A model to evaluate past exposure to 2,3,7,8-TCDD.
Data from several studies suggest that concentrations of dioxins rose in the environment from the 1930s to about the 1960s/70s and have been declining over the last decade or two. The most direct evidence of this trend comes from lake core sediments, which can be used to estimate past atmospheric depositions of dioxins. The primary source of human exposure to dioxins is through the food supply. The pathway relating atmospheric depositions to concentrations in food is quite complex, and accordingly, it is not known to what extent the trend in human exposure mirrors the trend in atmospheric depositions. This paper describes an attempt to statistically reconstruct the pattern of past human exposure to the most toxic dioxin congener, 2,3,7,8-TCDD (abbreviated TCDD), through use of a simple pharmacokinetic (PK) model which included a time-varying TCDD exposure dose. This PK model was fit to TCDD body burden data (i.e., TCDD concentrations in lipid) from five U.S. studies dating from 1972 to 1987 and covering a wide age range. A Bayesian statistical approach was used to fit TCDD exposure; model parameters other than exposure were all previously known or estimated from other data sources. The primary results of the analysis are as follows: (1) use of a time-varying exposure dose provided a far better fit to the TCDD body burden data than did using a dose that was constant over time; this is strong evidence that exposure to TCDD has, in fact, varied during the 20th century, (2) the year of peak TCDD exposure was estimated to be in the late 1960s, which coincides with peaks found in sediment core studies, (3) modeled average exposure doses during these peak years was estimated at 1.4-1.9 pg TCDD/kg-day, and (4) modeled exposure doses of TCDD for the late 1980s of less than 0.10 pg TCDD/kg-day correlated well with recent estimates of exposure doses around 0.17 pg TCDD/kg-day (recent estimates are based on food concentrations combined with food ingestion rates; food is thought to explain over 90% of total dioxin exposure). This paper describes these and other results, the goodness-of-fit between predicted and observed lipid TCDD concentrations, the modeled impact of breast feeding on lipid concentrations in young individuals, and sensitivity and uncertainty analyses.


Examining the Role of Supportive Family Connection in Violence Exposure Among Male Youth in Urban Environments.
Family connection has demonstrated protective effects on violence perpetration, victimization, and witnessing in the general U.S. adolescent population. However, several studies examining the impact of family connection on violence exposure in adolescents living in low-resource urban environments have failed to demonstrate similar protective effects. We interviewed male youth in low-resource neighborhoods in Philadelphia recruited through household random sampling. Adjusted logistic regression was used to test whether a supportive relationship with an adult family member was inversely associated with violence involvement and violence witnessing. In 283 youth participants aged 10 to 24 years, 33% reported high violence involvement, 30% reported high violence witnessing, and 17% reported both. Youth who identified at least one supportive adult family member were significantly less likely to report violence involvement (odds ratio [OR] = 0.35; 95% confidence interval [CI] = [0.18, 0.69]) and violence witnessing (OR = 0.46; 95% CI = [0.24, 0.88]). Youth with two supportive parents, and those with supportive mothers only, also demonstrated significant inverse associations with violence involvement. Supportive parental relationships were inversely but not significantly related to witnessing violence. The findings suggest that supportive parental relationships may not prevent youth in low-resource neighborhoods from witnessing violence but may help prevent direct violence involvement. Next studies should be designed such that the mechanisms that confer protection can be identified, and should identify opportunities to bolster family connection that may reduce adolescent violence involvement among youth in low-resource urban environments.


Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone.
The alpha(v)beta(3) integrin is abundantly expressed in osteoclasts and has been implicated in the regulation of osteoclast function, especially in cell attachment. However, in vivo studies have shown that echistatin, an RGD-containing disintegrin which binds to alpha(v)beta(3), inhibits bone resorption without changing the number of osteoclasts on the bone surface, suggesting inhibition of osteoclast activity. The objective of this study was to examine how occupancy of alpha(v)beta(3) integrins inhibits osteoclast function, using primary rat osteoclasts and murine pre-fusion osteoclast-like cells formed in a co-culture system. We show that: (1) echistatin inhibits bone resorption in vitro at lower concentrations (IC(50 )= 0.1 nM) than those required to detach osteoclasts from bone (IC(50 ) approximately 1 microM); (2) echistatin (IC(50 )= 0.1 nM) inhibits M-CSF-induced migration and cell spreading of osteoclasts; (3) alpha(v)beta(3) integrins are localized in podosomes at the leading edge of migrating osteoclasts, whereas, with echistatin treatment (0.1 nM), alpha(v)beta(3) disperses randomly throughout the adhesion surface; and (4) when bone resorption is fully inhibited with echistatin, there is visible disruption of the sealing zone (IC(50 )= 13 nM), and alpha(v)beta(3) visualized with confocal microscopy re-distributes from the basolateral membranes to intracellular vesicular structures. Taken together, these findings suggest that alpha(v)beta(3) integrin plays a role in the regulation of two processes required for effective osteoclastic bone resorption: cell migration (IC(50 )= 0.1 nM) and maintenance of the sealing zone (IC(50) approximately 10 nM).


Gaseous Emissions from Wastewater Facilities.
A review of the literature published in 2014 on topics relating to gaseous emissions from wastewater facilities is presented. This review is divided into the following sections: odorant emissions from wastewater treatment plants (WWTPs); greenhouse gas (GHG) emissions from WWTPs; gaseous emissions from wastewater collection systems; physiochemical odor/emissions control methods; biological odor/emissions control methods; odor characterization/monitoring; and odor impacts/risk assessments.


Imaging microscopic pigment chemistry in conjunctival melanocytic lesions using pump-probe laser microscopy.
To report the application of a novel imaging technique, pump-probe microscopy, to analyze patterns of pigment chemistry of conjunctival melanocytic lesion biopsies. Histopathologic specimens of eight previously excised conjunctival melanocytic lesions were analyzed with pump-probe microscopy. The technique uses a laser scanning microscope with a two-color pulsed laser source to distinguish hemoglobin, eumelanin, and pheomelanin pigment based on differences in transient excited state and ground state photodynamics. The pump-probe signatures of conjunctival melanins were compared with cutaneous melanins. The distributions of hemoglobin, eumelanin, and pheomelanin were analyzed, and pump-probe images were correlated with adjacent hematoxylin and eosin (H&E)-stained sections. The pump-probe signatures of conjunctival melanins are similar, but not identical to cutaneous melanins. In addition, there are qualitative and quantitative differences in the structure and pigment chemistry of conjunctival benign nevi, primary acquired melanosis of the conjunctiva (PAM), and conjunctival melanomas. The pump-probe images correlated well with histopathologic features observed in the adjacent H&E-stained sections, and provided a label-free means of discerning conjunctival anatomic features and pathologic benign or malignant tissue. Pump-probe laser microscopy shows promise as an adjuvant diagnostic tool in evaluation of ocular melanocytic lesions based on morphologic correlation with the histopathology results and pigment chemistry. This initial study suggests systematic differences in pigmentation patterns among conjunctival benign nevi, primary acquired melanosis, and melanomas. In addition, pump-probe microscopy has the potential for use as a noninvasive "in vivo" optical biopsy technique to aid clinical and surgical management of conjunctival melanocytic lesions.


Histone H2A monoubiquitination and Polycomb repression: the missing pieces of the puzzle.
Polycomb group (PcG) proteins were originally identified as negative regulators of HOX genes in Drosophila but have since emerged as a widely used transcriptional repression system that controls a variety of developmental processes in animals and plants. PcG proteins exist in multi-protein complexes that comprise specific chromatin-modifying enzymatic activities. Genome-wide binding studies in Drosophila and in mammalian cells revealed that these complexes co-localize at a large set of genes encoding developmental regulators. Recent analyses in Drosophila have begun to explore how the different chromatin-modifying activities of PcG protein complexes contribute to the repression of individual target genes. These studies suggest that monoubiquitination of histone H2A (H2Aub) by the PcG protein Sce is only essential for repression of a subset of PcG target genes but is not required for the Polycomb-mediated repression of other targets. Calypso/dBap1, a major deubiquitinase for H2Aub is also critically needed for repression of a subset of PcG target genes. Here, we review our current understanding of the role of H2A monoubiquitination and deubiquitination in Polycomb repression in Drosophila. We discuss unresolved issues concerning the immunological detection of H2Aub and critically evaluate experiments that used Sce and Ring1B point mutants with impaired H2A ubiquitinase activity to study H2Aub-dependent and -independent functions of these proteins in transcriptional repression.


Dual emission in asymmetric "giant" PbS/CdS/CdS core/shell/shell quantum dots.
Semiconducting nanocrystals optically active in the infrared region of the electromagnetic spectrum enable exciting avenues in fundamental research and novel applications compatible with the infrared transparency windows of biosystems such as chemical and biological optical sensing, including nanoscale thermometry. In this context, quantum dots (QDs) with double color emission may represent ultra-accurate and self-calibrating nanosystems. We present the synthesis of giant core/shell/shell asymmetric QDs having a PbS/CdS zinc blende (Zb)/CdS wurtzite (Wz) structure with double color emission close to the near-infrared (NIR) region. We show that the double emission depends on the excitation condition and analyze the electron-hole distribution responsible for the independent and simultaneous radiative exciton recombination in the PbS core and in the CdS Wz shell, respectively. These results highlight the importance of the driving force leading to preferential crystal growth in asymmetric QDs, and provide a pathway for the rational control of the synthesis of double color emitting giant QDs, leading to the effective exploitation of visible/NIR transparency windows.


Pharmacogenomics of chemotherapeutic susceptibility and toxicity.
The goal of personalized medicine is to tailor a patient's treatment strategy on the basis of his or her unique genetic make-up. The field of oncology is beginning to incorporate many of the strategies of personalized medicine, especially within the realm of pharmacogenomics, which is the study of how inter-individual genetic variation determines drug response or toxicity. A main objective of pharmacogenomics is to facilitate physician decision-making regarding optimal drug selection, dose and treatment duration on a patient-by-patient basis. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. This review focuses on the contribution of germline genetic variation to chemotherapeutic toxicity and response, and discusses the utility of genome-wide association studies and use of lymphoblastoid cell lines (LCLs) in pharmacogenomic studies. Furthermore, we highlight several recent examples of genetic variants associated with chemotherapeutic toxicity or response in both patient cohorts and LCLs, and discuss the challenges and future directions of pharmacogenomic discovery for cancer treatment.


Evaluation of bulk-fill systems: microtensile bond strength and non-destructive imaging of marginal adaptation.
The objective of this study was to investigate microtensile bond strength (MTBS) and interfacial adaptation (IA) of bulk-fill restorative systems bonded to dentin in Class-I-preparations. Box-shaped preparations (4-mm-long, 3-mm-wide, 2-mm-high) made in extracted molars, and Teflon matrix with the same dimensions positioned over the occlusal surface were restored, providing a total of 4-mm composite depth using three bulk-fill restorative systems: Tetric EvoCeram Bulk Fill with Tetric N-Bond (TEC/TNB), SureFil SDR Flow with XP Bond (SDR/XPB) and Filtek Bulk Fill Flowable Restorative with Scotchbond Universal (FBF/SBU); or incrementally restored with a conventional restorative system: Herculite Classic with OptiBond FL (HER/OBF). The specimens were sectioned into beams and the MTBS measured after 24-hours or one-year storage. For evaluation of IA, round-tapered tooth preparations (3-mm-diameter, 1.5-mm-deep) were made, restored with each material and their cross-sectional images were obtained after 24-hours using optical coherence tomography (OCT). The gap percentage for each restoration system was calculated using image analysis software. MTBS for both storage periods: HER/OBF=TEC/TNB=SDR/XPB>FBF/SBU (ANOVA, Tukey's post-hoc, P<0.05) differed significantly among groups, which values were significantly reduced after one-year. SDR/XPB showed comparatively lesser gap formation at the tooth-interface after 24 hours (ANOVA, Dunnett's T3 post-hoc, P<0.05). For deeper restorations, bond strength of TEC/TNB and SDR/XPB can be equal to that of HER/OBF after 24-hours and one-year; however, in a shallower preparation, SDR/XPB showed greater initial interfacial adaptation.


Myogenic specification in somites: induction by axial structures.
Specification of the myogenic phenotype in somites was examined in the early chick embryo using organotypic explant cultures stained with monoclonal antibodies to myosin heavy chain. It was found that myogenic specification (formation of muscle fibers in explants of somites or segmental plates cultured alone) does not occur until Hamburger and Hamilton stage 11 (12-14 somites). At this stage, only the somites in the rostral half of the embryo are myogenically specified. By Hamburger and Hamilton stage 12 (15-17 somites), the three most caudal somites were not specified to be myogenic while most or all of the more rostral somites are specified to myogenesis. Somites from older embryos (stage 13-15, 18-26 somites) showed the same pattern of myogenic specification--all but the three most caudal somites were specified. We investigated the effects of the axial structures, the notochord and neural tube, on myogenic specification. Both the notochord and neural tube were able to induce myogenesis in unspecified somites. In contrast, the neural tube, but not the notochord, was able to induce myogenesis in explants of segmental plate, a structure which is not myogenic when cultured alone. When explants of specified somites were stained with antibodies to slow or fast MyHC, it was found that myofiber diversity (fast and fast slow fibers) was established very early in development (as early as Hamburger and Hamilton stage 11). We also found fiber diversity in explants of unspecified somites (the three most caudal somites from stage 11 to 15) when they were recombined with notochord or neural tube. We conclude that myogenic specification in the embryo results in diverse fiber types and is an inductive process which is mediated by factors produced by the neural tube and notochord.


Quantitatively controlled in situ formation of hydrogel membranes in microchannels for generation of stable chemical gradients.
The in situ formation of membranes in microfluidic channels has been given attention because of their great potential in the separation of components, cell culture support for tissue engineering, and molecular transport for generation of chemical gradients. Among these, the porous membranes in microchannels are vigorously applied to generate stable chemical gradients for chemotaxis-dependent cell migration assays. Previous work on the in situ fabrication of membranes for generating the chemical gradient, however, has had several disadvantages, such as fluid leaking, uncontrollable membrane thickness, need of extra equipment, and difficulty in realizing stable interfacial layers. In this paper, we report a novel technique for the in situ formation of membranes within microchannels using enzymatically crosslinkable hydrogels and microfluidic techniques. The thickness of the membrane can be controlled quantitatively by adjusting the crosslinking reaction time and velocity of the microfluidics. By using these techniques, parallel dual hydrogel membranes were prepared within microchannels and these were used for the generation of stable concentration gradients. Moreover, the migration of Salmonella typhimurium was monitored to validate the efficacy of the chemical gradients. These results suggest that our in situ membrane system can be used as a simple platform to understand many cellular activities, including cell adhesion and migration directed by chemotaxis or complex diffusions from biological fluids in three-dimensional microstructures.


Clinical disease presentation and ECG characteristics of LMNA mutation carriers.
Mutations in the LMNA gene encoding lamins A and C of the nuclear lamina are a frequent cause of cardiomyopathy accounting for 5-8% of familial dilated cardiomyopathy (DCM). Our aim was to study disease onset, presentation and progression among LMNA mutation carriers. Clinical follow-up data from 27 LMNA mutation carriers and 78 patients with idiopathic DCM without an LMNA mutation were collected. In addition, ECG data were collected and analysed systematically from 20 healthy controls. Kaplan-Meier analysis revealed no difference in event-free survival (death, heart transplant, resuscitation and appropriate implantable cardioverter-defibrillator therapy included as events) between LMNA mutation carriers and DCM controls (p=0.5). LMNA mutation carriers presented with atrial fibrillation at a younger age than the DCM controls (47 vs 57 years, p=0.003). Male LMNA mutation carriers presented with clinical manifestations roughly a decade earlier than females. In close follow-up non-sustained ventricular tachycardia was detected in 78% of LMNA mutation carriers. ECG signs of septal remodelling were present in 81% of the LMNA mutation carriers, 21% of the DCM controls and none of the healthy controls giving a high sensitivity and specificity for the standard ECG in distinguishing LMNA mutation carriers from patients with DCM and healthy controls. Male LMNA mutation carriers present clinical manifestations at a younger age than females. ECG septal remodelling appears to distinguish LMNA mutation carriers from healthy controls and patients with DCM without LMNA mutations.


Total synthesis and functional analysis of microbial signalling molecules.
Communication is essential for all domains of life. Bacteria use a plethora of small molecules to sense and orchestrate intra- and interspecies communication. Within this review, we will discuss different groups of signalling molecules, including autoinducers, virulence factors and morphogenic substances. On selected examples, we will shortly discuss their ecological roles and biosynthetic proposals. The major part of this review will focus on a systematic overview of the different synthetic methods applied towards the synthesis of signalling molecules and derivatives thereof. The described examples highlight the importance of organic synthetic method development and diversity-oriented total syntheses for structure verification, structure-function analysis and target identification.


Phonological and articulation treatment approaches in Portuguese children with speech and language impairments: a randomized controlled intervention study.
In Portugal, the routine clinical practice of speech and language therapists (SLTs) in treating children with all types of speech sound disorder (SSD) continues to be articulation therapy (AT). There is limited use of phonological therapy (PT) or phonological awareness training in Portugal. Additionally, at an international level there is a focus on collecting information on and differentiating between the effectiveness of PT and AT for children with different types of phonologically based SSD, as well as on the role of phonological awareness in remediating SSD. It is important to collect more evidence for the most effective and efficient type of intervention approach for different SSDs and for these data to be collected from diverse linguistic and cultural perspectives. To evaluate the effectiveness of a PT and AT approach for treatment of 14 Portuguese children, aged 4.0-6.7 years, with a phonologically based SSD. The children were randomly assigned to one of the two treatment approaches (seven children in each group). All children were treated by the same SLT, blind to the aims of the study, over three blocks of a total of 25 weekly sessions of intervention. Outcome measures of phonological ability (percentage of consonants correct (PCC), percentage occurrence of different phonological processes and phonetic inventory) were taken before and after intervention. A qualitative assessment of intervention effectiveness from the perspective of the parents of participants was included. Both treatments were effective in improving the participants' speech, with the children receiving PT showing a more significant improvement in PCC score than those receiving the AT. Children in the PT group also showed greater generalization to untreated words than those receiving AT. Parents reported both intervention approaches to be as effective in improving their children's speech. The PT (combination of expressive phonological tasks, phonological awareness, listening and discrimination activities) proved to be an effective integrated method of improving phonological SSD in children. These findings provide some evidence for Portuguese SLTs to employ PT with children with phonologically based SSD.


Laboratory and clinical evaluation of conjugate vaccines composed of Staphylococcus aureus type 5 and type 8 capsular polysaccharides bound to Pseudomonas aeruginosa recombinant exoprotein A.
The synthesis, standardization, and immunogenicity in young outbred mice and clinical evaluation in adult volunteers of investigational vaccines designed to induce serum antibodies to the type 5 and type 8 capsular polysaccharides (CPs) of Staphylococcus aureus are described. Conjugates composed of the type 5 CP and a sonicated preparation of a high-molecular-weight type 8 CP bound to a nontoxic recombinant protein derived from Pseudomonas aeruginosa exotoxin A (rEPA) were synthesized. The conjugates were nontoxic and elicited serum CP antibodies after two subcutaneous injections into young outbred mice; a third injection elicited a booster response. The lower-molecular-weight type 8 CP was not immunogenic in the mice, and the high-molecular-weight type 8 CP elicited low levels of antibodies without a booster effect. In the volunteers, neither the conjugates nor the type 8 CP alone caused significant local reactions or fever. The conjugates elicited type-specific antibodies of both the immunoglobulin M (IgM) and IgG classes after the first injection; a second injection 6 weeks later did not stimulate a booster effect. The high-molecular-weight type 8 CP alone, injected once only, elicited levels of IgG and IgM type-specific antibodies similar to those of the conjugate. The vaccine-induced CP antibodies were mostly of the IgG1 and IgG2 subclasses and had opsonophagocytic activity. The conjugates elicited IgG antibodies to the native exotoxin A with neutralizing activity. In summary, the type 5 and type 8 conjugates were safe and elicited biologically active antibodies to both the CP and rEPA components.


Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR).
To investigate whether androgen conversion rates after supplementation with dehydroepiandrosterone (DHEA) differ, and whether differences between patients with diminished ovarian reserve (DOR) are predictive of pregnancy chances in association with in vitro fertilization (IVF). In a prospective cohort study we investigated 213 women with DOR, stratified for age (≤ 38 or >38 years) and ovarian FMR1 genotypes/sub-genotypes. All women were for at least 6 weeks supplemented with 75 mg of DHEA daily prior to IVF, between initial presentation and start of 1st IVF cycles. Levels of DHEA, DHEA-sulfate (DHEAS), total T (TT) and free T (FT) at baseline ((BL)) and IVF cycle start ((CS)) were then compared between conception and non-conception cycles. Mean age for the study population was 41.5 ± 4.4 years. Forty-seven IVF cycles (22.1 %) resulted in clinical pregnancy. Benefits of DHEA on pregnancy rates were statistically associated with efficiency of androgen conversion from DHEA to T and amplitude of T gain. Younger women converted significantly more efficiently than older females, and selected FMR1 genotypes/sub-genotypes converted better than others. FSH/androgen and AMH/androgen ratios represent promising new predictors of IVF pregnancy chances in women with DOR. DOR at all ages appears to represent an androgen-deficient state, benefitting from androgen supplementation. Efficacy of androgen supplementation with DHEA, however, varies depending on female age and FMR1 genotype/sub-genotype. Further clarification of FMR1 effects should lead to better individualization of androgen supplementation, whether via DHEA or other androgenic compounds.


What treatments for rheumatoid arthritis can best be assessed by large, simple, long-term trials?
If the really important questions in the long-term management of rheumatoid arthritis are to be answered reliably, then clinical trials may have to be undertaken that are very much larger and simpler than has previously been the case. For sufficient numbers of busy clinicians to collaborate wholeheartedly with such trials, the extra work per patient should be very slight. In addition, the collaborators should be more than recompensed for even that slight extra trouble by pro-rata secretarial and/or locum assistance, so that it will actually be less work for them to collaborate wholeheartedly in such a trial than not to do so. Two particular trials are discussed to illustrate these general principles.


Dopamine, uncertainty and TD learning.
Substantial evidence suggests that the phasic activities of dopaminergic neurons in the primate midbrain represent a temporal difference (TD) error in predictions of future reward, with increases above and decreases below baseline consequent on positive and negative prediction errors, respectively. However, dopamine cells have very low baseline activity, which implies that the representation of these two sorts of error is asymmetric. We explore the implications of this seemingly innocuous asymmetry for the interpretation of dopaminergic firing patterns in experiments with probabilistic rewards which bring about persistent prediction errors. In particular, we show that when averaging the non-stationary prediction errors across trials, a ramping in the activity of the dopamine neurons should be apparent, whose magnitude is dependent on the learning rate. This exact phenomenon was observed in a recent experiment, though being interpreted there in antipodal terms as a within-trial encoding of uncertainty.


A spatio-temporal framework for modelling wastewater concentration during the COVID-19 pandemic.
The potential utility of wastewater-based epidemiology as an early warning tool has been explored widely across the globe during the current COVID-19 pandemic. Methods to detect the presence of SARS-CoV-2 RNA in wastewater were developed early in the pandemic, and extensive work has been conducted to evaluate the relationship between viral concentration and COVID-19 case numbers at the catchment areas of sewage treatment works (STWs) over time. However, no attempt has been made to develop a model that predicts wastewater concentration at fine spatio-temporal resolutions covering an entire country, a necessary step towards using wastewater monitoring for the early detection of local outbreaks. We consider weekly averages of flow-normalised viral concentration, reported as the number of SARS-CoV-2N1 gene copies per litre (gc/L) of wastewater available at 303 STWs over the period between 1 June 2021 and 30 March 2022. We specify a spatially continuous statistical model that quantifies the relationship between weekly viral concentration and a collection of covariates covering socio-demographics, land cover and virus associated genomic characteristics at STW catchment areas while accounting for spatial and temporal correlation. We evaluate the model's predictive performance at the catchment level through 10-fold cross-validation. We predict the weekly viral concentration at the population-weighted centroid of the 32,844 lower super output areas (LSOAs) in England, then aggregate these LSOA predictions to the Lower Tier Local Authority level (LTLA), a geography that is more relevant to public health policy-making. We also use the model outputs to quantify the probability of local changes of direction (increases or decreases) in viral concentration over short periods (e.g. two consecutive weeks). The proposed statistical framework can predict SARS-CoV-2 viral concentration in wastewater at high spatio-temporal resolution across England. Additionally, the probabilistic quantification of local changes can be used as an early warning tool for public health surveillance.


Cytomegalovirus ischemic colitis and transverse myelitis in a renal transplant recipient.
We report a rare case of cytomegalovirus (CMV)-associated ischemic colitis and transverse myelitis (TM) occurring precociously after renal transplantation. A 57-year-old male was transplanted with a cadaveric kidney on 5 June 2009. The patient was CMV seropositive and the donor was seronegative. Transplantation was followed shortly by TM, which resulted in paraplegia. The results of magnetic resonance imaging of the spinal cord showed abnormalities. Twenty days after transplantation, he developed abdominal pain with melena and was diagnosed as having CMV-associated ischemic colitis confirmed by colonoscopy and biopsy. Serological data and identification of the viral genome by polymerase chain reaction were confirmatory for CMV. Treatment consisted of intravenous ganciclovir, followed by polyvalent immunoglobulin. The outcome was favorable. Symptomatic CMV infection is relatively common among the renal transplant population. Early colonoscopy is beneficial for making a quick diagnosis and therefore helps to institute a prompt management of CMV colitis. Myelitis is less common in transplant recipients and diagnosis, therefore, was more difficult.


Adrenomedullin and calcitonin gene-related peptide receptors in endocrine-related cancers: opportunities and challenges.
Adrenomedullin (AM), adrenomedullin 2 (AM2/intermedin) and calcitonin gene-related peptide (CGRP) are members of the calcitonin family of peptides. They can act as growth or survival factors for a number of tumours, including those that are endocrine-related. One mechanism through which this occurs is stimulating angiogenesis and lymphangiogenesis. AM is expressed by numerous tumour types and for some cancers, plasma AM levels can be correlated with the severity of the disease. In cancer models, lowering AM content or blocking AM receptors can reduce tumour mass. AM receptors are complexes formed between a seven transmembrane protein, calcitonin receptor-like receptor and one of the two accessory proteins, receptor activity-modifying proteins (RAMPs) 2 or 3 to give the AM1 and AM2 receptors respectively. AM also has affinity at the CGRP receptor, which uses RAMP1. Unfortunately, due to a lack of selective pharmacological tools or antibodies to distinguish AM and CGRP receptors, the precise receptors and signal transduction pathways used by the peptides are often uncertain. Two other membrane proteins, RDC1 and L1/G10D (the 'ADMR'), are not currently considered to be genuine CGRP or AM receptors. In order to properly evaluate whether AM or CGRP receptor inhibition has a role in cancer therapy, it is important to identify which receptors mediate the effects of these peptides. To effectively distinguish AM1 and AM2 receptors, selective receptor antagonists need to be developed. The development of specific CGRP receptor antagonists suggests that this is now feasible.


CDK8 is a positive regulator of transcriptional elongation within the serum response network.
The Mediator complex allows communication between transcription factors and RNA polymerase II (RNAPII). Cyclin-dependent kinase 8 (CDK8), the kinase found in some variants of Mediator, has been characterized mostly as a transcriptional repressor. Recently, CDK8 was demonstrated to be a potent oncoprotein. Here we show, using a human tumor cell line, that CDK8 is a positive regulator of genes within the serum response network, including several members of the activator protein 1 and early growth response family of oncogenic transcription factors. Mechanistic studies show that CDK8 is not required for RNAPII recruitment or promoter escape. Instead, CDK8 depletion leads to the appearance of slower elongation complexes carrying hypophosphorylated RNAPII. CDK8-Mediator regulates precise steps in the assembly of the RNAPII elongation complex, including the recruitment of positive transcription elongation factor b and BRD4. Furthermore, CDK8-Mediator specifically interacts with positive transcription elongation factor b. Thus, we have uncovered a role for CDK8 in transcriptional regulation that may contribute to its oncogenic effects.


Discriminant ECOC: a heuristic method for application dependent design of error correcting output codes.
We present a heuristic method for learning error correcting output codes matrices based on a hierarchical partition of the class space that maximizes a discriminative criterion. To achieve this goal, the optimal codeword separation is sacrificed in favor of a maximum class discrimination in the partitions. The creation of the hierarchical partition set is performed using a binary tree. As a result, a compact matrix with high discrimination power is obtained. Our method is validated using the UCI database and applied to a real problem, the classification of traffic sign images.


Health care practices in ancient Greece: The Hippocratic ideal.
Asclepius and Hippocrates focused medical practice on the natural approach and treatment of diseases, highlighting the importance of understanding the patient's health, independence of mind, and the need for harmony between the individual, social and natural environment, as reflected in the Hippocratic Oath. The aim of this study was to present the philosophy of care provision in ancient Greece and to highlight the influence of the Hippocratic ideal in modern health care practices. A literature review was carried out using browser methods in international databases. According to the literature, "healthy mind in a healthy body" was the main component of the Hippocratic philosophy. Three main categories were observed in the Hippocratic provision of care: health promotion, interventions on trauma care, and mental care and art therapy interventions. Health promotion included physical activity as an essential part of physical and mental health, and emphasized the importance of nutrition to improve performance in the Olympic Games. Interventions on trauma care included surgical practices developed by Hippocrates, mainly due to the frequent wars in ancient Greece. Mental care and art therapy interventions were in accordance with the first classification of mental disorders, which was proposed by Hippocrates. In this category music and drama were used as management tools in the treatment of illness and in the improvement of human behavior. The role of Asclepieion of Kos was highlighted which clearly indicates a holistic health care model in care provision. Finally, all practices regarded detailed recordings and evaluation of information within the guidelines. The Hippocratic philosophy on health care provision focused on the holistic health care model, applying standards and ethical rules that are still valid today.


Implementation of antibiotic rotation protocol improves antibiotic susceptibility profile in a surgical intensive care unit.
Antibiotic rotation has been proposed as a way to potentially reduce the development of antimicrobial resistant bacteria in intensive care units. We assessed the effect of an antibiotic rotation protocol on the antibiotic susceptibility profiles of three clinically relevant gram-negative microorganisms within our surgical intensive care unit (SICU). Our SICU implemented an antibiotic rotation protocol in 2003. Four antibiotics (piperacillin/tazobactam, imipenem/cilastin, ceftazidime, and ciprofloxacin) were rotated as the primary antibiotic used to treat suspected gram-negative infections every month, with the four-drug cycle being repeated every 4 months. Antibiotic susceptibility data for three microorganisms (Pseudomonas aeruginosa, Escherichia coli, and Klebsiella pneumoniae) were collected for the year before (2002) and the year after (2004) the implementation of the rotation protocol. Changes in antimicrobial susceptibility rates were analyzed for the three microorganisms. As a comparison, a similar analysis was conducted for microorganisms isolated from our medical intensive care unit, where no antibiotic rotation protocol was implemented. Implementation of an antibiotic rotation protocol in our SICU resulted in a significant increase in the percentage of P. aeruginosa isolates sensitive to ceftazidime (67% in 2002 vs. 92% in 2004, p = 0.002) and piperacillin/tazobactam (78% in 2002 vs. 92% in 2004, p = 0.043). Isolates from the medical intensive care unit did not demonstrate an increase in antimicrobial susceptibility. In fact, the susceptibility of E. coli to piperacillin/tazobactam decreased during this time period (p = 0.047). Implementation of an antibiotic rotation protocol in our SICU resulted in overall improvement in the antibiotic susceptibility profile of gram-negative microorganisms relative to our medical intensive care unit, where such a protocol was not used.


Bioethics training in Uganda: report on research and clinical ethics workshops.
This essay describes and critically evaluates a co-operative educational program to train Ugandan health care workers in bioethics. It describes one "bottom-up" effort, a week-long intensive workshop in bioethics provided by the authors to health care professionals in a developing country-Uganda. We will describe the background and circumstances that led to the organization of the workshop, and review its planning, design, curriculum, and outcome. We will focus especially on measures taken to make the workshop relevant for the audience of Ugandan professionals, and describe lessons learned after two presentations of the workshop. Finally, we will discuss the strengths and weaknesses of such a format, and its potential value in raising bioethical expertise in developing countries.


Characteristics of Newly Diagnosed Hepatocellular Carcinoma Patients Across Turkey: Prospective Multicenter Observational 3K Registry Study.
To evaluate patient profile for epidemiological and clinicopathological characteristics and potential risk/prognostic factors in newly diagnosed hepatocellular carcinoma (HCC) patients across Turkey. A total of 547 patients (mean (SD) age 62.6 (10.3) years, 81.9% were males) were included in this registry study. Data on patient characteristics, etiologies of HCC, laboratory values, and tumor characteristics and stages were recorded at study enrollment. HBV infection (68.2%) was the leading etiology, followed by HCV infection (17.2%), HDV infection (5.5%), alcohol (6.4%), and NAFLD (3.5%), as the major etiologies. Considering that 51.6% of the patients had >5 cm HCC, 44% were Child-Pugh B/C and 57% were BCLC B-D, it appears that a significant group of HCC patients were diagnosed at advanced stages. Of 540 patients, 271 (50.2%) were referred or applied with the diagnosis of HCC. Patients with HCC at presentation had larger tumor size (median (min-max) 6.6 (0-30) vs. 4.8 (0-90) cm, P < .001) and more advanced BCLC stage (Stage C-D in 40.8% vs. 26.4%, respectively, P = .005), compared to patients who were diagnosed during follow-up. Our findings revealed that HBV infection was the leading etiology and a moderate-to-advanced disease was evident in more than half of patients at the time of diagnosis. HCC patients diagnosed at follow-up had smaller tumor size and earlier BCLC stage.


Psychophysical Evaluation of Congenital Colour Vision Deficiency: Discrimination between Protans and Deutans Using Mollon-Reffin's Ellipses and the Farnsworth-Munsell 100-Hue Test.
We have used the Farnsworth-Munsell 100-hue (FM 100) test and Mollon-Reffin (MR) test to evaluate the colour vision of 93 subjects, 30.4 ± 9.7 years old, who had red-green congenital colour vision deficiencies. All subjects lived in Belém (State of Pará, Brazil) and were selected by the State of Pará Traffic Department. Selection criteria comprised the absence of visual dysfunctions other than Daltonism and no history of systemic diseases that could impair the visual system performance. Results from colour vision deficient were compared with those from 127 normal trichromats, 29.3 ± 10.3 years old. For the MR test, measurements were taken around five points of the CIE 1976 colour space, along 20 directions irradiating from each point, in order to determine with high-resolution the corresponding colour discrimination ellipses (MacAdam ellipses). Three parameters were used to compare results obtained from different subjects: diameter of circle with same ellipse area, ratio between ellipse's long and short axes, and ellipse long axis angle. For the FM 100 test, the parameters were: logarithm of the total number of mistakes and positions of mistakes in the FM diagram. Data were also simultaneously analysed in two or three dimensions as well as by using multidimensional cluster analysis. For the MR test, Mollon-Reffin Ellipse #3 (u' = 0.225, v' = 0.415) discriminated more efficiently than the other four ellipses between protans and deutans once it provided larger angular difference in the colour space between protan and deutan confusion lines. The MR test was more sensitive than the FM 100 test. It separated individuals by dysfunctional groups with greater precision, provided a more sophisticated quantitative analysis, and its use is appropriate for a more refined evaluation of different phenotypes of red-green colour vision deficiencies.


Control of seminal fluid protein expression via regulatory hubs in Drosophila melanogaster.
Highly precise, yet flexible and responsive coordination of expression across groups of genes underpins the integrity of many vital functions. However, our understanding of gene regulatory networks (GRNs) is often hampered by the lack of experimentally tractable systems, by significant computational challenges derived from the large number of genes involved or from difficulties in the accurate identification and characterization of gene interactions. Here we used a tractable experimental system in which to study GRNs: the genes encoding the seminal fluid proteins that are transferred along with sperm (the 'transferome') in Drosophila melanogaster fruit flies. The products of transferome genes are core determinants of reproductive success and, to date, only transcription factors have been implicated in the modulation of their expression. Hence, as yet, we know nothing about the post-transcriptional mechanisms underlying the tight, responsive and precise regulation of this important gene set. We investigated this omission in the current study. We first used bioinformatics to identify potential regulatory motifs that linked the transferome genes in a putative interaction network. This predicted the presence of putative microRNA (miRNA) 'hubs'. We then tested this prediction, that post-transcriptional regulation is important for the control of transferome genes, by knocking down miRNA expression in adult males. This abolished the ability of males to respond adaptively to the threat of sexual competition, indicating a regulatory role for miRNAs in the regulation of transferome function. Further bioinformatics analysis then identified candidate miRNAs as putative regulatory hubs and evidence for variation in the strength of miRNA regulation across the transferome gene set. The results revealed regulatory mechanisms that can underpin robust, precise and flexible regulation of multiple fitness-related genes. They also help to explain how males can adaptively modulate ejaculate composition.


Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans.
A powerful approach to understanding complex processes such as aging is to use model organisms amenable to genetic manipulation, and to seek relevant phenotypes to measure. Caenorhabditis elegans is particularly suited to studies of aging, since numerous single-gene mutations have been identified that affect its lifespan; it possesses an innate immune system employing evolutionarily conserved signaling pathways affecting longevity. As worms age, bacteria accumulate in the intestinal tract. However, quantitative relationships between worm genotype, lifespan, and intestinal lumen bacterial load have not been examined. We hypothesized that gut immunity is less efficient in older animals, leading to enhanced bacterial accumulation, reducing longevity. To address this question, we evaluated the ability of worms to control bacterial accumulation as a functional marker of intestinal immunity. We show that as adult worms age, several C. elegans genotypes show diminished capacity to control intestinal bacterial accumulation. We provide evidence that intestinal bacterial load, regulated by gut immunity, is an important causative factor of lifespan determination; the effects are specified by bacterial strain, worm genotype, and biologic age, all acting in concert. In total, these studies focus attention on the worm intestine as a locus that influences longevity in the presence of an accumulating bacterial population. Further studies defining the interplay between bacterial species and host immunity in C. elegans may provide insights into the general mechanisms of aging and age-related diseases.


Cross-talk between Tor1 and Sch9 regulates hyphae-specific genes or ribosomal protein genes in a mutually exclusive manner in Candida albicans.
The human fungal pathogen Candida albicans switches its morphology from yeast to hyphal forms. The morphological transition may render C. albicans virulent. Several signaling cascades, including those of the cyclic AMP-protein kinase A and mitogen-activated protein kinase pathways, are responsible for morphogenesis. In this study, we observed a reduction in gene transcription of ribosomal proteins during true hyphae formation. Moreover, morphogenesis-dependent decrease in ribosomal protein gene transcription was confirmed in constitutive yeast or filamentous growing strains. We consistently observed that polysome and monosome levels were decreased by hyphal stimuli through TORC1 and Sch9 kinases. Taken together, these results provide several lines of evidence to show that the Tor1-Sch9 kinase cascade, which stimulates transcription of ribosomal protein genes, exists in C. albicans. Thus, the present study revealed a novel link between ribosome biogenesis and morphogenesis in C. albicans that is mediated by Tor1 and Sch9.


Dietary pretreatment with green tea polyphenol, (-)-epigallocatechin-3-gallate reduces the bioavailability and hepatotoxicity of subsequent oral bolus doses of (-)-epigallocatechin-3-gallate.
Human case-studies have reported an association between green tea-based dietary supplements and hepatotoxicity. Studies have demonstrated the hepatotoxicity of high-dose oral bolus dosing with the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) in mice and dogs. We examined the effect of pretreatment with dietary EGCG on the hepatotoxicity and bioavailability of acute oral bolus dosing with EGCG in CF-1 mice. EGCG (750 mg/kg, i.g., once daily for 3 days) increased plasma alanine aminotransferase by 80-fold, decreased both reduced (by 59%) and total (by 33%) hepatic glutathione, and increased hepatic levels of phosphorylated histone 2AX. Pretreatment with dietary EGCG (3.2 mg/g diet) for 2 weeks mitigated hepatotoxicity. Acute oral EGCG also decreased mRNA expression of glutathione reductase. Dietary pretreatment prevented these decreased and increased glutathione peroxidase (Gpx)2, Gpx3, Gpx5, and Gpx7 expression. We found that dietary EGCG reduced the plasma (57% reduction) and hepatic (71% reduction) EGCG exposure following oral bolus dosing compared to mice that were not pre-treated. Overall, it appears that EGCG can modulate its own bioavailability and that dietary treatment may reduce the toxic potential of acute high oral bolus doses of EGCG. These data may partly explain the observed variation in hepatotoxic response to green tea-containing dietary supplements.


Multifaceted peptide assisted one-pot synthesis of gold nanoparticles for plectin-1 targeted gemcitabine delivery in pancreatic cancer.
An astute modification of the plectin-1-targeting peptide KTLLPTP by introducing a C-terminal cysteine preceded by a tyrosine residue imparted a reducing property to the peptide. This novel property is then exploited to fabricate gold nanoparticles (GNP) via an in situ reduction of gold(iii) chloride in a one-pot, green synthesis. The modified peptide KTLLPTPYC also acts as a template to generate highly monodispersed, spherical GNPs with a narrow size distribution and improved stability. Plectin-1 is known to be aberrantly expressed in the surface of pancreatic ductal adenocarcinoma (PDAC) cells while showing cytoplasmic expression in normal cells. The synthesized GNPs are thus in situ surface modified with the peptides via the cysteine residue leaving the N-terminal KTLLPTP sequence free for targeting plectin-1. The visual molecular dynamics based simulations support the experimental observations like particle size, gemcitabine conjugation and architecture of the peptide-grafted nanoassembly. Additionally, GNPs conjugated to gemcitabine demonstrate significantly higher cytotoxicity in vitro in two established PDAC cell lines (AsPC-1 and PANC-1) and an admirable in vivo antitumor efficacy in a PANC-1 orthotopic xenograft model through selective uptake in PDAC tumor tissues. Altogether, this strategy represents a unique method for the fabrication of a GNP based targeted drug delivery platform using a multifaceted peptide that acts as reducing agent, template for GNP synthesis and targeting agent to display remarkable selectivity towards PDAC.


Good outcomes of liver transplantation for hepatitis C at a low volume centre.
Concerns exist about outcomes of liver transplantation (LT) from low volume centres, especially for hepatitis C (HCV) patients. The aim of the study was to assess patient outcomes as well as their predictors post LT for HCV in a small volume Australian unit (< 25 LTs/year), comparing these with the average outcomes obtained from national and international transplant registries. Patients transplanted for HCV at the South Australian Liver Transplant Unit between 1992 and 2012 were studied. Outcomes assessed were patient and graft survival at 1,3, and 5 years. Factors independently associated with the outcomes were assessed using Cox regression model. 1, 3, and 5-year patient survival for HCV patients was 95.2, 82.9, and 78.2%, graft survival were 93.7, 80.1, and 75.5% respectively. The total follow-up time observed was 299.9 years amongst 61 patients in which there were 16 deaths. The expected number of deaths was 40.4 and the standardized mortality ratio 0.40 (95% CI = 0.24, 0.65). These results compared favourably to those obtained from the SRTR registry. Variables independently associated with lower patient survival: donor age (HR = 1.06, 95% CI 1.02 - 1.11; P = 0.003), and post LT cytomegalovirus (CMV) disease requiring treatment (HR = 4.03, 95% CI 1.48 - 10.92;P = 0.06). In conclusion, high rates of patient and graft survival for HCV liver transplantation can be obtained in a small volume unit. Young donor age and lack of CMV disease post-transplant were associated with better outcomes. Institutional factors may be influential determinants of outcomes.


Standardisation and quality control of ultrasound measurements taken in the INTERGROWTH-21st Project.
Meticulous standardisation and ongoing monitoring of adherence to measurement protocols during data collection are essential to ensure consistency and to minimise systematic error in multicentre studies. Strict ultrasound fetal biometric measurement protocols are used in the INTERGROWTH-21(st) Project so that data of the highest quality from different centres can be compared and potentially pooled. A central Ultrasound Quality Unit (USQU) has been set up to oversee this process. After initial training and standardisation, the USQU monitors the performance of all ultrasonographers involved in the project by continuously assessing the quality of the images and the consistency of the measurements produced. Ultrasonographers are identified when they exceed preset maximum allowable differences. Corrective action is then taken in the form of retraining or simply advice regarding changes in practice. This paper describes the procedures used, which can form a model for research settings involving ultrasound measurements.


Association between CYP1A2 and CYP1B1 polymorphisms and colorectal cancer risk: a meta-analysis.
The previous published data on the association between CYP1A2*F (rs762551), CYP1B1 Leu432Val (rs1056836), Asn453Ser (rs180040), and Arg48Gly (rs10012) polymorphisms and colorectal cancer risk remained controversial. The purpose of this study is to evaluate the role of CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly genotypes in colorectal cancer susceptibility. We performed a meta-analysis on all the eligible studies that provided 5,817 cases and 6,544 controls for CYP1A2*F (from 13 studies), 9219 cases and 10406 controls for CYP1B1 Leu432Val (from 12 studies), 6840 cases and 7761 controls for CYP1B1 Asn453Ser (from 8 studies), and 4302 cases and 4791 controls for CYP1B1Arg48Gly (from 6 studies). Overall, no significant association was found between CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly and colorectal cancer risk when all the eligible studies were pooled into the meta-analysis. And in the subgroup by ethnicity and source of controls, no evidence of significant association was observed in any subgroup analysis. In summary, this meta-analysis indicates that CYP1A2*F, CYP1B1 Leu432Val, Asn453Ser, and Arg48Gly polymorphisms do not support an association with colorectal cancer, and further studies are needed to investigate the association. In addition, our work also points out the importance of new studies for CYP1A2*F polymorphism in Asians, because high heterogeneity was found (dominant model: I(2) = 81.3%; heterozygote model: I(2) = 79.0).


[Stem cell transplantation for multiple sclerosis. Hamburg experiences and state of international research].
Autologous hematopoietic stem cell transplantation (aHSCT) is still not the standard treatment for highly inflammatory multiple sclerosis (MS). Even though randomized controlled trials are lacking, predictors for treatment response have been established. Since 2007, ten patients have received aHSCT in Hamburg. To present observational data from patients treated in Hamburg and a review of the literature. Descriptive statistics were used for evaluating the course of the expanded disability status scale (EDSS) as a measure for clinical outcome, magnetic resonance imaging (MRI) and neuropsychology. New gadolinium and T2-MRI uptake lesions per scan were compared. In addition, a systematic review of the currently available literature was performed. The Hamburg series can be divided in two groups, one group including four patients with chronic progressive MS with low inflammatory activity (median EDSS = 6.25, 0.5 relapses per year, no gadolinium-enhancing lesions) and the other group including six patients with mild to moderate disability, relapses and inflammatory activity (median EDSS = 4.25, 1 relapse per year, 2 gadolinium-enhancing lesions). The median follow-up was 2.4 years. While the first group did not seem to benefit from aHSCT, an improvement in five out of six patients was observed in the second group. New T2 lesions occurred within the first 6 months but gadolinium-enhancing lesions were not observed (p < 0.05). A systematic literature search identified a higher efficacy of aHSCT in younger, less disabled MS patients with inflammatory activity, similar to the findings from Hamburg. Cohort reports describe aHSCT as a safe and efficient treatment option in highly inflammatory MS. Based on these data aHSCT seems to be a reasonable option in selected patients with highly inflammatory MS but a randomized controlled trial is warranted.


Differential inhibition of human neutrophil activation by cyclosporins A, D, and H. Cyclosporin H is a potent and effective inhibitor of formyl peptide-induced superoxide formation.
Cyclosporin (Cs)A but not CsH inhibits activation of human lymphocytes. We studied the effects of CsA, CsD, and CsH on human neutrophil activation induced by chemoattractants and by various substances that circumvent receptor stimulation. CsH inhibited superoxide (O2-) formation induced by the chemotactic peptide, FMLP (30 nM), with a half-maximal effect at 40 nM. O2- formation was abolished by CsH at 1 microM. CsH increased the concentration of FMLP causing half-maximal activation of O2- formation from 30 nM to 0.8 microM and substantially reduced the stimulatory effect of FMLP at supra-maximally effective concentrations. The inhibitory effect of CsH on O2- formation was evident immediately after addition to neutrophils. CsH also markedly inhibited the increase in cytosolic Ca2+ ([Ca2+]i), beta-glucuronidase, and lysozyme release and aggregation stimulated by FMLP. CsA and CsD were considerably less effective than CsH to inhibit FMLP-induced O2- formation. CsA and CsD were without effect on exocytosis, rises in [Ca2+]i, and aggregation induced by the chemotactic peptide. Cyclosporines inhibited FMLP-induced O2- formation in an additive manner, indicating that they acted through a mechanism they had in common. Cyclosporines only slightly inhibited O2- formation and lysozyme release induced by C5a. Aggregation and rises in [Ca2+]i stimulated by C5a were not affected by cyclosporines, and they did not inhibit O2- formation and exocytosis induced by platelet-activating factor and leukotriene B4. Cyclosporines partially inhibited O2- formations induced by NaF and gamma-hexachlorocyclohexane. CsA marginally inhibited PMA-induced O2- formation and lysozyme release. CsA, CsD, and CsH did not inhibit arachidonic acid-induced O2- formation and its potentiation by NaF or stable guanine nucleotides in a cell-free system from DMSO-differentiated HL-60 cells. CsH partially inhibited binding of FML [3H]P to formyl peptide receptors in membranes from DMSO- or dibutyryl cAMP-differentiated HL-60 cells. Our data show that: 1) cyclosporines differentially inhibit activation of human neutrophils; and 2) CsH is, indeed, not immunologically inactive but is a potent and effective inhibitor of FMLP-induced O2- formation. 3) CsH interferes with agonist binding to formyl peptide receptors and in addition, cyclosporines may also act at sites distal to chemoattractant receptors.


Costs of bleeding on long-term antiplatelet treatment without routine co-prescription of proton-pump inhibitors.
Long-term antiplatelet treatment is associated with major bleeding. To determine the costs associated with major bleeding in patients treated with aspirin-based antiplatelet treatment for secondary prevention of vascular events without routine prescription of proton-pump inhibitors and to estimate the likely long-term savings from routine co-prescription. In a prospective population-based cohort study of TIA, ischemic stroke, and MI treated with antiplatelet drugs, we evaluated hospital care costs associated with bleed management during 10-year follow-up. Bleeding-associated costs were averaged across all patients. For upper GI-bleeds, mean costs were compared with the cost of routine co-prescription of proton-pump inhibitor. Among 3166 patients on antiplatelet therapy with 405 first bleeding events, the average cost of major bleeding was $13,093 (S.D. 20,501), with similar costs for upper GI bleeds and intracranial bleeds (p = 0.235). However, total costs among the 3166 patients were higher for upper GI bleeds ($1,158,385 vs. $740,123). Averaged across all patients, the 10-year cost of major bleeding was $838 (95%CI: 680-1007), $411 due to upper GI bleeding, the cost of which increased from $175 in those aged <75 years to $644 at age ≥75 years (p < 0.0001). The corresponding costs of routine life-long co-prescription of proton-pump inhibitor to those patients not on prior treatment were $85 (84-88) and $39 (38-42). In secondary prevention with aspirin-based antiplatelet treatment without routine proton-pump inhibitor use, the long-term costs of upper-GI bleeding at age ≥75 years are much higher than at younger age groups, and are at least 10-fold greater than the drug cost of routine co-prescription of proton-pump inhibitor.


Enhancing doctor-patient communication using email: a pilot study.
The doctor-patient relationship has been eroded by many factors. Would e-mail enhance communication and address some of the barriers inherent to our medical practices? Of our study population, 4 physicians offered e-mail communication to participating patients and 4 did not. Both patients and physicians completed questionnaires regarding satisfaction, perceived quality, convenience, and promptness of the communication. Patient satisfaction significantly increased in the e-mail group compared with the control group in the areas of convenience (P < .0001) and the amount of time spent contacting their physician (P < .0001). Physician satisfaction in the e-mail group increased regarding convenience, amount of time spent on messages, and volume of messages. The response time was longer with e-mail. When asked if patients should be able to e-mail their physicians, most patients in the e-mail group and all but 2 of the physicians in the non-e-mail group responded "yes." E-mail communication was found to be a more convenient form of communication. Satisfaction by both patients and physicians improved in the e-mail group. The volume of messages and the time spent answering messages for the e-mail group physicians was not increased. E-mail has the potential to improve the doctor-patient relationship as a result of better communication.


The Status of Fusarium Mycotoxins in Sub-Saharan Africa: A Review of Emerging Trends and Post-Harvest Mitigation Strategies towards Food Control.
Fusarium fungi are common plant pathogens causing several plant diseases. The presence of these molds in plants exposes crops to toxic secondary metabolites called Fusarium mycotoxins. The most studied Fusarium mycotoxins include fumonisins, zearalenone, and trichothecenes. Studies have highlighted the economic impact of mycotoxins produced by Fusarium. These arrays of toxins have been implicated as the causal agents of wide varieties of toxic health effects in humans and animals ranging from acute to chronic. Global surveillance of Fusarium mycotoxins has recorded significant progress in its control; however, little attention has been paid to Fusarium mycotoxins in sub-Saharan Africa, thus translating to limited occurrence data. In addition, legislative regulation is virtually non-existent. The emergence of modified Fusarium mycotoxins, which may contribute to additional toxic effects, worsens an already precarious situation. This review highlights the status of Fusarium mycotoxins in sub-Saharan Africa, the possible food processing mitigation strategies, as well as future perspectives.


Dimethyl sulfoxide (DMSO) exposure to human peripheral blood mononuclear cells (PBMCs) abolish T cell responses only in high concentrations and following coincubation for more than two hours.
Immunotherapies based on reinfusion of autologous cells incubated ex vivo with peptides reconstituted in toxic solvents, such as DMSO, are now performed on a routine basis. However, the toxic effects of the most common solvent used, DMSO, on T cell responses from human PBMCs, have not previously been evaluated in detail. Here, in preparation for a first-in-man human phase I vaccine trial comprising reinfusion of autologous HIV peptide-pulsed PBMCs, human PBMCs from healthy and HIV-infected donors were exposed in vitro to a range of DMSO concentrations, and for a range of time periods. Polychromatic flow cytometry was used to evaluate the influence of DMSO on functional T cell responses. We report that high concentrations of up to 10% of DMSO for 1 hour do not affect the cell viability, the magnitude or the functional profile of CD4(+) and CD8(+) T cell responses, regardless of antigen specificity and HLA class I restriction. In contrast, >2% for >2 hours compromises these responses. These data are relevant in the design of immunotherapies based on pulsing a large number of peptides onto antigen presenting cells prior to reinfusion.


Pseudogenes.
Pseudogenes are ubiquitous and abundant in genomes. Pseudogenes were once called "genomic fossils" and treated as "junk DNA" several years. Nevertheless, it has been recognized that some pseudogenes play essential roles in gene regulation of their parent genes, and many pseudogenes are transcribed into RNA. Pseudogene transcripts may also form small interfering RNA or decrease cellular miRNA concentration. Thus, pseudogenes regulate tumor suppressors and oncogenes. Their essential functions draw the attention of our research group in my current work on heat shock protein 90: a chaperone of oncogenes. The paper reviews our current knowledge on pseudogenes and evaluates preliminary results of the chaperone data. Current efforts to understand pseudogenes interactions help to understand the functions of a genome.


Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, preclinical and clinical research with PARPi has revealed multiple resistance mechanisms, highlighting the need for identification of novel functional biomarkers and combination treatment strategies. Functional genetic screens performed in cells and organoids that acquired resistance to PARPi by loss of 53BP1 identified loss of LIG3 as an enhancer of PARPi toxicity in BRCA1-deficient cells. Enhancement of PARPi toxicity by LIG3 depletion is dependent on BRCA1 deficiency but independent of the loss of 53BP1 pathway. Mechanistically, we show that LIG3 loss promotes formation of MRE11-mediated post-replicative ssDNA gaps in BRCA1-deficient and BRCA1/53BP1 double-deficient cells exposed to PARPi, leading to an accumulation of chromosomal abnormalities. LIG3 depletion also enhances efficacy of PARPi against BRCA1-deficient mammary tumors in mice, suggesting LIG3 as a potential therapeutic target.


Evolving insights regarding mechanisms for the inhibition of insulin release by norepinephrine and heterotrimeric G proteins.
Norepinephrine has for many years been known to have three major effects on the pancreatic β-cell which lead to the inhibition of insulin release. These are activation of K(+) channels to hyperpolarize the cell and prevent the gating of voltage-dependent Ca(2+) channels that increase intracellular Ca(2+) concentration ([Ca(2+)](i)) and trigger release; inhibition of adenylyl cyclases, thus preventing the augmentation of stimulated insulin release by cyclic AMP; and a "distal" effect that occurs downstream of increased [Ca(2+)](i) to inhibit exocytosis. All three are mediated by the pertussis toxin (PTX)-sensitive heterotrimeric Gi and Go proteins. The distal inhibitory effect on exocytosis is now known to be due to the binding of G protein βγ subunits to the synaptosomal-associated protein of 25 kDa (SNAP-25) on the soluble NSF attachment protein receptor (SNARE) complex. Recent studies have uncovered two more actions of norepinephrine on the β-cell: 1) retardation of the refilling of the readily releasable granule pool after it has been discharged, an action that is mediated by Gαi(1) and/or Gαi(2); and 2) inhibition of endocytosis that is mediated by Gz. Of importance also are new findings that Gαo regulates the number of docked granules in the β-cell, and that Gαo(2) maintains a tonic inhibitory influence on secretion. The latter provides another explanation as to why PTX, which blocks the effect of Gαo(2), was initially called "islet activating protein." Finally, there is clear evidence that overexpression of α(2A)-adrenergic receptors in β-cells can cause type 2 diabetes.


Comparative Proteomic Analysis of Mycobacterium tuberculosis Lineage 7 and Lineage 4 Strains Reveals Differentially Abundant Proteins Linked to Slow Growth and Virulence.
In order to decipher the nature of the slowly growing Mycobacterium tuberculosis (M.tuberculosis) lineage 7, the differentially abundant proteins in strains of M. tuberculosis lineage 7 and lineage 4 were defined. Comparative proteomic analysis by mass spectrometry was employed to identify, quantitate and compare the protein profiles of strains from the two M. tuberculosis lineages. Label-free peptide quantification of whole cells from M. tuberculosis lineage 7 and 4 yielded the identification of 2825 and 2541 proteins, respectively. A combined total of 2867 protein groups covering 71% of the predicted M. tuberculosis proteome were identified. The abundance of 125 proteins in M. tuberculosis lineage 7 and 4 strains was significantly altered. Notably, the analysis showed that a number of M. tuberculosis proteins involved in growth and virulence were less abundant in lineage 7 strains compared to lineage 4. Five ABC transporter proteins, three phosphate binding proteins essential for inorganic phosphate uptake, and six components of the type 7 secretion system ESX-3 involved in iron acquisition were less abundant in M. tuberculosis lineage 7. This proteogenomic analysis provided an insight into the lineage 7-specific protein profile which may provide clues to understanding the differential properties of lineage 7 strains in terms of slow growth, survival fitness, and pathogenesis.


Holistic but with reduced right-hemisphere involvement: The case of dyslexia in Chinese character recognition.
Recent research on visual object recognition has suggested that the right hemisphere can engage either holistic or part-based processing depending on whether the recognition relies on configural (exact distances among features) or featural information, respectively. Consistent with this finding, expert Chinese reading has been marked by a left-side bias (an indication of right-hemisphere lateralization) with decreased holistic processing (as assessed using the composite paradigm) due to its reliance on featural information. Here we examine two common perceptual expertise phenomena in object recognition - holistic processing and left-side bias - of Chinese characters in adolescents with developmental dyslexia and matched controls. We found that those with dyslexia showed stronger holistic processing, a weaker left-side bias, and worse performance in Chinese character dictation than controls. This was in contrast to Limited writers (proficient readers with limited writing experience) reported in Tso, Au, and Hsiao (Psychological Science, 25, 1757-1767, 2014), who showed stronger holistic processing and worse dictation performance, but the same level of left-side bias as controls. This result demonstrated two different perceptual mechanisms underlying holistic processing: Limited writers' holistic processing may be due to difficulties in de-emphasizing configural information unimportant to Chinese characters, whereas readers with dyslexia may have deficits selectively attending to character components to form appropriate part-based representations in the right hemisphere.


Comparison of nine methods to estimate ear-canal stimulus levels.
The reliability of nine measures of the stimulus level in the human ear canal was compared by measuring the sensitivity of behavioral hearing thresholds to changes in the depth of insertion of an otoacoustic emission probe. Four measures were the ear-canal pressure, the eardrum pressure estimated from it and the pressure measured in an ear simulator with and without compensation for insertion depth. The remaining five quantities were derived from the ear-canal pressure and the Thévenin-equivalent source characteristics of the probe: Forward pressure, initial forward pressure, the pressure transmitted into the middle ear, eardrum sound pressure estimated by summing the magnitudes of the forward and reverse pressure (integrated pressure) and absorbed power. Two sets of behavioral thresholds were measured in 26 subjects from 0.125 to 20 kHz, with the probe inserted at relatively deep and shallow positions in the ear canal. The greatest dependence on insertion depth was for transmitted pressure and absorbed power. The measures with the least dependence on insertion depth throughout the frequency range (best performance) included the depth-compensated simulator, eardrum, forward, and integrated pressures. Among these, forward pressure is advantageous because it quantifies stimulus phase.


Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden.
Active perinatal care increases the rate of survival of extremely preterm infants, but there are concerns that improved survival might increase the rate of disabled survivors. To determine the neurodevelopmental outcomes of a national cohort of children 6.5 years of age who had been born extremely preterm (<27 weeks' gestational age) in Sweden. Population-based prospective cohort study of consecutively born extremely preterm infants. All of these infants were born in Sweden during the period from April 1, 2004, to March 31, 2007. Of 707 live-born extremely preterm infants, 486 (68.7%) survived to 6.5 years of age. These children were assessed and compared with matched controls who had been born at term. Comparison estimates were adjusted for demographic differences. Assessments ended in February 2014, and analysis started thereafter. Cognitive ability was measured with the fourth edition of the Wechsler Intelligence Scale for Children (WISC-IV), and the mean (SD) scores of the children who had been born extremely preterm were compared with those of the controls. Clinical examinations and parental questionnaires were used for diagnosis of cerebral palsy, hearing and vision impairments, and cognition for the children who were not assessed with the WISC-IV. Of 486 eligible infants who were born extremely preterm, 441 (90.7%) were assessed at 6.5 years of age (59 by medical record review only) alongside 371 controls. The adjusted mean (SD) full-scale WISC-IV score was 14.2 (95% CI, 12.1-16.3) points lower for children who had been born extremely preterm than for controls. Cognitive disability was moderate for 18.8% of extremely preterm children and 2.2% of controls (P < .001), and it was severe for 11.1% of extremely preterm children and 0.3% of controls (P < .001). Cerebral palsy was observed in 9.5% of extremely preterm children and 0.0% of controls (P < .001), blindness was observed in 2.0% of extremely preterm children and 0.0% of controls (P < .001), and hearing impairment was observed in 2.1% of extremely preterm children and 0.5% of controls (P = .07). Overall, 36.1% (95% CI, 31.7%-40.6%) of extremely preterm children had no disability, 30.4% (95% CI 26.3%-34.8%) had mild disability, 20.2% (95% CI, 16.6%-24.2%) had moderate disability, and 13.4% (95% CI, 10.5%-16.9%) had severe disability. For extremely preterm children, moderate or severe overall disability decreased with gestational age at birth (adjusted odds ratio per week, 0.65 [95% CI, 0.54-0.79]; P < .001) and increased from 26.6% to 33.5% (P = .01) for children assessed both at 2.5 and 6.5 years. Of the 441 extremely preterm infants who had received active perinatal care, 293 (66.4%) had no or mild disability at 6.5 years; of the 371 controls, 11 (3.0%) had moderate or severe disability. Disability rates at 6.5 years increased relative to the rates at 2.5 years. Results are relevant for health care professionals and planners, and for clinicians counseling families facing extremely preterm births.


Review: Metabolic cardiomyopathy and conduction system defects in children.
Metabolic cardiomyopathies include amino acid, lipid and mitochondrial disorders, as well as storage diseases. A number of metabolic disorders are associated with both myopathy and cardiomyopathy. These include the glycogen storage diseases, ie, acid maltase deficiency (infantile, childhood, and adult onset), McArdle disease, and debrancher and brancher deficiencies. Disorders of lipid metabolism include systemic carnitine deficiency and abnormalities of carnitine palmitoyltransferase (CPT), long-chain acyl-CoA dehydrogenase, and multiple acyl-CoA dehydrogenase. Disorders of mitochondrial metabolism affect complex I, II, III, IV and V, in addition to multiple respiratory chain defects. These may cause either hypertrophic or dilated cardiomyopathy. In addition, cardiomyopathy is frequently a component part of the storage disorders, including mucopolysaccharidosis, mucolipidosis, Fabry disease, gangliosidosis, and neuronal ceroid lipofuscinosis. Primary hypertrophic cardiomyopathy is caused by mutations in one of the genes that encode proteins of the cardiac sarcomere. Mutations in different genes are attended by different prognoses and different risks of sudden death. Mutations of the genes for myosin binding protein C (MBPC) and tropomyosin have low penetrance and cause mild forms of primary hypertrophic cardiomyopathy, while mutations of the troponin T and B-myosin genes carry a worse prognosis. Conduction disorders result in cardiac arrhythmias that may be fatal. Histiocytoid cardiomyopathy is usually an autosomal recessive disorder that results in the presence of abnormal Purkinje cells that interfere with normal cardiac conduction. Other conduction defects include arrhythmogenic right ventricular dysplasia (ARVD), congenital heart block, noncompaction of the left ventricle, and long Q-T syndrome (LQTS). The genetic loci for LQTS reside usually in the potassium channel, and, less frequently, in the sodium channel (channelopathies). Although the histological appearance of some of these disorders may be diagnostic, molecular analysis is necessary to define clearly the particular type of cardiomyopathy.


Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity.
Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis.


Histochemical and fatigue characteristics of conditioned canine latissimus dorsi muscle.
To induce fatigue resistance in the latissimus dorsi muscle of the dog in preparation for possible myocardial assistance, eight adult male beagles underwent unilateral electrical stimulation of the thoracodorsal nerve at a frequency of 2 Hz (120 stimuli/min) and 10 Hz (600 stimuli/min) for a 6-week period. The conditioned muscles were compared with their unconditioned contralateral controls by fiber typing, pyrophosphate gel electrophoresis, isometric characteristics, and fatigue rates. At the end of the period of stimulation, the conditioned muscles had a greater percentage of slow-twitch, fatigue-resistant fibers on acid and alkaline stains (100 +/- 0.7% and 83 +/- 15.3%), respectively, than did their contralateral controls (45 +/- 7.6% and 43 +/- 7.0). Pyrophosphate gel electrophoresis revealed an increase in the slow myosin and a decrease in the fast myosin content in the conditioned muscles; the stimulated muscles also demonstrated a slower contraction time (87 +/- 20 msec vs. 57 +/- 17.9 msec), a lower initial tension (4.4 +/- 1.45 kg vs. 7.2 +/- 2.11 kg), and a slower fatigue rate during a 30-minute fatigue test than did their contralateral controls. The muscles stimulated at 2 Hz had fatigue rates similar to those stimulated at 10 Hz, but generally had less diminution in muscle fiber diameters and less interfiber connective tissue. Thus, it is possible to make canine latissimus dorsi muscles more fatigue resistant, and, theoretically, more capable of myocardial assistance by electrical stimulation of the thoracodorsal nerve at a frequency as low as 2 Hz--the natural canine heart rate.


Protective effect of synaptic inhibition during cerebral ischemia in rats and rabbits.
Excitatory neurotransmitters appear to cause cell death during ischemia by inducing depolarization, influx of ions, and metabolic failure in the postsynaptic neuron. If this hypothesis is correct, then postsynaptic membrane hyperpolarization and inhibition of metabolism may be protective. Antagonists of the excitotoxic amino acid glutamate protect neurons in culture and in animal models of stroke but appear to cause unacceptable side effects in humans. We propose an alternative strategy of protection using agonists of the inhibitory neurotransmitter gamma-aminobutyric acid. We caused multifocal cerebral ischemia in rats and rabbits by injecting microspheres into the carotid circulation. We administered saline, muscimol, or MK-801 within 5 minutes of stroke onset. We used a bioassay to measure outcome. In rats, we also used learning to assess cortical function, and we performed detailed quantitative brain morphometry 3 months after infarction. Using the bioassay, we found that muscimol exerted a protective effect in rats (p less than 0.01). There was a dose-response effect seen in muscimol-treated rabbits. Rats treated with muscimol or MK-801 exhibited significantly better visual-spatial learning compared with saline-treated subjects (p less than 0.001). Hemisphere volume after ischemia was comparable in all groups. Agonists of gamma-aminobutyric acid and antagonists of glutamate appear to protect brain during ischemia. Since agonists of gamma-aminobutyric acid are known to have fewer side effects in humans, they may prove more useful in the clinical setting as neuroprotective agents.


Neural mass activity, bifurcations, and epilepsy.
In this letter, we propose a general framework for studying neural mass models defined by ordinary differential equations. By studying the bifurcations of the solutions to these equations and their sensitivity to noise, we establish an important relation, similar to a dictionary, between their behaviors and normal and pathological, especially epileptic, cortical patterns of activity. We then apply this framework to the analysis of two models that feature most phenomena of interest, the Jansen and Rit model, and the slightly more complex model recently proposed by Wendling and Chauvel. This model-based approach allows us to test various neurophysiological hypotheses on the origin of pathological cortical behaviors and investigate the effect of medication. We also study the effects of the stochastic nature of the inputs, which gives us clues about the origins of such important phenomena as interictal spikes, interictal bursts, and fast onset activity that are of particular relevance in epilepsy.


'The whole is always smaller than its parts': a digital test of Gabriel Tardes' monads.
In this paper we argue that the new availability of digital data sets allows one to revisit Gabriel Tarde's (1843-1904) social theory that entirely dispensed with using notions such as individual or society. Our argument is that when it was impossible, cumbersome or simply slow to assemble and to navigate through the masses of information on particular items, it made sense to treat data about social connections by defining two levels: one for the element, the other for the aggregates. But once we have the experience of following individuals through their connections (which is often the case with profiles) it might be more rewarding to begin navigating datasets without making the distinction between the level of individual component and that of aggregated structure. It becomes possible to give some credibility to Tarde's strange notion of 'monads'. We claim that it is just this sort of navigational practice that is now made possible by digitally available databases and that such a practice could modify social theory if we could visualize this new type of exploration in a coherent way.


Evaluation of arch form between Vietnamese and North American Caucasians using 3-dimensional virtual models.
The purpose of this study was to investigate the three-dimensional (3D) morphologic differences in the mandibular arch of Vietnamese and North American White subjects. The sample included 113 Vietnamese subjects (41 Class I, 37 Class II and 35 Class III) and 96 White subjects (29 Class I, 30 Class II and 37 Class III). The samples were regrouped according to arch form types (tapered, ovoid, and square) to compare the frequency distribution of the three arch forms between ethnic groups in each angle classification. The facial axis point of each tooth was digitized on 3D virtual models. Four linear and two ratio variables were measured. In comparing arch dimensions, the intercanine and intermolar widths were wider in Vietnamese than in Whites (p < 0.001, p = 0.042, respectively). In the White group, there was even frequency distribution of the three arch forms. However, in the Vietnamese group, the square arch form was the most frequent followed by tapered and ovoid arch forms. The arch forms of Whites were narrower than Vietnamese. In North American Whites, the distribution of the arch form types showed similar frequency. In Vietnamese, the square arch form was more frequent.


IQ in childhood and vegetarianism in adulthood: 1970 British cohort study.
To examine the relation between IQ in childhood and vegetarianism in adulthood. Prospective cohort study in which IQ was assessed by tests of mental ability at age 10 years and vegetarianism by self-report at age 30 years. Great Britain. 8170 men and women aged 30 years participating in the 1970 British cohort study, a national birth cohort. Self-reported vegetarianism and type of diet followed. 366 (4.5%) participants said they were vegetarian, although 123 (33.6%) admitted eating fish or chicken. Vegetarians were more likely to be female, to be of higher social class (both in childhood and currently), and to have attained higher academic or vocational qualifications, although these socioeconomic advantages were not reflected in their income. Higher IQ at age 10 years was associated with an increased likelihood of being vegetarian at age 30 (odds ratio for one standard deviation increase in childhood IQ score 1.38, 95% confidence interval 1.24 to 1.53). IQ remained a statistically significant predictor of being vegetarian as an adult after adjustment for social class (both in childhood and currently), academic or vocational qualifications, and sex (1.20, 1.06 to 1.36). Exclusion of those who said they were vegetarian but ate fish or chicken had little effect on the strength of this association. Higher scores for IQ in childhood are associated with an increased likelihood of being a vegetarian as an adult.


SU-E-T-226: Clinical Implementation of a Gravity-Oriented Wedge for Total Body Irradiation.
To describe a TBI technique designed within the limits of a small-room geometry and its clinical implementation. Following construction of the universal treatment devices, including the double-wedge, beam spoiler table, and patient support table, commissioning consists of measurements to determine the output, tissue-phantom ratio, effective source distance, and off-axis factor. Dose is calculated by applying these factors per patient-specific measurements to arbitrary point in the patient. Typically, ten calculation points are located at mid-separation along the mid-sagittal plane from the head to the ankles. When areas of unacceptably high dose are calculated, custom compensators are constructed from 5-mm sheets of PMMA and placed over the patient on top of the beam spoiler table. The typical dose homogeneity of the planning calculations is within 2% of the prescribed dose. To verify the accuracy of the technique, an anthropomorphic phantom was simulated and treated. In total, 128 thermoluminescent dosimeters (TLDs) were irradiated within the phantom. Concentrations of TLDs were located in the planes of selected calculation points, i.e. the head, neck, sternum, lung, umbilicus, and pelvis. Results showed the average dose to these locations differed from the intended dose by -3.5%, 3.4%, 2.6%, 9.5%, 2.8%, and 0.5%, respectively. Due to its heterogeneous material, a higher discrepancy in the lung dose was anticipated. To demonstrate the dosimetric size of the radiation field, ionization chamber measurements were taken on one lateral side of the treatment area at a constant depth of 5 cm. A few measurements on the contralateral side were within 1 %, verifying the field's lateral symmetry. The approximate treatment area for the current technique is approximately 180×50 cm. We have demonstrated a small-room technique capable of meeting the dosimetric goal of TBI. To improve the dosimetric characteristics, new universal treatment devices are currently being designed and constructed.


The self to other model of empathy: providing a new framework for understanding empathy impairments in psychopathy, autism, and alexithymia.
Despite increasing empirical and theoretical work on empathy, particularly on the content of empathic representations, there is a relative lack of consensus regarding the information processing necessary for empathy to occur. Here we attempt to delineate a mechanistic cognitive model of empathy in order to provide a framework within which neuroimaging work on empathy can be located, and which may be used in order to understand various disorders characterised by atypical levels of empathy. To this end data from individuals with psychopathy, autism, and alexithymia inform the model, and the model is used to provide a unifying framework for any empathy impairments seen in these disorders. The model adopts a developmental framework and tries to address the four difficult questions of empathy: How do we know what another is feeling? What is the role of theory of mind in empathy? How does the state of another cause a corresponding state in the self? How do we represent another's emotion once emotional contagion has taken place?


A Streptomyces coelicolor host for the heterologous expression of Type III polyketide synthase genes.
Recent advances in genome sequencing, combined with bioinformatic analysis, has led to the identification of numerous novel natural product gene clusters, particularly in actinomycetes of terrestrial and marine origin. Many of these gene clusters encode uncharacterised Type III polyketide synthases. To facilitate the study of these genes and their potentially novel products, we set out to construct an actinomycete expression host specifically designed for the heterologous expression of Type III PKS genes and their gene clusters. A derivative of Streptomyces coelicolor A3(2) designed for the expression of Type III polyketide synthase (PKS) genes was constructed from the previously engineered expression strain S. coelicolor M1152 [Δact Δred Δcpk Δcda rpoB(C1298T)] by removal of all three of the endogenous Type III PKS genes (gcs, srsA, rppA) by PCR targeting. The resulting septuple deletion mutant, M1317, proved to be an effective surrogate host for the expression of actinobacterial Type III PKS genes: expression of the reintroduced gcs gene from S. coelicolor and of the heterologous rppA gene from Streptomyces venezuelae under the control of the constitutive ermE* promoter resulted in copious production of germicidin and flaviolin, respectively. The newly constructed expression host S. coelicolor M1317 should be particularly useful for the discovery and analysis of new Type III polyketide metabolites.


Smoking behavior among low-income black adults: patterns and correlates of smoking trajectories.
Limited research has focused on identifying smoking patterns and correlates of cigarette use among low-income Blacks. Identifying smoking patterns and correlates of use would assist health providers to develop more culturally sensitive interventions. A semiparametric group-based trajectory modeling strategy was used to empirically identify patterns of cigarette use among 947 low-income Black adults (47% women) enrolled in a sexual risk reduction intervention at a sexually transmitted disease clinic. Patients' cigarette use was assessed 4 times over a 12-month period; correlates of cigarette use were examined. Six smoking trajectories were empirically identified: none/rare smokers (n = 536), decreasing light smokers (n = 69), increasing light smokers (n = 51), low light smokers (n = 112), upper light smokers (n = 142), and moderate smokers (n = 33). Smoking trajectories were predicted by alcohol use, prior substance use treatment, marijuana use, and other illegal drug use, but the patterns varied by trajectory. Results from this study show that Blacks' smoking patterns are associated with several risk factors. These findings suggest that development of prevention and cessation programs should be targeted to the specific needs of Blacks' smoking trajectories.


A national general practice census: characteristics of rural general practices.
The aim of the present study was to describe, using a national census, the characteristics of rural general practices and compare these with city and town general practices. A previously piloted, anonymous but linked, questionnaire was issued to all GPs in Ireland. A liaison network covering the country was developed to increase the response rate. Respondents were asked to designate the location of their main surgery as being city (>20 000 population), town (>5000) or rural (<5000). Each responding practice was asked to nominate one partner to complete a specific section on practice information. Completed individual questionnaires were returned from 2093 GPs (86% response rate). Information on 1429 practice centres was provided; 488 (34%) of these were designated as city, 405 (28%) as town and 536 (38%) as rural. Rural practices reported fewer private patients (P < 0.001) and more socio-economically deprived patients (P < 0.001) than those in towns or cities. The mean number (SD) of total scheduled hours per average week per GP was 77.95 (37.0) for city practices, 80.6 (35.9) for town and 103.6 (39.0) for rural (P < 0.001). Rural practices are more likely, in comparison with those in cities and towns, to have attached staff working from purpose-built premises which are publicly owned. Rural practices also have more contacts with members of the primary care team such as Public Health Nurses, and the quality of these contacts is described more positively. The range of available services is broadly similar, with emergency medical equipment being available more frequently in rural practices. This study suggests that rural practitioners and their practices differ from their urban counterparts in many important aspects. Consideration should be given to the development of formal under- and postgraduate rural general practice programmes to prepare new, and continue to enthuse present, rural GPs.