality of life issues may make chemoprevention a more attractive option for young women at high genetic risk.


Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double-blind, placebo-controlled, multicenter study.
We randomized 389 symptomatic patients with human immunodeficiency virus (HIV) infection to ditiocarb sodium (400 mg/m2 orally for 24 weeks) or a placebo. Patients were well balanced according to Centers for Disease Control (CDC) group, CD4+ cell number, and duration of disease prior to entry. Ten new acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections occurred in the treated patients and 21 in the controls. Reduction of new opportunistic infections in the ditiocarb group was significant in all patients (relative risk [RR], 0.44) and in patients with AIDS (CDC groups IV-C1 and IV-D) (RR, 0.12). The size of the effect of ditiocarb was maintained when data were reanalyzed after exclusion of a patient who progressed to Pneumocystis carinii pneumonia who was not strictly CDC-defined (RR, 0.46), or when considering as new opportunistic infections three events, which were clinically active at entry, but for which the definitive diagnosis was made during study (RR, 0.49). The administration of ditiocarb did not induce any major adverse clinical or biological reactions. We conclude that, in this study, ditiocarb was safe and reduced the incidence of opportunistic infections in patients with symptomatic HIV infection.


Impact of high coverage of monovalent human rotavirus vaccine on Emergency Department presentations for rotavirus gastroenteritis.
Australia was one of the first countries to introduce nationally funded rotavirus vaccination. The program has had a substantial impact on both rotavirus and all-cause acute gastroenteritis (AGE) hospitalisations and rotavirus laboratory tests. Evidence for an impact on Emergency Department (ED) presentations is limited. This study assessed changes in ED presentations for rotavirus in children aged <5 years in New South Wales, Australia, following introduction of monovalent human rotavirus vaccine (RV1, Rotarix(®), GlaxoSmithKline Australia Pty Ltd., Victoria, Australia). A time series analysis to examine trends in total non-admitted ED presentations for all-cause AGE and in the rotavirus-attributable fraction using data on rotavirus positive laboratory tests. A decline in the rate of non-admitted ED presentations for all-cause AGE was observed for all ages, being most notable in 1 year old children. Compared with the pre-vaccination period, we estimated the average weekly rate was lower across the first 4.5 years of the program for both all-cause AGE (18.3%; 70.5 versus 57.5 per 100,000 population) and rotavirus attributable (55.4%; 17.3 versus 7.7 per 100,000 population) presentations. In the fourth year of the program, estimated annual rotavirus attributable presentations were 77% lower than the pre-vaccination annual mean (996 versus 4300 per year). The program was associated with a substantial decline in rotavirus attributable non-admitted AGE presentations to ED among children aged <5 years.


Carbon monoxide and nitric oxide mediate cytoskeletal reorganization in microvascular cells via vasodilator-stimulated phosphoprotein phosphorylation: evidence for blunted responsiveness in diabetes.
We examined the effect of the vasoactive agents carbon monoxide (CO) and nitric oxide (NO) : n the phosphorylation and intracellular redistribution of vasodilator-stimulated phosphoprotein (VASP), a critical actin motor protein required for cell migration that also controls vasodilation and platelet aggregation. We examined the effect of donor-released CO and NO in endothelial progenitor cells (EPCs) and platelets from nondiabetic and diabetic subjects and in human microvascular endothelial cells (HMECs) cultured under low (5.5 mmol/l) or high (25 mmol/l) glucose conditions. VASP phosphorylation was evaluated using phosphorylation site-specific antibodies. In control platelets, CO selectively promotes phosphorylation at VASP Ser-157, whereas NO promotes phosphorylation primarily at Ser-157 and also at Ser-239, with maximal responses at 1 min with both agents on Ser-157 and at 15 min on Ser-239 with NO treatment. In diabetic platelets, neither agent resulted in VASP phosphorylation. In nondiabetic EPCs, NO and CO increased phosphorylation at Ser-239 and Ser-157, respectively, but this response was markedly reduced in diabetic EPCs. In endothelial cells cultured under low glucose conditions, both CO and NO induced phosphorylation at Ser-157 and Ser-239; however, this response was completely lost when cells were cultured under high glucose conditions. In control EPCs and in HMECs exposed to low glucose, VASP was redistributed to filopodia-like structures following CO or NO exposure; however, redistribution was dramatically attenuated under high glucose conditions. Vasoactive gases CO and NO promote cytoskeletal changes through site- and cell type-specific VASP phosphorylation, and in diabetes, blunted responses to these agents may lead to reduced vascular repair and tissue perfusion.


Degradation of coeliac disease-inducing rye secalin by germinating cereal enzymes: diminishing toxic effects in intestinal epithelial cells.
Currently the only treatment for coeliac disease is a lifelong gluten-free diet excluding food products containing wheat, rye and barley. There is, however, only scarce evidence as to harmful effects of rye in coeliac disease. To confirm the assumption that rye should be excluded from the coeliac patient's diet, we now sought to establish whether rye secalin activates toxic reactions in vitro in intestinal epithelial cell models as extensively as wheat gliadin. Further, we investigated the efficacy of germinating cereal enzymes from oat, wheat and barley to hydrolyse secalin into short fragments and whether secalin-induced harmful effects can be reduced by such pretreatment. In the current study, secalin elicited toxic reactions in intestinal Caco-2 epithelial cells similarly to gliadin: it induced epithelial cell layer permeability, tight junctional protein occludin and ZO-1 distortion and actin reorganization. In high-performance liquid chromatography and mass spectroscopy (HPLC-MS), germinating barley enzymes provided the most efficient degradation of secalin and gliadin peptides and was thus selected for further in vitro analysis. After germinating barley enzyme pretreatment, all toxic reactions induced by secalin were ameliorated. We conclude that germinating enzymes from barley are particularly efficient in the degradation of rye secalin. In future, these enzymes might be utilized as a novel medical treatment for coeliac disease or in food processing in order to develop high-quality coeliac-safe food products.


Students' perceptions of a multimedia computer-aided instruction resource in histology.
To develop an interactive multimedia-based computer-aided instruction (CAI) programme, to determine its educational worth and efficacy in a multicultural academic environment and to evaluate its usage by students with differing levels of computer literacy. A prospective descriptive study evaluating pre- and post-module testing, student usage tracking and a questionnaire survey. University of Natal Medical School. Thirty-four volunteers from the class of 125 second-year M.B. Ch.B. students who participated in the CAI study; 13 of these were not computer-literate. The study group used the CAI module for 2 weeks as part of the course. Post-test scoring and evaluation of questionnaire responses. Results of pre- and post-tests show that CAI users' scores were slightly lower on pre-testing (22.1% v. 23.2%), while their post-test scores were higher (65.6% v. 60.7%). Lack of computer literacy did not restrict or hinder students in their use of the programme. Responses to a questionnaire completed by all CAI users indicate consensus that the programme helped the students to learn (94%), that it provided important basic knowledge (88%) and that it was a helpful learning experience (88%). All but 1 student wished to have more programmes like this available in histology. The CAI programme reduced the time spent by students in the histology microscopy laboratory and did not negatively affect their marks in post-course evaluation. The concept of multimedia-based CAI in medical education was positively received by the students who participated.


Magma storage beneath Axial volcano on the Juan de Fuca mid-ocean ridge.
Axial volcano, which is located near the intersection of the Juan de Fuca ridge and the Cobb-Eickelberg seamount chain beneath the northeast Pacific Ocean, is a locus of volcanic activity thought to be associated with the Cobb hotspot. The volcano rises 700 metres above the ridge, has substantial rift zones extending about 50 kilometres to the north and south, and has erupted as recently as 1998 (ref. 2). Here we present seismological data that constrain the three-dimensional velocity structure beneath the volcano. We image a large low-velocity zone in the crust, consisting of a shallow magma chamber and a more diffuse reservoir in the lower crust, and estimate the total magma volume in the system to be between 5 and 21 km3. This volume is two orders of magnitude larger than the amount of melt emplaced during the most recent eruption (0.1-0.2 km3). We therefore infer that such volcanic events remove only a small portion of the reservoir that they tap, which must accordingly be long-lived compared to the eruption cycle. On the basis of magma flux estimates, we estimate the crustal residence time of melt in the volcanic system to be a few hundred to a few thousand years.


Skeletal muscle loss in the postoperative acute phase after esophageal cancer surgery as a new prognostic factor.
The postoperative survival rate of patients with esophageal squamous cell carcinoma (ESCC) remains poor compared with other gastrointestinal cancers. We hypothesized that skeletal muscle loss in the postoperative acute phase might be a new predictor for long-term prognosis after highly invasive surgery such as ESCC surgery. The following items were retrospectively investigated. First, whether skeletal muscle loss occurred in the postoperative acute phase of ESCC was verified. Second, the preoperative and intraoperative factors involved in skeletal muscle loss in the postoperative acute phase of ESCC were investigated. Then, whether skeletal muscle loss in the postoperative acute phase affected long-term prognosis was examined. The medical records of consecutive patients who underwent radical esophagectomy for ESCC between January 2010 and February 2015 were retrospectively reviewed; 72 cases were eligible for this study. The total psoas major muscle mass index (TPI) at the level of the third lumbar vertebra (L3) was measured using computed tomography (CT) before surgery and 3 days after surgery. The long-term prognosis was estimated by the Kaplan-Meier method and the multivariate logistic regression model. There was already a significant reduction of TPI in the acute phase up to POD 3 after ESCC surgery in comparison with the preoperative baseline TPI (P < 0.001). The TPI reduction rate was significantly milder in cases with less blood loss during surgery and in cases that underwent thoracoscopic esophagectomy than in cases that underwent open esophagectomy. The 3-year overall survival rate was significantly different between the TPI reduction rate severe group and the TPI reduction rate mild group. Skeletal muscle loss occurred even in the postoperative acute phase. Furthermore, it is very significant that skeletal muscle loss in the postoperative acute phase of ESCC surgery is involved in the long-term prognosis.


Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract.
The murine genes, Foxc1 and Foxc2 (previously, Mf1 and Mfh1), encode forkhead/winged helix transcription factors with virtually identical DNA-binding domains and overlapping expression patterns in various embryonic tissues. Foxc1/Mf1 is disrupted in the mutant, congenital hydrocephalus (Foxc1/Mf1(ch)), which has multiple developmental defects. We show here that, depending on the genetic background, most Foxc1 homozygous mutants are born with abnormalities of the metanephric kidney, including duplex kidneys and double ureters, one of which is a hydroureter. Analysis of embryos reveals that Foxc1 homozygotes have ectopic mesonephric tubules and ectopic anterior ureteric buds. Moreover, expression in the intermediate mesoderm of Glial cell-derived neurotrophic factor (Gdnf), a primary inducer of the ureteric bud, is expanded more anteriorly in Foxc1 homozygous mutants compared with wild type. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities (Mackie, G. G. and Stephens, F. G. (1975) J. Urol. 114, 274-280). Previous studies established that most Foxc1(lacZ )Foxc2(tm1) compound heterozygotes have the same spectrum of cardiovascular defects as single homozygous null mutants, demonstrating interaction between the two genes in the cardiovascular system. Here, we show that most compound heterozygotes have hypoplastic kidneys and a single hydroureter, while all heterozygotes are normal. This provides evidence that the two genes interact in kidney as well as heart development.


Generation and characterization of mouse monoclonal antibodies against NS4B protein of dengue virus.
Dengue virus (DENV) non-structural protein 4B (NS4B) has been demonstrated to be an attractive antiviral target. Due to its nature as an integral membrane protein, NS4B remains poorly characterized. In this study, we generated and characterized two monoclonal antibodies (mAb) that selectively bind to DENV NS4B protein. One mAb, 10-3-7, is specific for DENV-2 NS4B, and its epitope was mapped to residues 5-15 of NS4B. The other mAb, 44-4-7, cross-reacts with all the four serotypes of DENV NS4B, and its epitope was mapped to residues 141-147 of NS4B. Using the mAbs, we probed the intracellular orientation of the epitopes of NS4B by an epitope accessibility assay. The results showed that the N-terminus of NS4B is located in the ER lumen, whereas amino acids 130-148 of NS4B are located in the cytosol. The study demonstrates that the two anti-NS4B mAbs will be useful for future structural and functional analyses of DENV NS4B.


Influence of HFE variants and cellular iron on monocyte chemoattractant protein-1.
Polymorphisms in the MHC class 1-like gene known as HFE have been proposed as genetic modifiers of neurodegenerative diseases that include neuroinflammation as part of the disease process. Variants of HFE are relatively common in the general population and are most commonly associated with iron overload, but can promote subclinical cellular iron loading even in the absence of clinically identified disease. The effects of the variants as well as the resulting cellular iron dyshomeostasis potentially impact a number of disease-associated pathways. We tested the hypothesis that the two most common HFE variants, H63D and C282Y, would affect cellular secretion of cytokines and trophic factors. We screened a panel of cytokines and trophic factors using a multiplexed immunoassay in human neuroblastoma SH-SY5Y cells expressing different variants of HFE. The influence of cellular iron secretion on the potent chemokine monocyte chemoattractant protein-1 (MCP-1) was assessed using ferric ammonium citrate and the iron chelator, desferroxamine. Additionally, an antioxidant, Trolox, and an anti-inflammatory, minocycline, were tested for their effects on MCP-1 secretion in the presence of HFE variants. Expression of the HFE variants altered the labile iron pool in SH-SY5Y cells. Of the panel of cytokines and trophic factors analyzed, only the release of MCP-1 was affected by the HFE variants. We further examined the relationship between iron and MCP-1 and found MCP-1 secretion tightly associated with intracellular iron status. A potential direct effect of HFE is considered because, despite having similar levels of intracellular iron, the association between HFE genotype and MCP-1 expression was different for the H63D and C282Y HFE variants. Moreover, HFE genotype was a factor in the effect of minocycline, a multifaceted antibiotic used in treating a number of neurologic conditions associated with inflammation, on MCP-1 secretion. Our results demonstrate that HFE polymorphisms influence the synthesis and release of MCP-1. The mechanism of action involves cellular iron status but it appears there could be additional influences such as ER stress. Finally, these data demonstrate a pharmacogenetic effect of HFE polymorphisms on the ability of minocycline to inhibit MCP-1 secretion.


More Challenging Diets Sustain Feeding Performance: Applications Toward the Captive Rearing of Wildlife.
The rescue and rehabilitation of young fauna is of substantial importance to conservation. However, it has been suggested that incongruous diets offered in captive environments may alter craniofacial morphology and hinder the success of reintroduced animals. Despite these claims, to what extent dietary variation throughout ontogeny impacts intrapopulation cranial biomechanics has not yet been tested. Here, finite element models were generated from the adult crania of 40 rats (n = 10 per group) that were reared on 4 different diet regimes and stress magnitudes compared during incisor bite simulations. The diets consisted of (1) exclusively hard pellets from weaning, (2) exclusively soft ground pellet meal from weaning, (3) a juvenile switch from pellets to meal, and (4) a juvenile switch from meal to pellets. We hypothesized that a diet of exclusively soft meal would result in the weakest adult skulls, represented by significantly greater stress magnitudes at the muzzle, palate, and zygomatic arch. Our hypothesis was supported at the muzzle and palate, indicating that a diet limited to soft food inhibits bone deposition throughout ontogeny. This finding presents a strong case for a more variable and challenging diet during development. However, rather than the "soft" diet group resulting in the weakest zygomatic arch as predicted, this region instead showed the highest stress among rats that switched as juveniles from hard pellets to soft meal. We attribute this to a potential reduction in number and activity of osteoblasts, as demonstrated in studies of sudden and prolonged disuse of bone. A shift to softer foods in captivity, during rehabilitation after injury in the wild for example, can therefore be detrimental to healthy development of the skull in some growing animals, potentially increasing the risk of injury and impacting the ability to access full ranges of wild foods upon release. We suggest captive diet plans consider not just nutritional requirements but also food mechanical properties when rearing wildlife to adulthood for reintroduction.


The Cacti Microbiome: Interplay between Habitat-Filtering and Host-Specificity.
Cactaceae represents one of the most species-rich families of succulent plants native to arid and semi-arid ecosystems, yet the associations Cacti establish with microorganisms and the rules governing microbial community assembly remain poorly understood. We analyzed the composition, diversity, and factors influencing above- and below-ground bacterial, archaeal, and fungal communities associated with two native and sympatric Cacti species: Myrtillocactus geometrizans and Opuntia robusta. Phylogenetic profiling showed that the composition and assembly of microbial communities associated with Cacti were primarily influenced by the plant compartment; plant species, site, and season played only a minor role. Remarkably, bacterial, and archaeal diversity was higher in the phyllosphere than in the rhizosphere of Cacti, while the opposite was true for fungi. Semi-arid soils exhibited the highest levels of microbial diversity whereas the stem endosphere the lowest. Despite their taxonomic distance, M. geometrizans and O. robusta shared most microbial taxa in all analyzed compartments. Influence of the plant host did only play a larger role in the fungal communities of the stem endosphere. These results suggest that fungi establish specific interactions with their host plant inside the stem, whereas microbial communities in the other plant compartments may play similar functional roles in these two species. Biochemical and molecular characterization of seed-borne bacteria of Cacti supports the idea that these microbial symbionts may be vertically inherited and could promote plant growth and drought tolerance for the fitness of the Cacti holobiont. We envision this knowledge will help improve and sustain agriculture in arid and semi-arid regions of the world.


Genetic and Proteomic Interrogation of Lower Confidence Candidate Genes Reveals Signaling Networks in β-Catenin-Active Cancers.
Genome-scale expression studies and comprehensive loss-of-function genetic screens have focused almost exclusively on the highest confidence candidate genes. Here, we describe a strategy for characterizing the lower confidence candidates identified by such approaches. We interrogated 177 genes that we classified as essential for the proliferation of cancer cells exhibiting constitutive β-catenin activity and integrated data for each of the candidates, derived from orthogonal short hairpin RNA (shRNA) knockdown and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated gene editing knockout screens, to yield 69 validated genes. We then characterized the relationships between sets of these genes using complementary assays: medium-throughput stable isotope labeling by amino acids in cell culture (SILAC)-based mass spectrometry, yielding 3,639 protein-protein interactions, and a CRISPR-mediated pairwise double knockout screen, yielding 375 combinations exhibiting greater- or lesser-than-additive phenotypic effects indicating genetic interactions. These studies identify previously unreported regulators of β-catenin, define functional networks required for the survival of β-catenin-active cancers, and provide an experimental strategy that may be applied to define other signaling networks.


A Ca(2+)-dependent K+ current is enhanced in arterial membranes of hypertensive rats.
This study was designed to investigate the role and regulation of arterial membrane K+ channels in hypertension. Aortic segments from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were suspended for isometric tension recording. In other experiments, proximal aortic segments (PS) (exposed to high pressure) and distal aortic segments (DS) (exposed to lower pressure) were removed from surgically coarcted Sprague-Dawley rats and similarly prepared. Aortas from SHR and PS dose-dependently contracted to the K+ channel blocker tetraethylammonium (TEA) (0.1-10 mM), and this contraction was abolished by preincubation with 0.1 microM nifedipine. In contrast, the same concentrations of TEA did not contract either WKY or DS aortas. Since block of K+ channels by TEA had a different effect on aortic segments exposed to high versus low blood pressure, we compared whole-cell K+ currents in isolated vascular cells from the same aortas. The reversal potentials of depolarization-induced outward currents in WKY, SHR, DS, and PS aortic cells showed a Nernst relation to external K+ concentration indicative of selective K+ permeability. TEA (1 and 10 mM) was equipotent in blocking these K+ currents in patch-clamped cells from all aortic preparations, suggesting that the lack of TEA-induced contractions in WKY and DS aortas was not due to an absence of TEA-sensitive K+ channels in these arterial membranes. However, when the Ca2+ ionophore A23187 (10 microM) was used to increase the level of cytosolic Ca2+ in patch-clamped cells, the K+ current density in SHR and PS aortic cells was twofold or more higher than in WKY and DS cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Functional Segregation of the Entopallium in Pigeons.
In birds, the entopallium is the primary telencephalic target of the major visual ascending route called the tectofugal pathway. Often functionally compared to the primate geniculo-striate pathway and its subsequent telencephalic (cortical) regions, the latter processes visual information in a parallel fashion in terms of anatomy, physiology, and function. Little is known, however, about the exact mechanism of whether or how information is segregated or integrated in the avian tectofugal pathway including the telencephalon. Testing four pigeons, we examined whether or not color, form, and motion information is selectively processed by different portions of the entopallium. Each learned three distinct visual tasks requiring discrimination of different combinations of color, form and motion cues. After learning and pre-lesion testing, two pigeons received lesions to the anterior portion of the entopallium and two received lesions to the posterior entopallium. During post-lesion testing the pigeons with anterior lesions exhibited significant deficits in those tasks most dependent on color and form discrimination, but showed no deficit on a task that had involved discriminating among forms that were moving. Pigeons with posterior lesions showed a different pattern of deficits, exhibiting significant reductions in discriminating both moving and static forms, but little or no deficits in color discrimination. These divergent profiles of effects for each lesion suggest there is a functional segregation of visual information processing in the pigeon telencephalon. This indicates a convergence between birds and primates regarding the parallel processing and separation of information within their phylogenetically distinct major visual pathways.


Hydrogel electrodeposition based on bipolar electrochemistry.
Bipolar electrochemistry has attracted great interest for applications based on sensing, electrografting, and electrodeposition, because the technique enables electrochemical reactions to be induced at multiple bipolar electrodes (BPEs) with only a single power supply. However, there are only a few reports on the biofabrication of hydrogels using BPEs. In this study, we applied bipolar electrochemistry to achieve the electrodeposition of calcium-alginate hydrogels at specified target areas, which is possible because of the use of water electrolysis to obtain acidification at the anodic pole. This scheme was used to successfully fabricate an array of hydrogel deposits at a BPE array. In addition, hydrogels were successfully fabricated either at only the target BPEs or only the target areas of BPEs by repositioning the driving electrodes. Furthermore, a hydrogel was drawn on a large BPE as a canvas by using small driving electrodes. As a demonstration of the electrodeposited hydrogels for bioapplications, mammal cells were cultured in the hydrogels. Because the amount and shape of the hydrogel deposits can be controlled by using the bipolar system, the system we developed can be used for biosensors and cell culture platforms.


Refractive-index sensor based on long-range surface plasmon mode excitation with long-period waveguide grating.
We propose a refractive-index sensor that operates on the principle of exciting the long-range surface plasmon mode of a metal-coated waveguide with a long-period grating formed in the waveguide, where the wavelength at which the mode excitation occurs serves as a measure of the refractive index of the external medium. We analyze the sensor with a coupled-mode theory and highlight the effects of the waveguide parameters on the loss of the surface plasmon mode and the performance of the sensor. Our results show that the sensor can provide a sharp resonance for high precision measurements and a high sensitivity comparable to that of an optimized bulk prism-based surface plasmon sensor. Our sensor also offers much flexibility in the choice of waveguide parameters for different applications.


Obtaining an isolate of Ancylostoma braziliense from cats without the need for necropsy.
Because the eggs of Ancylostoma species of dogs and cats are difficult to readily distinguish morphologically, isolation of a certain species often requires the humane death of the source animal or holding an animal after treatment to obtain worms for specific identification or to harvest ex utero eggs. The objective of this study was to obtain an isolate of Ancylostoma braziliense from 1-time, field-collected samples of feline feces without the need for the killing of any animals. During a collection trip to Florida, fecal samples (n = 40) were collected and identified as containing A. braziliense eggs (n = 26) using centrifugal sugar flotation. Eggs from hookworm-positive slides were washed into tubes, DNA was extracted, and 10 samples were identified as containing A. braziliense using restriction fragment length polymorphism (RFLP) with Hinf1. Six of these samples also contained DNA of Ancylostoma tubaeforme and, thus, only 4 samples were from cats infected only with A. braziliense. Larvae cultured from two of the latter samples were used to subcutaneously inoculate a purpose-bred puppy with the intention to inhibit the growth of any potentially contaminating A. tubaeforme larvae in the culture. The infection was patent at 14 days after inoculation, and the eggs were identified as A. braziliense by RFLP and DNA sequencing. Larvae were cultured from the feces of this dog and used to infect a laboratory-reared, specific-pathogen-free cat; the eggs and larvae produced by the cat were also identified molecularly as those of A. braziliense. The larvae from this cat were used to infect other cats to maintain the isolate for further research. Both the puppy and the first cat used in this study were treated to clear their infections and have since been adopted by new owners.


Effect of Genistein in Comparison with Trichostatin A on Reactivation of DNMTs Genes in Hepatocellular Carcinoma.
Background and Aims: DNA methylation and histone modification are epigenetic modifications essential for normal function of mammalian cells. The processes are mediated by biochemical interactions between DNA methyltransferases (DNMTs) and histone deacetylases. Promoter hypermethylation and deacetylation of tumor suppressor genes play major roles in cancer induction, through transcriptional silencing of these genes. DNA hypermethylation is carried out by a family of DNMTs including DNMT1, DNMT3a and DNMT3b. In hepatocellular carcinoma, a significant positive correlation between over-expression of these genes and cancer induction has been reported. The DNA demethylating agent genistein (GE) has been demonstrated to reduce different cancers. Previously, we reported that GE can induce apoptosis and inhibit proliferation in hepatocellular carcinoma PLC/PRF5 and HepG2 cell lines. Besides, histone deacetylase inhibitors, such as trichostatin A (TSA), were successfully used to inhibit cancer cell growth. The present study was designed to assess the effect of GE in comparison with TSA on DNMT1, DNMT3a and DNMT3b gene expression, cell growth inhibition and apoptosis induction in the HepG2 cell line. Methods: Cells were seeded and treated with various doses of GE and TSA. The MTT assay, flow cytometry assay, and real-time RT-PCR were used to determine viability, apoptosis, and DNMT1, DNMT3a and DNMT3b gene expression respectively. Results: Both agents inhibited cell growth, induced apoptosis and reactivated DNMT1, DNMT3a and DNMT3b gene expression. Furthermore, TSA demonstrated a significantly greater apoptotic effect than the other agent, whereas GE improved gene expression more significantly than TSA. Conclusions: Our findings suggest that GE and TSA can significantly inhibit cell growth, induce apoptosis and restore DNMT1, DNMT3a and DNMT3b gene reactivation.


A histologic scoring system for prognosis of patients with alcoholic hepatitis.
There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.


Edmund Engelman. Photographer of Sigmund Freud's home and offices.
Over the course of several days in May 1938, Edmund Engelman, a young, talented and resourceful Viennese photographer, immortalised the home and offices of Sigmund Freud in a series of pictures that represent the fullest visual documentation of the setting in which Freud lived and worked throughout almost his entire career. He also photographed Freud, his daughter and his wife. These photographs are best known through a book that also contains a memoir of Engelman (Engelman, 1976). The photographs have been recognised primarily for their documentary value and not appreciated for their artistic merit. Through a series of interviews with Engelman and members of his family, biographical data about the artist and information about the photographs has been gathered that heretofore has not been published. This historical note elaborates on Engelman's life before and after taking the photographs, and places the photographs in the context of the life of the photographer.


Molecular Modes and Dynamics of HCl and DCl Guests of Gas Clathrate Hydrates.
Recent years have yielded advances in the placement of unusual molecules as guests within clathrate hydrates (CHs) without severe distortion of the classic lattice structures. Reports describing systems for which observable but limited distortion does occur are available for methanol, ammonia, acetone, and small ether molecules. In these particular examples, the large-cage molecules often participate as non-classical guests H-bonded to the cage walls. Here, we expand the list of such components to include HCl/DCl and HBr as small-cage guests. Based on FTIR spectra of nanocrystalline CHs from two distinct preparative methods combined with critical insights derived from on-the-fly molecular dynamics and ab initio computational data, a coherent argument emerges that these strong acids serve as a source of molecular small-cage guests, ions, and orientational defects. Depending on the HCl/DCl content the ions, defects and molecular guests determine the CH structures, some of which form in sub-seconds via an all-vapor preparative method.


Diagnostic Performance of an Advanced Modeled Iterative Reconstruction Algorithm for Low-Contrast Detectability with a Third-Generation Dual-Source Multidetector CT Scanner: Potential for Radiation Dose Reduction in a Multireader Study.
To assess the effect of radiation dose reduction on low-contrast detectability by using an advanced modeled iterative reconstruction (ADMIRE; Siemens Healthcare, Forchheim, Germany) algorithm in a contrast-detail phantom with a third-generation dual-source multidetector computed tomography (CT) scanner. A proprietary phantom with a range of low-contrast cylindrical objects, representing five contrast levels (range, 5-20 HU) and three sizes (range, 2-6 mm) was fabricated with a three-dimensional printer and imaged with a third-generation dual-source CT scanner at various radiation dose index levels (range, 0.74-5.8 mGy). Image data sets were reconstructed by using different section thicknesses (range, 0.6-5.0 mm) and reconstruction algorithms (filtered back projection [FBP] and ADMIRE with a strength range of three to five). Eleven independent readers blinded to technique and reconstruction method assessed all data sets in two reading sessions by measuring detection accuracy with a two-alternative forced choice approach (first session) and by scoring the total number of visible object groups (second session). Dose reduction potentials based on both reading sessions were estimated. Results between FBP and ADMIRE were compared by using both paired t tests and analysis of variance tests at the 95% significance level. During the first session, detection accuracy increased with increasing contrast, size, and dose index (diagnostic accuracy range, 50%-87%; interobserver variability, ±7%). When compared with FBP, ADMIRE improved detection accuracy by 5.2% on average across the investigated variables (P < .001). During the second session, a significantly increased number of visible objects was noted with increasing radiation dose index, section thickness, and ADMIRE strength over FBP (up to 80% more visible objects, P < .001). Radiation dose reduction potential ranged from 56% to 60% and from 4% to 80% during the two sessions, respectively. Low-contrast detectability performance increased with increasing object size, object contrast, dose index, section thickness, and ADMIRE strength. Compared with FBP, ADMIRE allows a substantial radiation dose reduction while preserving low-contrast detectability. Online supplemental material is available for this article.


MicroRNAs and cardiac sarcoplasmic reticulum calcium ATPase-2 in human myocardial infarction: expression and bioinformatic analysis.
Cardiac sarco(endo)plasmic reticulum calcium ATPase-2 (SERCA2) plays one of the central roles in myocardial contractility. Both, SERCA2 mRNA and protein are reduced in myocardial infarction (MI), but the correlation has not been always observed. MicroRNAs (miRNAs) act by targeting 3'-UTR mRNA, causing translational repression in physiological and pathological conditions, including cardiovascular diseases. One of the aims of our study was to identify miRNAs that could influence SERCA2 expression in human MI. The protein SERCA2 was decreased and 43 miRNAs were deregulated in infarcted myocardium compared to corresponding remote myocardium, analyzed by western blot and microRNA microarrays, respectively. All the samples were stored as FFPE tissue and in RNAlater. miRNAs binding prediction to SERCA2 including four prediction algorithms (TargetScan, PicTar, miRanda and mirTarget2) identified 213 putative miRNAs. TAM and miRNApath annotation of deregulated miRNAs identified 18 functional and 21 diseased states related to heart diseases, and association of the half of the deregulated miRNAs to SERCA2. Free-energy of binding and flanking regions (RNA22, RNAfold) was calculated for 10 up-regulated miRNAs from microarray analysis (miR-122, miR-320a/b/c/d, miR-574-3p/-5p, miR-199a, miR-140, and miR-483), and nine miRNAs deregulated from microarray analysis were used for validation with qPCR (miR-21, miR-122, miR-126, miR-1, miR-133, miR-125a/b, and miR-98). Based on qPCR results, the comparison between FFPE and RNAlater stored tissue samples, between Sybr Green and TaqMan approaches, as well as between different reference genes were also performed. Combing all the results, we identified certain miRNAs as potential regulators of SERCA2; however, further functional studies are needed for verification. Using qPCR, we confirmed deregulation of nine miRNAs in human MI, and show that qPCR normalization strategy is important for the outcome of miRNA expression analysis in human MI.


Haploinsufficiency of the E3 ubiquitin ligase C-terminus of heat shock cognate 70 interacting protein (CHIP) produces specific behavioral impairments.
The multifunctional E3 ubiquitin ligase CHIP is an essential interacting partner of HSP70, which together promote the proteasomal degradation of client proteins. Acute CHIP overexpression provides neuroprotection against neurotoxic mitochondrial stress, glucocorticoids, and accumulation of toxic amyloid fragments, as well as genetic mutations in other E3 ligases, which have been shown to result in familial Parkinson's disease. These studies have created a great deal of interest in understanding CHIP activity, expression and modulation. While CHIP knockout mice have the potential to provide essential insights into the molecular control of cell fate and survival, the animals have been difficult to characterize in vivo due to severe phenotypic and behavioral dysfunction, which have thus far been poorly characterized. Therefore, in the present study we conducted a battery of neurobehavioral and physiological assays of adult CHIP heterozygotic (HET) mutant mice to provide a better understanding of the functional consequence of CHIP deficiency. We found that CHIP HET mice had normal body and brain weight, body temperature, muscle tone and breathing patterns, but do have a significant elevation in baseline heart rate. Meanwhile basic behavioral screens of sensory, motor, emotional and cognitive functions were normative. We observed no alterations in performance in the elevated plus maze, light-dark preference and tail suspension assays, or two simple cognitive tasks: novel object recognition and spontaneous alternation in a Y maze. Significant deficits were found, however, when CHIP HET mice performed wire hang, inverted screen, wire maneuver, and open field tasks. Taken together, our data indicate a clear subset of behaviors that are altered at baseline in CHIP deficient animals, which will further guide whole animal studies of the effects of CHIP dysregulation on cardiac function, brain circuitry and function, and responsiveness to environmental and cellular stress.


A New Era of Low-Dose Radiation Epidemiology.
The last decade has introduced a new era of epidemiologic studies of low-dose radiation facilitated by electronic record linkage and pooling of cohorts that allow for more direct and powerful assessments of cancer and other stochastic effects at doses below 100 mGy. Such studies have provided additional evidence regarding the risks of cancer, particularly leukemia, associated with lower-dose radiation exposures from medical, environmental, and occupational radiation sources, and have questioned the previous findings with regard to possible thresholds for cardiovascular disease and cataracts. Integrated analysis of next generation genomic and epigenetic sequencing of germline and somatic tissues could soon propel our understanding further regarding disease risk thresholds, radiosensitivity of population subgroups and individuals, and the mechanisms of radiation carcinogenesis. These advances in low-dose radiation epidemiology are critical to our understanding of chronic disease risks from the burgeoning use of newer and emerging medical imaging technologies, and the continued potential threat of nuclear power plant accidents or other radiological emergencies.


Changes to virus taxonomy and to the International Code of Virus Classification and Nomenclature ratified by the International Committee on Taxonomy of Viruses (2021).
This article reports the changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses (ICTV) in March 2021. The entire ICTV was invited to vote on 290 taxonomic proposals approved by the ICTV Executive Committee at its meeting in October 2020, as well as on the proposed revision of the International Code of Virus Classification and Nomenclature (ICVCN). All proposals and the revision were ratified by an absolute majority of the ICTV members. Of note, ICTV mandated a uniform rule for virus species naming, which will follow the binomial 'genus-species' format with or without Latinized species epithets. The Study Groups are requested to convert all previously established species names to the new format. ICTV has also abolished the notion of a type species, i.e., a species chosen to serve as a name-bearing type of a virus genus. The remit of ICTV has been clarified through an official definition of 'virus' and several other types of mobile genetic elements. The ICVCN and ICTV Statutes have been amended to reflect these changes.


Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level.
Medication development for alcohol relapse prevention or reduction of consumption is highly challenging due to methodological issues of pharmacotherapy trials. Existing approved medications are only modestly effective with many patients failing to benefit from these therapies. Therefore, there is a pressing need for other effective treatments with a different mechanism of action, especially for patients with very high (VH) drinking risk levels (DRL) because this is the most severely affected population of alcohol use disorder patients. Life expectancy of alcohol-dependent patients with a VH DRL is reduced by 22 years compared with the general population and approximately 90 000 alcohol-dependent subjects with a VH DRL die prematurely each year in the EU (Rehm et al. ). A promising new medication for this population is sodium oxybate, a compound that acts on GABAB receptors and extrasynaptic GABAA receptors resulting in alcohol-mimetic effects. In this article, a European expert group of alcohol researchers and clinicians summarizes data (a) from published trials, (b) from two new-as yet unpublished-large clinical trials (GATE 2 (n = 314) and SMO032 (n = 496), (c) from post hoc subgroup analyses of patients with different WHO-defined DRLs and (d) from multiple meta-analyses. These data provide convergent evidence that sodium oxybate is effective especially in a subgroup of alcohol-dependent patients with VH DRLs. Depending on the study, abstinence rates are increased up to 34 percent compared with placebo with risk ratios up to 6.8 in favor of sodium oxybate treatment. These convergent data are supported by the clinical use of sodium oxybate in Austria and Italy for more than 25 years. Sodium oxybate is the sodium salt of γ-hydroxybutyric acid that is also used as a recreational (street) drug suggestive of abuse potential. However, a pharmacovigilance database of more than 260 000 alcohol-dependent patients treated with sodium oxybate reported very few adverse side effects and only few cases of abuse. We therefore conclude that sodium oxybate is an effective, well-tolerated and safe treatment for withdrawal and relapse prevention treatment, especially in alcohol-dependent patients with VH DRL.


Unique Properties of SBN and Their Use in a Layered Optical Memory.
Holographic storage experiments using crystal Sr(0.75)Ba(0.25)Nb(2)O(6) (SBN 75/25) as a volume-phase holographic medium show that this material is the most sensitive crystalline storage medium yet discovered. An exposure level of 0.003 J/cm(2) at 0.488 microm produces a 1% diffraction efficiency in a 5-mm length of crystal. In addition to high recording sensitivity, SBN 75-25 exhibits interesting electric-field induced effects that include electric-field enhanced recording sensitivity and voltage-switchable latent-to-active holographic reconstruction efficiency. These effects are explained in terms of drift and diffusion of photoionized carriers coupled with the nonlinear electrooptic behavior characteristic of this low Curie temperature ferroelectric crystal. Detailed measurements of the holographic recording and reconstruction properties of thick phase-volume holograms stored in SBN 75/25 are reported. A mechanism is proposed that correlates the observed electrically controlled holographic response with the dielectric behavior of the crystal. These interesting effects are used to implement a novel, layered optical memory having no moving parts and having electrical access for writing or reading selected layers. An experimental model of the layered memory was constructed to demonstrate the interrelation of the several phenomena involved in the layered concept.


Dialysis outcomes in India: a pilot study.
Long-term prospective studies of health outcomes for dialysis patients are common in many parts of the world but have been rare in India. As renal replacement therapy becomes more widespread and more affordable, the measurement of patient outcomes and comparison with national and international benchmarks will be a valuable tool in planning health services and demonstrating effective use of resources. To this end, we describe a pilot study of dialysis outcomes in India which could form the basis of a comprehensive national programme of data collection. One hundred incident patients commencing chronic haemodialysis in two north Indian nephrology centres will be followed prospectively for 12 months. Clinical outcome data will be collected comparable with that used by established dialysis registries in other countries. The economic impact of dialysis upon patients is central to the use of this treatment, so data will be collected on the direct and indirect costs of the treatment and the economic impact of dialysis on the patient and their family. This prospective cohort study of dialysis outcomes in northern India is a pilot for the collection of similar comparative data in dialysis centres in different states across the country with a view to the development of a national dialysis registry. The information on the economic impact of dialysis on patients and their families will provide one of the first detailed insights into this critical aspect of dialysis services.


Sun protection education for adolescents: a feasibility study of a wait-list controlled trial of an intervention involving a presentation, action planning, and SMS messages and using objective measurement of sun exposure.
People increase their risk of melanoma unless they are protected from the harmful effects of sun exposure during childhood and adolescence. We aimed to assess the feasibility of a three-component sun protection intervention- presentation, action planning, and SMS messages - and trial parameters. This feasibility wait-list trial was conducted in the United Kingdom in 2018. Students aged 13-15 years were eligible. Feasibility outcomes were collected for recruitment rates; data availability rates for objective measurements of melanin and erythema using a Mexameter and self-reported sunburn occurrences, severity and body location, tanning, sun protection behaviours and Skin Self-Examination (SSE) collected before (baseline) and after the school summer holidays (follow-up); intervention reach, adherence, perceived impact and acceptability. Quantitative data were analysed using descriptive statistics; qualitative data were analysed thematically. Five out of eight schools expressing an interest in participating with four allocated to act as intervention and one control. Four parents/carers opted their child out of the study. Four hundred and eighty-seven out of 724 students on the school register consented to the study at baseline (67%). Three hundred and eighty-five were in intervention group schools. Objective skin measurements were available for 255 (66%) of the intervention group at baseline and 237 (61%) of the group at follow up. Melanin increased; erythema decreased. Complete self-report data were available for 247 (64%) students in the intervention group. The number of students on the school register who attended the presentation and given the booklet was 379 (98%) and gave their mobile phone number was 155 (40%). No intervention component was perceived as more impactful on sun protection behaviours. Adolescents did not see the relevance of sun protection in the UK or for their age group. This is the first study to use a Mexameter to measure skin colour in adolescents. Erythema (visible redness) lasts no more than three days and its measurement before and after a six week summer holiday may not yield relevant or meaningful data. A major challenge is that adolescents do not see the relevance of sun protection and SSE. International Standard Randomised Controlled Trial Number ISRCTN11141528. Date registered 0/2/03/2018; last edited 31/05/2018. Retrospectively registered.


Model-based detection of heart rate turbulence.
In this study, the integral pulse frequency modulation model is extended to account for the presence of ectopic beats and heart rate turbulence (HRT). Based on this model, a new statistical approach to the detection and characterization of HRT is presented. The detector structure involves a set of Karhunen-LoEve basis functions and a generalized likelihood ratio test statistic T(x) . The three most significant basis functions reflect the difference in heart rate prior to a ventricular ectopic beat (VEB) compared to after HRT, the "average" HRT, and a delayed contribution to HRT, respectively. Detector performance was studied on both simulated and ECG signals. Three different simulations were performed for the purpose of studying the influence of SNR, QRS jitter, and ECG sampling rate. The results show that the HRT test statistic T(x) performs better in all simulations than do the commonly used parameters known as turbulence onset (TO) and turbulence slope (TS). In order to attain the same performance as T(x), TS needs at least twice the amount of VEBs for averaging, and TO at least four times. The detector performance was also studied on ECGs acquired from eight patients who underwent hemodialysis treatment with the goal to discriminate between patients considered to be hypotension-resistant (HtR) and hypotension-prone (HtP). The results show that T(x) exhibits larger mean values in HtR patients than in HtP, suggesting that HRT is mostly present in HtR patients. The overlap between the two groups was larger for TO and TS than for T(x).


Evaluating a new method for reconstructing forest conditions from General Land Office survey records.
Historical forest conditions are often used to inform contemporary management goals because historical forests are considered to be resilient to ecological disturbances. The General Land Office (GLO) surveys of the late 19th and early 20th centuries provide regionally quasi-contiguous data sets of historical forests across much of the Western United States. Multiple methods exist for estimating tree density from point-based sampling such as the GLO surveys, including distance-based and area-based approaches. Area-based approaches have been applied in California mixed-conifer forests but their estimates have not been validated. To assess the accuracy and precision of plotless density estimators with potential for application to GLO data in this region, we imposed a GLO sampling scheme on six mapped forest stands of known densities (159-784 trees/ha) in the Sierra Nevada in California, USA, and Baja California Norte, Mexico. We compared three distance-based plotless density estimators (Cottam, Pollard, and Morisita) as well as two Voronoi area (VA) estimators, the Delincé and mean harmonic Voronoi density (MHVD), to the true densities. We simulated sampling schemes of increasing intensity to assess sampling error. The relative error (RE) of density estimates for the GLO sampling scheme ranged from 0.36 to 4.78. The least biased estimate of tree density in every stand was obtained with the Morisita estimator and the most biased was obtained with the MHVD estimator. The MHVD estimates of tree density were 1.2-3.8 times larger than the true densities and performed best in stands subject to fire exclusion for 100 yr. The Delincé approach obtained accurate estimates of density, implying that the Voronoi approach is theoretically sound but that its application in the MHVD was flawed. The misapplication was attributed to two causes: (1) the use of a crown scaling factor that does not correct for the number of trees sampled and (2) the persistent underestimate of the true VA due to a weak relationship between tree size and VA. The magnitude of differences between true densities and MHVD estimates suggest caution in using results based on the MHVD to inform management and restoration practices in the conifer forests of the American West.


Guidance of neuronal growth cones in the grasshopper embryo. III. Recognition of specific glial pathways.
In the previous 2 papers, we focused on the selective affinities that growth cones display for specific axonal pathways. Little is known, however, about how this orthogonal scaffold of axonal pathways in the CNS is established in the first place, and what, if any, role glia might play in these events. Here we show an important relationship between pioneering growth cones and primitive glial cells in the developing longitudinal connectives and peripheral nerve roots of the grasshopper embryo. We describe a preformed glial pathway for the formation of the intersegmental nerve, one of the major roots exiting the CNS. The growth cones that pioneer this nerve display a selective affinity for the segment boundary cell (SBC), a primitive glial cell that establishes the location of this nerve root. Similar glial cells are also found along the pathway where the longitudinal connectives form, and they too may play an important role in the formation of the first longitudinal axonal pathways. Experimental analysis shows that when the SBC is ablated, the growth cones that normally turn laterally to pioneer the intersegmental nerve do not do so, thus confirming the importance of the guiding role of this glial cell. We postulate that a simple orthogonal scaffold of primitive glia is involved in the initial patterning of axonal pathways within and exiting the insect CNS; this concept is remarkably similar to the blueprint hypothesis proposed by Singer et al. (1979) to explain the development of axon pathways in vertebrates.


A distinct urinary biomarker pattern characteristic of female Fabry patients that mirrors response to enzyme replacement therapy.
Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naïve female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2% sensitivity and 97.8% specificity when tested in an independent validation cohort consisting of 17 treatment-naïve Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.


Temporary inhibition of Moloney-murine sarcoma virus (M-MSV) induced-tumours by adoptive transfer of ricin-treated T-lymphocytes.
The potential use of tumour-specific T-lymphocytes loaded with ricin in cell targeting experiments was investigated. Moloney-murine sarcoma virus (M-MSV)-specific T-lymphocytes, obtained in mass mixed leucocyte-tumour cell culture (MLTC) and a M-MSV-specific cytotoxic T-lymphocyte (CTL) clone, were incubated with 125I-labelled ricin in order to evaluate toxin uptake and release. The internalized ricin (4.5 X 10(-17) mol and 6.5 X 10(-17) mol per 10(2) MLTC and CTL clone cells, respectively) was released rapidly during the first 30 min following treatment, and at a constant but slower rate over the next few hours. The cytotoxic activity of ricin-treated cells evaluated against antigen-related target cells, in a short term incubation 51Cr release assay, was unaffected during the first 30 min after treatment but decreased with time over the next few hours. However, the growth of antigen related as well as of unrelated tumour cells was strongly inhibited by the addition of ricin-treated cells to the culture system, thus indicating that released ricin is toxic for untreated target cells. The in vivo localization pattern of ricin-treated radiolabelled MLTC cells was found to be comparable with that of untreated cells 1 h after i.v. injection into syngeneic sublethally irradiated mice. After 6 h, however, more radiolabel was recovered from the liver of mice receiving ricin-treated MLTC cells. Ricin-treated M-MSV-specific T-lymphocytes were injected i.v. into tumour bearing sublethally irradiated mice. A temporary tumour growth inhibition (up to 6 days) was achieved following transfer of low doses of ricin-treated MLTC or CTL clone cells (1 X 10(6) and 0.5 X 10(6), respectively). In contrast, in M-MSV injected control mice, receiving only free toxin (from 5 to 20 ng) or untreated tumour-specific effector cell tumours grew progressively. The therapeutic effect was apparently specific since the injection of ricin-treated alloreactive T-lymphocytes did not influence tumour growth. These results suggest that M-MSV-specific T-lymphocytes loaded with ricin can deliver toxin to the target tumour mass and have a transient therapeutic effect.


Patterns of chronic hand eczema: a semantic map analysis of the CARPE registry data.
Hand eczema has a high incidence and prevalence and has a negative impact on both physical and psychological well-being, with the risk of persistence as a chronic condition. Epidemiological studies on hand eczema provided mainly descriptive and risk analyses, but pattern analyses of variables associated with hand eczema, in particular chronic hand eczema, have not been explored to date. To investigate and display the semantics of associations between variables of hand eczema obtained from the Swiss and German registries of chronic hand eczema (CARPE) to dissect patterns and novel links. This was a cross-sectional study on selected variables from the CARPE registries. Associations between variables were analysed by means of an autoassociative system. A semantic connectivity map was generated by using a maximum spanning tree algorithm. Baseline datasets of 1466 patients with chronic hand eczema (Switzerland: 199; Germany: 1267) were analysed. Occupational exposure had the highest impact in the total and country cohorts. We identified two areas of exposure linked to corresponding occupations that clearly demarcated the sexes. This study, using semantic connectivity as a novel method of data analysis, reveals the complexity of features characterizing chronic hand eczema as well as novel association patterns that deserve further investigation.


Surface protonation at the rutile (110) interface: explicit incorporation of solvation structure within the refined MUSIC model framework.
The detailed solvation structure at the (110) surface of rutile (alpha-TiO2) in contact with bulk liquid water has been obtained primarily from experimentally verified classical molecular dynamics (CMD) simulations of the ab initio-optimized surface in contact with SPC/E water. The results are used to explicitly quantify H-bonding interactions, which are then used within the refined MUSIC model framework to predict surface oxygen protonation constants. Quantum mechanical molecular dynamics (QMD) simulations in the presence of freely dissociable water molecules produced H-bond distributions around deprotonated surface oxygens very similar to those obtained by CMD with nondissociable SPC/E water, thereby confirming that the less computationally intensive CMD simulations provide accurate H-bond information. Utilizing this H-bond information within the refined MUSIC model, along with manually adjusted Ti-O surface bond lengths that are nonetheless within 0.05 A of those obtained from static density functional theory (DFT) calculations and measured in X-ray reflectivity experiments (as well as bulk crystal values), give surface protonation constants that result in a calculated zero net proton charge pH value (pHznpc) at 25 degrees C that agrees quantitatively with the experimentally determined value (5.4+/-0.2) for a specific rutile powder dominated by the (110) crystal face. Moreover, the predicted pHznpc values agree to within 0.1 pH unit with those measured at all temperatures between 10 and 250 degrees C. A slightly smaller manual adjustment of the DFT-derived Ti-O surface bond lengths was sufficient to bring the predicted pHznpcvalue of the rutile (110) surface at 25 degrees C into quantitative agreement with the experimental value (4.8+/-0.3) obtained from a polished and annealed rutile (110) single crystal surface in contact with dilute sodium nitrate solutions using second harmonic generation (SHG) intensity measurements as a function of ionic strength. Additionally, the H-bond interactions between protolyzable surface oxygen groups and water were found to be stronger than those between bulk water molecules at all temperatures investigated in our CMD simulations (25, 150 and 250 degrees C). Comparison with the protonation scheme previously determined for the (110) surface of isostructural cassiterite (alpha-SnO2) reveals that the greater extent of H-bonding on the latter surface, and in particular between water and the terminal hydroxyl group (Sn-OH) results in the predicted protonation constant for that group being lower than for the bridged oxygen (Sn-O-Sn), while the reverse is true for the rutile (110) surface. These results demonstrate the importance of H-bond structure in dictating surface protonation behavior, and that explicit use of this solvation structure within the refined MUSIC model framework results in predicted surface protonation constants that are also consistent with a variety of other experimental and computational data.


Creating a national citizen engagement process for energy policy.
This paper examines some of the science communication challenges involved when designing and conducting public deliberation processes on issues of national importance. We take as our illustrative case study a recent research project investigating public values and attitudes toward future energy system change for the United Kingdom. National-level issues such as this are often particularly difficult to engage the public with because of their inherent complexity, derived from multiple interconnected elements and policy frames, extended scales of analysis, and different manifestations of uncertainty. With reference to the energy system project, we discuss ways of meeting a series of science communication challenges arising when engaging the public with national topics, including the need to articulate systems thinking and problem scale, to provide balanced information and policy framings in ways that open up spaces for reflection and deliberation, and the need for varied methods of facilitation and data synthesis that permit access to participants' broader values. Although resource intensive, national-level deliberation is possible and can produce useful insights both for participants and for science policy.


Recruitment of Atg9 to the preautophagosomal structure by Atg11 is essential for selective autophagy in budding yeast.
Autophagy is a conserved degradative pathway that is induced in response to various stress and developmental conditions in eukaryotic cells. It allows the elimination of cytosolic proteins and organelles in the lysosome/vacuole. In the yeast Saccharomyces cerevisiae, the integral membrane protein Atg9 (autophagy-related protein 9) cycles between mitochondria and the preautophagosomal structure (PAS), the nucleating site for formation of the sequestering vesicle, suggesting a role in supplying membrane for vesicle formation and/or expansion during autophagy. To better understand the mechanisms involved in Atg9 cycling, we performed a yeast two-hybrid-based screen and identified a peripheral membrane protein, Atg11, that interacts with Atg9. We show that Atg11 governs Atg9 cycling through the PAS during specific autophagy. We also demonstrate that the integrity of the actin cytoskeleton is essential for correct targeting of Atg11 to the PAS. We propose that a pool of Atg11 mediates the anterograde transport of Atg9 to the PAS that is dependent on the actin cytoskeleton during yeast vegetative growth.


Modeling of environmental effects in genome-wide association studies identifies SLC2A2 and HP as novel loci influencing serum cholesterol levels.
Genome-wide association studies (GWAS) have identified 38 larger genetic regions affecting classical blood lipid levels without adjusting for important environmental influences. We modeled diet and physical activity in a GWAS in order to identify novel loci affecting total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels. The Swedish (SE) EUROSPAN cohort (N(SE) = 656) was screened for candidate genes and the non-Swedish (NS) EUROSPAN cohorts (N(NS) = 3,282) were used for replication. In total, 3 SNPs were associated in the Swedish sample and were replicated in the non-Swedish cohorts. While SNP rs1532624 was a replication of the previously published association between CETP and HDL cholesterol, the other two were novel findings. For the latter SNPs, the p-value for association was substantially improved by inclusion of environmental covariates: SNP rs5400 (p(SE,unadjusted) = 3.6 x 10(-5), p(SE,adjusted) = 2.2 x 10(-6), p(NS,unadjusted) = 0.047) in the SLC2A2 (Glucose transporter type 2) and rs2000999 (p(SE,unadjusted) = 1.1 x 10(-3), p(SE,adjusted) = 3.8 x 10(-4), p(NS,unadjusted) = 0.035) in the HP gene (Haptoglobin-related protein precursor). Both showed evidence of association with total cholesterol. These results demonstrate that inclusion of important environmental factors in the analysis model can reveal new genetic susceptibility loci.


Episode sensitivity in association with process indicators in the Finnish breast cancer screening program.
We assessed the episode sensitivity of the Finnish mammography program for women aged 50-59 (partly 60-64) years and explored associations between the episode sensitivity and the screening process indicators from 1991 to 1999. For the study period, data were available from 10 screening centers. Records of 721,000 screening visits were linked to the files of the nationwide Finnish Cancer Registry from 1991 to 2001 at an individual level. The rates of screen-detected and interval breast cancers were calculated at the first and at the subsequent screens. The episode sensitivity was determined by contrasting the incidence of interval cancers with the expected population incidence rate without screening (incidence method) and as a proportion of interval cancers out of all cancers detected (detection method). At the subsequent screens, the episode sensitivity determined by the incidence method was 54% and by the detection method 65%. The sensitivity 0-11 and 12-23 months after the screening was 70% and 38%, respectively. The episode sensitivity decreased toward the end of the study period and increased with age. The center-specific sensitivity increased 13% per 1% absolute increase in the recall rate. In general, our study provides further information on the effectiveness of screening programs. The sensitivity estimates were comparable with those from other European service screening programs. The variability in the episode sensitivity suggests potential for variations in the future screening outcome.


Low knowledge and awareness of monoclonal gammopathy of undetermined significance (MGUS) among general practitioners.
While multiple myeloma (MM) is a rare diagnosis within primary care, its precursor MGUS (monoclonal gammopathy of undetermined significance) is more common, particularly among older populations. Upon first detection, the majority of MGUS patients will be under the care of their General Practitioner (GP)/Family Doctor who is also often the first healthcare professional that patients report symptoms of progression to. However, our previous work with MGUS patients and haematology healthcare professionals has suggested that knowledge and awareness of MGUS is low among GPs. An online survey was undertaken to investigate knowledge and awareness of MGUS and services needed by GPs/GP trainees to support these patients. The survey was promoted at a large European primary care conference and via social media. Descriptive statistics were utilised to compare participant responses. In total 58 GPs (n = 35 GPs and n = 23 GP trainees) from 24 countries responded. Overall, self-reported familiarity with the term MGUS was low (mean score: 2.21/5, standard deviation (SD): 1.09), but higher among GPs who reported having at least one MGUS patient (mean score: 2.83/5, SD 0.99). The majority (88.2%) of GPs/GP trainees stated they would feel uncomfortable discussing MGUS with patients. The increased risk of haematological malignancies was identified by 62.1% of GPs/GP trainees with MM, lymphoma and myelodysplastic syndromes the most commonly reported cancers associated with MGUS. The majority (81.6%) of GPs/GP trainees were supportive of patient follow-up via telephone clinics (phlebotomy performed in GP practice with patient management maintained by haematology) but only 27.1% stated they would be happy to solely manage all low/low-intermediate risk MGUS patients. A laboratory report alerting to the possibility of MGUS or a haematological malignancy was reported as the most useful service which could be implemented to help GPs manage MGUS patients. The need for MGUS focused information and education resources for GPs was also highlighted. The findings of this study highlight a lack of knowledge and awareness of MGUS among GPs/ GP trainees. The majority of GPs/GP trainees are happy to support haematology in managing these patients but require assistance and support in providing these services.


Prostate Cancer Development Is Not Affected by Statin Use in Patients with Elevated PSA Levels.
Background: The role of statins in prostate cancer (PCa) remains unclear. Conflicting evidence has been found concerning risk reduction with the use of statins on biochemical recurrence (BCR). In this study, we evaluated whether statin use decreases the incidence of advanced PCa in males with elevated prostate-specific antigen (PSA; ≥4.0 ng/mL) levels and determined whether statin use reduces the risk of BCR after radical prostatectomy (RP). Methods: Patients visiting the outpatient urology clinic of the VU Medical Center between 2006 and 2018 with elevated PSA were retrospectively analyzed. Biochemical recurrence after RP was defined as a PSA level of ≥0.2 ng/mL (measured twice). Results: A total of 1566 patients were included, of which 1122 (72%) were diagnosed with PCa. At the time of diagnosis, 252 patients (23%) used statins compared to 83 patients (19%) in the non-malignancy group (p = 0.10). No differences were found in the use of statins between the different risk groups. No correlation was found between the risk of BCR after RP and the use of statins in the total (p = 0.20), the intermediate-risk group (p = 0.63) or the high-risk group (p = 0.14). Conclusion: The use of statins does not affect PCa development/progression in patients with elevated PSA levels, nor the development of BCR after RP.


Nuclear medicine in Vietnam.
Despite the presence of many bright Vietnamese nuclear medicine physicians and scientists, the level of clinical practice languishes seriously behind that of Europe, the United States, Japan and most other parts of the world. This is directly attributable to the country's severe poverty, which places serious constraints on the number of available pieces of functioning imaging equipment, the ability to service equipment and establish appropriate quality assurance and preventative maintenance programs and the ability to purchase adequate radiopharmaceuticals to serve their patients' needs. At this time, the Vietnamese nuclear medicine community is anxious to enhance its contact with colleagues throughout the world. They need and welcome help in obtaining instrumentation, in vivo and in vitro diagnostic kits and educational aids from outside agencies, commercial countries and medical centers that are able to assist them. They would be most appreciative to receive and encourage visits from professional colleagues who would be able to provide lectures, seminars, books, journals and other teaching tools that would contribute to the upgrading of their clinical practice of nuclear medicine.


Student-teacher relationship trajectories and mental health problems in young children.
This longitudinal study classified groups of children experiencing different trajectories of student-teacher relationship quality over the transition from preschool into school, and determined the strength of the association between different student-teacher relationship trajectories and childhood mental health problems in the second year of primary school. A community sample of 460 Australian children were assessed in preschool (age 4), the first school year (age 5), and second school year (age 6). Teachers at all three assessments reported on student-teacher relationship quality with the Student Teacher Relationship Scale. When the children were at preschool and in their second school year, parents and teachers rated children's mental health problems using the Strengths and Difficulties Questionnaire. Latent-class growth modelling identified two trajectories of student-teacher relationship quality: (1) a stable-high student-teacher relationship quality and (2) a moderate/declining student-teacher relationship quality trajectory. Generalised linear models found that after adjusting for family demographic characteristics, having a stable high quality student-teacher relationship trajectory was associated with fewer parent-rated and teacher-rated total mental health problems, and fewer conduct, hyperactivity, and peer problems, and greater prosocial behaviour at age 6. A stable high quality trajectory was also associated with fewer teacher-rated, but not parent-rated emotional symptoms. These effects remained after adjustment for levels of mental health problems at age 4. Findings suggest that early intervention and prevention strategies that focus on building stable high quality student-teacher relationships during preschool and children's transition into formal schooling, may help reduce rates of childhood mental health problems during the early school years.


Experimental exposure of swallow bugs (Hemiptera: Cimicidae) to West Nile virus.
The cliff swallow (Petrochelidon pyrrhonota, Vieillot) could potentially play an important role in the transmission of West Nile virus (WNV) because of its breeding ecology, reservoir competence status, and potentially high natural exposure rates. These birds nest in colonies and their nests are occupied year round by swallow bugs (Oeciacus vicarius, Hovarth), hematophagus ectoparasites that feed primarily on cliff swallows. Swallow bugs are most likely exposed to WNV while feeding on infectious blood of cliff swallows and, thus, if competent vectors, could contribute to initiation and maintenance of seasonal WNV transmission. In addition, swallow bugs remain within nests year round and, therefore, if persistently infected and competent vectors, they could provide an overwintering mechanism for WNV. We tested the hypothesis that swallow bugs become infected with WNV through direct abdominal inoculation or ingestion of infectious blood meals. We observed that swallow bugs did not maintain or amplify WNV, and infectious virus titers within bugs declined over 15 d postexposure. These results suggest that swallow bugs may not be competent vectors of WNV, and therefore are unlikely to play a significant role in transmission.


Risk score model for the assessment of coronary artery disease in asymptomatic patients with type 2 diabetes.
No model has been developed to predict significant coronary artery disease (CAD) on coronary computed tomographic angiography (CCTA) in asymptomatic type 2 diabetes. Therefore, we sought to develop a model for the prediction of significant CAD on CCTA in these patients. We analyzed 607 asymptomatic patients with type 2 diabetes who underwent CCTA. The cardiac event was defined as a composite of cardiac death, nonfatal myocardial infarction, acute coronary syndrome, and coronary revascularization. Significant CAD (diameter stenosis ≥50%) in at least one coronary artery on CCTA was observed in 188 (31.0%). During the follow-up period (median 4.3 [interquartile range, 3.7-4.8] years), 71 patients had 83 cardiac events. Clinical risk factors for significant CAD were age, male gender, duration of diabetes, hypertension, current smoking, family history of premature CAD, previous history of stroke, ratio of total cholesterol to high-density lipoprotein cholesterol, and neuropathy. Using these variables, we formulated a risk score model, and the scores ranged from 0 to 17 (area under the curve = 0.727, 95% confidence interval = 0.714-0.739, P < 0.001). Patients were categorized into low (≤3), intermediate (4-6), or high (≥7) risk group. There were significant differences between the risk groups in the probability of significant CAD (12.6% vs 29.4% vs 57.7%, P for all < 0.001) and 5-year cardiac event-free survival rate (96.6% ± 1.5% vs 88.9% ± 1.8% vs 73.8% ± 4.1%, log-rank P for trend < 0.001). This model predicts significant CAD on CCTA and has the potential to identify asymptomatic type 2 diabetes with high risk.


Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies.
Patients with high levels of low-density lipoprotein cholesterol (LDL-C) might not tolerate 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") because of adverse effects (AEs) and might not respond well enough to nonstatin lipid-lowering therapies (LLTs) to meet LDL-C goals. The purpose of this study was to assess the acceptability, effectiveness, and safety profile of rosuvastatin 5 and 10 mg/d in consecutively referred patients with primary high LDL-C who were unable to tolerate other statins because of myalgia and, subsequently in some cases, unable to reach LDL-C goals with nonstatin LLT. This prospective, open-label pilot study was conducted in consecutively referred male and female patients aged 38 to 80 years with primary high LDL-C (mean, 177 mg/dL) at The Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. Patients were instructed in the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) therapeutic lifestyle changes diet. Rosuvastatin 5 mg/d was administered to patients categorized by NCEP ATP III risk stratification as moderately high risk, and rosuvastatin 10 mg/d was administered to patients categorized as high or very high risk. End points included acceptability (assessed using patient-initiated discontinuation of rosuvastatin), effectiveness (absolute and percentage reductions in LDL-C and triglycerides), and safety profile (aspartate and alanine aminotransferases [AST and ALT, respectively] >3 times the laboratory upper limit of normal [xULN] or elevations in creatine kinase [CK]>10xULN). A total of 61 patients were enrolled (41 women, 20 men; mean [SD] age, 60 [10] years; 5-mg/d dose, 25 patients; 10-mg/d dose, 36 patients). Myalgia, a predominant AE, had caused 50 patients to previously discontinue treatment with atorvastatin; 30, simvastatin; 19, pravastatin; 5, fluvastatin; 2, ezetimibe/simvastatin; and 1, lovastatin. Eighteen patients subsequently failed to reach LDL-C goals with nonstatin LLT(s) alone (colesevelam, 10 patients; ezetimibe, 8; niacin extended release, 2; and fenofibrate, 1). After a median treatment duration of 16 weeks, rosuvastatin 5 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 75 (34) mg/dL (mean [SD] %Delta, -42% [18%]) (P<0.001 vs baseline). After a median treatment duration of 44 weeks, rosuvastatin 10 mg/d+diet was associated with a mean (SD) decrease from baseline in LDL-C of 79 (49) mg/dL (mean [SD] %Delta, -42% [24%]) (P<0.001 vs baseline). Of the 61 patients, 1 receiving the 10-mg/d dose discontinued rosuvastatin treatment because of unilateral muscular pain after 4 weeks; no AST or ALT levels were >3xULN, and no CK levels were >10xULN. In these 61 hypercholesterolemic patients unable to tolerate other statins and, subsequently in some cases, unable to meet LDL-C goals while receiving nonstatin LIT monotherapy, these preliminary observations suggest that rosuvastatin at doses of 5 and 10 mg/d+diet was well tolerated, effective, and had a good safety profile.