Minor malformations, hyperactivity, and learning disabilities.
Standardized minor malformation scores have been reported to predict and identify children with attentional problems and hyperactivity. The reason why this marker works for only a subset of children with attention deficit hyperactivity disorder remains unclear. The dysmorphology scores on all children presenting for a multidisciplinary team evaluation of developmental disorders were examined for diagnostic correlations after children with chromosomal disorders and recognized dysmorphic syndromes were excluded. For 1233 subjects, the mean minor malformation score was 2.94 (SD = 2.05). A significant association between minor malformation scores and IQ (mean = 80.95, SD = 23.67) was accounted for by the group with IQs greater than 100 exhibiting the higher dysmorphology scores. An analysis of variance revealed no significant association between minor malformation scores and hyperactivity or attention deficit disorder. Indeed, the presence of an attention deficit disorder yielded lower mean dysmorphology scores. When the minor malformation scores were compared for those subgroups of children with and without specific learning disabilities, the learning-disabled subjects had significantly higher dysmorphology scores. Minor dysmorphic features do not relate to the presence or absence of attentional problems or hyperactivity in referred children. Rather they appear to characterize that subpopulation of children with attention deficit disorder and learning disabilities as well as a group of learning-disabled children without attentional disorders.


Perioperative chemotherapy in gastroesophageal cancer. A retrospective monocenter evaluation of 42 cases.
Perioperative chemotherapy increases the overall and progression-free survival of patients suffering from resectable adenocarcinomas of the lower esophagus, gastroesophageal junction and stomach (GEC). Comparing different chemotherapy regimens platin-based protocols with 5-fluorouracil (5-FU)/calcium folinate (CF) or oral fluoropyrimidines were favorable in terms of efficacy and side-effects. However, there is no consensus which regimen is the most efficacious. 42 consecutive patients with resectable GEC (UICC II and III) were treated with 3 pre- and postoperative chemotherapy cycles each consisting of epirubicin, oxaliplatin and capecitabine (EOX). We analyzed the overall survival, progression-free survival and toxicity retrospectively in comparison to published data. The median overall survival in our cohort was 29 months and the progression-free survival was 17 months. The most frequent grade 3 and 4 toxicities during preoperative chemotherapy were diarrhea (16.7%), leukocytopenia (9.5%) and nausea (9.5%); overall 38.1% of our patients suffered from grade 3 or 4 toxicity. Surgery was carried out in 83% of our patients, 69% of those achieved R0 resection. Comparing our data with the results of previously published randomized trials EOX is at least non-inferior with regard to overall survival, progression-free survival and toxicity. In conclusion, EOX is an appropriate perioperative therapy for patients with resectable GEC.


Norepinephrine promotes triglyceride storage in macrophages via beta2-adrenergic receptor activation.
Tissue-resident macrophages are required for homeostasis, but also contribute to tissue dysfunction in pathophysiological states. The sympathetic neurotransmitter norepinephrine (NE) induces an anti-inflammatory and tissue-reparative phenotype in macrophages. As NE has a well-established role in promoting triglyceride lipolysis in adipocytes, and macrophages accumulate triglyceride droplets in various physiological and disease states, we investigated the effect of NE on primary mouse bone marrow-derived macrophage triglyceride metabolism. Surprisingly, our data show that in contrast to the canonical role of NE in stimulating lipolysis, NE acting via beta2-adrenergic receptors (B2ARs) in macrophages promotes extracellular fatty acid uptake and their storage as triglycerides and reduces free fatty acid release from triglyceride-laden macrophages. We demonstrate that these responses are mediated by a B2AR activation-dependent increase in Hilpda and Dgat1 gene expression and activity. We further show that B2AR activation favors the storage of extracellular polyunsaturated fatty acids. Finally, we present evidence that macrophages isolated from hearts after myocardial injury, for which survival critically depends on leukocyte B2ARs, have a transcriptional signature indicative of a transient triglyceride accumulation. Overall, we describe a novel and unexpected role of NE in promoting triglyceride storage in macrophages that could have potential implications in multiple diseases.


Medical and Research Consent Decision-Making Capacity in Patients with Alzheimer's Disease: A Systematic Review.
The capacity to make decisions is an important feature of daily living, which is closely linked to proper cognitive functioning. In conditions in which cognitive functioning becomes compromised, such as in Alzheimer's disease (AD), decision-making capacity can also get affected. Especially in AD, this has important implications, since over the course of the condition many important clinical decisions have to be made. For caregivers as well as physicians, it is sometimes difficult to determine how and when to intervene in the decision-making process. The aim of this systematic literature review was to identify studies that have evaluated medical and research consent decision-making capacity in patients with AD. Studies consistently show that decision-making capabilities are impaired in patients with AD. The cognitive and neuronal correlates of this process are, however, poorly studied. The few studies that investigated correlations have shown worse cognitive performance, mainly on the MMSE, to be related to poorer decision-making capacity. As most of these correlations have been performed in groups combining patients and controls, it remains unknown if these associations are disease specific. There is a need to study more systematically the decision-making process in relation to cognitive functioning and neural correlates to be able to develop a framework of decision-making capacity in AD, ultimately aiding clinicians and caregivers to understand and evaluate those capabilities in patients.


A review of health utilities across conditions common in paediatric and adult populations.
Cost-utility analyses are commonly used in economic evaluations of interventions or conditions that have an impact on health-related quality of life. However, evaluating utilities in children presents several challenges since young children may not have the cognitive ability to complete measurement tasks and thus utility values must be estimated by proxy assessors. Another solution is to use utilities derived from an adult population. To better inform the future conduct of cost-utility analyses in paediatric populations, we reviewed the published literature reporting utilities among children and adults across selected conditions common to paediatric and adult populations. An electronic search of Ovid MEDLINE, EMBASE, and the Cochrane Library up to November 2008 was conducted to identify studies presenting utility values derived from the Health Utilities Index (HUI) or EuroQoL-5Dimensions (EQ-5D) questionnaires or using time trade off (TTO) or standard gamble (SG) techniques in children and/or adult populations from randomized controlled trials, comparative or non-comparative observational studies, or cross-sectional studies. The search was targeted to four chronic diseases/conditions common to both children and adults and known to have a negative impact on health-related quality of life (HRQoL). After screening 951 citations identified from the literature search, 77 unique studies included in our review evaluated utilities in patients with asthma (n = 25), cancer (n = 23), diabetes mellitus (n = 11), skin diseases (n = 19) or chronic diseases (n = 2), with some studies evaluating multiple conditions. Utility values were estimated using HUI (n = 33), EQ-5D (n = 26), TTO (n = 12), and SG (n = 14), with some studies applying more than one technique to estimate utility values. 21% of studies evaluated utilities in children, of those the majority being in the area of oncology. No utility values for children were reported in skin diseases. Although few studies provided comparative information on utility values between children and adults, results seem to indicate that utilities may be similar in adolescents and young adults with asthma and acne. Differences in results were observed depending on methods and proxies. This review highlights the need to conduct future research regarding measurement of utilities in children.


[Biological shedders of Opisthorchis cercariae (experimental research)].
To elaborate biological controlling measures and enhance the biological shedding [correction of bioeliminating] potential of biocenosis, 12 species of hydrobionts from 7 orders were tested for eliminating activity. The larvae of dragonflies and scale insects revealed the highest activity (eliminated from 67 to 77% cercaria). It has been established that, with the test exposition time of 3 hours, maximum elimination of cercaria takes place in the first hour of the experiment.


Evidence of cellulose metabolism by the giant panda gut microbiome.
The giant panda genome codes for all necessary enzymes associated with a carnivorous digestive system but lacks genes for enzymes needed to digest cellulose, the principal component of their bamboo diet. It has been posited that this iconic species must therefore possess microbial symbionts capable of metabolizing cellulose, but these symbionts have remained undetected. Here we examined 5,522 prokaryotic ribosomal RNA gene sequences in wild and captive giant panda fecal samples. We found lower species richness of the panda microbiome than of mammalian microbiomes for herbivores and nonherbivorous carnivores. We detected 13 operational taxonomic units closely related to Clostridium groups I and XIVa, both of which contain taxa known to digest cellulose. Seven of these 13 operational taxonomic units were unique to pandas compared with other mammals. Metagenomic analysis using ~37-Mbp contig sequences from gut microbes recovered putative genes coding two cellulose-digesting enzymes and one hemicellulose-digesting enzyme, cellulase, β-glucosidase, and xylan 1,4-β-xylosidase, in Clostridium group I. Comparing glycoside hydrolase profiles of pandas with those of herbivores and omnivores, we found a moderate abundance of oligosaccharide-degrading enzymes for pandas (36%), close to that for humans (37%), and the lowest abundance of cellulases and endohemicellulases (2%), which may reflect low digestibility of cellulose and hemicellulose in the panda's unique bamboo diet. The presence of putative cellulose-digesting microbes, in combination with adaptations related to feeding, physiology, and morphology, show that giant pandas have evolved a number of traits to overcome the anatomical and physiological challenge of digesting a diet high in fibrous matter.


Preclinical activity of the rational combination of selumetinib (AZD6244) in combination with vorinostat in KRAS-mutant colorectal cancer models.
Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%, supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Transcriptional profiling and gene set enrichment analysis (baseline and posttreatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, (18)F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G(1), and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects.


The CaSR in Pathogenesis of Breast Cancer: A New Target for Early Stage Bone Metastases.
The Ca2+-sensing receptor (CaSR) is a class-C G protein-coupled receptor which plays a pivotal role in calciotropic processes, primarily in regulating parathyroid hormone secretion to maintain systemic calcium homeostasis. Among its non-calciotropic roles, where the CaSR sits at the intersection of myriad processes, it has steadily garnered attention as an oncogene or tumor suppressor in different organs. In maternal breast tissues the CaSR promotes lactation but in breast cancer it acts as an oncoprotein and has been shown to drive the pathogenesis of skeletal metastases from breast cancer. Even though research has made great strides in treating primary breast cancer, there is an unmet need when it comes to treatment of metastatic breast cancer. This review focuses on how the CaSR leads to the pathogenesis of breast cancer by contrasting its role in healthy tissues and tumorigenesis, and by drawing brief parallels with the tissues where it has been implicated as an oncogene. A class of compounds called calcilytics, which are CaSR antagonists, have also been surveyed in the instances where they have been used to target the receptor in cancerous tissues and constitute a proof of principle for repurposing them. Current clinical therapies for treating bone metastases from breast cancer are limited to targeting osteoclasts and a deeper understanding of the CaSR signaling nexus in this context can bolster them or lead to novel therapeutic interventions.


Interplay between Nutrition and Hearing Loss: State of Art.
Hearing loss has been recently ranked as the fifth leading cause of years lived with disability, ahead of many other chronic diseases such as diabetes, dementia, or chronic obstructive pulmonary disease. Moreover, according to the World Health Organization, moderate-to-profound hearing loss affects about 466 million people worldwide. Its incidence varies in each population segment, affecting approximately 10% of children and increasing to 30% of the population over 65 years. However, hearing loss receives still very limited research funding and public awareness. This sensory impairment is caused by genetic and environmental factors, and among the latter, the nutritional status has acquired relevance due its association to hearing loss detected in recent epidemiological studies. Several experimental models have proved that the onset and progression of hearing loss are closely linked to the availability of nutrients and their metabolism. Here, we have reviewed studies focused on nutrient effects on auditory function. These studies support the potential of nutritional therapy for the protection against hearing loss progression, which is especially relevant to the aging process and related quality of life.


[Pathological changes of the optic nerve from compression by the internal carotid artery].
The optic nerve in relation to the internal carotid artery was anatomically and pathologically studied in 51 adult brain specimens. There were obvious impressions on the optic nerves from compression by the sclerosed internal carotid arteries, and pathological changes in the optic nerves, such as atrophy, were observed in 6.9% of the specimens. This fact suggests that clinical visual defects of unknown explanation may be caused by the indurative internal carotid artery compressing the optic nerve.


Intractable Seizures and Rehabilitation in Ciguatera Poisoning.
Ciguatera fish poisoning is the most frequently reported seafood toxin illness associated with the ingestion of contaminated tropical fish. Diagnosis relies on a history of recent tropical fish ingestion and subsequent development of gastrointestinal, cardiovascular, and neurological symptoms. Ciguatera poisoning usually has a self-limited time course, and its management involves symptomatic control and supportive care. This case report presents an uncommon case of ciguatera poisoning with prolonged intractable seizures refractory to standard antiseizure medications. The patient also had significant functional decline that responded to rigorous inpatient rehabilitation not previously described in literature.


Vascular Ehlers-Danlos syndrome (OMIM 130050, 1/150,000 birth) is caused by mutations in collagen 3A1 gene. It is associated with severe phenotype associating early arterial dissection and rupture, digestive and uterine perforations, and skin and joints fragility. Until recently, no treatment was available. Celiprolol, a beta1 antagonist with beta2 partial antagonist properties betablocker was tested in a randomized, controlled trial. We could show that this compound was associated with a 3-fold decrease in major events related to the disease. This effect was similar in molecular-proven patients. Administration of celiprolol in a cohort of patients followed routinely in France was accompanied to similar benefit. Celiprolol is unavailable in the USA. The ACER Therapeutics company applied for new drug application (NDA) to the Food and Drug Administration.


Risk indicators for HIV-associated jointly occurring oral candidiasis and oral hairy leukoplakia.
Joint occurrence of two or more diseases may impact their transmission, clinical presentation, management approaches, and treatment efficacy. Although oral candidiasis (OC) and oral hairy leukoplakia (OHL) are the most commonly occurring opportunistic oral diseases of HIV-infected patients, literature describing their joint occurrence is sparse. The purpose of this project was to develop an explanatory multivariable model for joint occurrence of OC and OHL (OC-OHL). This cross-sectional study examined 631 adult dentate HIV-1 seropositive persons for OC and OHL from 1995-2000 at the University of North Carolina Hospitals in Chapel Hill, NC. Data collected from medical record review, interviews and clinical examinations were analyzed using chi(2) tests, t itests, and nonparametric tests. Multivariable proportional odds models were developed, using the likelihood ratio test and adjusting for several demographic, behavioral, and biological factors. Thirteen percent of participants had OC only; 12.8% had OHL only; 4.6% had OC-OHL; whereas 69.7% had neither. Occurrence of OC-OHL was independently associated with CD4+ counts less than 200 cells per microliter (adjusted odds ratio [OR] (95% confidence interval {CI}) = 13.4 (6.6, 27.2) and CD4+ counts 200-499 cells per microliter (OR = 3.9 [1.9, 8.1]); current smokers (OR = 2.3 [1.4, 3.8]); and whites (OR = 1.7 [1.1, 2.5]). Combination antiretroviral therapy was protective (OR = 0.5 [0.3, 0.9]). In an HIV-1-infected population, lower CD4+ cell counts and smoking were important independent risk indicators for joint occurrence of OC and OHL.


Rate variation of DNA sequence evolution in the Drosophila lineages.
Rate constancy of DNA sequence evolution was examined for three species of Drosophila, using two samples: the published sequences of eight genes from regions of the normal recombination rates and new data of the four AS-C (ac, sc, l'sc and ase) and ci genes. The AS-C and ci genes were chosen because these genes are located in the regions of very reduced recombination in Drosophila melanogaster and their locations remain unchanged throughout the entire lineages involved, yielding less effect of ancestral polymorphism in the study of rate constancy. The synonymous substitution pattern of the three lineages was found to be erratic in both samples. The dispersion index for replacement substitution was relatively high for the per, G6pd and ac genes. A significant heterogeneity was found in the number of synonymous substitutions in the three lineages between the two samples of genes with different recombination rates. This is partly due to a lack of the lineage effect in the D. melanogaster and Drosophila simulans lineages in the AS-C and ci genes in contrast to Akashi's observation of genes in regions of normal recombination. The higher codon bias in Drosophila yakuba as compared with D. melanogaster and D. simulans was observed in the four AS-C genes, which suggests change(s) in action of natural selection involved in codon usage on these genes. Fluctuating selection intensity may also be responsible for the observed locus-lineage interaction effects in synonymous substitution.


Cell respiration and formation of reactive oxygen species: facts and artefacts.
It is generally taken as an established fact that mitochondrial respiration is associated with the generation of small amounts of ROS (reactive oxygen species). There are many arguments supporting this side activity. A major argument is the particular physico-chemical configuration of dioxygen, which prevents the transfer of a pair of electrons. Instead, oxygen is reduced by the successive transfer of single electrons, necessarily leading to intermediates with odd electrons. The high rate of turnover of oxygen in the respiratory chain in combination with the existence of single-electron carriers supports the concept of mitochondria as the major cellular ROS generator. Experimental evidence on the ability of mitochondria to generate ROS was, however, based essentially on in vitro experiments with isolated mitochondria. A variety of structural and functional alterations associated with the removal of mitochondria from the cell, as well as the routinely applied ROS detection methods, may lead to artefactual deviation of odd electrons to dioxygen. We therefore checked these correlations in view of ROS formation, including the often reported effect of the membrane potential on the establishment of a redox couple with oxygen out of sequence. For this purpose we developed novel methods to prove the authenticity of mitochondria for ROS generation in the living cell. Based on our experiments, we can exclude spontaneous release of ROS from mitochondria. However, we describe conditions under which mitochondria can be transformed to mild ROS generators. The site of single-electron deviation to dioxygen was found to be ubiquinol interacting with the Rieske iron-sulphur protein and low-potential cytochrome b of the bc (1) complex.


[Knowledge and well-being of patients before and after preoperative findings disclosed by gynecologic surgery (hysterectomy and plastic breast surgery)].
Ten patients with gynecological problems were examined in the context of a preoperative discussion for informed consent. The Patients were tested before and following the discussion with questionnaires and partly standardized interviews regarding their condition and knowledge and the evaluation of the information style of the physician. The informative discussions were taped and evaluated for duration and informative content. The patients usually were able to quote important informations regarding the planned hysterectomies or cosmetic breasts operations. The patients were best informed about risks and least about the post-operative treatment and healing. The informative discussion showed a function of conveying information. The patients retained many of the informations given to them by the physicians. The operation and the risks were best covered. In addition, the informative discussion reduced anxiety. The anxiety and tenseness of the patients was obviously less following the discussion. The positive condition of the patient showed a correlation to the style of information displayed by the physician. It became obvious that less anxious patients absorbed information easier than anxious patients who profited less from the informative discussion. Redundant informations appear to be of significance. New informations were considered to be stressful by the patients although the transmission of information was important for the patients and all patients desired complete information. In our opinion, the results allow the conclusion that the pre-operative informative discussion has important functions to relieve anxiety by cognitive orientation about the planned procedure as long as the pre-operative discussion is part of continual transmission of information.


Drosophila polymorphism database (DPDB): a portal for nucleotide polymorphism in Drosophila.
As a growing number of haplotypic sequences from resequencing studies are now accumulating for Drosophila in the main primary sequence databases, collectively they can now be used to describe the general pattern of nucleotide variation across species and genes of this genus. The Drosophila Polymorphism Database (DPDB) is a secondary database that provides a collection of all well-annotated polymorphic sequences in Drosophila together with their associated diversity measures and options for reanalysis of the data that greatly facilitate both multi-locus and multi-species diversity studies in one of the most important groups of model organisms. Here we describe the state-of-the-art of the DPDB database and provide a step-by-step guide to all its searching and analytic capabilities. Finally, we illustrate its usefulness through selected examples. DPDB is freely available at http://dpdb.uab.cat.


[Increase in thyroxine level in blood plasma of hypothyroid rats after administering histones].
It has been shown that the administration of total histones (H1, H3, H2B, H2A, H4), the total histones without histones H4 (H1, H3, H2B, H2A), H1 histones at concentrations of 0.001 and 1 microgram per 100 g of body weight (low and high concentrations) to intact rats during 6 days leads to the decrease of T4 amount in the blood plasm. The total histones and histone H1 at low concentration decrease the T4 amount by the coefficients 5.2 and 5.8 respectively. The corresponding coefficients for high concentration are 2.6 and 1.2. There is no difference in the action of the total histones and H1 histone at low concentration. Low concentration of histones is more effective for the decrease of T4 amount than the high one or than the antithyroid agents mercasolyl and LiCl (3 mg and 2 mM per .100 g of body weight), which decrease the amount of T4 in intact rats by the coefficient 3.6 in 38 days. Administration of histones decreases the amount of T4 in the intact rats but, on the contrary, the 3-4 fold increase is observed in hypothyroid rats, so the amount of T4 is practically reverted to the level of intact rats. The mechanism of regulation of the amount of T4 by histones is discussed.


Rescuing Troves of Hidden Ecological Data to Tackle Emerging Mosquito-Borne Diseases.
Despite the major impact of mosquitoes on human health, knowledge gaps exist regarding their natural population dynamics. Even the most basic information-such as spatiotemporal abundance-is mostly unavailable. In the USA, municipalities have created agencies for mosquito control and monitoring, yet no national open-access repository for mosquito surveillance data exists. Vectors, and the pathogens they transmit, know no jurisdictions. We identify >1,000 mosquito control agencies and identify those which make their population abundance surveillance data publicly available. We directly survey Floridian mosquito districts to estimate, from one state alone, the potential amount of hidden data. We generate a large, standardized data set from publicly available online data and demonstrate that spatiotemporal population abundance can be reconstructed and analyzed across data generators. We propose that the ensemble of US mosquito control agencies can, and should, be used to develop a national-and potentially international-open-access repository of mosquito surveillance data, generating the data capital needed to gain a mechanistic understanding of vector population dynamics, and identify existing digital infrastructure that could be leveraged for digitizing and collating extant and future surveillance data for such a repository.


Neural representation of three-dimensional features of manipulation objects with stereopsis.
In the first part of this article, we review our neurophysiological studies of the hand-manipulation-related neurons in the anterior part of the lateral bank of the intraparietal sulcus (area AIP). We describe the properties of visually responsive neurons in area AIP. Object-type visual-dominant neurons responded to the sight of objects and showed selectivity not only for simple geometrical shapes, but also for complex objects such as a knob-in-groove and a plate-in-groove. Some of the object-type visual-dominant neurons showed selectivity for the orientation of the longitudinal axis or the plane (surface) of a plate or a ring. In the second part of this article, we review our study of binocular visual neurons in the caudal part of the lateral bank of the intraparietal sulcus (c-IPS area), in particular, of axis-orientation-selective (AOS) neurons and surface-orientation-selective (SOS) neurons. AOS neurons preferred long and thin stimuli, were sensitive to binocular disparity, and tuned to the axis orientation in three-dimensional (3D) space. SOS neurons preferred broad and flat stimuli and were tuned to the surface orientation in depth. Some SOS neurons responded to a square in a random dot stereogram (RDS) with orientation tuning, suggesting that they encode surface orientation from a disparity gradient. Others responded to solid figure stereograms with orientation disparity and/or width disparity. It was concluded that the c-IPS area is a higher center for stereopsis, which integrates various binocular disparity signals received from the V3 complex and other prestriate areas to represent the neural code for 3D features. It may send projections to the AIP area and contribute to visual adjustment of the shape of the handgrip and/or hand orientation for manipulation and grasping. Neurons of the AIP area may also receive monocular cues of depth from the ventral visual pathway to discriminate the 3D shape of the object of manipulation.


Fast data acquisition techniques in magnetic resonance spectroscopic imaging.
Magnetic resonance spectroscopic imaging (MRSI) is an important technique for assessing the spatial variation of metabolites in vivo. The long scan times in MRSI limit clinical applicability due to patient discomfort, increased costs, motion artifacts, and limited protocol flexibility. Faster acquisition strategies can address these limitations and could potentially facilitate increased adoption of MRSI into routine clinical protocols with minimal addition to the current anatomical and functional acquisition protocols in terms of imaging time. Not surprisingly, a lot of effort has been devoted to the development of faster MRSI techniques that aim to capture the same underlying metabolic information (relative metabolite peak areas and spatial distribution) as obtained by conventional MRSI, in greatly reduced time. The gain in imaging time results, in some cases, in a loss of signal-to-noise ratio and/or in spatial and spectral blurring. This review examines the current techniques and advances in fast MRSI in two and three spatial dimensions and their applications. This review categorizes the acceleration techniques according to their strategy for acquisition of the k-space. Techniques such as fast/turbo-spin echo MRSI, echo-planar spectroscopic imaging, and non-Cartesian MRSI effectively cover the full k-space in a more efficient manner per TR . On the other hand, techniques such as parallel imaging and compressed sensing acquire fewer k-space points and employ advanced reconstruction algorithms to recreate the spatial-spectral information, which maintains statistical fidelity in test conditions (ie no statistically significant differences on voxel-wise comparisions) with the fully sampled data. The advantages and limitations of each state-of-the-art technique are reviewed in detail, concluding with a note on future directions and challenges in the field of fast spectroscopic imaging.


Pregnancy in phenylketonuria: dietary treatment aimed at normalising maternal plasma phenylalanine concentration.
The transport characteristics of the placenta, which favour higher phenylalanine concentrations in the fetus than in the mother, and regression data of head circumference at birth against phenylalanine concentration at conception in maternal phenylketonuria (PKU), suggest that treatment of maternal PKU should ideally aim to maintain plasma phenylalanine concentration within the normal range throughout pregnancy. A patient with classical PKU was treated from before conception by aiming to maintain plasma phenylalanine concentration within the range 50-150 mumol/l and tyrosine within the range 60-90 mumol/l. The diet was supplemented with phenylalanine-free amino acids (100-180 g/day) and tyrosine (0-5 g/day). Plasma amino acid concentrations were monitored weekly by amino acid analyser. Dietary phenylalanine intake ranged from 6 mg/kg/day at conception to 30 mg/kg/day at delivery. Normal weight gain and fetal growth were maintained throughout the pregnancy. A normal baby was born at term with a head circumference of 35.5 cm; at 1 year of age no abnormality is detectable. These results show that with careful monitoring and compliance it is possible, and may be advisable, to maintain plasma phenylalanine concentration within the normal range in the management of PKU pregnancy.


Exploring the relationship between Faecalibacterium duncaniae and Escherichia coli in inflammatory bowel disease (IBD): Insights and implications.
Inflammatory bowel disease (IBD) is a group of disorders characterized by an inflammation of the gastrointestinal tract (GIT) and represents a major social and economic burden. Despite ongoing research into the etiology and pathophysiology of this multifactorial disease, treatment options remain limited. From this perspective, the gut microbiota has emerged as a potential player in the pathogenesis of IBD, and animal and human studies support this hypothesis. Indeed, the human gut is one of the most complex ecological communities (composed of 1013-1014 microorganisms) that plays a critical role in human health by influencing normal physiology and disease susceptibility through its collective metabolic activities and host interactions. In addition, live probiotic bacteria present in some food products (which transit through the GIT) have been shown to interact with the host immune system and confer several health benefits. The aim of this review is to provide an overview of the link between Faecalibacterium duncaniae and Escherichia coli and IBD, highlighting the main areas of research in this field. An ecological perspective on the gut microbiota may offer new insights for the development of clinical therapies targeting this bacterial community to improve human health.


Cow effects and estimation of success of first and following inseminations in Dutch dairy cows.
The objective of this research was to determine the contribution of cow factors to the probability of successful insemination accounting for the serial number of inseminations in analysis. The investigation was performed with 101,297 insemination records in 51,525 lactations of different cows from 1368 herds obtained from the Dutch milk production recording database. Cows that had a first insemination (AI) between 40 and 150 days post-partum with one or more inseminations (≤6 inseminations) were selected. An insemination was defined successful when not followed by another insemination and when the cow calved between 267 and 295 days after insemination, or when the cow was culled between 135 and 295 days after the last insemination. Breed, parity, days in milk, lactation curve characteristics, milk production traits, moment of AI related to peak milk yield time (before or after peak milk yield), the last calf (female, male, twin or stillbirth) and season of insemination were selected as independent parameters for a model with successful rate of insemination as dependent parameter. A multivariable logistic regression model was used within cow and farm as a random effect. The probability of successful insemination was the highest in the first insemination and decreased in the following inseminations. However, the success rate of all inseminations increased in a later stage of lactation. The improvement in the successful inseminations in a later stage of lactation was better in multiparous cows than in first parity cows. Insemination in summer and before peak milk yield time reduced the success of insemination. The success rate was the lowest in 100% Holstein Friesian cows compared with other breeds and was the highest when the last calf was a female calf compared to a male calf, twin or stillbirth. In conclusion, the success of first and following inseminations depended on parity, breed, season of insemination, last calf status, daily milk yield at insemination date, serial insemination number and days in milk at insemination date.


Laparoscopic cholecystectomy--comparison of early postoperative results in an Australian rural centre and a German university hospital.
Laparoscopic cholecystectomy is the treatment of choice for symptomatic gallstone disease. Cultural as well as organisational differences can result in significant variations of postoperative length of stay. AIM OF THE PRESENT STUDY: The aim of this study is to evaluate whether differences in postoperative length of stay and early postoperative outcome can be observed by comparison of an Australian rural centre and a German university hospital. Between February 2006 and August 2007 (18 months), 359 patients (140 Australia, 219 Germany) underwent laparoscopic cholecystectomy. Mean patient age was 50.4 +/- 1.5 and 53.5 +/- 1.0 years, respectively. Seventy-seven percent of the Australian and 62% of the German patients were female. Twenty-one percent and 20% of the procedures were emergencies, respectively. Median American Society of Anaesthesiologists score of all patients was two. The conversion rate was 8% in both centres. A 4% complication rate was observed in Australia (N = 5, 3x bile leak, 1x postoperative bleeding and 1x wound infection) as opposed to 3% in Germany (N = 7, 2x bile leak, 2x postoperative bleeding and 3x wound infection). Postoperative length of stay in Australia was 1.8 +/- 0.1 days (median 1 day) and was significantly longer in patients after emergency surgery (1.6 +/- 0.1 versus 2.6 +/- 0.3 days, p < 0.018). Postoperative length of stay in Germany was 3.7 +/- 0.2 days (median 3 days), and no significant differences were observed when elective and emergency procedures were compared (3.5 +/- 0.2 versus 3.9 +/- 0.5 days, p > 0.05). Comparison of treatment results indicates a significantly shorter postoperative stay in Australia (3 days versus 1 day, p < 0.001). In rural Australia, a median postoperative stay of 1 day after laparoscopic cholecystectomy can be safely achieved. Postoperative length of stay is significantly longer in the German setting with otherwise comparable patients and surgical techniques. Simple changes of pre- and postoperative management of elective as well as emergency laparoscopic cholecystectomy will allow, for substantial cost savings, for the German health system.


Sonodynamically-induced anticancer effects by functionalized fullerenes.
Functionalized fullerenes, such as polyhydroxy fullerenes (PHF), have attracted particular attention due to their water solubility and their potential application in tumor imaging and therapy as carbon nanomaterials. In this study, the sonodynamically-induced antitumor effect of PHF was investigated. Sonodynamically-induced antitumor effects of PHF in combination with ultrasound were investigated using isolated sarcoma 180 cells and solid tumor from colon 26 carcinoma cells. The cell damage induced by sonication was enhanced by two-fold in the presence of 80 μM PHF. Histidine significantly inhibited this enhancement. This inhibitory effect suggests that the sonodynamically-induced antitumor effect was mediated by sonodynamically-generated reactive oxygen species. The combined treatment of ultrasonic exposure with PHF suppressed the growth of implanted colon 26 tumors. The destruction of tumor tissue was observed with the ultrasonic treatment in combination with PHF, while neither the treatment with PHF alone nor that with ultrasound alone caused necrosis. These results suggest that PHF is a potential sonosensitizer for sonodynamic treatment of solid tumors.


The Lunchbox Study: A Pilot Examination of Packed Lunches of Children with Autism Spectrum Disorder.
Background: This study examined foods packed and consumed by children with autism spectrum disorder (ASD) and calculated the percentage of packed school lunches meeting National School Lunch Program (NSLP) standards. Fruit and vegetable (FV) consumption was further examined by investigating its association with the number and type of foods packed. Methods: Participants included 59 private school students observed for five school meals. Servings of foods and beverages packed and consumed and the percentages of correspondence between food packed and consumed were calculated. Next, the percentages of lunches meeting NSLP guidelines were calculated. Finally, mealtime means were calculated for the number of foods packed, FVs packed, and FVs consumed. Results: There was a high correspondence between foods packed and consumed. Fresh fruits and sugar-added drinks were most often packed and consumed. The percentage of meals meeting NSLP guidelines was higher than previous non-ASD samples. More FV consumption was associated with more FVs packed and fewer total foods packed. FV consumption was highest with 4 < 5 foods packed, including 2+ FVs. Conclusions: Future studies should compare foods packed and consumed by children with and without ASD. The FV consumption findings suggest parents may increase children's FV consumption by packing approximately four total foods with two FVs.


LncRNA ZNF667-AS1 inhibits inflammatory response and promotes recovery of spinal cord injury via suppressing JAK-STAT pathway.
The aim of this study was to explore the role of lncRNA ZNF667-AS1 in the recovery of spinal cord injury (SCI), and to investigate its underlying mechanism. Mice were randomly assigned to the SCI group, the sham group and the lncRNA ZNF667-AS1 group, with 10 mice in each group. With Infinite Horizon device at a dose of 80 Kdyn, mice in the SCI group and the lncRNA ZNF667-AS1 group experienced SCI by an acute hit on the C5 spinous process. Before animal procedures, mice in the lncRNA ZNF667-AS1 group were additionally injected with overexpression lentivirus of lncRNA ZNF667-AS1. On the contrary, mice in the sham group only received laminectomy. After successful construction of the SCI model in mice, grip strength was accessed. LncRNA ZNF667-AS1 expression in spinal cord tissues before and after SCI was detected by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), respectively. Meanwhile, the protein expression levels of relative genes in Janus Kinase-signal transducer and activator of transcription (JAK-STAT) pathway were detected by Western blot. Grip strength of forelimb in the SCI group recovered significantly slower than that of the sham group. With the prolongation of SCI, the expression of lncRNA ZNF667-AS1 was gradually decreased. However, the expression levels of JAK2, STAT3 and iNOS were upregulated in a time-dependent manner. In addition, mice in the lncRNA ZNF667-AS1 group presented remarkable grip strength recovery of forelimb after SCI. LncRNA ZNF667-AS expression is gradually downregulated after SCI. Meanwhile, it inhibits the inflammatory response and promotes SCI recovery via suppressing the JAK-STAT pathway.


Comparison of Microbiomes between Red Poultry Mite Populations (Dermanyssus gallinae): Predominance of Bartonella-like Bacteria.
Blood feeding red poultry mites (RPM) serve as vectors of pathogenic bacteria and viruses among vertebrate hosts including wild birds, poultry hens, mammals, and humans. The microbiome of RPM has not yet been studied by high-throughput sequencing. RPM eggs, larvae, and engorged adult/nymph samples obtained in four poultry houses in Czechia were used for microbiome analyses by Illumina amplicon sequencing of the 16S ribosomal RNA (rRNA) gene V4 region. A laboratory RPM population was used as positive control for transcriptome analysis by pyrosequencing with identification of sequences originating from bacteria. The samples of engorged adult/nymph stages had 100-fold more copies of 16S rRNA gene copies than the samples of eggs and larvae. The microbiome composition showed differences among the four poultry houses and among observed developmental stadia. In the adults' microbiome 10 OTUs comprised 90 to 99% of all sequences. Bartonella-like bacteria covered between 30 and 70% of sequences in RPM microbiome and 25% bacterial sequences in transcriptome. The phylogenetic analyses of 16S rRNA gene sequences revealed two distinct groups of Bartonella-like bacteria forming sister groups: (i) symbionts of ants; (ii) Bartonella genus. Cardinium, Wolbachia, and Rickettsiella sp. were found in the microbiomes of all tested stadia, while Spiroplasma eriocheiris and Wolbachia were identified in the laboratory RPM transcriptome. The microbiomes from eggs, larvae, and engorged adults/nymphs differed. Bartonella-like symbionts were found in all stadia and sampling sites. Bartonella-like bacteria was the most diversified group within the RPM microbiome. The presence of identified putative pathogenic bacteria is relevant with respect to human and animal health issues while the identification of symbiontic bacteria can lead to new control methods targeting them to destabilize the arthropod host.


Delivery systems for acute migraine medications.
To discuss advantages and disadvantages of various routes of administration and delivery systems for acute migraine medications, and to assist family physicians in optimizing treatment for individual patients. A MEDLINE search from January 1966 to October 2000 and a Current Contents search for the year 1999 to October 2000 were conducted. Randomized controlled trials were selected, when available. Also included are guidelines (Canadian), non-blinded trials, systematic reviews, and population-based studies. Selecting an appropriate way to deliver medication is important in acute migraine therapy. The parenteral route has advantages, such as rapid onset, greater efficacy, and the possibility of use during nausea and vomiting. Disadvantages include local site discomfort, inconvenience, and patients' dislike of needles. Most patients prefer oral therapy, but gastric stasis and nausea and vomiting during a migraine attack might limit its use. The intranasal route usually provides fairly rapid onset, but side effects, such as disturbances in taste, can occur. The rectal route is another option, but absorption is sometimes erratic, rectal irritation can occur, and few migraine medications are available in rectal formulation. Selection of appropriate medications and suitable delivery systems for individual patients, based on the characteristics of their attacks (e.g., severity, speed of progression to severe intensity, degree of associated symptoms), ease of administration, and patient preference, will optimize therapy for acute migraine attacks.


Smartphone-Assisted Telecytopathology: An Intraobserver Concordance Study.
Telecytology is the practice of cytology at a distance. The images captured by a camera are sent to the cytopathologist at a different location who views the images and reaches a diagnosis. Recently, smartphone-assisted telepathology has been evaluated for different subspecialities of pathology including cytology for second opinion. For the purpose of the study, a total of 151 cases of fine needle aspiration and 10 cases of urine cytology reported by a single pathologist were retrieved from the records. The images of all the cases were captured by a trained pathologist using the primary camera of a smartphone from the ocular of a binocular microscope. The images were sent by WhatsApp to the same pathologist who had made the conventional microscopy diagnosis. The images were viewed on the smartphone screen by the pathologist who replied with the diagnosis after analysing all the images with or without digital zoom. A total of 154 cases out of 161 were correctly diagnosed on smartphone-assisted telepathology (overall intraobserver concordance of 95.6%). For head and neck swellings, the concordance was 65/70 (92.9%), for breast lesions, it was 23/24 (95.8%), and for miscellaneous swellings, it was 57/57 (100%). For urine cytology, the concordance rate was 9/10 (90%). Though the results of this study are encouraging, further improvement in the smartphone camera resolution and internet connectivity would enhance the utility of smartphone-assisted telecytopathology.


MG53 as a Novel Therapeutic Protein to Treat Acute Lung Injury.
Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.


Effect of variable transmission on body-powered prosthetic grasping.
Body-powered upper-limb prostheses remain a popular option for those with limb absence due to their passive nature. These devices typically feature a constant transmission ratio between the forces input by the user and the grasp forces output by the prosthetic gripper. Work incorporating continuously variable transmissions into robotic hands has demonstrated a number of benefits in terms of their motion and forces. In this work, we use a custom prosthesis emulator to evaluate the viability of applying variable transmissions to a body-powered prosthetic context. With this haptics test bed, we measured user performance during a grasping and lift task under a variety of transmission ratio conditions and with three different test objects. Results indicate that use of a variable transmission leads to the successful manipulation of a wider variety of objects than the constant transmission ratio systems, while requiring less shoulder motion. Analysis also shows a potential tendency for users to apply higher grasp forces than necessary, when compared to constant transmission conditions. These findings suggest a multifaceted effect on grasp performance with both benefits and drawbacks when considering a variable approach that supports the continued study of variable transmissions in assisted grasping.


Characterization and regulation of an additional actin-filament-binding site in large isoforms of the stereocilia actin-bundling protein espin.
The espin actin-bundling proteins, which are produced as isoforms of different sizes from a single gene, are required for the growth of hair cell stereocilia. We have characterized an additional actin-filament-binding site present in the extended amino-termini of large espin isoforms. Constitutively active in espin 2, the site increased the size of actin bundles formed in vitro and inhibited actin fluorescence recovery in microvilli. In espin 1, which has an N-terminal ankyrin repeat domain, the site was autoinhibited by binding between the ankyrin repeat domain and a peptide near the actin-binding site. Deletion of this peptide from espin 1 activated its actin-binding site. The peptide resembled tail homology domain I of myosin III, a ligand of the ankyrin repeat domain localized with espin 1 at the tip of stereocilia. A myosin III tail homology domain I peptide, but not scrambled control peptides, inhibited internal binding of the ankyrin repeat domain and released the espin 1 actin-binding site from autoinhibition. Thus, this regulation could result in local activation of the additional actin-binding site of espin 1 by myosin III in stereocilia.


Brain responses to sexual images in 46,XY women with complete androgen insensitivity syndrome are female-typical.
Androgens, estrogens, and sex chromosomes are the major influences guiding sex differences in brain development, yet their relative roles and importance remain unclear. Individuals with complete androgen insensitivity syndrome (CAIS) offer a unique opportunity to address these issues. Although women with CAIS have a Y chromosome, testes, and produce male-typical levels of androgens, they lack functional androgen receptors preventing responding to their androgens. Thus, they develop a female physical phenotype, are reared as girls, and develop into women. Because sexually differentiated brain development in primates is determined primarily by androgens, but may be affected by sex chromosome complement, it is currently unknown whether brain structure and function in women with CAIS is more like that of women or men. In the first functional neuroimaging study of (46,XY) women with CAIS, typical (46,XX) women, and typical (46, XY) men, we found that men showed greater amygdala activation to sexual images than did either typical women or women with CAIS. Typical women and women with CAIS had highly similar patterns of brain activation, indicating that a Y chromosome is insufficient for male-typical human brain responses. Because women with CAIS produce male-typical or elevated levels of testosterone which is aromatized to estradiol these results rule out aromatization of testosterone to estradiol as a determinate of sex differences in patterns of brain activation to sexual images. We cannot, however, rule out an effect of social experience on the brain responses of women with CAIS as all were raised as girls.


131I-Metaiodobenzylguanidine therapy in children with advanced neuroblastoma.
Neuroblastoma is an aggressive childhood cancer, with a propensity for early widespread metastasis. Approximately 90% of tumors accumulate the norepinephrine analogue metaiodobenzylguanidine (MIBG) avidly, allowing the use of radiolabeled MIBG for targeted imaging and radiotherapy. After preclinical studies demonstrated activity of 131I-MIBG in models of neuroblastoma, clinical development of this agent ensued. Early clinical trials of 131I-MIBG in patients with relapsed or refractory neuroblastoma defined the toxicity profile of this agent, with myelosuppression as the main dose-limiting toxicity. Subsequent trials defined the activity of 131I-MIBG, with response rates of 20-40% in patients with relapsed or refractory disease. More recent clinical trials have tested 131I-MIBG in combination with chemotherapy or as a component of myeloablative therapies. Given the documented activity of 131I-MIBG, future studies will need to evaluate the impact of radiation sensitizers on this activity and define the role of this agent in treating patients with newly diagnosed high-risk neuroblastoma.


[The influence of age and sex on fat- and water-soluble vitamins sufficiency of adulthood].
Serum concentrations of vitamins A, B2, B6, C, E and beta-carotene were determined in 174 healthy individuals ages 22-59 years. It was been shown that only 11% of examined men and 24% of women were well provided with all vitamins-antioxidants and beta-carotene. 38% cent of women and 67% cent of men had the combined insufficiency of 2-3 antioxidants (more often of vitamin C, B2 and beta-carotene). Men presented significantly higher serum retinol concentrations and lower concentrations of vitamin C and beta-carotene--than women. Serum concentrations of retinol for women and tocopherols for both men and women increased by 0.3% and 0.4% per year, respectively.


Pericytes in Ischemic Stroke.
Recent stroke research has shifted the focus to the microvasculature from neuron-centric views. It is increasingly recognized that a successful neuroprotection is not feasible without microvascular protection. On the other hand, recent studies on pericytes, long-neglected cells on microvessels have provided insight into the regulation of microcirculation. Pericytes play an essential role in matching the metabolic demand of nervous tissue with the blood flow in addition to regulating the development and maintenance of the blood-brain barrier (BBB), leukocyte trafficking across the BBB and angiogenesis. Pericytes appears to be highly vulnerable to injury. Ischemic injury to pericytes on cerebral microvasculature unfavorably impacts the stroke-induced tissue damage and brain edema by disrupting microvascular blood flow and BBB integrity. Strongly supporting this, clinical imaging studies show that tissue reperfusion is not always obtained after recanalization. Therefore, prevention of pericyte dysfunction may improve the outcome of recanalization therapies by promoting microcirculatory reperfusion and preventing hemorrhage and edema. In the peri-infarct tissue, pericytes are detached from microvessels and promote angiogenesis and neurogenesis, and hence positively effect stroke outcome. Expectedly, we will learn more about the place of pericytes in CNS pathologies including stroke and devise approaches to treat them in the next decades.


Toll-like receptor 4 mediates endothelial cell activation through NF-κB but is not associated with endothelial dysfunction in patients with rheumatoid arthritis.
To investigate the effects of TLR4 antagonism on human endothelial cells activation and cytokine expression, and whether the Asp299Gly TLR4 polymorphism is associated with better endothelial function in patients with rheumatoid arthritis (RA). Human aortic endothelial cells (HAECs) were treated with lipopolysaccharide (LPS), OxPAPC, and free fatty acids (FFA) at baseline and after incubation with the TLR4 antagonist eritoran (E5564). Cytokine expression was assessed by quantitative real-time PCR. In vivo endothelial function was assessed as brachial artery flow-mediated dilation (FMD) in RA patients with the wild type gene (aa) and with the Asp299Gly TLR4 polymorphic variant (ag). In HAEC, TLR4 antagonism with eritoran inhibited LPS-induced mRNA expression of IL-6, IL-8, TNFα, CCL-2, VCAM and ICAM (P<0.05 for all) and inhibited Ox-PAPC-induced mRNA expression of IL-8 (P<0.05) and IL-6, albeit not to a statistically significant level (p = 0.07). In contrast, eritoran did not affect FFA-induced mRNA expression of IL-6 (P>0.05). In 30 patients with RA (15 with the ag allele) undergoing measurement of FMD, no differences in FMD and plasma levels of IL-6, IL-8, VCAM, and ICAM were found between the aa and the ag phenotype (P>0.05 for all). TLR4 signaling in endothelial cells may be triggered by LPS and oxidized phospholipids, leading to endothelial activation and inflammation, which are inhibited by eritoran. Our in vivo investigation, however, does not support an association between the Asp299Gly TLR4 polymorphism and improved endothelium-dependent vasodilator function in patients with RA. Further study is needed to better understand the potential role of TLR4 on endothelial dysfunction in this and other patient populations.


The Effects of Plasmacytoid Dendritic Cell-Stimulative Lactic Acid Bacteria, Lactococcus lactis Strain Plasma, on Exercise-Induced Fatigue and Recovery via Immunomodulatory Action.
The unique lactic acid bacteria, Lactococcus lactis strain plasma (LC-Plasma), stimulates plasmacytoid dendritic cells, which play an important role in viral infection. The authors previously reported that LC-Plasma reduced the number of days athletes experienced cold-like symptoms and fatigue feelings after high-intensity exercise training; however, the mechanism was unclear. In this study, the authors investigated the effect of LC-Plasma on recovery from physical damage after single exercise on a treadmill in BALB/c mice model. Oral administration of LC-Plasma (AIN-93G + 0.029% LC-Plasma) for 4 weeks significantly improved the locomotor reduction after treadmill exercise. This effect was not detected in mice receiving Lactobacillus rhamnosus GG, representative probiotics strain. LC-Plasma also improved voluntary locomotor activity after exercise. Blood and muscle sample analysis indicated that LC-Plasma affects plasmacytoid dendritic cell activation, which, in turn, attenuates muscle degenerative genes and the concentration of fatigue-controlled cytokine transforming growth factor-β.


The efficacy of ProTaper Universal rotary retreatment instrumentation to remove single gutta-percha cones cemented with several endodontic sealers.
To evaluate residual root filling material following removal of three newly developed root canal sealers used with a matched-taper single-cone root filling technique and to compare the efficacy of ProTaper Universal rotary retreatment instruments with that of a conventional manual technique. The canals of 120 palatal roots in maxillary molar teeth were instrumented with EndoWave nickel-titanium rotary instruments and filled using Hybrid Root SEAL, EndoSequence BC Sealer, Activ GP system or AH Plus with matched-taper single gutta-percha cones. The root fillings were then removed with ProTaper Universal retreatment rotary instruments or a manual technique. Buccolingual and proximal digital radiographs of the roots were exposed to determine the area of remaining filling material in the coronal, middle and apical thirds. The area percentages of remaining filling material in each third and total canal area were calculated. Data were analysed statistically with Kruskal-Wallis and Mann-Whitney U-tests. The level of significance was set at P<0.05. Irrespective of the sealer type and retreatment technique, filling material could not be removed completely from the root canals. Significantly, more remaining filling material was observed in the apical third (P<0.05). When comparing the sealers, the only significant difference was detected between AH Plus/manual and Activ GP/manual groups with respect to residual material in the total canal area (P<0.05). There were no significant differences between manual and ProTaper groups. When using gross radiographic criteria, the Activ GP was more effectively removed from root canals than AH Plus with hand instrumentation. Hybrid Root SEAL, EndoSequence BC Sealer and AH Plus were removed to a similar extent. ProTaper Universal retreatment instruments were as safe and effective as hand instruments in reaching the working length.


Characterization of expression, and cloning, of beta-D-xylosidase and alpha-L-arabinofuranosidase in developing and ripening tomato (Lycopersicon esculentum Mill.) fruit.
Modifications to the cell wall of developing and ripening tomato fruit are mediated by cell wall-degrading enzymes, including a beta-d-xylosidase or alpha-l-arabinofuranosidase, which participate in the breakdown of xylans and/or arabinoxylans. The activity of both enzymes was highest during early fruit growth, before decreasing during later development and ripening. Two beta-d-xylosidase cDNAs, designated LeXYL1 and LeXYL2, and an alpha-l-arabinofuranosidase cDNA, designated LeARF1, were obtained. Accumulation of mRNAs for beta-d-xylosidase and alpha-l-arabinofuranosidase was examined during fruit development and ripening. LeARF1 and LeXYL2 genes were relatively highly expressed during fruit development and decreased after the onset of ripening. By contrast, LeXYL1 was not expressed during fruit development, but was expressed later, particularly during over-ripening. The expression of all three genes was also followed in ripening-impaired mutants, Nr, Nr2, nor, and rin of cv. Ailsa Craig fruit. LeXYL2 mRNA was detected in the ripe fruits of all the mutants and its abundance was similar to that in mature green wild-type fruit. By contrast, LEXYL1 mRNA was expressed only in the ripe fruits of the Nr mutant, suggesting that the two beta-d-xylosidase genes are subject to distinct regulatory control during fruit development and ripening. LeARF1 mRNA was detected in ripe fruits of Nr2, nor and rin, and not in ripe fruit of the Nr mutant. The accumulation of LeARF1 in ripe fruit was restored by 1-methylcyclopropene (1-MCP), an inhibitor of ethylene action, while 1-MCP had no effect on the expression of LeXYL1 or LeXYL2. This suggests that LeARF1 expression is subject to negative regulation by ethylene and that the two beta-d-xylosidase genes are independent of ethylene action.


Illness absence at an oil refinery and petrochemical plant.
Results from a prospective illness-absence surveillance of refinery and petrochemical workers from 1986 through 1994 are presented. Illness absence data for this study were extracted from the morbidity section of the Shell Oil Company's Health Surveillance System, which includes records of all illness absences in excess of 5 days. The majority of employees (59%) had no illness absence during the 9-year period studied. The 13% of the population who had three or more absences accounted for 63% of the total illness absence episodes and 62% of the total work days lost. Frequency rate and duration of absence increased with increasing age. The increased illness absence was associated with the presence of known health risk factors, such as smoking, elevated blood pressure, high cholesterol, and obesity. For example, obese women had a twofold increased illness absence rate compared with nonobese women and the rate for male smokers doubled that of nonsmoking men. These health risk factors are also more common among employees with three or more absences than those with fewer or no absences. The goal of this analysis is to quantify the impact of illness absence to develop disease prevention strategies to maximize good health in employees and to minimize both the frequency and duration of illness absence.


Predictors of intact and C-terminal fibroblast growth factor 23 in Gambian children.
Elevated C-terminal fibroblast growth factor 23 (C-FGF23) concentrations have been reported in Gambian children with and without putative Ca-deficiency rickets. The aims of this study were to investigate whether i) elevated C-FGF23 concentrations in Gambian children persist long term; ii) they are associated with higher intact FGF23 concentrations (I-FGF23), poor iron status and shorter 25-hydroxyvitamin D half-life (25OHD-t1/2); and iii) the persistence and predictors of elevated FGF23 concentrations differ between children with and without a history of rickets. Children (8-16 years, n=64) with a history of rickets and a C-FGF23 concentration >125 RU/ml (bone deformity (BD), n=20) and local community children with a previously measured elevated C-FGF23 concentration (LC+, n=20) or a previously measured C-FGF23 concentration within the normal range (LC-, n=24) participated. BD children had no remaining signs of bone deformities. C-FGF23 concentration had normalised in BD children, but remained elevated in LC+ children. All the children had I-FGF23 concentration within the normal range, but I-FGF23 concentration was higher and iron status poorer in LC+ children. 1,25-dihydroxyvitamin D was the strongest negative predictor of I-FGF23 concentration (R(2)=18%; P=0.0006) and soluble transferrin receptor was the strongest positive predictor of C-FGF23 concentration (R(2)=33%; P≤0.0001). C-FGF23 and I-FGF23 concentrations were poorly correlated with each other (R(2)=5.3%; P=0.07). 25OHD-t1/2 was shorter in BD children than in LC- children (mean (s.d.): 24.5 (6.1) and 31.5 (11.5) days respectively; P=0.05). This study demonstrated that elevated C-FGF23 concentrations normalised over time in Gambian children with a history of rickets but not in local children, suggesting a different aetiology; that children with resolved rickets had a shorter 25OHD-t1/2, suggesting a long-standing increased expenditure of 25OHD, and that iron deficiency is a predictor of elevated C-FGF23 concentrations in both groups of Gambian children.


A Bayesian approach to retrospective exposure assessment.
A variety of health effects are caused by chronic, cumulative exposure over time to pollutants. In these cases, to establish dose-response relationships for epidemiological and risk assessment purposes, it is vital to determine the exposures of individuals or cohorts as functions of time. Most existing occupational exposure databases, however, do not contain continuous records of historical exposures to airborne contaminants. These gaps in the historical record may be filled by using the knowledge base that experts and professionals in the field possess. In this article we present a new framework, based on Bayesian probabilistic reasoning, for obtaining estimates of exposure histories for airborne particulates from limited historical measurements, using subjective expert judgment. The framework has great potential applications in instances where there is sparse information or missing data on past exposures. Expert judgment, in the form of inputs to physical models, provides additional knowledge to retrospectively estimate exposure as a function of time from discrete and incomplete measurements. The expert judgments are informed by knowledge of historical plant conditions and work practices, and models describing process-dependent aerosol generation, ventilation, and worker activity patterns. The result will be probability distributions of the exposure of task-groups of workers as a function of time, in the form of a matrix.


Characteristics of older adults who meet the annual prescription drug expenditure threshold for medicare medication therapy management programs.
The Medicare Modernization Act of 2003 requires drug plan sponsors to provide medication therapy management programs (MTMPs) to beneficiaries with (1) drug expenditures above $4,000, (2) multiple comorbidities, and (3) multiple prescription drugs. The Medical Expenditure Panel Survey (MEPS) is a national probability survey conducted annually by the Agency for Healthcare Research and Quality and the National Center for Health Statistics to provide nationally representative estimates of health care use, expenditures, sources of payments, and insurance coverage for the U.S. civilian noninstitutionalized population. MEPS comprises 3 components, including the household component (HC) in which households and individuals within households are sampled. The medical provider component (MPC) supplements the HC by contacting providers (hospitals, outpatient offices, home health agencies, and pharmacies) reported in the HC, and the insurance component collects data on health insurance plans and is separate from the HC. The purpose of this study was to estimate from MEPS data for 2002-2003 (1) the proportion of older adults who may have met the $4,000 expenditure component of the MTMP criteria and (2) the patient-specific risk factors associated with meeting the $4,000 expenditure threshold. This study is a cross-sectional analysis of MEPS respondents aged 65 years or older. Data came from both the MEPS-HC and the supplemental MEPS-MPC for 2002 and 2003. Specific data files were pooled and included the Full Year Consolidated files, Prescribed Medicines files, and the Medical Conditions files for both the 2002 and the 2003 MEPS-HC. Variables extracted from the MEPS data files included demographics, socioeconomic status, functional limitations, health status, presence and number of chronic conditions, body mass index, medical and prescription drug insurance, and health care utilization measures. The expenditure threshold of $4,000 was adjusted to $3,810 in 2003 U.S. dollars. Survey-weighted logistic regression identified factors associated with meeting the expenditure threshold. Unbiased population point estimates were obtained by adjusting for survey nonresponse, poststratification, and oversampling of blacks and Hispanics using MEPS person-level weights. In all analyses, standard errors were adjusted for nonindependence of observations due to complex multistage sampling by specifying the strata and primary sampling units for each respondent. Based on a sample of 8,035 noninstitutionalized persons aged 65 years or older in the United States, representing a population of 36.5 million older adults, MEPS data estimate that approximately 3.3 million (9.2%) incurred annual drug expenditures greater than $3,810, accounting for 35% of $55.3 billion in drug expenditures among all older adults. Older adults meeting the $3,810 prescription expenditure threshold reported an average 10.8 (SE=0.2) unique medications, 82.2 (SE=1.8) prescriptions, and 5.2 (SE=0.1) chronic conditions. Prescription expenditures accounted for 33.9% of total health care expenditures compared with 15.8% for persons who did not meet the $3,810 criterion and an average 19.5% for all persons aged 65 years or older (n=8,035). Factors that predicted meeting the expenditure threshold included age in 10-year increments (odds ratio [OR]=0.81; 95% confidence interval [CI], 0.68-0.97), requiring help with activities of daily living (OR=1.53; 95% CI, 1.19-1.97), having functional limitations (OR=1.67; 95% CI, 1.30-2.14), having TRICARE (military health care services) benefits (OR=0.54; 95% CI, 0.33-0.86), and being on Medicaid (OR=1.36; 95% CI, 1.02-1.81). Other factors that were also predictive of meeting the expenditure threshold included mental health disorders, ulcers, diabetes, dyslipidemia, cardiac disease, chronic obstructive pulmonary disorder, and the number of chronic conditions. MEPS survey respondents aged 65 years or older with drug expenditures exceeding the MTMP threshold of $4,000 per year obtain substantially more drugs and have a higher disease burden than those with lower drug expenditures. Characteristics other than drug use, such as having functional limitations or requiring help with activities of daily living, can be used to identify potential MTMP candidates.


Allogeneic interactions in Hydractinia: is the transitory chimera beneficial?
The colonial marine hydroid, Hydractinia, exhibits four possible outcomes to allogeneic contacts: passive rejection, aggressive rejection, stable fusion and transitory fusion. In the special case of transitory fusion, Hydractinia colonies undergo tissue fusion, followed by tissue death at the original contact area, and colony separation. This type of rejection is different in several aspects from the rejection process that accompanies incompatible encounters. It has been suggested that in transitory fusion, the colonies gain immediate benefits from fusion, mainly due to size increase, without succumbing to costs associated with fusion (germ line parasitism). We report a long-term observation of repeated fusion and separation cycles in clones featuring transitory fusion that revealed a slow-down of specific growth rates following fusion, and recovery in growth rates following separation. Very rapid transfer of stained material between partners in transitory chimeras provides suggestive evidence that protection against germ line parasitism is far from being guaranteed by separation. Our data cast doubt as to whether the benefits considered for transitory fusion are sustainable and support the already made suggestion that fusion with self, rather than fusion with kin, has been the major selective force governing the evolution of allorecognition in colonial invertebrates.


Analysis of FOXD3 sequence variation in human ocular disease.
The migratory neural crest cell population makes a significant contribution to the anterior segment structures of the eye. Consequently, several anterior segment dysgenesis phenotypes are associated with mutations in genes expressed during neural crest development. The forkhead box D3 (FOXD3) gene encodes a forkhead transcription factor that plays an important role in neural crest specification in vertebrates and therefore may be involved in human eye disease. We screened 310 probands with developmental ocular conditions for variations in FOXD3. Six nonsynonymous FOXD3 variants were identified. Four of these changes, c.47C>T (p.Thr16Met), c.359C>T (p.Pro120Leu), c.517A>C (p.Asn173His), and c.818_829dup (p.Arg273_Gly276dup), affected conserved regions and were observed primarily in probands with aniridia or Peters anomaly; out of these four variants, one, p.Arg273_Gly276dup, was not detected in control populations and two, p.Pro120Leu and p.Asn173His, were statistically enriched in cases with aniridia or Peters anomaly. The p.Arg273_Gly276dup variant was seen in a proband with aniridia as well as two additional unrelated probands affected with anophthalmia or congenital cataracts. The p.Asn173His variant affects Helix 2 of the DNA-binding domain and was observed in two unrelated patients with Peters anomaly or aniridia; in both cases, one parent carried the same allele. FOXD3 variants increase the risk of anterior segment dysgenesis phenotypes in humans. The p.Asn173His mutation affects a residue in the forkhead domain that is 100% conserved among vertebrate orthologs and is predicted to participate in protein-protein interactions. Its phenotypic effects may be modulated by transcriptional cofactors which have yet to be identified.


[Curcumin promoted the apoptosis of cisplain-resistant human lung carcinoma cells A549/DDP through down-regulating miR-186*].
Curcumin, a natural compound, is derived from the rthizom of Curcuma longa. In vitro and in vivo preclinical studies have shown its anti-inflammatory, antioxidant, anticancer activities and so on. miR-186*, which was found by microarray technology, was highly expressed in lung carcinoma cells A549/DDP. The aim of this study is to illustrate whether Curcumin could promote the apoptosis of A549/DDP cells through regulating the expression of miR-186*. An oligonucleotide microarray chip was used to profile microRNA (miRNA) expressions in A549/DDP cells treated with and without Curcumin. The significantly differentially expressed miRNA, which was selected from microarray chip, validated by quantitative real-time PCR. Ultimately, the remarkably expressed miRNA modulated the apoptosis assaying by flow cytometry expriments and the survival rate was measured by MTT method. The microarray chip results demonstrated: Curcumin altered the expression level of miRNAs compared with untreated control in A549/DDP cell line, miR-186* was significantly down-regulated after Curcumin treatment, which confirmed by quantitative real-time PCR. Down-regulation of miR-186* expression by curcumin elevated the apoptosis, and the survival rate of A549/DDP cells decreased; but up-regulation of miR-186* expression by transfection its mimics restrained the apoptosis, the survival rate of A549/DDP cells increased, which were assayed by flow cytometry expriments and MTT method. Modulation of miRNAs expression may be an important mechanism underlying the biological roles of Curcumin.


[Relationship Between Age of School Entry and Behaviour Problems].
Relationship Between Age of School Entry and Behaviour Problems Recent studies demonstrated that children who are relatively young within a school year show more behaviour problems, are at greater risk of being diagnosed with attention- eficit/hyperactivity disorder (ADHD) and treated with stimulants compared to their older classmates. In this paper we examine the association of age at school entry and behavioural problems for a German sample of elementary school children, who were enrolled in 2009 (N = 928). We used teacher ratings on the Strengths and Difficulties Questionnaire (SDQ) as well as the prevalence of ADHD diagnosis and medication. Our analyses showed that those children with a relatively younger age at school entry were judged more hyperactive than their older peers when sex was controlled for. After stratifying for sex, the effect of age at school entry on hyperactivity was now only significant for boys. No association with age at school entry could be found for the other SDQ-subscales as well as for ADHD diagnosis and medication. Although we could only partially demonstrate a significant relationship between age at school entry and behavioral problems in German elementary school-children, understanding these associations may help to consider children´s maturity differences when evaluating the child´s behavior.


Pipe smoking and cancers of the upper digestive tract.
Pipe smoking has been related to the risk of cancers of the upper digestive and respiratory tract, but quantification of the risk for exclusive pipe smokers is still limited. To analyse the association between exclusive pipe smoking and cancers of the upper digestive tract, we used data from a series of case-control studies conducted in Italy and Switzerland between 1984 and 1999. After excluding cigarette and cigar smokers, 41 male oral and pharyngeal cancer cases, 52 male oesophageal cancer cases and 1,032 male controls were included in the present analysis. Odds ratios (OR) of cancers were estimated by the mean of unconditional multivariate logistic regression, including terms for age, study centre, education, body mass index, and alcohol drinking. Compared to never smokers, exclusive pipe smokers had an OR of 8.7 [95% confidence intervals (CI): 4.0-18.9] of all upper digestive tract cancers. The OR was 12.6 for oral and pharyngeal and 7.2 for oesophageal cancer. Pipe smokers who were also heavy alcohol drinkers had an OR of 38.8 (95% CI: 13.6-110.9) as compared to never smokers and light drinkers. Thus, pipe smoking and heavy alcohol drinking appears to interact at least on a multiplicative model.


Smoking, p53 mutation, and lung cancer.
This issue marks the 50th anniversary of the release of the U.S. Surgeon General's Report on Smoking and Health. Perhaps no other singular event has done more to highlight the effects of smoking on the development of cancer. Tobacco exposure is the leading cause of cancers involving the oral cavity, conductive airways, and the lung. Owing to the many carcinogens in tobacco smoke, smoking-related malignancies have a high genome-wide burden of mutations, including in the gene encoding for p53. The p53 protein is the most frequently mutated tumor suppressor in cancer, responsible for a range of critical cellular functions that are compromised by the presence of a mutation. Herein, we review the epidemiologic connection between tobacco exposure and cancer, the molecular basis of p53 mutation in lung cancer, and the normal molecular and cellular roles of p53 that are abrogated during lung tumor development and progression as defined by in vitro and in vivo studies. We also consider the therapeutic potential of targeting mutant p53 in a clinical setting based upon the cellular role of mutant p53 and data from genetic murine models.


Micro-stepping extended focus reduces photobleaching and preserves structured illumination super-resolution features.
Despite progress made in confocal microscopy, even fast systems still have insufficient temporal resolution for detailed live-cell volume imaging, such as tracking rapid movement of membrane vesicles in three-dimensional space. Depending on the shortfall, this may result in undersampling and/or motion artifacts that ultimately limit the quality of the imaging data. By sacrificing detailed information in the Z-direction, we propose a new imaging modality that involves capturing fast 'projections' from the field of depth and shortens imaging time by approximately an order of magnitude as compared to standard volumetric confocal imaging. With faster imaging, radiation exposure to the sample is reduced, resulting in less fluorophore photobleaching and potential photodamage. The implementation minimally requires two synchronized control signals that drive a piezo stage and trigger the camera exposure. The device generating the signals has been tested on spinning disk confocal and instant structured-illumination-microscopy (iSIM) microscopes. Our calibration images show that the approach provides highly repeatable and stable imaging conditions that enable photometric measurements of the acquired data, in both standard live imaging and super-resolution modes.This article has an associated First Person interview with the first author of the paper.


Comparison of photoacoustic imaging and histopathological examination in determining the dimensions of 52 human melanomas and nevi ex vivo.
Surgical excision followed by histopathological examination is the gold standard for the diagnosis and staging of melanoma. Reoperations and unnecessary removal of healthy tissue could be reduced if non-invasive imaging techniques were available for presurgical tumor delineation. However, no technique has gained widespread clinical use to date due to shallow imaging depth or the absence of functional imaging capability. Photoacoustic (PA) imaging is a novel technology that combines the strengths of optical and ultrasound imaging to reveal the molecular composition of tissue at high resolution. Encouraging results have been obtained from previous animal and human studies on melanoma, but there is still a lack of clinical data. This is the largest study of its kind to date, including 52 melanomas and nevi. 3D multiwavelength PA scanning was performed ex vivo, using 59 excitation wavelengths from 680 nm to 970 nm. Spectral unmixing over this broad wavelength range, accounting for the absorption of several tissue chromophores, provided excellent contrast between healthy tissue and tumor. Combining the results of spectral analysis with spatially resolved information provided a map of the tumor borders in greater detail than previously reported. The tumor dimensions determined with PA imaging were strongly correlated with those determined by histopathological examination for both melanomas and nevi.


Open versus closed kinetic chain exercises for patellofemoral pain. A prospective, randomized study.
The goal of this prospective study was to evaluate the efficacy of open versus closed kinetic chain exercises in the nonoperative management of patellofemoral pain. Sixty patients were randomized into a 5-week program that consisted of only closed kinetic chain exercises or only open kinetic chain exercises. Muscle characteristics, subjective symptoms, and functional performance were evaluated in this study at the time of the initial physical examination, at the end of the treatment period, and 3 months later. Both groups experienced a statistically significant decrease in pain and an increase in functional performance. This study shows that both open and closed kinetic chain exercise programs lead to an improved subjective and clinical outcome in patients with anterior knee pain. The few significantly better functional results for some of the tested parameters in the closed kinetic chain group suggest that this type of treatment is a little more effective than the open kinetic chain program in the treatment of these patients.


Bacteriocin production and gene sequencing analysis from vaginal Lactobacillus strains.
The human vagina is a complex and dynamic ecosystem containing an abundance of microorganisms. In women of childbearing age, this system is dominated by Lactobacillus spp. In the present work, seventeen newly isolated vaginal strains were identified by 16S rDNA sequencing and were investigated for their antimicrobial properties. Twelve of the isolated Lactobacillus strains showed activity against one or more microorganisms. Six and five of them produced substances that inhibited the growth of two different Klebsiella strains and Staphylococcus aureus, respectively. Two lactobacilli strains were active against an Escherichia coli strain, one isolate was active against an Enterococus faecalis strain and another lactobacilli strain showed antimicrobial activity against a Candida parapsilosis strain. The nature of the active compounds was additionally studied, and the presence of bacteriocin-like substances was proved. The genes related to the bacteriocin production in three of the newly isolated strains were identified and sequenced. The presence of gassericin A operon in the genome of the species Lactobacillus crispatus was described for the first time. The presence of antimicrobial activity contributes to their possible use as potential probiotic strains after further research.


Injection anxiety and pain in men using intracavernosal injection therapy after radical pelvic surgery.
Intracavernosal injection (ICI) therapy is a well-recognized treatment strategy with high success rates for men with erectile dysfunction. Despite this, injection anxiety and pain related to injection are significant barriers to its use. This study aims to examine injection anxiety and injection pain in patients using ICI. Men starting ICI therapy post radical pelvic surgery completed questionnaires at initial visit, at each of the two ICI training sessions and at a 4-month follow-up visit. Injection Anxiety Scale, Injection Pain Scale, Injection Reaction Inventory, and the Erectile Function Domain of the International Index of Erectile Function. Average age of the 68 men was 60±8 years. At 4 months, the self-reported frequency of ICI use was: 29%<1/week, 26% 1/week, 40% 2/week, and 5% 3/week. Mean injection anxiety score at first injection was 5.7±2.8 (range 0-10) and significantly decreased to a 4.1±3 at 4 months (P<0.001). At first injection, 65% reported high injection anxiety (≥5) and this significantly decreased to 42% (P=0.003) at 4 months. Anxiety at first injection was negatively related to ICI frequency at 4 months (r=-0.23, P=0.08). Mean injection pain score at first injection was low (2.2±1.8, range 0-10) and 59% rated injection pain≤2. Injection pain remained consistent across time periods. At first injection, injection anxiety (assessed prior to injection) was related to injection pain (r=0.21, P=0.04) and subjects (n=21) who reported high injection anxiety (≥5) across time points, reported an increase in injection pain scores from first injection to 4 months (2.7 vs. 3.7, P=0.05). Although injection anxiety decreased with ICI use, mean injection anxiety remained at a moderate level (4.4) and 42% of men continued to report "high" injection anxiety at 4 months. While injection pain was low, injection anxiety and pain were related. These data suggest the need for a psychological intervention to help lower injection anxiety related to ICI.


NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis.
Most cases with anti-tuberculosis drug-induced hepatotoxicity (ATDH) have been attributed to isoniazid. To evaluate whether the polymorphisms of the cytochrome P450 2EI (CYP2E1) and N-acetyltransferase 2 (NAT2) gene are associated with ATDH. A total of 140 tuberculosis (TB) patients without liver diseases before treatment who received anti-tuberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using the TaqMan polymerase chain reaction assay. Forty-five (32.1%) patients were diagnosed with ATDH. No significant differences were reported in age and sex between patients with and without ATDH. Slow acetylators defined by NAT2 genotypes had a higher risk of hepatotoxicity than rapid acetylators (51.2% vs. 25.2%, P = 0.0026). Odds ratio (OR) analysis showed that slow acetylator status (OR 3.15, 95%CI 1.47-6.48) was the only independent risk factor for ATDH. Pyrazinamide co-administration induced hepatitis was also associated with NAT2 acetylator status. CYP2E1 c1/c1 homozygotes are prone to developing more severe hepatotoxicity than other c1/c2 and c2/c2 genotypes. The slow acetylator status of NAT2 is a significant susceptibility risk factor for ATDH. CYP2E1 is associated with the severity of ATDH.


Possible Human Papillomavirus 38 Contamination of Endometrial Cancer RNA Sequencing Samples in The Cancer Genome Atlas Database.
Viruses are causally associated with a number of human malignancies. In this study, we sought to identify new virus-cancer associations by searching RNA sequencing data sets from >2,000 patients, encompassing 21 cancers from The Cancer Genome Atlas (TCGA), for the presence of viral sequences. In agreement with previous studies, we found human papillomavirus 16 (HPV16) and HPV18 in oropharyngeal cancer and hepatitis B and C viruses in liver cancer. Unexpectedly, however, we found HPV38, a cutaneous form of HPV associated with skin cancer, in 32 of 168 samples from endometrial cancer. In 12 of the HPV38-positive (HPV38(+)) samples, we observed at least one paired read that mapped to both human and HPV38 genomes, indicative of viral integration into the host DNA, something not previously demonstrated for HPV38. The expression levels of HPV38 transcripts were relatively low, and all 32 HPV38(+) samples belonged to the same experimental batch of 40 samples, whereas none of the other 128 endometrial carcinoma samples were HPV38(+), raising doubts about the significance of the HPV38 association. Moreover, the HPV38(+) samples contained the same 10 novel single nucleotide variations (SNVs), leading us to hypothesize that one patient was infected with this new isolate of HPV38, which was integrated into his/her genome and may have cross-contaminated other TCGA samples within batch 228. Based on our analysis, we propose guidelines to examine the batch effect, virus expression level, and SNVs as part of next-generation sequencing (NGS) data analysis for evaluating the significance of viral/pathogen sequences in clinical samples. High-throughput RNA sequencing (RNA-Seq), followed by computational analysis, has vastly accelerated the identification of viral and other pathogenic sequences in clinical samples, but cross-contamination during the processing of the samples remain a major problem that can lead to erroneous conclusions. We found HPV38 sequences specifically present in RNA-Seq samples from endometrial cancer patients from TCGA, a virus not previously associated with this type of cancer. However, multiple lines of evidence suggest possible cross-contamination in these samples, which were processed together in the same batch. Despite this potential cross-contamination, our data indicate that we have detected a new isolate of HPV38 that appears to be integrated into the human genome. We also provide general guidelines for computational detection and interpretation of pathogen-disease associations.


A systematic review of parent and clinician views and perceptions that influence prescribing decisions in relation to acute childhood infections in primary care.
To investigate the views of parents, clinicians, and children pertaining to prescribing decisions for acute childhood infection in primary care. A systematic review of qualitative studies. Meta-ethnographic methods were used, with data drawn from the primary studies in an interpretive analysis. A total of 15 studies met the inclusion criteria. The literature was dominated by concerns about antibiotic over-prescription. Children's views were not reported. Clinicians prescribed antibiotics when they felt pressured by parents or others (e.g. employers) to do so, when they believed there was a clear clinical indication, but also when they felt uncertain of clinical or social outcomes they prescribed "just in case". Parents wanted antibiotics when they felt they would improve the current illness, and when they felt pressure from daycare providers or employers. Clinicians avoided antibiotics when they were concerned about adverse reactions or drug resistance, when certain they were not indicated, and when there was no perceived pressure from parents. Parents also wished to avoid adverse effects of antibiotics, and did not want antibiotics when they would not relieve current symptoms. Some parents preferred to avoid medication altogether. Within paediatric consultations, parents sought a medical evaluation and decision. Primary care clinicians want satisfied parents and short consultations. Antibiotic prescriptions for childhood infections in primary care often result from "just in case" prescribing. These findings suggest that interventions which reduce clinician uncertainty regarding social or clinical outcomes and provide strategies to meet parents' needs within a short consultation are most likely to reduce antibiotic prescribing.