Electrical stimulation of the lower esophageal sphincter to address gastroesophageal reflux disease after sleeve gastrectomy.
Laparoscopic sleeve gastrectomy (LSG) can result in de novo and worsen preexisting gastroesophageal reflux disease (GERD). Post-LSG patients with GERD refractory to proton pump inhibitors (PPI) usually undergo more invasive, anatomy-altering Roux-en-Y gastric bypass surgery. Lower esophageal sphincter (LES) electrical stimulation (ES) preserves the anatomy and has been shown to improve outcomes in GERD patients. To evaluate the safety and efficacy of LES-ES in post-LSG patients with GERD not controlled with maximal PPI therapy. Prospective, international, multicenter registry. Patients with LSG-associated GERD partially responsive to PPI underwent LES-ES. GERD outcomes pre- and poststimulation were evaluated based on quality of life, esophageal acid exposure (after 6-12 mo), and PPI use. Seventeen patients (11 female, 65%), treated at 6 centers between May 2014 and October, 2016 with a median follow-up of 12 months (range 6-24), received LES-ES. Median age was 48.6 years (interquartile range, 40.5-56), median body mass index 31.7 kg/m2 (27.9-39.3). All patients were on at least daily PPI preoperatively; at last follow-up, 7 (41%) were completely off PPI, 5 (29%) took PPI on an intermittent basis, and 5 (29%) were on single-dose PPI. Median GERD-health-related quality of life scores improved from 34 (on-PPI, 25-41) at baseline to 9 (6-13) at last follow-up (off-PPI, P<.001). Percentage of time with esophageal pH<4 improved from 13.2% (3.7-30.7) to 5.8% (1.1-54.4), P = .01. LES-ES in post-LSG patients suffering from symptomatic, PPI-refractory GERD resulted in significant improvement of GERD-symptoms, esophageal acid exposure, and need for PPI. Preserving the post-LSG anatomy, it offers a valid option for patients unable or unwilling to undergo Roux-en-Y gastric bypass surgery.


NEK1 mutations cause short-rib polydactyly syndrome type majewski.
Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype.


Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs.
Chondroitin sulfate (CS) is the most abundant and widely distributed glycosaminoglycan (GAG) in the human body. As a component of proteoglycans (PGs) it has numerous roles in matrix stabilization and cellular regulation. This chapter highlights the roles of CS and CS-PGs in the central and peripheral nervous systems (CNS/PNS). CS has specific cell regulatory roles that control tissue function and homeostasis. The CNS/PNS contains a diverse range of CS-PGs which direct the development of embryonic neural axonal networks, and the responses of neural cell populations in mature tissues to traumatic injury. Following brain trauma and spinal cord injury, a stabilizing CS-PG-rich scar tissue is laid down at the defect site to protect neural tissues, which are amongst the softest tissues of the human body. Unfortunately, the CS concentrated in gliotic scars also inhibits neural outgrowth and functional recovery. CS has well known inhibitory properties over neural behavior, and animal models of CNS/PNS injury have demonstrated that selective degradation of CS using chondroitinase improves neuronal functional recovery. CS-PGs are present diffusely in the CNS but also form denser regions of extracellular matrix termed perineuronal nets which surround neurons. Hyaluronan is immobilized in hyalectan CS-PG aggregates in these perineural structures, which provide neural protection, synapse, and neural plasticity, and have roles in memory and cognitive learning. Despite the generally inhibitory cues delivered by CS-A and CS-C, some CS-PGs containing highly charged CS disaccharides (CS-D, CS-E) or dermatan sulfate (DS) disaccharides that promote neural outgrowth and functional recovery. CS/DS thus has varied cell regulatory properties and structural ECM supportive roles in the CNS/PNS depending on the glycoform present and its location in tissue niches and specific cellular contexts. Studies on the fruit fly, Drosophila melanogaster and the nematode Caenorhabditis elegans have provided insightful information on neural interconnectivity and the role of the ECM and its PGs in neural development and in tissue morphogenesis in a whole organism environment.


Growth and maintenance respiration rates of aspen, black spruce and jack pine stems at northern and southern BOREAS sites.
We measured stem respiration rates during and after the 1994 growing season of three common boreal tree species at sites near the northern and southern boundaries of the closed-canopy boreal forest in central Canada. The growth respiration coefficient (r(g); carbon efflux per micro mole of carbon incorporated in structural matter) varied between 0.25 and 0.76, and was greatest for black spruce (Picea mariana (Mill.) B.S.P.), least for jack pine (Pinus banksiana Lamb.) and intermediate for trembling aspen (Populus tremuloides Michx.). There was a consistent trend for higher r(g) at northern sites than at southern sites. Maintenance respiration rates at 15 degrees C (r(m)) varied from 0.5 to 2.7 nmol C mol(-1) C(sapwood) s(-1). Values of r(m) were high at sapling-stage jack pine sites and mature black spruce sites, and low at mature trembling aspen and mature jack pine sites. We found significant relationships between annual maintenance respiration and sapwood relative growth rate and sapwood volume per unit of stem surface area that explained much of the within-stand and between-stand variability. Because of the large differences in parameter values among sites, we conclude that the use of stand-specific respiratory parameters may improve model predictions of ecosystem process models over the use of generic parameter values.


Identification of candidate biomarkers in ovarian cancer serum by depletion of highly abundant proteins and differential in-gel electrophoresis.
Ovarian cancer is the fifth leading cause of cancer death for women in the US, yet survival rates are over 90% when it is diagnosed at an early stage, highlighting the need for biomarkers for early detection. To enhance the discovery of tumor-specific proteins that could represent novel serum biomarkers for ovarian cancer, we depleted serum of highly abundant proteins which can mask the detection of proteins present in serum at low concentrations. Three commercial immunoaffinity columns were used in parallel to deplete the highly abundant proteins in serum from 60 patients with serous ovarian carcinoma and 60 non-cancer controls. Medium and low abundance serum proteins from each serum pool were then evaluated by the quantitative proteomic technique of differential in-gel electrophoresis. The number of protein spots that were elevated in ovarian cancer sera by at least twofold ranged from 36 to 248, depending upon the depletion and separation methods. From the 33 spots picked for MS analysis, nine different proteins were identified, including the novel candidate ovarian cancer biomarkers leucine-rich alpha2 glycoprotein-1 and ficolin 3. Western blotting validated the relative increases in serum protein levels for three of the proteins identified, demonstrating the utility of this approach for the identification of novel serum biomarkers for ovarian cancer.


Parkinsonism: a rare manifestation of craniopharyngioma.
Craniopharyngioma is a non-glial, non-malignant intracranial tumor of ectodermal origin, which arises from a remnant of Rathke's pouch. This tumor accounts for 5.6 to 13% of intracranial tumors in children. This paper discusses a case of craniopharyngioma in a five-year-old boy. An MRI scan of his brain showed a huge sella and supra sella cystic-solid lesion that had invaded the prepontine and interpeduncular cisterns, filling of 3rd ventricle and hydrocephalus. The patient operated via interhemispheric subfrontal through lamina terminalis and the tumor dissected from all part of brain stem and total resection achieved. After surgery Parkinsonism was worse for 3 days and levodopa started for 3 days. Parkinsonism was gone and after one week levodopa discontinued. This case practically implied that decompression of mass effect of tumor on brain stem and short-term management with levodopa can improve Parkinsonism due to midline compressive brain tumors without basal ganglia involvement.


Mutation-Specific Phenotypes in hiPSC-Derived Cardiomyocytes Carrying Either Myosin-Binding Protein C Or α-Tropomyosin Mutation for Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease, which affects the structure of heart muscle tissue. The clinical symptoms include arrhythmias, progressive heart failure, and even sudden cardiac death but the mutation carrier can also be totally asymptomatic. To date, over 1400 mutations have been linked to HCM, mostly in genes encoding for sarcomeric proteins. However, the pathophysiological mechanisms of the disease are still largely unknown. Two founder mutations for HCM in Finland are located in myosin-binding protein C (MYBPC3-Gln1061X) and α-tropomyosin (TPM1-Asp175Asn) genes. We studied the properties of HCM cardiomyocytes (CMs) derived from patient-specific human induced pluripotent stem cells (hiPSCs) carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn mutation. Both types of HCM-CMs displayed pathological phenotype of HCM but, more importantly, we found differences between CMs carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation in their cellular size, Ca(2+) handling, and electrophysiological properties, as well as their gene expression profiles. These findings suggest that even though the clinical phenotypes of the patients carrying either MYBPC3-Gln1061X or TPM1-Asp175Asn gene mutation are similar, the genetic background as well as the functional properties on the cellular level might be different, indicating that the pathophysiological mechanisms behind the two mutations would be divergent as well.


Lipid and ultrastructural characterization of reconstructed skin models.
The study aimed at evaluating tissue architecture and quality of the permeability barrier in commercially available reconstructed human skin models; EpiDerm, SkinEthic and Episkin in comparison to native tissue. For this purpose, tissue architecture was examined by electron microscopy and epidermal lipid composition was analyzed by HPTLC. Stratum corneum lipid organization was investigated by electron microscopy in combination with RuO(4) post-fixation and by SAXD. Ultrastructurally, the overall tissue architecture showed high similarities with native epidermis. In the stratum corneum extracellular space, lipid lamellae consisting of multiple alternating electron-dense and electron-lucent bands were present. This regular pattern was not seen throughout the whole stratum corneum probably due to the observed irregular lamellar body extrusion in some areas. Lipid analyses revealed the presence of all major epidermal lipid classes. Compared with native epidermis the content of polar ceramides 5 and 6 was lower, ceramide 7 was absent, and the content of free fatty acids was very low. These differences in lipid composition may account for differences observed in SAXD pattern of Episkin and EpiDerm penetration models. In the latter only the long-distance periodicity unit of about 12 nm was observed and the short periodicity unit was missing. In conclusion, all three skin models provide a promising means for studying the effects of topically applied chemicals, although the observed deviations in tissue homeostasis and barrier properties need to be optimized.


Can counter-advertising reduce pre-adolescent children's susceptibility to front-of-package promotions on unhealthy foods? Experimental research.
This study aimed to test whether counter-advertisements (i.e. messages contesting industry marketing) make pre-adolescent children less susceptible to the influence of food promotions. Since children have lower media literacy levels due to their immature cognitive abilities, specific research questions explored were: (1) whether the effectiveness of counter-ads is contingent on children having understood them; and (2) whether counter-ads may be detrimental when they are misinterpreted. A between-subjects experimental design using a web-based methodology was employed. 1351 grade 5-6 students (mean age 11 years) from schools located in metropolitan Melbourne, Australia participated. Participants were randomly shown an animated web banner advertisement (counter-ad challenging front-of-package promotion or control ad) and a pair of food packages from the same product category comprising an unhealthy product featuring a front-of-package promotion (nutrient content claim or sports celebrity endorsement) and a healthier control pack without a front-of-package promotion. Responses to the assigned advertisement, choice of product (healthy versus unhealthy) and ratings of the unhealthy product and front-of-package promotion on various nutritional and image-related attributes were recorded for each child. Sixty-six percent of children who viewed a counter-ad understood its main message. These children rated the front-of-package promotion as less believable and rated the unhealthy product bearing the front-of-package promotion as less healthy compared to the control group. However, children who misunderstood the counter-ad rated the unhealthy product bearing a front-of-package promotion as more healthy and rated the front-of-package promotion more favourably than those who correctly understood the counter-ad. Counter-advertising may have unintended consequences when misunderstood. If public health organizations or government pursue counter-advertising as a strategy to reduce the negative influence of unhealthy food marketing among children, caution is needed in designing counter-ads to guard against possible contradictory effects.


Pax6 regulation in retinal cells by CCCTC binding factor.
A previous study demonstrated that CTCF (CCCTC binding factor) regulates homeobox Pax6 gene expression in early embryonic stages and plays a dominant role in eye development. The purpose of the present study was to explore further the mechanism of CTCF controlling Pax6 gene expression in human retinoblastoma (Rb) cells and in the development of chicken and mouse retinas. Northern and Western analyses were used to detect expressions of CTCF and Pax6 in Rb cells. Pax6 transcription reporter and deletion mutants were used to study the regulatory interaction between CTCF and Pax6 in Rb cells and in the retina of chicken embryos. CTCF transgenic chicken embryos and mice were established by lipofection and microinjection of linearized cytomegalovirus (CMV)-CTCF construct into fertilized eggs and mouse oocytes, respectively. Injected oocytes were implanted in the uterus of foster mothers through microinjection into the ovarian duct. The expression of CTCF and Pax6 was determined in embryo sections by immunochemistry. Stimulation of Rb cells with 10% FBS resulted in an increase in CTCF expression and a decrease in Pax6 expression. To study the regulatory mechanism, the Pax6 reporter and its deletion mutant activities were determined in transfected Rb cells and chicken embryonic retinas, revealing that CTCF interacts with the Pax6 gene in Rb cells through transcription control in the 5'-flanking region upstream from the Pax6 P0 promoter. Overexpression of CTCF in Rb cells suppressed Pax6 reporter activity and downregulated endogenous Pax6 expression. In contrast, downregulation of CTCF expression by knockdown of CTCF mRNA using specific small interfering (si)RNA markedly enhanced Pax6 expression in Rb cells. Further study in CTCF transgenic mouse embryos verified that overexpression of CTCF suppressed Pax6 gene expression in the retina. CTCF plays an important role in regulating Pax6 expression in Rb cells and in the developmental retina, and the regulation of Pax6 gene expression by CTCF in the retina is through transcriptional regulation.


Health Workers' Awareness and Knowledge of Current Recommendation of Intermittent Preventive Treatment in Pregnancy in South-Western Nigeria.
Malaria in pregnancy is of public health significance because of its associated maternal and fetal complications. This study aimed to assess health workers' awareness and knowledge of the current World Health Organisation (WHO) recommendation of intermittent preventive treatment in pregnancy with Sulfadoxine-Pyrimethamine (IPTp-SP). A cross-sectional study among 148 health workers who offer obstetrics care in selected health facilities in Ibadan, Nigeria using a self-administered questionnaire to evaluate their awareness and knowledge of the current WHO IPTp-SP. Information on their socio-demographic and professional characteristics, awareness, knowledge and practice of the current IPTp recommendation were obtained. Data analysis involved descriptive and bivariate analyses using SPSS version 20.0 with level of significance set at p<0.05. The majority, 85(57.4%), of the health workers had been providing obstetrics care for less than 5 years with most of them, 114(77.0%), practicing at tertiary health facility. More than half, 92(62.2%), of them were aware of the current WHO IPTp-SP recommendation while about two-fifth (39.1%) had its correct knowledge. Of the health workers who were knowledgeable of the current IPTp-SP recommendation almost three-quarter, 29(72.2%) of them prescribed it. The health workers' professional cadre (p<0.001) and duration of providing obstetrics care (p=0.012) were significantly associated with their awareness and correct knowledge of the current IPTp-SP recommendation. Most of the health workers are aware but not knowledgeable of the correct administration of the current IPTp-SP recommendation. Likewise, many of them do not prescribe it. This calls for regular training and update of health workers and institutional protocol so as to effectively reduce the prevalence of malaria in pregnancy and its complications.


The effects of inhibitory control training on alcohol consumption, implicit alcohol-related cognitions and brain electrical activity.
This study aimed to replicate findings that alcohol consumption and positive implicit beer-related cognitions can be reduced using inhibitory control (IC) training, with the addition of an active training control. Frontal EEG asymmetry, an objective psychophysiological index of approach motivation, was used as a dependent measure to examine training outcomes. Participants were randomly assigned to one of two IC training conditions (Beer NoGo or Beer Go) or a Brief Alcohol Intervention (BAI) (i.e. the active training control). The IC training tasks consistently paired a stimulus that required a response with images of water (Beer NoGo) or images of beer (Beer Go). Alcohol consumption and implicit beer-related cognitions were measured at pre-training, post-training and at one week follow-up. Frontal EEG asymmetry was recorded during a passive image viewing task that presented neutral, healthy, and beer stimuli - at pre-training, post-training and follow-up. Participants in the Beer NoGo and BAI conditions consumed less beer in a taste test immediately after training than Beer Go participants, suggesting that IC training may be as effective as the already established BAI. The taste test findings were in line with the frontal EEG asymmetry data, which indicated that approach motivation for beer stimuli was altered in the expected directions. However, the positive correlation between post-training frontal EEG asymmetry data and taste test consumption was not significant. While there were no significant changes in implicit beer-related cognitions following training, a trending positive relationship between implicit beer-related cognitions at post-training and taste test consumption was reported. Further exploration addressing the limitations of the current study is required in order to clarify the implications of these findings.


IL-27 targets Foxp3+ Tregs to mediate antiinflammatory functions during experimental allergic airway inflammation.
Foxp3+ CD4 Tregs are central regulators of inflammation, including allergic inflammation in the lung. There is increasing evidence that inflammatory factors undermine adequate Treg functions and homeostasis, resulting in prolonged and exacerbated inflammation. Therefore, identifying the factors is of the utmost important. IL-27 is an antiinflammatory cytokine implicated in immune regulation and tolerance. However, the cellular mechanisms underlying IL-27-mediated immune regulation in vivo remain largely unknown. Utilizing a cockroach antigen-induced allergic inflammation model in mice, we sought to test the roles of Tregs during IL-27-mediated regulation of allergic inflammation. Intranasally delivered IL-27 significantly reduced the development of airway inflammation. Unexpectedly, the IL-27-induced reduction occurred only in the presence of Tregs. Il27ra-/- and Treg-specific Il27ra-/- mice developed severe airway inflammation, and IL-27 treatment had little impact on diminishing the inflammatory responses. IL-27-induced treatment was restored following transfer of WT Tregs but not of Tregs deficient in Lag3, a molecule induced by IL-27 in Tregs. Finally, Tregs from asthmatic patients exhibited blunted STAT1 phosphorylation following IL-27 stimulation. Taken together, our results uncover that Tregs are the primary target cells of IL-27 in vivo to mediate its antiinflammatory functions, suggesting that altered IL-27 responsiveness in Tregs may underlie inadequate Treg functions and perpetuation of inflammation.


Effects of guidelines on adeno-tonsillar surgery on the clinical behaviour of otorhinolaryngologists in Italy.
Several guidelines on adeno-tonsillar disease have been proposed in recent years and some discrepancies in relation both to clinical manifestations and indications for surgical treatment have emerged. The aim of the study was to verify what influence (adeno)-tonsillectomy guidelines have had on the clinical behaviour of ENT specialists in Italy. Our study is a retrospective and multi-centre case series with chart review. The survey involved 14,770 children, aged between the ages of 2 and 11, who had undergone adeno-tonsillar surgery between 2002 and 2008 in fourteen Italian tertiary and secondary referral centres. Anova test was used for the statistical analysis, assuming p < 0.05 as the minimum statistical significance value. The frequency of adeno-tonsillar surgeries did not change significantly (p>0.05) during the study period and following the Italian policy document publication. Overall, adeno-tonsillectomy was the most frequent intervention (64.1%), followed by adenoidectomy (31.1%) and tonsillectomy (4.8%). The indications for surgery did not change significantly for each of the operations (p>0.05), with the exception of adeno-tonsillectomy in case of feverish episodes due to acute recurrent tonsillitis ≥ 5 without nasal obstruction (decreased p= 0.010) , even when the feverish episodes due to acute recurrent tonsillitis were < 5 over the last year. Nasal obstruction was associated with feverish episodes due to acute recurrent tonsillitis in 65.2% of operated cases, while otitis media had been diagnosed in 43.3% of the patients studied. The recommendations first developed in Italy in a 2003 policy document and then resumed in guidelines in 2008, were not implemented by ENT units involved in the survey. The study highlights the fact that the indications for adeno-tonsillar operations are based on the overall clinical presentation (comorbidity) rather than on a single symptom. Guidelines are necessary to give coherent recommendations based on both the findings obtained through randomized controlled trials and the data collected from observational studies.


Magnesium status and the physical performance of volleyball players: effects of magnesium supplementation.
The aim of this study was to test the hypothesis that magnesium supplementation influences the physical performance of volleyball players, as the efficacy of this approach remains questionable. Twenty-five professional male volleyball players were assigned randomly to experimental (350 mg Mg · d(-1), 4 weeks) and control groups (500 mg maltodextrin · d(-1), 4 weeks) maintaining inter-group homogeneity of urinary magnesium. Erythrocyte, plasma and urinary magnesium levels, plasma creatine kinase activity, lactate production, maximal oxygen uptake (VO2 max) and plyometric (squat jump, countermovement jump, countermovement jump with arm swing) and isokinetic (peak torque, potency and total work) performances were evaluated before (T0) and after (T1) supplementation. Levels of erythrocyte and urinary magnesium and creatine kinase activity and VO2 max remained within normal ranges in both groups. Plasma magnesium decreased significantly only within the experimental group. Significant decreases in lactate production and significant increases (of up to 3 cm) in countermovement jump and countermovement jump with arm swing values were detected in the experimental group following magnesium supplementation, but not in the control group at T1. It is concluded that magnesium supplementation improved alactic anaerobic metabolism, even though the players were not magnesium-deficient.


Comparison between histochemical and immunohistochemical methods for diagnosis of sporotrichosis.
To compare the efficacy of histochemical and immunohistochemical methods in detecting forms of Sporothrix schenckii in tissue. Thirty five cutaneous biopsy specimens from 27 patients with sporotrichosis were stained by histochemical haematoxylin and eosin, periodic acid Schiff, and Gomori's methenamine silver methods and an immunohistochemical (avidin-biotin complex immunoperoxidase) (ABC) technique associated with a newly produced rabbit polyclonal antibody anti-Sporothrix schenckii. A total of 29 (83%) cases were positive by the ABC method used in association with anti-Sporothrix schenckii rabbit polyclonal antibodies. Histochemical methods, using silver staining, periodic acid Schiff, and conventional haematoxylin and eosin detected 37%, 23%, and 23% of forms of S schenckii, respectively. The ABC technique was significantly more reliable than periodic acid Schiff and silver staining techniques. It is concluded that immunostaining is an easy and rapid method which can efficiently increase the accuracy of the diagnosis of sporotrichosis in human tissue.


Opposite effects of low and high dose supplementation of vitamin E on survival of MRL/lpr mice.
The purpose of this study is to investigate the effects of vitamin E supplementation on the autoimmune disease course in MRL/lymphoproliferative mice. Three-month-old MRL/lymphoproliferative lpr female mice were fed an AIN-76 diet containing 50 mg/kg (control), 250 mg/kg (E5), 375 mg/kg (E7.5), or 500 mg/kg (E10) all-rac-alpha-tocopheryl acetate. Eight mice per group were killed for analysis after two months of experimental diets, and the rest of the mice were followed up to observe their proteinuria levels and life span. The data suggest that the life span of the E5 group was longer than the E10 group. Though alpha-tocopherol content in the plasma, liver, and kidneys increased in the mice fed the diet supplemented with vitamin E, the thiobarbituric acid reactive substance values in the liver and kidneys among these groups were not significantly different. IgM anti-ds-DNA and anticardiolipin antibodies were significantly higher in the E10 group than in those of the other groups. Phytohemagglutinin-stimulated interleukin (IL)-2 secretion was significantly lower, but concanavalinA-stimulated IL-4 and IL-10 production was significantly higher in the E10 group compared with the control group. The in vitro study also showed decreased IL-2 secretion and messenger RNA expression in phytohemagglutinin-stimulated splenocytes cultured in medium supplemented with high doses of vitamin E, but increased IL-2 with low doses of vitamin E. Our data suggest that low and high dose supplementation of vitamin E has the opposite effect on the survival of MRL/lpr mice. The inhibitory effect of Th1 from high vitamin E content may not be beneficial for those suffering from Th2 prone autoimmune diseases, such as systemic lupus erythematosus.


The characteristic trajectory of a fixing allele: a consequence of fictitious selection that arises from conditioning.
This work is concerned with the historical progression, to fixation, of an allele in a finite population. This progression is characterized by the average frequency trajectory of alleles that achieve fixation before a given time, T. Under a diffusion analysis, the average trajectory, conditional on fixation by time T, is shown to be equivalent to the average trajectory in an unconditioned problem involving additional selection. We call this additional selection "fictitious selection"; it plays the role of a selective force in the unconditioned problem but does not exist in reality. It is a consequence of conditioning on fixation. The fictitious selection is frequency dependent and can be very large compared with any real selection that is acting. We derive an approximation for the characteristic trajectory of a fixing allele, when subject to real additive selection, from an unconditioned problem, where the total selection is a combination of real and fictitious selection. Trying to reproduce the characteristic trajectory from the action of additive selection, in an infinite population, can lead to estimates of the strength of the selection that deviate from the real selection by >1000% or have the opposite sign. Strong evolutionary forces may be invoked in problems where conditioning has been carried out, but these forces may largely be an outcome of the conditioning and hence may not have a real existence. The work presented here clarifies these issues and provides two useful tools for future analyses: the characteristic trajectory of a fixing allele and the force that primarily drives this, namely fictitious selection. These should prove useful in a number of areas of interest including coalescence with selection, experimental evolution, time series analyses of ancient DNA, game theory in finite populations, and the historical dynamics of selected alleles in wild populations.


Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice.
During development, the retinal vasculature grows toward hypoxic areas in an organized fashion. By contrast, in ischemic retinopathies, new blood vessels grow out of the retinal surfaces without ameliorating retinal hypoxia. Restoration of proper angiogenic directionality would be of great benefit to reoxygenize the ischemic retina and resolve disease pathogenesis. Here, we show that binding of the semaphorin 3E (Sema3E) ligand to the transmembrane PlexinD1 receptor initiates a signaling pathway that normalizes angiogenic directionality in both developing retinas and ischemic retinopathy. In developing mouse retinas, inhibition of VEGF signaling resulted in downregulation of endothelial PlexinD1 expression, suggesting that astrocyte-derived VEGF normally promotes PlexinD1 expression in growing blood vessels. Neuron-derived Sema3E signaled to PlexinD1 and activated the small GTPase RhoJ in ECs, thereby counteracting VEGF-induced filopodia projections and defining the retinal vascular pathfinding. In a mouse model of ischemic retinopathy, enhanced expression of PlexinD1 and RhoJ in extraretinal vessels prevented VEGF-induced disoriented projections of the endothelial filopodia. Remarkably, intravitreal administration of Sema3E protein selectively suppressed extraretinal vascular outgrowth without affecting the desired regeneration of the retinal vasculature. Our study suggests a new paradigm for vascular regeneration therapy that guides angiogenesis precisely toward the ischemic retina.


Long-, intermediate- and short-term growth studies in asthmatic children treated with inhaled glucocorticosteroids.
During recent years, new auxological techniques have been introduced for assessment of the risk of growth suppression in asthmatic children treated with exogeneous glucocorticosteroids. Assessment of lower leg growth rates with the knemometer has made short-term studies of growth processes under strictly controlled conditions possible. However, short-term lower leg growth rates cannot be used for estimations of intermediate-term height growth rates or long-term evaluations of final height. Consequently, the distinctions between the various types of growth studies in asthmatic children treated with inhaled glucocorticosteroids have become important and need to be discussed. The present paper presents a review of the long-, intermediate- and short-term growth studies available. The bulk of evidence from intermediate- and short-term evaluations indicates that growth rate is not affected when standard paediatric doses of inhaled glucocorticosteroids are used. However, further focus needs to be placed on differences between specific glucocorticosteroids, doses and delivery systems. Intermediate- and short-term growth data should be evaluated in the long-term perspective.


Interaction studies reveal specific recognition of an anti-inflammatory polyphosphorhydrazone dendrimer by human monocytes.
Dendrimers are nano-materials with perfectly defined structure and size, and multivalency properties that confer substantial advantages for biomedical applications. Previous work has shown that phosphorus-based polyphosphorhydrazone (PPH) dendrimers capped with azabisphosphonate (ABP) end groups have immuno-modulatory and anti-inflammatory properties leading to efficient therapeutic control of inflammatory diseases in animal models. These properties are mainly prompted through activation of monocytes. Here, we disclose new insights into the molecular mechanisms underlying the anti-inflammatory activation of human monocytes by ABP-capped PPH dendrimers. Following an interdisciplinary approach, we have characterized the physicochemical and biological behavior of the lead ABP dendrimer with model and cell membranes, and compared this experimental set of data to predictive computational modelling studies. The behavior of the ABP dendrimer was compared to the one of an isosteric analog dendrimer capped with twelve azabiscarboxylate (ABC) end groups instead of twelve ABP end groups. The ABC dendrimer displayed no biological activity on human monocytes, therefore it was considered as a negative control. In detail, we show that the ABP dendrimer can bind both non-specifically and specifically to the membrane of human monocytes. The specific binding leads to the internalization of the ABP dendrimer by human monocytes. On the contrary, the ABC dendrimer only interacts non-specifically with human monocytes and is not internalized. These data indicate that the bioactive ABP dendrimer is recognized by specific receptor(s) at the surface of human monocytes.


Cariogenicity of Streptococcus mutans V403 glucosyltransferase and fructosyltransferase mutants constructed by allelic exchange.
Streptococcus mutans produces several enzymes which metabolize sucrose. Three glucosyltransferase genes (gtfB, gtfC, and gtfD) and a single fructosyltransferase gene (ftf) encode enzymes which are important in formation of exopolysaccharides. Mutants of S. mutans V403 carrying single and multiple mutations of the gtfB, gtfC, gtfD, and ftf genes recently have been constructed by allelic exchange in our laboratory. Using selected strains from this panel of mutants, we examined the importance of water-insoluble glucan, water-soluble glucan, and fructan production in cariogenicity while controlling for the effects of strain and species variability. Genetic and biochemical characterization of mutants and assays of glucosyltransferase and fructosyltransferase activities were performed to ensure that the phenotypes of strains coincided with deficiencies predicted by genotype. The young gnotobiotic rat model of cariogenicity was used to assess virulence of the wild-type strain and isogenic mutants. Mutant strains were less virulent than the wild type in almost every location examined for caries on tooth surfaces and level of involvement of lesions (depth and severity). Inactivation of either gtfB and gtfC or ftf dramatically reduced virulence; the subsequent inactivation of gtfD did not enhance the effect of reduced virulence.


Improved Accuracy of High-Throughput Phenotyping From Unmanned Aerial Systems by Extracting Traits Directly From Orthorectified Images.
The development of high-throughput genotyping and phenotyping has provided access to many tools to accelerate plant breeding programs. Unmanned Aerial Systems (UAS)-based remote sensing is being broadly implemented for field-based high-throughput phenotyping due to its low cost and the capacity to rapidly cover large breeding populations. The Structure-from-Motion photogrammetry processes aerial images taken from multiple perspectives over a field to an orthomosaic photo of a complete field experiment, allowing spectral or morphological trait extraction from the canopy surface for each individual field plot. However, some phenotypic information observable in each raw aerial image seems to be lost to the orthomosaic photo, probably due to photogrammetry processes such as pixel merging and blending. To formally assess this, we introduced a set of image processing methods to extract phenotypes from orthorectified raw aerial images and compared them to the negative control of extracting the same traits from processed orthomosaic images. We predict that standard measures of accuracy in terms of the broad-sense heritability of the remote sensing spectral traits will be higher using the orthorectified photos than with the orthomosaic image. Using three case studies, we therefore compared the broad-sense heritability of phenotypes in wheat breeding nurseries including, (1) canopy temperature from thermal imaging, (2) canopy normalized difference vegetation index (NDVI), and (3) early-stage ground cover from multispectral imaging. We evaluated heritability estimates of these phenotypes extracted from multiple orthorectified aerial images via four statistical models and compared the results with heritability estimates of these phenotypes extracted from a single orthomosaic image. Our results indicate that extracting traits directly from multiple orthorectified aerial images yielded increased estimates of heritability for all three phenotypes through proper modeling, compared to estimation using traits extracted from the orthomosaic image. In summary, the image processing methods demonstrated in this study have the potential to improve the quality of the plant trait extracted from high-throughput imaging. This, in turn, can enable breeders to utilize phenomics technologies more effectively for improved selection.


Modeling material stress using integrated Gaussian Markov random fields.
The equations of a physical constitutive model for material stress within tantalum grains were solved numerically using a tetrahedrally meshed volume. The resulting output included a scalar vonMises stress for each of the more than 94,000 tetrahedra within the finite element discretization. In this paper, we define an intricate statistical model for the spatial field of vonMises stress which uses the given grain geometry in a fundamental way. Our model relates the three-dimensional field to integrals of latent stochastic processes defined on the vertices of the one- and two-dimensional grain boundaries. An intuitive neighborhood structure of the said boundary nodes suggested the use of a latent Gaussian Markov random field (GMRF). However, despite the potential for computational gains afforded by GMRFs, the integral nature of our model and the sheer number of data points pose substantial challenges for a full Bayesian analysis. To overcome these problems and encourage efficient exploration of the posterior distribution, a number of techniques are now combined: parallel computing, sparse matrix methods, and a modification of a block update strategy within the sampling routine. In addition, we use an auxiliary variables approach to accommodate the presence of outliers in the data.


Development of a PCR assay followed by nonradioactive hybridization using oligonucleotides covalently bound to CovaLink NH microwells for detection of four Plasmodium species in blood samples from humans.
We developed and evaluated a PCR-based assay to detect four Plasmodium species in 79 blood samples from 56 travelers returning from areas where malaria is endemic. DNA amplification targeting a small region of the 18S rRNA gene was performed with Plasmodium genus-specific primers. The biotinylated PCR products were then identified by PCR-colorimetric Covalink NH microwell plate hybridization (CMPH) using species-specific phosphorylated probes covalently bound to a pretreated polystyrene surface. The results from PCR-CMPH showed high specificity, and for 47 of the 56 patients (84%), microscopy and PCR-CMPH results were in agreement. Discordant results were reevaluated with microscopy examination, other molecular methods, and DNA sequencing. Except for one patient, discrepancies were resolved in favor of PCR-CMPH: three mixed infections were detected, four species identification errors were corrected, and two negative results were shown to be positive. Our results indicate that PCR-CMPH is a simple, rapid, and specific method for malaria diagnosis. It employs stable reagents and inexpensive equipment, making it suitable for routine epidemiological use.


Low-Burden Mobile Monitoring, Intervention, and Real-Time Analysis Using the Wear-IT Framework: Example and Usability Study.
Mobile health (mHealth) methods often rely on active input from participants, for example, in the form of self-report questionnaires delivered via web or smartphone, to measure health and behavioral indicators and deliver interventions in everyday life settings. For short-term studies or interventions, these techniques are deployed intensively, causing nontrivial participant burden. For cases where the goal is long-term maintenance, limited infrastructure exists to balance information needs with participant constraints. Yet, the increasing precision of passive sensors such as wearable physiology monitors, smartphone-based location history, and internet-of-things devices, in combination with statistical feature selection and adaptive interventions, have begun to make such things possible. In this paper, we introduced Wear-IT, a smartphone app and cloud framework intended to begin addressing current limitations by allowing researchers to leverage commodity electronics and real-time decision making to optimize the amount of useful data collected while minimizing participant burden. The Wear-IT framework uses real-time decision making to find more optimal tradeoffs between the utility of data collected and the burden placed on participants. Wear-IT integrates a variety of consumer-grade sensors and provides adaptive, personalized, and low-burden monitoring and intervention. Proof of concept examples are illustrated using artificial data. The results of qualitative interviews with users are provided. Participants provided positive feedback about the ease of use of studies conducted using the Wear-IT framework. Users expressed positivity about their overall experience with the framework and its utility for balancing burden and excitement about future studies that real-time processing will enable. The Wear-IT framework uses a combination of passive monitoring, real-time processing, and adaptive assessment and intervention to provide a balance between high-quality data collection and low participant burden. The framework presents an opportunity to deploy adaptive assessment and intervention designs that use real-time processing and provides a platform to study and overcome the challenges of long-term mHealth intervention.


Comparison of IVF/ICSI outcome in patients with polycystic ovarian syndrome or tubal factor infertility.
One of the recognized treatment options for patients with polycystic ovarian syndrome (PCOS) is in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Fears are however sometimes raised concerning the likely outcome of treatment in such patients compared with their counterparts with tubal factor infertility. To compare the IVF/ICSI performance in women with PCOS and those with tubal factor infertility. A retrospective analysis. Case notes of 30 patients, 35 years and below, with PCOS and who underwent 33 IVF/ICSI cycles and those of 42 age-controlled patients with tubal factor infertility and who had 43 cycles between December 2004 and April 2008 were retrieved. Data including duration of down-regulation, dose of human Menopausal Gonadotropin (hMG), number of cancelled treatments, endometrial thickness, number of oocytes retrieved and fertilization rate, in addition to the number of embryos transferred with resultant pregnancy outcome were compared between the two groups. The main outcome measures were response to gonadotropin stimulation, fertilization rate and clinical pregnancy rate. There was no significant difference between the PCOS group and the tubal factor infertility group in the hMG dose (2.7 vs. 3.4 vials, respectively), endometrial thickness (10.5 vs. 10.1 mm, respectively) and embryos transferred (3.1 vs. 2.9, respectively). The fertilization rate was significantly higher in the tubal factor infertility group, which was 81.48% as against 63.24% for the PCOS group ( P < 0.0001). While more cases of ovarian hyperstimulation syndrome (OHSS) occurred in the PCOS group ( P = 0.049), overall clinical pregnancy rate per embryo transfer was similar (45.45% vs. 42.85%; P = 1), with similar miscarriage rates. IVF/ICSI performance in patients with PCOS is probably similar to their counterparts with tubal factor infertility with, however, a reduced fertilization rate and higher incidence of OHSS.


A boosting approach to structure learning of graphs with and without prior knowledge.
Identifying the network structure through which genes and their products interact can help to elucidate normal cell physiology as well as the genetic architecture of pathological phenotypes. Recently, a number of gene network inference tools have appeared based on Gaussian graphical model representations. Following this, we introduce a novel Boosting approach to learn the structure of a high-dimensional Gaussian graphical model motivated by the applications in genomics. A particular emphasis is paid to the inclusion of partial prior knowledge on the structure of the graph. With the increasing availability of pathway information and large-scale gene expression datasets, we believe that conditioning on prior knowledge will be an important aspect in raising the statistical power of structural learning algorithms to infer true conditional dependencies. Our Boosting approach, termed BoostiGraph, is conceptually and algorithmically simple. It complements recent work on the network inference problem based on Lasso-type approaches. BoostiGraph is computationally cheap and is applicable to very high-dimensional graphs. For example, on graphs of order 5000 nodes, it is able to map out paths for the conditional independence structure in few minutes. Using computer simulations, we investigate the ability of our method with and without prior information to infer Gaussian graphical models from artificial as well as actual microarray datasets. The experimental results demonstrate that, using our method, it is possible to recover the true network topology with relatively high accuracy. This method and all other associated files are freely available from http://www.stats.ox.ac.uk/~anjum/.


Effects of a restrictive blood transfusion protocol on acute pediatric burn care: Transfusion threshold in pediatric burns.
Blood transfusion is costly and associated with various medical risks. Studies in critically ill adult and pediatric patients suggest that implementation of more restrictive transfusion protocols based on lower threshold hemoglobin concentrations can be medically and economically advantageous. The purpose of this study was to evaluate the implications of a hemoglobin threshold change in pediatric burn patients. We implemented a change in hemoglobin threshold from 10 g/dL to 7 g/dL and compared data from patients before and after this protocol change in a retrospective review. Primary endpoints were hemoglobin concentration at baseline, before transfusion, and after transfusion; amount of blood product administered; and mortality. Secondary endpoints were the incidence of sepsis based on the American Burn Association physiological criteria for sepsis and mean number of septic days per patient. All endpoint analyses were adjusted for relevant clinical covariates via generalized additive models or Cox proportional hazard model. Statistical significance was accepted at p less than 0.05. Patient characteristics and baseline hemoglobin concentrations (pre, 13.5 g/dL; post, 13.3 g/dL; p > 0.05) were comparable between groups. The group transfused based on the more restrictive hemoglobin threshold had lower hemoglobin concentrations before and after transfusion throughout acute hospitalization, received lower volumes of blood during operations (pre, 1012 mL; post, 824 mL; p < 0.001) and on days without surgical procedures (pre, 602 mL; post, 353 mL; p < 0.001), and had a lower mortality (pre, 8.0%; post, 3.9%; mortality hazard decline, 0.55 [45%]; p < 0.05). Both groups had a comparable incidence of physiological sepsis, though the more restrictive threshold group had a lower number of sepsis days per patient. More restrictive transfusion protocols are safe and efficacious in pediatric burn patients. The associated reduction of transfused blood may lessen medical risks of blood transfusion and lower economic burden. Therapeutic, level IV.


Measuring the Level of Reflective Ability of Predoctoral Dental Students: Early Outcomes in an e-Portfolio Reflection.
Learning to evaluate one's own skills through reflection and self-assessment prepares dental graduates for successfully navigating an ever-changing work environment throughout their careers, but the search continues for the most effective teaching and assessment strategies to develop students' skills in these areas. Beginning with the Class of 2017, the University of Missouri-Kansas City School of Dentistry adopted e-portfolios as a programmatic (four-year) global assessment measure in the predoctoral dental program, in large part to encourage the development of reflection. The aim of this study was twofold: to examine interrater reliability among raters when scoring reflective writing using a validated measure of reflection skill and to analyze students' level of reflective ability as fourth-year dental students. Reflections of all 102 students were independently evaluated by the three investigators using a grading rubric based on Bain's 5 Rs (reporting, responding, relating, reasoning/deconstructing, reconstructing). Intra-class correlation was used to assess interrater reliability among the three raters, resulting in a good range for agreement (ICC=0.67; 95% CI 0.54, 0.77). The results showed that the majority (70%) of the global reflections were rated at Level 2 (responding) and Level 3 (relating). Approximately 15% of the global reflections reached Level 4 (reasoning/deconstructing), and only one was rated at the highest level (Level 5, reconstructing). This study confirmed that reflection and reflective writing were difficult for students to accomplish. As a result, curricular enhancements at this school have been implemented that involve both faculty and student development. Ongoing evaluation is required to determine if those changes result in higher levels of reflective ability. The positive outcomes of reflection and writing warrant continued examination in how to improve this educational strategy across the curriculum.


Effect of Adalimumab on Visual Functioning in Patients With Noninfectious Intermediate Uveitis, Posterior Uveitis, and Panuveitis in the VISUAL-1 and VISUAL-2 Trials.
Adalimumab was recently approved for the treatment of noninfectious intermediate uveitis, posterior uveitis, and panuveitis. To assess the effect of adalimumab on the visual functioning and quality of life in patients with corticosteroid-dependent noninfectious intermediate uveitis, posterior uveitis, and panuveitis. A post hoc analysis of clinical trials of adults with active (VISUAL-1) and inactive (VISUAL-2) noninfectious intermediate uveitis, posterior uveitis, and panuveitis was conducted in the United States, Canada, Europe, Israel, Australia, Latin America, and Japan. A total of 217 patients (110 adalimumab, 107 placebo) in VISUAL-1 and 226 patients (115 adalimumab, 111 placebo) in VISUAL-2 were studied using intent-to-treat analyses. The clinical trials were conducted between August 10, 2010, and May 14, 2015. In VISUAL-1 and VISUAL-2, patients were randomized to receive adalimumab, 80-mg, subcutaneous loading dose followed by 40 mg every other week or placebo for 80 weeks. All patients underwent prednisone tapering, with patients in VISUAL-1 receiving an initial prednisone burst. The 25-item National Eye Institute Vision Function Questionnaire (NEI VFQ-25) composite score questionnaire assessed the impact of visual impairment from the patient's perspective; scores on the questionnaire range from 0 to 100, with higher scores indicating better vision-related quality of life. The change in NEI VFQ-25 from best state achieved prior to week 6 (VISUAL-1) and from baseline state (VISUAL-2) to the final or early termination visit was determined in each group and statistically compared using analysis of variance. The temporal effects of adalimumab and placebo on NEI VFQ-25 were investigated using a longitudinal model. Of the 217 patients in VISUAL-1, 124 (57.1%) were women; the mean (SD) age was 42.7 (14.9) years. Of the 226 patients in VISUAL-2, 138 (61.1%) were women; the mean (SD) age was 42.5 (13.4). In VISUAL-1, the change from final score to best score in NEI VFQ-25 was -1.30 for adalimumab and -5.50 for placebo-a difference of 4.20 (95% CI, 1.04 to 7.36; P = .01) associated with adalimumab compared with placebo. In VISUAL-2, the change from baseline NEI VFQ-25 was 3.36 for adalimumab and 1.24 for placebo-a difference of 2.12 (95% CI, -0.81 to 5.04; P = .16). In both trials, the longitudinal models showed a significant difference in NEI VFQ-25 between adalimumab and placebo of 3.07 (95% CI, 2.09 to 4.06; P < .001) and 4.66 (95% CI, 0.05 to 9.26; P = .048) in the VISUAL-1 (74.15 vs 71.08) and VISUAL-2 (82.39 vs 77.73) trials, respectively. This post hoc analysis suggests that adalimumab is associated with statistically significant and clinically meaningful improvements in patient-reported visual functioning for patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis. clinicaltrials.gov Identifiers: NCT01138657 (VISUAL-1) and NCT01124838 (VISUAL-2).


Comparing Readmissions and Infectious Complications of Blunt Splenic Injuries Using a Statewide Database.
Although non-operative management of blunt splenic injury (BSI) is increasingly common, the long-term infectious complications after adjunct splenic artery embolization (SAE) are not well described. Patients aged 18-64 y with BSI were identified in the California State Inpatient Database (2007-2011) and categorized as receiving either non-operative management (NOM) without SAE, NOM with SAE, or operative management (OM). The cumulative incidence of infections (surgical site infections [SSI], pneumonia, urinary tract infections, and sepsis) requiring readmission at different times up to one y after injury were calculated. Patient and treatment factors associated with infectious readmissions were determined using multivariable logistic regression models. Of the 4,360 patients with BSI, 61.6% had NOM without SAE, 5.8% had NOM with SAE, and 32.6% had OM. The cumulative incidences of infectious complications after each of the management modes were 1.27%, 1.59%, and 1.76%, respectively, during admission (p = 0.446); 2.16%, 5.18%, and 4.85%, respectively, at 30 d after injury (p < 0.001); and 4.69%, 9.16%, and 8.85%, respectively, at one y after injury (p < 0.001). Risk factors for infection-associated readmissions within one y after injury were Charlson score ≥2 (adjusted odds ratio [AOR] 3.9; 95% confidence interval [CI] 2.61-6.02), length of stay >seven d (AOR 2.47; 95% CI 1.58-3.85), NOM with SAE (AOR 2.00; 95% CI 1.19-3.34), and OM (AOR 1.47; 95% CI 1.05-2.07). The long-term risk of infectious complications in patients with BSI who have NOM with SAE is similar to that in patients who are treated with OM, indicating the need for pro-active strategies to reduce long-term infectious complications after SAE.


Common Bile Duct Dilatation With Stones Indicates Requirement for Early Drainage in Patients With or Without Cholangitis.
Some patients with common bile duct (CBD) stones develop cholangitis requiring drainage, while others do not. The aims of this study were to elucidate the clinical differences among patients with CBD stones who required and did not require emergent drainage, and to identify risk factors for the development of cholangitis requiring emergent drainage in patients with silent CBD stones. Clinical characteristics of consecutive patients with CBD stones who underwent endoscopic removal of stones or biliary drainage were analyzed retrospectively. Of 101 patients analyzed, 32 had moderate or severe cholangitis as the indication for emergent drainage, and the remaining 69 did not. Patients who required emergent drainage were more likely to have gallstones (P = 0.029), dilated CBD (> 10 mm) (P = 0.004) and larger CBD stones (P = 0.019). By multivariate analysis, CBD dilation was the only significant differentiating clinical characteristic of the patients who required emergent drainage (OR = 3.75, 95% CI: 1.41-9.96, P = 0.008). Of the 35 patients with silent bile duct stones, eight required emergent endoscopic drainage during the waiting period. CBD dilation was also the only significant risk factor for the development of moderate or severe cholangitis among patients with silent bile duct stones (OR = 10.18, 95% CI: 1.09-94.73, P = 0.042). Dilated CBD (> 10 mm) was the only risk factor identified for requirement of early drainage in patients with CBD stones. Those who have silent CBD stones with CBD dilatation should undergo early drainage.


Two alleles of NF-kappaB in the sea anemone Nematostella vectensis are widely dispersed in nature and encode proteins with distinct activities.
NF-kappaB is an evolutionarily conserved transcription factor that controls the expression of genes involved in many key organismal processes, including innate immunity, development, and stress responses. NF-kappaB proteins contain a highly conserved DNA-binding/dimerization domain called the Rel homology domain. We characterized two NF-kappaB alleles in the sea anemone Nematostella vectensis that differ at nineteen single-nucleotide polymorphisms (SNPs). Ten of these SNPs result in amino acid substitutions, including six within the Rel homology domain. Both alleles are found in natural populations of Nematostella. The relative abundance of the two NF-kappaB alleles differs between populations, and departures from Hardy-Weinberg equilibrium within populations indicate that the locus may be under selection. The proteins encoded by the two Nv-NF-kappaB alleles have different molecular properties, in part due to a Cys/Ser polymorphism at residue 67, which resides within the DNA recognition loop. In nearly all previously characterized NF-kappaB proteins, the analogous residue is fixed for Cys, and conversion of human RHD proteins from Cys to Ser at this site has been shown to increase DNA-binding ability and increase resistance to inhibition by thiol-reactive compounds. However, the naturally-occurring Nematostella variant with Cys at position 67 binds DNA with a higher affinity than the Ser variant. On the other hand, the Ser variant activates transcription in reporter gene assays more effectively, and it is more resistant to inhibition by a thiol-reactive compound. Reciprocal Cys<->Ser mutations at residue 67 of the native Nv-NF-kappaB proteins affect DNA binding as in human NF-kappaB proteins, e.g., a Cys->Ser mutation increases DNA binding of the native Cys variant. These results are the first demonstration of a naturally occurring and functionally significant polymorphism in NF-kappaB in any species. The functional differences between these alleles and their uneven distribution in the wild suggest that different genotypes could be favored in different environments, perhaps environments that vary in their levels of peroxides or thiol-reactive compounds.


Evidence for a polymorphism in gametic segregation using a malate dehydrogenase locus in the tetraploid treefrog Hyla versicolor.
Artificial cross combinations of tetraploid Hyla versicolor were analyzed electrophoretically using a polymorphic malate dehydrogenase locus (MDH-1) to determine the mechanism of chromosome segregation. Models for differentiating between disomic and tetrasomic inheritance are presented and tested. In some crosses progeny genotypes fit a disomic mode of segregation. In other crosses there is only evidence for a tetrasomic mode of segregation. Additional crosses produced genotypic ratios which conformed to either a disomic or tetrasomic mode of segregation. The same type of inheritance was demonstrated for any individual when used in multiple cross combinations. These results suggest that there exists in H. versicolor a polymorphism with respect to segregation of gametes, resulting from differences in chromosome pairings during meiosis I.


[Molecule based diagnosis].
Based on reviews of the concept of diagnostics and in general and in specific tumour areas it was clear that development of diagnostic procedures involving genomics will allow for much better targeted and tailored treatments in the future. This will result in better efficacy and better tolerability of cancer treatments, but will also allow for progress in prediction, diagnosis and dose selection. Large collaborative projects studying the efficacy and safety of drugs on the genome level is promising to bring important benefits to both patients and the national economy by reducing useless drug therapy. In colorectal cancer there are several genetic defects identified that can act as the target for directed therapy in the future. Expressions of tumour specific antigens open the way for immunological targeted therapies. Developments in the understanding of the genomic basis for resistance to anti-tumour therapy is promising to help targeting patients likely to respond and not develop resistance. A Japanese model is being developed to determine the relative risk of breast cancer of Japanese women. Based on this prevention therapies can be instigated. The last four years have seen the introduction of four novel targeted therapies. If this model should become a standard in the future, much stronger collaboration between academic research and pharmaceutical industry need to develop.


Is Metal Particle Release Associated with Peri-implant Bone Destruction? An Emerging Concept.
Peri-implant diseases affecting the surrounding structures of endosseous dental implants include peri-implant mucositis and peri-implantitis. The prevalence of peri-implantitis ranges between 15% and 20% after 10 y, highlighting the major challenge in clinical practice in the rehabilitation of dental implant patients. The widespread nature of peri-implant bone loss poses difficulties in the management of biological complications affecting the long-term success of osseointegrated implant reconstructions. Metal and titanium particles have been detected in peri-implant supporting tissues. However, it remains unclear what mechanisms could be responsible for the elicitation of particle and ion release and whether these released implant-associated materials have a local and/or systemic impact on the peri-implant soft and hard tissues. Metal particle release as a potential etiologic factor has been intensively studied in the field of orthopedics and is known to provoke aseptic loosening around arthroplasties and is associated with implant failures. In dental medicine, emerging information about metal/titanium particle release suggests that the potential impact of biomaterials at the abutment or bone interfaces may have an influence on the pathogenesis of peri-implant bone loss. This mini-review highlights current evidence of metal particle release around dental implants and future areas for research.


Collagen cross-linkage: a comprehensive review and directions for future research.
Individuals with keratoconus form a significant proportion of patients for a practitioner specialising in corneal diseases. Yet it is a disease where the pathogenesis is poorly understood, and until recently, there has been no treatment apart from transplantation that could be offered that was curative or even capable of slowing the progression of the disease. Collagen cross-linking treatment using riboflavin and UV light has been developed to address this need, and the initial results are promising. The purpose of this review is to critically evaluate this treatment in light of the scientific basis for cross-linking, to highlight the strengths and limitations of the evidence in terms of efficacy and long-term safety, and finally to identify areas for future research in this area with a significant potential to change the way we treat our keratoconus patients. In addition, we hope that our unbiased review for the first time would bring together, in a concise fashion, scientific information for a practitioner contemplating on offering this treatment and to help inform their patients of its potential risks and benefits.


Consensus research priorities for cerebral palsy: a Delphi survey of consumers, researchers, and clinicians.
Research funds for cerebral palsy are scarce and competition for them is strong. This study aimed to identify questions for future research that were agreed to be a high priority. An expert panel of consumers, researchers, and clinicians was assembled (n=127) and surveyed using a Delphi survey comprising three rounds. In round I, participants identified three important research topics. Three parallel surveys were constructed: (1) consumers; (2) intervention researchers and clinicians; and (3) aetiology and prevention researchers. In rounds II and III, participants rated priorities using a seven-point Likert scale. Questions reaching consensus were itemized and those not reaching consensus were discarded. Consumers identified questions in the themes of prevention/cure, quality of life/community participation, and service provision/intervention. Intervention researchers/clinicians identified questions in the themes of effective outcomes and effective research/services. Aetiology and prevention researchers identified questions in the themes of infection/inflammation, focus on timing, haematology, research tools, neuroregeneration, and genetics. Fifty per cent of the consumers' priorities were also identified by professionals. Research priorities change as evidence is established. Phase II of this project is to develop a web portal with international collaboration. As evidence builds for one research question, it will be added to the web portal and unanswered questions will become the priority.


HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus.
Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.


Influences of situational factors and alcohol expectancies on sexual desire and arousal among heavy-episodic drinking women: acute alcohol intoxication and condom availability.
Although studies suggest that alcohol increases women's sexual desire, no studies to our knowledge have examined the effects of acute alcohol intoxication on women's sexual desire. The majority of research examining alcohol's effects on sexual arousal in women suggests that alcohol increases self-reported arousal. In an alcohol administration study in which women projected themselves into an eroticized scenario depicting a consensual sexual encounter with a new male partner, we examined the effects of alcohol and condom condition on women's sexual desire and arousal. The moderating effects of sex-related alcohol expectancies were also examined. Results revealed that alcohol intoxication was related to less desire to engage in sex with a new partner and condom presence was related to more desire. Alcohol interacted with sexual disinhibition alcohol expectancies, indicating that more expectancy endorsement was associated with greater sexual desire and self-reported arousal in the alcohol condition, but not the control condition. Condom condition had no effect on self-reported sexual arousal. The present research suggests that sexual desire merits research attention in non-clinical samples, and experimental methodology can provide valuable information about alcohol's influence on women's sexual desire, thus advancing our understanding of this relationship beyond cross-sectional correlations. The current findings also provide evidence that sex-related alcohol expectancies may play an important role in alcohol-involved sexual experiences including desire and arousal.


Confidence intervals rather than P values: estimation rather than hypothesis testing.
Overemphasis on hypothesis testing--and the use of P values to dichotomise significant or non-significant results--has detracted from more useful approaches to interpreting study results, such as estimation and confidence intervals. In medical studies investigators are usually interested in determining the size of difference of a measured outcome between groups, rather than a simple indication of whether or not it is statistically significant. Confidence intervals present a range of values, on the basis of the sample data, in which the population value for such a difference may lie. Some methods of calculating confidence intervals for means and differences between means are given, with similar information for proportions. The paper also gives suggestions for graphical display. Confidence intervals, if appropriate to the type of study, should be used for major findings in both the main text of a paper and its abstract.


Antimicrobial resistance in bacteria from horses: Epidemiology of antimicrobial resistance.
Antimicrobial resistance poses a significant threat to the continued successful use of antimicrobial agents for the treatment of bacterial infections. While the epidemiology of antimicrobial resistance in bacteria from man has been studied extensively, less work has been undertaken in companion animals, particularly horses. Methicillin-resistant Staphylococcus aureus has been identified as a cause of infections, with a low prevalence of nasal carriage by horses in the community but higher for hospitalised horses. Molecular characterisation has shown methicillin-resistant Staphylococcus aureus strains either to be predominantly of types associated with horses or of sequence type ST398. Antimicrobial-resistant Escherichia coli (including multidrug-resistant and extended spectrum β-lactamase-producing isolates) have caused infections and been documented in faecal carriage by horses, with many significant resistance mechanisms identified. More sporadic reports and molecular characterisation exist for resistance in other bacteria such as enterococci, Salmonella, Acinetobacter and Pseudomonas species. Limited work has been undertaken evaluating risk factors and much of the epidemiology of antimicrobial resistance in bacteria from horses remains to be determined.


Developing nucleic acid-based electrical detection systems.
Development of nucleic acid-based detection systems is the main focus of many research groups and high technology companies. The enormous work done in this field is particularly due to the broad versatility and variety of these sensing devices. From optical to electrical systems, from label-dependent to label-free approaches, from single to multi-analyte and array formats, this wide range of possibilities makes the research field very diversified and competitive. New challenges and requirements for an ideal detector suitable for nucleic acid analysis include high sensitivity and high specificity protocol that can be completed in a relatively short time offering at the same time low detection limit. Moreover, systems that can be miniaturized and automated present a significant advantage over conventional technology, especially if detection is needed in the field. Electrical system technology for nucleic acid-based detection is an enabling mode for making miniaturized to micro- and nanometer scale bio-monitoring devices via the fusion of modern micro- and nanofabrication technology and molecular biotechnology. The electrical biosensors that rely on the conversion of the Watson-Crick base-pair recognition event into a useful electrical signal are advancing rapidly, and recently are receiving much attention as a valuable tool for microbial pathogen detection. Pathogens may pose a serious threat to humans, animal and plants, thus their detection and analysis is a significant element of public health. Although different conventional methods for detection of pathogenic microorganisms and their toxins exist and are currently being applied, improvements of molecular-based detection methodologies have changed these traditional detection techniques and introduced a new era of rapid, miniaturized and automated electrical chip detection technologies into pathogen identification sector. In this review some developments and current directions in nucleic acid-based electrical detection are discussed.


Computer-aided detection in chest radiography based on artificial intelligence: a survey.
As the most common examination tool in medical practice, chest radiography has important clinical value in the diagnosis of disease. Thus, the automatic detection of chest disease based on chest radiography has become one of the hot topics in medical imaging research. Based on the clinical applications, the study conducts a comprehensive survey on computer-aided detection (CAD) systems, and especially focuses on the artificial intelligence technology applied in chest radiography. The paper presents several common chest X-ray datasets and briefly introduces general image preprocessing procedures, such as contrast enhancement and segmentation, and bone suppression techniques that are applied to chest radiography. Then, the CAD system in the detection of specific disease (pulmonary nodules, tuberculosis, and interstitial lung diseases) and multiple diseases is described, focusing on the basic principles of the algorithm, the data used in the study, the evaluation measures, and the results. Finally, the paper summarizes the CAD system in chest radiography based on artificial intelligence and discusses the existing problems and trends.


TNF inhibits production of stromal cell-derived factor 1 by bone stromal cells and increases osteoclast precursor mobilization from bone marrow to peripheral blood.
The objective of the present study was to investigate the role of the stromal cell-derived factor 1 (SDF-1)/CXCR4 axis in TNF-induced mobilization of osteoclast precursors (OCPs) from bone marrow. OCPs were generated from bone marrow cells of TNF-transgenic mice or wild-type mice treated with TNF or PBS. The percentage of CD11b+/Gr-1-/lo OCPs was assessed by fluorescence-activated cell sorting. OCP migration to the SDF-1 gradient and the osteoclast forming potency were assessed in chemotaxis/osteoclastogenic assays. SDF-1 expression was assessed by real-time RT-PCR, ELISA and immunostaining in primary bone marrow stromal cells, in the ST2 bone marrow stromal cell line, and in bones from TNF-injected mice. OCPs generated in vitro from wild-type mice migrated to SDF-1 gradients and subsequently gave rise to osteoclasts in response to RANKL and macrophage colony-stimulating factor. TNF reduced SDF-1 expression by ST2 cells. Bone marrow stromal cells from TNF-transgenic mice produced low levels of SDF-1. TNF treatment of wild-type mice decreased the SDF-1 concentration in bone marrow extracts and decreased the SDF-1 immunostaining of bone marrow stromal cells, and it also increased the circulating OCP numbers. The percentage of bone marrow CXCR4+ OCPs was similar in TNF-transgenic mice and wild-type littermates and in TNF-treated and PBS-treated wild-type mice. Systemically elevated TNF levels inhibit bone marrow stromal cell production of SDF-1 and increase the release of bone marrow OCPs to the peripheral blood. Disruption of the SDF-1/CXCR4 axis by TNF may play an important role in mediating OCP mobilization from the bone marrow cavity in chronic inflammatory arthritis.


Impact of ABCB1, ABCG2, and CYP3A5 polymorphisms on plasma trough concentrations of apixaban in Japanese patients with atrial fibrillation.
During anticoagulant therapy, major bleeding is one of the most severe adverse effects. This study aimed to evaluate the relationships between ABCB1, ABCG2, and CYP3A5 polymorphisms and plasma trough concentrations of apixaban, a direct inhibitor of coagulation factor X. A total of 70 plasma concentrations of apixaban from 44 Japanese patients with atrial fibrillation were analyzed. In these analyses, the plasma trough concentration/dose (C/D) ratio of apixaban was used as a pharmacokinetic index and all data were stratified according to the presence of ABCB1 (ABCB1 1236C>T, 2677G>T/A, and 3435C>T), ABCG2 (ABCG2 421C>A), and CYP3A5 (CYP3A5*3) polymorphisms. Influences of various clinical laboratory parameters (age, serum creatinine, estimated glomerular filtration rate, aspartate amino transferase, and alanine amino transferase) on the plasma trough C/D ratio of apixaban were included in analyses. Although no ABCB1 polymorphisms affected the plasma trough C/D ratio of apixaban, the plasma trough C/D ratio of apixaban was significantly higher in patients with the ABCG2 421A/A genotype than in patients with the ABCG2 421C/C genotype (P<0.01). The plasma trough C/D ratio of apixaban in patients with CYP3A5*1/*3 or *3/*3 genotypes was also significantly higher than that in patients with the CYP3A5*1/*1 genotype (P<0.05). Furthermore, the plasma trough C/D ratio of apixaban decreased with increased estimated glomerular filtration rate. These results indicate that ABCG2 421A/A and CYP3A5*3 genotypes and renal function are considered potential factors affecting trough concentrations of apixaban.


In vitro analysis of a nanocrystalline silver-coated surgical mesh.
One million nosocomial infections occur each year in patients with prosthetic devices. We analyzed a polypropylene mesh coated with nanocrystalline silver particles (NCSP) as a means of preventing such infections. Nanocrystalline silver was applied to polypropylene mesh using physical vapor deposition in three doses: low (0.31 mg/cm(2)), medium (0.64 mg/cm(2)), and high (1.13 mg/cm(2)). The zone of inhibition (ZOI) test was conducted by incubating either uncoated polypropylene mesh (UM) or silver-coated mesh (CM) with and without various amounts of bovine serum albumin (BSA) and then on agar plates with Staphylococcus aureus and calculating the ZOI. The bactericidal effects of the NCSP-coated meshes were assessed by incubating either UM or CM in medium with S. aureus and performing serial dilutions at 4 and 8 h. Scanning electron microscopy (SEM) was used to examine the surface of UM and CM with and without bacterial incubation. There was an increasing ZOI for low-, medium-, and high-dose CM and no ZOI for UM (p < 0.001 for all CM compared with UM). Incubating the mesh with various amounts of BSA produced persistent ZOIs with the medium- and high-dose CM; however, the low-dose CM became attenuated by such treatment, with no ZOI being seen with meshes incubated in 10% BSA. All concentrations of CM were bactericidal, as no bacteria grew at 8 h of incubation. The SEM images showed clusters of S. aureus on the surface of UM and no clusters on CM. The CM demonstrated significant bactericidal activity compared with UM. Nanocrystalline silver particles may decrease the incidence of postoperative prosthetic mesh infections and be useful as a coating for other prosthetic materials.


Does tacrolimus offer virtual freedom from chronic rejection after primary liver transplantation? Risk and prognostic factors in 1,048 liver transplantations with a mean follow-up of 6 years.
Tacrolimus has proven to be a potent immunosuppressive agent in liver transplantation (LT). Its introduction has led to significantly less frequent and severe acute rejection. Little is known about the rate of chronic rejection (CR) in primary LT using tacrolimus therapy. The aim of the present study is to examine the long-term incidence of CR, risk factors, prognostic factors, and outcome after CR. The present study evaluated the development of CR in 1,048 consecutive adult primary liver allograft recipients initiated and mostly maintained on tacrolimus-based immunosuppressive therapy. They were evaluated with a mean follow-up of 77.3 +/- 14.7 months (range, 50.7 to 100.1 months). To assess the impact of primary diagnosis on the rate and outcome of CR, the population was divided into 3 groups. Group I included patients with hepatitis C virus (HCV)- or hepatitis B virus (HBV)-induced cirrhosis (n = 312); group II included patients diagnosed with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH; n = 217); and group III included patients with all other diagnoses (n = 519). Overall, 32 of 1,048 patients (3.1%) developed CR. This represented 13 (4.1%), 12 (5.5%), and 7 patients (1.3%) in groups I, II, and III, respectively. The relative risk for developing CR was 3.2 times greater for group I and 4.3 times greater for group II compared with group III. This difference was statistically significant (P =.004). The incidence of acute rejection and total number of acute rejection episodes were significantly greater in patients who developed CR compared with those who did not (P <.0001). Similarly, the mean donor age for CR was significantly older than for patients without CR (43.0 v 36.2 years; P =.02). Thirteen of the 32 patients (40.6%) who developed CR retained their original grafts for a mean period of 54 +/- 25 months after diagnosis. Seven patients (21.9%) underwent re-LT, and 12 patients (38.3%) died. Serum bilirubin levels and the presence of arteriopathy, arterial loss, and duct loss on liver biopsy at the time of diagnosis of CR were significantly greater among the 3 groups of patients. In addition, patient and graft survival for group I were significantly worse compared with groups II and III. We conclude that CR occurred rarely among patients maintained long term on tacrolimus-based immunosuppressive therapy. When steroid use is controlled, the incidence of acute rejection, mean donor age, HBV- and/or HCV-induced cirrhosis, or a diagnosis of PBC, PSC, or AIH were found to be predictors of CR. Greater values for serum bilirubin level, duct loss, arteriopathy, arteriolar loss, and presence of HCV or HBV were found to be poor prognostic factors for the 3 groups; greater total serum bilirubin value (P =.05) was the only factor found to be significant between patients who had graft loss versus those who recovered.


Workaholism on Job Burnout: A Comparison Between American and Chinese Employees.
Past research frequently reports significant relation between workaholism and job burnout, and some studies further indicate workaholism varies across countries. Surprisingly, there is no study that directly examines whether country moderates the workaholism-burnout association. To address this research question, we have collected independent work samples from two culturally diverse countries, namely the People's Republic of China and the United States. A total of 2243 participants (1243 American respondents and 1000 Chinese respondents) were recruited. Preliminary group comparison suggested that there were statistical differences among participants from different industries on the key variables, including workaholism, job demands, autonomy and emotional exhaustion. Therefore, we have divided our participants into three subsamples [i.e., (1) natural resources, mining and construction industry, (2) manufacturing industry, and (3) service industry] and separate analyses were conducted. In the moderated regression analyses, workaholism significantly predicted two dimensions of job burnout, namely emotional exhaustion and depersonalization, even when job demand and job autonomy were controlled. Finally, although two significant moderating effects were found, there was a lack of consistent empirical support to the hypothesized moderating effect of country on workaholism-burnout association. Implications and limitations were discussed.


An allosteric mechanism of inactivation in the calcium-dependent chloride channel BEST1.
Bestrophin proteins are calcium (Ca2+)-activated chloride channels. Mutations in bestrophin 1 (BEST1) cause macular degenerative disorders. Whole-cell recordings show that ionic currents through BEST1 run down over time, but it is unclear whether this behavior is intrinsic to the channel or the result of cellular factors. Here, using planar lipid bilayer recordings of purified BEST1, we show that current rundown is an inherent property of the channel that can now be characterized as inactivation. Inactivation depends on the cytosolic concentration of Ca2+, such that higher concentrations stimulate inactivation. We identify a C-terminal inactivation peptide that is necessary for inactivation and dynamically interacts with a receptor site on the channel. Alterations of the peptide or its receptor dramatically reduce inactivation. Unlike inactivation peptides of voltage-gated channels that bind within the ion pore, the receptor for the inactivation peptide is on the cytosolic surface of the channel and separated from the pore. Biochemical, structural, and electrophysiological analyses indicate that binding of the peptide to its receptor promotes inactivation, whereas dissociation prevents it. Using additional mutational studies we find that the "neck" constriction of the pore, which we have previously shown to act as the Ca2+-dependent activation gate, also functions as the inactivation gate. Our results indicate that unlike a ball-and-chain inactivation mechanism involving physical occlusion of the pore, inactivation in BEST1 occurs through an allosteric mechanism wherein binding of a peptide to a surface-exposed receptor controls a structurally distant gate.


Methodological considerations for meal-induced thermogenesis: measurement duration and reproducibility.
Meal-induced thermogenesis (MIT) research findings have been highly inconsistent, in part, due to the variety of durations and protocols used to measure MIT. In the present study, we aimed to determine the following: (1) the proportion of a 6 h MIT response completed at 3, 4 and 5 h; (2) the associations between the shorter durations and the 6 h measures; (3) whether shorter durations improved the reproducibility of the measurement. MIT was measured in response to a 2410 kJ mixed composition meal in ten individuals (five males and five females) on two occasions. Energy expenditure was measured continuously for 6 h post-meal using indirect calorimetry, and MIT was calculated as the increase in energy expenditure above the pre-meal RMR. On average, 76, 89 and 96 % of the 6 h MIT response was completed within 3, 4 and 5 h, respectively, and MIT at each of these time points was strongly correlated with the 6 h MIT response (range for correlations, r 0·990-0·998; P< 0·01). The between-day CV for the 6 h measurement was 33 %, but it was significantly lower after 3 h of measurement (CV 26 %; P= 0·02). Despite variability in the total MIT between days, the proportion of MIT that was completed at 3, 4 and 5 h was reproducible (mean CV: 5 %). While 6 h are typically required to measure the complete MIT response, the 3 h measures provide sufficient information about the magnitude of the MIT response and may be applicable for testing individuals on repeated occasions.


The expression of positive and negative schizotypy in daily life: an experience sampling study.
Psychometrically identified positive schizotypy and negative schizotypy are differentially related to psychopathology, personality and social functioning. However, little is known about the experience and expression of schizotypy in daily life and the psychological mechanisms that trigger psychotic-like experiences. The present study employed experience sampling methodology (ESM) to assess positive and negative schizotypy in daily life in a non-clinical sample of 412 young adults. ESM is a structured diary technique in which participants are prompted at random times during the day to complete assessments of their current experiences. As hypothesized, positive schizotypy was associated with increased negative affect, thought impairment, suspiciousness, negative beliefs about current activities and feelings of rejection, but not with social disinterest or decreased positive affect. Negative schizotypy, on the other hand, was associated with decreased positive affect and pleasure in daily life, increased negative affect, and decreases in social contact and interest. Both positive schizotypy and negative schizotypy were associated with the desire to be alone when with others. However, this was moderated by anxiety in positive schizotypy and by diminished positive affect in negative schizotypy. The results support the construct validity of a multidimensional model of schizotypy and the ecological validity of the positive and negative schizotypy dimensions. ESM appears to be a promising method for examining the daily life experiences of schizotypic individuals.


Fermented foods, neuroticism, and social anxiety: An interaction model.
Animal models and clinical trials in humans suggest that probiotics can have an anxiolytic effect. However, no studies have examined the relationship between probiotics and social anxiety. Here we employ a cross-sectional approach to determine whether consumption of fermented foods likely to contain probiotics interacts with neuroticism to predict social anxiety symptoms. A sample of young adults (N=710, 445 female) completed self-report measures of fermented food consumption, neuroticism, and social anxiety. An interaction model, controlling for demographics, general consumption of healthful foods, and exercise frequency, showed that exercise frequency, neuroticism, and fermented food consumption significantly and independently predicted social anxiety. Moreover, fermented food consumption also interacted with neuroticism in predicting social anxiety. Specifically, for those high in neuroticism, higher frequency of fermented food consumption was associated with fewer symptoms of social anxiety. Taken together with previous studies, the results suggest that fermented foods that contain probiotics may have a protective effect against social anxiety symptoms for those at higher genetic risk, as indexed by trait neuroticism. While additional research is necessary to determine the direction of causality, these results suggest that consumption of fermented foods that contain probiotics may serve as a low-risk intervention for reducing social anxiety.


Cortical dynamics of visual motion perception: short-range and long-range apparent motion.
This article describes further evidence for a new neural network theory of biological motion perception. The theory clarifies why parallel streams V1----V2, V1----MT, and V1----V2----MT exist for static form and motion form processing among the areas V1, V2, and MT of visual cortex. The theory suggests that the static form system (Static BCS) generates emergent boundary segmentations whose outputs are insensitive to direction-of-contrast and to direction-of-motion, whereas the motion form system (Motion BCS) generates emergent boundary segmentations whose outputs are insensitive to direction-of-contrast but sensitive to direction-of-motion. The theory is used to explain classical and recent data about short-range and long-range apparent motion percepts that have not yet been explained by alternative models. These data include beta motion, split motion, gamma motion and reverse-contrast gamma motion, delta motion, and visual inertia. Also included are the transition from group motion to element motion in response to a Ternus display as the interstimulus interval (ISI) decreases; group motion in response to a reverse-contrast Ternus display even at short ISIs; speed-up of motion velocity as interflash distance increases or flash duration decreases; dependence of the transition from element motion to group motion on stimulus duration and size, various classical dependencies between flash duration, spatial separation, ISI, and motion threshold known as Korte's laws; dependence of motion strength on stimulus orientation and spatial frequency; short-range and long-range form-color interactions; and binocular interactions of flashes to different eyes.


Improvement of ischemia/reperfusion-induced contractile dysfunction of perfused hearts by class Ic antiarrhythmic agents.
The present study was undertaken to determine whether class Ic antiarrhythmic agents, flecainide and pilsicainide, improve ischemia/reperfusion-induced cardiac contractile dysfunction. Isolated rat hearts were subjected to a 35-min global ischemia, followed by a 60-min reperfusion, and the functional and metabolic consequences were examined. Ischemia/reperfusion resulted in no recovery of contractile function and a sustained rise in left ventricular and diastolic pressure of the perfused heart during reperfusion. The ischemia/reperfusion also induced increases in tissue sodium and calcium levels, decreases in potassium and magnesium ion contents and the release of creatine kinase and purine nucleosides and bases (ATP metabolites) from the heart, suggesting a pronounced change in cardiac transmembrane flux of ions, substrates and macromolecules. Treatment of the perfused heart with either 5 to 50 microM flecainide or 10 to 100 microM pilsicainide during preischemia resulted in diminishing the postischemic contractile dysfunction; suppressing the changes in tissue sodium, potassium, calcium and magnesium contents; and attenuating the release of creatine kinase and ATP metabolites in a concentration-dependent manner. Tissue sodium accumulation and potassium loss were also observed at the end of ischemia, which was attenuated by pretreatment with these agents. These results provided evidence that class Ic antiarrhythmic agents are capable of diminishing ischemia/reperfusion-induced contractile dysfunction and tissue ionic disturbance.


Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment.
In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.