A microarray analysis of the XX Wnt4 mutant gonad targeted at the identification of genes involved in testis vascular differentiation.
One of the earliest morphological changes during testicular differentiation is the establishment of an XY specific vasculature. The testis vascular system is derived from mesonephric endothelial cells that migrate into the gonad. In the XX gonad, mesonephric cell migration and testis vascular development are inhibited by WNT4 signaling. In Wnt4 mutant XX gonads, endothelial cells migrate from the mesonephros and form a male-like coelomic vessel. Interestingly, this process occurs in the absence of other obvious features of testis differentiation, suggesting that Wnt4 specifically inhibits XY vascular development. Consequently, the XX Wnt4 mutant mice presented an opportunity to focus a gene expression screen on the processes of mesonephric cell migration and testicular vascular development. We compared differences in gene expression between XY Wnt4+/+ and XX Wnt4+/+ gonads and between XX Wnt4-/- and XX Wnt4+/+ gonads to identify sets of genes similarly upregulated in wildtype XY gonads and XX mutant gonads or upregulated in XX gonads as compared to XY gonads and XX mutant gonads. We show that several genes identified in the first set are expressed in vascular domains, and have predicted functions related to cell migration or vascular development. However, the expression patterns and known functions of other genes are not consistent with roles in these processes. This screen has identified candidates for regulation of sex specific vascular development, and has implicated a role for WNT4 signaling in the development of Sertoli and germ cell lineages not immediately obvious from previous phenotypic analyses.


A study of the association between urinary aluminum concentration and pre-clinical findings among aluminum-handling and non-handling workers.
Aluminum is considered to be a relatively safe metal for humans. However, there are some reports that aluminum can be toxic to humans and animals. In order to estimate the toxicity of aluminum with respect to humans, we measured the aluminum concentration in urine of aluminum-handling and non-handling workers and investigated the relationships between their urinary aluminum concentrations and pre-clinical findings. Twenty-three healthy aluminum-handling workers and 10 healthy non-aluminum-handling workers participated in this study. Their medical examinations, which were otherwise unremarkable, included the collection of urine and blood. Urinary aluminum levels were analyzed using ICP analysis. As pre-clinical tests, we measured KL-6, SP-D, TRCP-5b, IL-6, and IL-8 in blood and δ-ALA and β2-microglobulin in urine. These were considered to be lung, bone, kidney and inflammation markers. Moreover, we measured 8-OHdG in urine as an oxidative DNA damage marker. The aluminum concentration in urine ranged from 6.9 to 55.1 μg/g cre (median: 20.1 μg/g cre) in the aluminum-handling workers and from 5.6 to 15.6 μg/g cre (median: 8.8 μg/g cre) in the non-aluminum-handling workers, with a significant difference between them. In the pre-clinical findings, there were no significant differences between these two groups except in the case of δ-ALA. However, there were no significant relationships between aluminum concentration and the pre-clinical findings, work years, age or 8-OHdG in the aluminum-handling workers. While the excretion of aluminum in urine was elevated in aluminum-handling workers, our findings suggest that low-dose aluminum is not directly harmful to humans, at least when workers' urinary aluminum concentration is below 55 μg/g cre.


Transdermal Diagnosis of Malaria Using Vapor Nanobubbles.
A fast, precise, noninvasive, high-throughput, and simple approach for detecting malaria in humans and mosquitoes is not possible with current techniques that depend on blood sampling, reagents, facilities, tedious procedures, and trained personnel. We designed a device for rapid (20-second) noninvasive diagnosis of Plasmodium falciparum infection in a malaria patient without drawing blood or using any reagent. This method uses transdermal optical excitation and acoustic detection of vapor nanobubbles around intraparasite hemozoin. The same device also identified individual malaria parasite-infected Anopheles mosquitoes in a few seconds and can be realized as a low-cost universal tool for clinical and field diagnoses.


Synthesis and characterization of selective fluorescent ligands for the neurokinin NK2 receptor.
Several fluorescent probes for the NK2 receptor were designed, synthesized, and pharmacologically characterized. These fluorescent ligands are analogues of the selective NK2 heptapeptide antagonist N-alpha-benzoyl-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (1, GR94800). They were obtained by substitution of 2,n-diaminoalkyl amino acid (n = 3-6) for Ala1 and the subsequent coupling of the fluorophore NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) or fluoresceinthiocarbamyl to the N-omega amino group. The fluorescent derivatives retained high binding affinities for the NK2 receptor in transfected CHO cells. In contrast, fluorescent derivatives made by replacing the N-alpha-benzoyl group of 1 by NBD or fluorescein were considerably less active. The effect on ligand potency of varying the length of the spacer arm between the peptide moiety and the fluorescent group was also studied. The most potent fluorescent antagonists were N-alpha-benzoyl-Dab(gamma-NBD)-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (5B), pKi = 8.87 for NK2; N-alpha-benzoyl-Orn (delta-NBD)-Ala-D-Trp-Phe- D-Pro-Pro-Nle-NH2 (4B), pKi = 8.84; and N-alpha-benzoyl-Lys(epsilon-NBD)-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH2 (3B), pKi = 8.83. These three compounds were highly selective for NK2 over NK3 and NK1 receptors. We show that these fluorescent ligands are useful tools for the detection of NK2 receptor expression by flow cytometry. Additionally, these fluorescent probes should prove valuable for fluorescence microscopy and study of ligand-receptor interaction by spectrofluorimetry.


Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells.
Idiosyncratic hepatotoxicity has been associated with the oral tyrosine kinase inhibitor lapatinib, which is used in metastatic breast cancer therapy. Lapatinib is extensively metabolized by cytochrome P450 3A4/5 to yield an O-debenzylated metabolite, which can undergo further oxidation to a reactive quinone imine. A recent clinical study reported that concomitant use of lapatinib with dexamethasone increased the incidence of hepatotoxicity in metastatic breast cancer patients treated with lapatinib, and so we hypothesized that induction of CYP3A enhances the bioactivation of lapatinib to reactive intermediates that contribute to hepatotoxicity. Therefore, we examined the effect of CYP3A4 induction on the cytotoxicity and metabolism of lapatinib in the HepaRG human hepatic cell line. Differentiated HepaRG cells were pretreated with dexamethasone (100 μM) or the prototypical CYP3A4 inducer rifampicin (4 μM) for 72 hours, followed by incubation with lapatinib (0-100 μM) for 24 hours. Cell viability was monitored using WST-1 assays, and metabolites were quantified by liquid chromatography coupled to tandem mass spectrometry. Induction of CYP3A4 by dexamethasone or rifampicin enhanced lapatinib-induced cytotoxicity, compared with treatment with lapatinib alone. A direct comparison of the cytotoxicity of lapatinib versus O-debenzylated lapatinib demonstrated that the O-debenzylated metabolite was significantly more cytotoxic than lapatinib itself. Furthermore, pretreatment with 25 μM l-buthionine sulfoximine to deplete intracellular glutathione markedly enhanced lapatinib cytotoxicity. Cytotoxicity was correlated with increased formation of O-debenzylated lapatinib and cysteine adducts of the putative quinone imine intermediate. Collectively, these data suggest that CYP3A4 induction potentiates lapatinib-induced hepatotoxicity via increased reactive metabolite formation.


Fabrication-tolerant high quality factor photonic crystal microcavities.
A two-dimensional photonic crystal microcavity design supporting a wavelength-scale volume resonant mode with a calculated quality factor (Q) insensitive to deviations in the cavity geometry at the level of Q~2x10(4) is presented. The robustness of the cavity design is confirmed by optical fiber-based measurements of passive cavities fabricated in silicon. For microcavities operating in the lambda = 1500 nm wavelength band, quality factors between 1.3-4.0x10(4) are measured for significant variations in cavity geometry and for resonant mode normalized frequencies shifted by as much as 10% of the nominal value.


Hybrid sequencing-based personal full-length transcriptomic analysis implicates proteostatic stress in metastatic ovarian cancer.
Comprehensive molecular characterization of myriad somatic alterations and aberrant gene expressions at personal level is key to precision cancer therapy, yet limited by current short-read sequencing technology, individualized catalog of complete genomic and transcriptomic features is thus far elusive. Here, we integrated second- and third-generation sequencing platforms to generate a multidimensional dataset on a patient affected by metastatic epithelial ovarian cancer. Whole-genome and hybrid transcriptome dissection captured global genetic and transcriptional variants at previously unparalleled resolution. Particularly, single-molecule mRNA sequencing identified a vast array of unannotated transcripts, novel long noncoding RNAs and gene chimeras, permitting accurate determination of transcription start, splice, polyadenylation and fusion sites. Phylogenetic and enrichment inference of isoform-level measurements implicated early functional divergence and cytosolic proteostatic stress in shaping ovarian tumorigenesis. A complementary imaging-based high-throughput drug screen was performed and subsequently validated, which consistently pinpointed proteasome inhibitors as an effective therapeutic regime by inducing protein aggregates in ovarian cancer cells. Therefore, our study suggests that clinical application of the emerging long-read full-length analysis for improving molecular diagnostics is feasible and informative. An in-depth understanding of the tumor transcriptome complexity allowed by leveraging the hybrid sequencing approach lays the basis to reveal novel and valid therapeutic vulnerabilities in advanced ovarian malignancies.


Upregulation of connexin43 expression in corneal fibroblasts by corneal epithelial cells.
The authors have previously shown that the expression of tight-junction proteins in corneal epithelial cells is regulated by corneal fibroblasts in a coculture system. They have now examined the effect of corneal epithelial cells on the expression of the gap-junction protein connexin43 in corneal fibroblasts. Human corneal fibroblasts and simian virus 40-transformed human corneal epithelial (HCE) cells were cultured on opposite sides of a collagen vitrigel membrane. Expression of junctional proteins in corneal fibroblasts was examined by reverse transcription-polymerase chain reaction, immunoblot, and immunofluorescence analyses. The effect of a small interfering RNA specific for insulin-like growth factor-1 (IGF-1) mRNA on connexin43 expression was determined by transfection. The amounts of connexin43 mRNA and protein in corneal fibroblasts were increased by the presence of HCE cells. HCE cells had no effect on the expression of the tight-junction proteins ZO-1, occludin, and claudin in corneal fibroblasts. The effect of HCE cells on connexin43 expression was mimicked by exposure of corneal fibroblasts to IGF-1. Furthermore, depletion of IGF-1 in HCE cells by RNA interference largely abolished the effect of these cells on connexin43 expression in corneal fibroblasts. Finally, the upregulation of connexin43 expression in corneal fibroblasts by HCE cells was blocked by inhibitors of signaling by the mitogen-activated protein kinases ERK (PD98059) and p38 MAPK (SB203580). The presence of corneal epithelial cells upregulated the expression of connexin43 in corneal fibroblasts, suggesting that corneal epithelial cells are important for the maintenance of gap junction-mediated communication among corneal fibroblasts.


Functional roles of ST8SIA3-mediated sialylation of striatal dopamine D2 and adenosine A2A receptors.
Sialic acids are typically added to the end of glycoconjugates by sialyltransferases. Among the six ST8 α-N-acetyl-neuraminide α-2,8-sialyltransferases (ST8SIA) existing in adult brains, ST8SIA2 is a schizophrenia-associated gene. However, the in vivo substrates and physiological functions of most sialyltransferases are currently unknown. The ST8SIA3 is enriched in the striatum. Here, we showed that ablation of St8sia3 in mice (St8sia3-KO) led to fewer disialylated and trisialylated terminal glycotopes in the striatum of St8sia3-KO mice. Moreover, the apparent sizes of several striatum-enriched G-protein-coupled receptors (GPCRs) (including the adenosine A2A receptor (A2AR) and dopamine D1/D2 receptors (D1R and D2R)) were smaller in St8sia3-KO mice than in WT mice. A sialidase treatment removed the differences in the sizes of these molecules between St8sia3-KO and WT mice, confirming the involvement of sialylation. Expression of ST8SIA3 in the striatum of St8sia3-KO mice using adeno-associated viruses normalized the sizes of these proteins, demonstrating a direct role of ST8SIA3. The lack of ST8SIA3-mediated sialylation altered the distribution of these proteins in lipid rafts and the interaction between D2R and A2AR. Locomotor activity assays revealed altered pharmacological responses of St8sia3-KO mice to drugs targeting these receptors and verified that a greater population of D2R formed heteromers with A2AR in the striatum of St8sia3-KO mice. Since the A2AR-D2R heteromer is an important drug target for several basal ganglia diseases (such as schizophrenia and Parkinson's disease), the present study not only reveals a crucial role for ST8SIA3 in striatal functions but also provides a new drug target for basal ganglia-related diseases.


Fixation tack penetration into the maxillary sinus: A case report of a guided bone regeneration procedure complication.
Guided bone regeneration (GBR) is an established and predictable procedure used to obtain adequate alveolar bone for the placement of dental implants. Anatomical challenges, such as the proximity of the maxillary sinus, may lead to complications during a GBR procedure. The purpose of this report is to present a unique and hitherto unreported complication of a GBR procedure, i.e., the penetration of a titanium fixation tack into the maxillary sinus. A unique GBR is presented, where a titanium tack penetrated the maxillary sinus with subsequent migration and loss. Attempts to locate the tack visually during the procedure were unsuccessful. The GBR procedure was aborted and dental radiographs were immediately obtained. The patient was completely asymptomatic during the healing period. Eight weeks later a cone beam computed tomography revealed a non-inflamed sinus with no pathology evident. However, the tack could not be visualized. An otolaryngology consultation was requested and the ensuing sinus endoscopy did not reveal any evidence of the penetrated tack. It is thought that the loose tack migrated completely out of the sinus through the nasal passage. The use of a pre-operative cone beam computed tomography (CBCT) would have allowed the clinician to assess the exact thickness of the lateral wall of the maxillary sinus and better determine the ideal placement location and/or the feasibility of using a fixation tack in the posterior upper jaw.


Comprehensive profiling of translation initiation in influenza virus infected cells.
Translation can initiate at alternate, non-canonical start codons in response to stressful stimuli in mammalian cells. Recent studies suggest that viral infection and anti-viral responses alter sites of translation initiation, and in some cases, lead to production of novel immune epitopes. Here we systematically investigate the extent and impact of alternate translation initiation in cells infected with influenza virus. We perform evolutionary analyses that suggest selection against non-canonical initiation at CUG codons in influenza virus lineages that have adapted to mammalian hosts. We then use ribosome profiling with the initiation inhibitor lactimidomycin to experimentally delineate translation initiation sites in a human lung epithelial cell line infected with influenza virus. We identify several candidate sites of alternate initiation in influenza mRNAs, all of which occur at AUG codons that are downstream of canonical initiation codons. One of these candidate downstream start sites truncates 14 amino acids from the N-terminus of the N1 neuraminidase protein, resulting in loss of its cytoplasmic tail and a portion of the transmembrane domain. This truncated neuraminidase protein is expressed on the cell surface during influenza virus infection, is enzymatically active, and is conserved in most N1 viral lineages. We do not detect globally higher levels of alternate translation initiation on host transcripts upon influenza infection or during the anti-viral response, but the subset of host transcripts induced by the anti-viral response is enriched for alternate initiation sites. Together, our results systematically map the landscape of translation initiation during influenza virus infection, and shed light on the evolutionary forces shaping this landscape.


[Cross-sectional study of factors related to Achilles bone mineral density measured by an ultrasound system].
A cross-sectional study was conducted to examine the relationship between bone mineral density (BMD) and life-style related factors including exercise and dietary habits in 1016 pre-menopausal women and 856 post-menopausal women in Ishikawa Prefecture, Japan. The achilles BMD in 1,872 women ages between 19 and 85 years were measured from 1995 to 1996 by an ultrasound system. The stiffness index calculated by the Lunar Achilles ultrasound machine was used as the BMD in this analysis. Self-administered questionnaires were used to obtain the following information: medical history, pregnancy, delivery and menstrual history, height at 20-years of age, present number of teeth, fracture history, sports exercise history, food intake frequency, smoking and drinking history, and daily physical activity. Analysis of covariance and multiple regression analysis were performed to evaluate the contribution of life-style related factors to BMD after adjustment for age and BMI (Body mass index) in pre- and post-menopausal women, respectively. Results were as follow: 1) BMD was inversely associated with increasing age in pre- and post-menopausal women. The BMD level of post-menopausal women were lower than that of pre-menopausal women in each 5-year age group. The pearson's correlatin coefficient between age and BMD was significant at -0.25 and -0.44 in pre- and post-menopausal women, respectively. 2) Body mass index (BMI) and BMD were positively correlated in pre- and post-menopausal women. 3) In pre-menopausal women, lower BMD was associated with the following factors: age, lower BMI, no history of joining a sports club in junior high school, absence of current regular sports, being inactive in daily life, having joint pains, lower number of remaining teeth and lower dairy product intake. 4) In post-menopausal women, lower BMD was associated with the following factors: age, lower BMI, no history of joining a sports club in junior high school, past history of fracture and longer post-menopausal years. Factors associated with lower BMD in this study were regarded as risk factors for future osteoporotic fractures in the elderly, or signs of lower BMD. Therefore, the information of these factors should be employed in health education for the prevention of osteoporosis. Especially, participating in a sports club while in junior high school may be a recommendation for acquiring higher BMD even in the post-menopausal period.


FT-IR spectroscopy as a tool for rapid identification and intra-species characterization of airborne filamentous fungi.
Identification of microfungi is time-consuming due to cultivation and microscopic examination and can be influenced by the interpretation of the macro- and micro-morphological characters observed. Fungal conidia contain mycotoxins that may be present in bioaerosols and thus the capacity for production of mycotoxins (and allergens) needs to be investigated to create a basis for reliable risk assessment in environmental and occupational hygiene. The present investigation aimed to create a simple but sophisticated method for the preparation of samples and the identification of airborne fungi by FT-IR spectroscopy. The method was suited to reproducibly differentiate Aspergillus and Penicillium species on the generic, the species, and the strain level. There are strong indications that strains of one taxon differing in metabolite production can be reliably distinguished by FT-IR spectroscopy (e.g. Aspergillus parasiticus). On the other hand, species from different taxa being similar in secondary metabolite production showed comparably higher similarities. The results obtained here can serve as a basis for the development of a database for species identification and strain characterization of microfungi. The method presented here will improve and facilitate the risk assessment in case of bioaerosol exposure, as strains with different physiological properties (e.g. toxic, non-toxic) could be differentiated. Moreover, it has the potential to significantly improve the identification of microfungi in various fields of applied microbiological research, e.g. high throughput screening in view of specific physiological properties, biodiversity studies, inventories in environmental microbiology, and quality control measures.


National and State Trends in Sales of Cigarettes and E-Cigarettes, U.S., 2011-2015.
In recent years, self-reported cigarette smoking has declined among youth and adults, while electronic cigarette (e-cigarette) use has increased. However, sales trends for these products are less certain. This study assessed national and state patterns of U.S. cigarette and e-cigarette unit sales. Trends in cigarette and e-cigarette unit sales were analyzed using retail scanner data from September 25, 2011 through January 9, 2016 for: (1) convenience stores; and (2) all other outlets combined, including supermarkets, mass merchandisers, drug, dollar, and club stores, and military commissaries (online, tobacco-only, and "vape" shops were not available). Data by store type were available for the total contiguous U.S. and 29 states; combined data were available for the remaining states, except Alaska, Hawaii, and DC. During 2011-2015, cigarette sales exhibited a small, significant decrease; however, positive year-over-year growth occurred in convenience stores throughout most of 2015. E-cigarette unit sales significantly increased during 2011-2015, but year-over-year growth slowed and was occasionally negative. Cigarette unit sales exceeded e-cigarettes by 64:1 during the last 4-week period. During 2014-2015, cigarette sales increases occurred in 15 of 48 assessed states; e-cigarette sales increased in 18 states. Despite overall declines during 2011-2015, cigarette sales in 2015 grew for the first time in a decade. E-cigarette sales growth was positive, but slowed over the study period in assessed stores. Cigarette sales continued to exceed e-cigarette sales, reinforcing the importance of efforts to reduce the appeal and accessibility of cigarettes and other combusted tobacco products.


Why some MSM present late for HIV testing: a qualitative analysis.
Although initiatives are under way in the UK to diagnose HIV infection early, late presentation is still a major issue and often results in serious health complications for the individual and has implications for society, including high costs and increased rates of transmission. Intervention strategies in the UK have aimed at increasing testing opportunities but still a significant proportion of those with HIV infection either decline testing or continue to test late. The main objective of this study is to identify ideas and themes as to why testing was not carried out earlier in men who have sex with men (MSM) who presented with late HIV infection. Semi-structured interviews were carried out with MSM presenting late with a CD4 cell count of <200. A structured framework approach was used to analyse the data collected and generate ideas as to why they did not seek testing earlier. Seventeen MSM were interviewed and four main themes were identified: psychological barriers, including fear of illness and dying, stigma surrounding testing for HIV and in living with a positive diagnosis, perceived low risk for contracting HIV despite participants reporting having a good understanding of HIV and its transmission and strong views that a more active approach by healthcare services, including general practice, is necessary if the uptake of HIV testing is to increase. Late presentation with HIV infection continues to be a problem in the UK despite government initiatives to expand opportunities for testing. Recurring themes for late testing were a low perceived risk for HIV infection and a fear of HIV and a positive diagnosis. Population-targeted health promotion alongside a more proactive approach by healthcare professionals and making HIV testing more convenient and accessible may result in earlier testing.


Discrete Trajectories of Resolving and Persistent Pain in People With Rheumatoid Arthritis Despite Undergoing Treatment for Inflammation: Results From Three UK Cohorts.
Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesized that discrete RA subgroups might display favorable or unfavorable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation. Growth mixture modelling was used to identify discrete trajectories of Short Form-36 bodily pain scores during 3 years in 3 RA cohorts (Early RA Network (n = 683), British Society for Rheumatology Biologics Register Biologics (n = 7,090) and nonbiologics (n = 1,720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years. The mean Short Form-36 bodily pain scores in each cohort improved but remained throughout 3 years of follow-up of >1 standard deviation worse than the UK general population average. Discrete persistent pain (59-79% of cohort participants) and resolving pain (19-27%) trajectories were identified in each cohort. In Early RA Network, a third trajectory displaying persistently low pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% were found to follow a persistent pain trajectory. When trajectories were compared, greater disability (adjusted odds ratio = 2.3-2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (adjusted odds ratio = 1.6-1.8) were risk factors for persistent pain trajectories in each cohort. In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during treatment for RA. Inflammation does not fully explain the pain trajectories, and noninflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long-term burden of arthritis pain. PERSPECTIVE: Immunosuppression decreases inflammation in RA, but pain outcomes are less favorable. Discrete persistent and resolving pain trajectories were identified after treatment, both in early and established RA. Smoking and greater disability at baseline predicted persistent pain. Identifying patient subgroups with a poor pain prognosis could enable adjunctive treatment to improve outcomes.


Gaussian mixture model of heart rate variability.
Heart rate variability (HRV) is an important measure of sympathetic and parasympathetic functions of the autonomic nervous system and a key indicator of cardiovascular condition. This paper proposes a novel method to investigate HRV, namely by modelling it as a linear combination of Gaussians. Results show that three Gaussians are enough to describe the stationary statistics of heart variability and to provide a straightforward interpretation of the HRV power spectrum. Comparisons have been made also with synthetic data generated from different physiologically based models showing the plausibility of the Gaussian mixture parameters.


Are you talking to me? Neural activations in 6-month-old infants in response to being addressed during natural interactions.
Human interactions are guided by continuous communication among the parties involved, in which verbal communication plays a primary role. However, speech does not necessarily reveal to whom it is addressed, especially for young infants who are unable to decode its semantic content. To overcome such difficulty, adults often explicitly mark their communication as infant-directed. In the present study we investigated whether ostensive signals, which would disambiguate the infant as the addressee of a communicative act, would modulate the brain responses of 6-month-old infants to speech and gestures in an ecologically valid setting. In Experiment 1, we tested whether the gaze direction of the speaker modulates cortical responses to infant-direct speech. To provide a naturalistic environment, two infants and their parents participated at the same time. In Experiment 2, we tested whether a similar modulation of the cortical response would be obtained by varying the intonation (infant versus adult directed speech) of the speech during face-to-face communication, one on one. The results of both experiments indicated that only the combination of ostensive signals (infant directed speech and direct gaze) led to enhanced brain activation. This effect was indicated by responses localized in regions known to be involved in processing auditory and visual aspects of social communication. This study also demonstrated the potential of fNIRS as a tool for studying neural responses in naturalistic scenarios, and for simultaneous measurement of brain function in multiple participants.


Benefits and implementation of home hemodialysis: A narrative review.
Home hemodialysis (HD) is a modality of renal replacement therapy that can be safely and independently performed at home by end-stage renal disease (ESRD) patients. Home HD can be performed at the convenience of the patients on a daily basis, every other day and overnight (nocturnal). Despite the great and many perceived benefits of home HD, including the significant improvements in health outcomes and resource utilization, the adoption of home HD has been limited; lack or inadequate pre-dialysis education and training constitute a major barrier. The lack of self-confidence and/or self-efficacy to manage own therapy, lack of family and/or social support, fear of machine and cannulation of blood access and worries of possible catastrophic events represent other barriers for the implementation of home HD besides inadequate competence and/or expertise in caring for home HD patients among renal care providers (nephrologists, dialysis nurses, educators). A well-studied, planned and prepared and carefully implemented central country program supported by adequate budget can play a positive role in overcoming the challenges to home HD. Healthcare authorities, with the increasingly financial and logistic demands and the relatively higher mortality and morbidity rates of the conventional in-center HD, should tackle home HD as an attractive and cost-effective modality with more freedom, quality of life and improvement of clinical outcomes for the ESRD patients.


Emotion and language: valence and arousal affect word recognition.
Emotion influences most aspects of cognition and behavior, but emotional factors are conspicuously absent from current models of word recognition. The influence of emotion on word recognition has mostly been reported in prior studies on the automatic vigilance for negative stimuli, but the precise nature of this relationship is unclear. Various models of automatic vigilance have claimed that the effect of valence on response times is categorical, an inverted U, or interactive with arousal. In the present study, we used a sample of 12,658 words and included many lexical and semantic control factors to determine the precise nature of the effects of arousal and valence on word recognition. Converging empirical patterns observed in word-level and trial-level data from lexical decision and naming indicate that valence and arousal exert independent monotonic effects: Negative words are recognized more slowly than positive words, and arousing words are recognized more slowly than calming words. Valence explained about 2% of the variance in word recognition latencies, whereas the effect of arousal was smaller. Valence and arousal do not interact, but both interact with word frequency, such that valence and arousal exert larger effects among low-frequency words than among high-frequency words. These results necessitate a new model of affective word processing whereby the degree of negativity monotonically and independently predicts the speed of responding. This research also demonstrates that incorporating emotional factors, especially valence, improves the performance of models of word recognition.


Thy-1 triggers mouse thymocyte apoptosis through a bcl-2-resistant mechanism.
Programmed cell death plays an important role during thymocyte development, since a vast majority (97%) of mouse cortical thymocytes die in thymus, whereas only 3% of these cells are rescued from cell death and positively selected. Although it seems well established that thymocyte fate depends upon appropriate surface-expressed T cell receptor, little is known about the molecular mechanism(s) responsible for the massive thymocyte elimination that occurs in the thymus. We report here that Thy-1 is capable of triggering mouse thymocyte death in vitro through a bcl-2-resistant mechanism. We have previously shown that Thy-1 is involved in mouse thymocyte adhesion to thymic stroma through interaction with an epithelial cell ligand. To examine the Thy-1 signaling function in thymocytes, we have mimicked its interaction with stromal cells by culturing mouse thymocytes onto tissue culture plates coated with monoclonal antibodies (mAb) directed at distinct Thy-1 epitope regions. mAb recognizing determinants in a defined Thy-1 structural domain, but not others, were found to induce marked thymocyte apoptosis as evidenced by morphological and biochemical data. Use of a quantitative DNA dot blot assay indicated that Thy-1-mediated thymocyte apoptosis was not blocked by RNA or protein synthesis inhibitors, EGTA, or by cyclosporin A, and differed, therefore, from "activation-driven cell death". Moreover, Thy-1(+)-transfected, but not wild-type AKR1 (Thy-1-d) thymoma cells underwent apoptosis after ligation with apoptosis-inducing, Thy-1-specific mAb. In contrast to thymocytes, the latter event was inhibitable by RNA and protein synthesis inhibitors, an indication that thymocytes, but not thymoma cells, contain the molecular components necessary for Thy-1-driven apoptosis. We further showed that Thy-1-triggered thymocyte death is a developmentally regulated process operative in fetal thymocytes from day 17 of gestation, but not in peripheral T cells. Indeed, the target of apoptosis by anti-Thy-1 was found to reside mainly within the CD4+8+3- and CD4+8+3lo double positive immature thymocyte subsets. Finally, it is of major interest that Thy-1-mediated apoptosis, which was found to be readily detectable in thymocytes from bcl-2-transgenic mice, represents a thus far unique experimental system for studying bcl-2-resistant thymocyte death mechanism(s).


Test of precoat filtration technology for treatment of swimming pool water.
The technical performance of a precoat filter was compared with that of a traditional sand filter. Particle concentration and size distribution were measured before and after the filtration of swimming pool water. Both the sand and precoat filters could reduce the particle concentration in the effluent. However, higher particle removal efficiency was generally observed for the precoat filter, especially for particles smaller than 10 μm in diameter. Adding flocculant improved the removal efficiency of the sand filter, resulting in removal efficiencies comparable to those of the precoat filter. Three powders, i.e., two types of perlite (Harbolite® and Aquatec perlite) and cellulose fibers (Arbocel®), were tested for the precoat filter, but no significant difference in particle removal efficiency was observed among them. The maximum efficiency was reached within 30-40 min of filtration. The energy required for the pumps increased by approximately 35% over a period of 14 days. The energy consumption could be reduced by replacing the powder on the filter cloth. The sand filter was backwashed once a week, while the powder on the precoat filter was replaced every two weeks. Under these conditions, it was possible to reduce the water used for cleaning by 88% if the precoat filter was used instead of the sand filter.


The objects of attention: Causes and targets.
The objects of attention can be located anywhere along the causal link from the source of stimuli to the final output of the vision system. As causes, they attract and control attention, and as products, they constitute targets of analysis and explicit comments. Stimulus-driven indexing creates pointers that support fast and frugal cognition.


Activated oncogenes in B6C3F1 mouse liver tumors: implications for risk assessment.
The validity of mouse liver tumor end points in assessing the potential hazards of chemical exposure to humans is a controversial but important issue, since liver neoplasia in mice is the most frequent tumor target tissue end point in 2-year carcinogenicity studies. The ability to distinguish between promotion of background tumors versus a genotoxic mechanism of tumor initiation by chemical treatment would aid in the interpretation of rodent carcinogenesis data. Activated oncogenes in chemically induced and spontaneously occurring mouse liver tumors were examined and compared as one approach to determine the mechanism by which chemical treatment caused an increased incidence of mouse liver tumors. Data suggest that furan and furfural caused an increased incidence in mouse liver tumors at least in part by induction of novel weakly activating point mutations in ras genes even though both chemicals did not induce mutations in Salmonella assays. In addition to ras oncogenes, two activated raf genes and four non-ras transforming genes were detected. The B6C3F1 mouse liver may thus provide a sensitive assay system to detect various classes of proto-oncogenes that are susceptible to activation by carcinogenic insult. As illustrated with mouse liver tumors, analysis of activated oncogenes in spontaneously occurring and chemically induced rodent tumors will provide information at a molecular level to aid in the use of rodent carcinogenesis data for risk assessment.


Stem cells for liver tissue repair: current knowledge and perspectives.
Stem cells from extra- or intrahepatic sources have been recently characterized and their usefulness for the generation of hepatocyte-like lineages has been demonstrated. Therefore, they are being increasingly considered for future applications in liver cell therapy. In that field, liver cell transplantation is currently regarded as a possible alternative to whole organ transplantation, while stem cells possess theoretical advantages on hepatocytes as they display higher in vitro culture performances and could be used in autologous transplant procedures. However, the current research on the hepatic fate of stem cells is still facing difficulties to demonstrate the acquisition of a full mature hepatocyte phenotype, both in vitro and in vivo. Furthermore, the lack of obvious demonstration of in vivo hepatocyte-like cell functionality remains associated to low repopulation rates obtained after current transplantation procedures. The present review focuses on the current knowledge of the stem cell potential for liver therapy. We discuss the characteristics of the principal cell candidates and the methods to demonstrate their hepatic potential in vitro and in vivo. We finally address the question of the future clinical applications of stem cells for liver tissue repair and the technical aspects that remain to be investigated.


An evaluation of single nucleotide polymorphisms in the human heat shock protein 90 kDa α and β isoforms.
Single nucleotide polymorphisms (SNPs) in genes coding for proteins that maintain the cytosolic aryl hydrocarbon receptor (AHR) complex may affect individual susceptibility to dioxin-like compound (DLC)-induced toxicity. The cytosolic 90 kDa heat shock proteins (HSP90s) are ubiquitous chaperone proteins that bind to and stabilize numerous client proteins, including non-ligand-bound AHR. The objective of this study was to characterize SNPs in the human cytosolic HSP90 genes (HSP90AA1 and HSP90AB1). DNA sequencing of 101 human samples detected eight and seven unique SNPs at the HSP90AA1 and HSP90AB1 loci, respectively. For HSP90AA1, two non-synonymous (L71M and E554D) and one rare early termination (Q107X) SNP were observed. One SNP (E554D) was a rare novel polymorphism located in the middle substrate binding region. All SNPs detected in the HSP90AB1 gene were synonymous. With the exception of Q107X, in silico analyses predicted all HSP90 SNPs would have very low to medium risk of affecting the regulation of alternative splicing in gene transcription or protein function. Overall, a very limited presence of SNPs with predicted functional consequence in key domains of the human HSP90 proteins was observed in this study.


Cervical cancer: epidemiology, prevention and the role of human papillomavirus infection.
Organized screening has contributed to a decline in cervical cancer incidence and mortality over the past 50 years. However, women in developing countries are yet to profit extensively from the benefits of screening programs, and recent trends show a resurgence of the disease in developed countries. The past 2 decades have witnessed substantial progress in our understanding of the natural history of cervical cancer and in major treatment advances. Human papillomavirus (HPV) infection is now recognized as the main cause of cervical cancer, the role of coexisting factors is better understood, a new cytology reporting terminology has improved diagnosis and management of precursor lesions, and specific treatment protocols have increased survival among patients with early or advanced disease. Current research has focused on the determinants of infection with oncogenic HPV types, the assessment of prophylactic and therapeutic vaccines and the development of screening strategies incorporating HPV testing and other methods as adjunct to cytology. These are fundamental stepping stones for the implementation of effective public health programs aimed at the control of cervical cancer.


Contributions of the social environment to first-onset and recurrent mania.
In treated cohorts, individuals with bipolar disorder are more likely to report childhood adversities and recent stressors than individuals without bipolar disorder; similarly, in registry-based studies, childhood adversities are more common among individuals who later become hospitalized for bipolar disorder. Because these types of studies rely on treatment-seeking samples or hospital diagnoses, they leave unresolved the question of whether or not social experiences are involved in the etiology of bipolar disorder. We investigated the role of childhood adversities and adulthood stressors in liability for bipolar disorder using data from the National Epidemiologic Survey on Alcohol and Related Conditions (n=33 375). We analyzed risk for initial-onset and recurrent DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) manic episodes during the study's 3-year follow-up period. Childhood physical abuse and sexual maltreatment were associated with significantly higher risks of both first-onset mania (odds ratio (OR) for abuse: 2.23; 95% confidence interval (CI)=1.71, 2.91; OR for maltreatment: 2.10; CI=1.55, 2.83) and recurrent mania (OR for abuse: 1.55; CI=1.00, 2.40; OR for maltreatment: 1.60; CI=1.00, 2.55). In addition, past-year stressors in the domains of interpersonal instability and financial hardship were associated with a significantly higher risk of incident and recurrent mania. Exposure to childhood adversity potentiated the effects of recent stressors on adult mania. Our findings demonstrate a role of social experiences in the initial onset of bipolar disorder, as well as in its prospective course, and are consistent with etiologic models of bipolar disorder that implicate deficits in developmentally established stress-response pathways.


A study of burns for wound ageing reveals changes in unburnt skin with implications for future research.
Thirty-three punch biopsy sets of burn wound edge and adjacent unburnt skin from burn wounds aged six hours to 23 days were obtained from 18 patients. Immunohistochemical staining was performed for transforming growth factor beta receptor, epidermal growth factor receptor and MIB-1 (which stains the cell cycle associated antigen ki-67) in addition to integrins alpha V, 5 and 3 to assess for temporal patterns that might assist in the ageing of burn wounds. There was an early (12hr-4day) rise in integrin alpha V expression, an increasing expression of transforming growth factor beta receptor from 12 hours onwards, and increased expression of MIB-1 commencing at 2 days. In biopsy samples from the edge of the burn there was a trend for an early (6 hr-4 day) rise in epidermal growth factor receptor expression. There were no discernable changes in integrin alpha 5 or 3. The striking feature was that biopsy samples from the adjacent, unburnt skin showed similar temporal staining patterns. A further study would be required to determine if the effect was generalised or local, but the observation of changes in unburnt tissue implies that careful consideration must be given to selecting control tissue.


Management of fibromyalgia syndrome.
The optimal management of fibromyalgia syndrome (FMS) is unclear and comprehensive evidence-based guidelines have not been reported. To provide up-to-date evidence-based guidelines for the optimal treatment of FMS. DATA SOURCES, SELECTION, AND EXTRACTION: A search of all human trials (randomized controlled trials and meta-analyses of randomized controlled trials) of FMS was made using Cochrane Collaboration Reviews (1993-2004), MEDLINE (1966-2004), CINAHL (1982-2004), EMBASE (1988-2004), PubMed (1966-2004), Healthstar (1975-2000), Current Contents (2000-2004), Web of Science (1980-2004), PsychInfo (1887-2004), and Science Citation Indexes (1996-2004). The literature review was performed by an interdisciplinary panel, composed of 13 experts in various pain management disciplines, selected by the American Pain Society (APS), and supplemented by selected literature reviews by APS staff members and the Utah Drug Information Service. A total of 505 articles were reviewed. There are major limitations to the FMS literature, with many treatment trials compromised by short duration and lack of masking. There are no medical therapies that have been specifically approved by the US Food and Drug Administration for management of FMS. Nonetheless, current evidence suggests efficacy of low-dose tricyclic antidepressants, cardiovascular exercise, cognitive behavioral therapy, and patient education. A number of other commonly used FMS therapies, such as trigger point injections, have not been adequately evaluated. Despite the chronicity and complexity of FMS, there are pharmacological and nonpharmacological interventions available that have clinical benefit. Based on current evidence, a stepwise program emphasizing education, certain medications, exercise, cognitive therapy, or all 4 should be recommended.


Induction of apoptosis by grape seed extract (Vitis vinifera) in oral squamous cell carcinoma.
Development of novel therapeutic modalities is crucial for the treatment of oral squamous cell carcinoma (OSCC). Recent scientific studies have been focused on herbal medicines as potent anti-cancer drug candidates. This study is the first to investigate the cytotoxic effects and the mechanism of cell death induced by grape seed extract (GSE) in oral squamous cell carcinoma (KB cells). MTT (3-(4,5-dimetylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) and trypan blue assays were performed in KB cells as well as human umbilical vein endothelial cells (HUVEC) were used to analyze the cytotoxic activity of GSE. Furthermore, the apoptosis-inducing action of the extract was determined by TUNEL, DNA fragmentation and cell death analysis. Statistical significance was determined by analysis of variance (ANOVA), followed by Duncan's test at a significance level of P≤0.05. The results showed apoptotic potential of GSE, confirmed by significant inhibition of cell growth and viability in a dose- and time- dependent manner without inducing damage to non-cancerous cell line HUVEC. The results of this study suggest that this plant contains potential bioactive compound(s) for the treatment of oral squamous cell carcinoma.


Effect of heart rate reduction by 4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride on infarct size in dog.
Heart rate (HR) reduction may reduce the severity of myocardial ischemia. ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium++ + chloride) is a novel bradycardic agent with a specific effect on the sinoatrial node without having any other direct effects on the heart. In the present study, the effect of ZD7288 on infarct size and regional myocardial function during regional myocardial ischemia and reperfusion was investigated. Seventeen anesthetized open chest dogs (control, n = 8, and ZD7288, n = 9) underwent 1 h of left anterior descendent artery (LAD) occlusion followed by 6 h of reperfusion. In one group, ZD7288 was given intravenously (0.7 mg/kg body weight) 45 min before LAD occlusion. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening fraction (sWTF) in the anteroapical (interest region, IR) and the posterobasal wall (control region, CR). Ischemic regional myocardial blood flow (RMBF) was determined by colored microspheres and infarct size (IS) by triphenyltetrazolium staining. ZD7288 injection decreased HR from 104 +/- 5 to 74 +/- 3 bpm (mean +/- SEM, p < 0.001 vs control, vs baseline), but did not change sWTF. During reperfusion, sWTF of the IR was significantly greater in the ZD7288 group (26 +/- 12 vs -14 +/- 13%, 1 h reperfusion, p < 0.05), while sWTF of CR stayed equal (120 +/- 13 vs 111 +/- 16%, p = ns). IS was markedly reduced in the ZD7288 group (4.7 +/- 1.8 vs 18.0 +/- 5.2% of IR, p < 0.05). There was no difference in ischemic endocardial RMBF (ZD7288 11.0 +/- 4.3 vs control 12.3 +/- 6.5 ml/min/100 g, p = ns). ZD7288 reduces HR without having direct effects on regional myocardial function. This HR reduction leads to a smaller IS and to a better regional functional recovery.


A proposed mechanism for mind-brain interaction using extended Bohmian quantum mechanics in Avicenna's monotheistic perspective.
In quantum approaches to consciousness, the authors try to propose a model and mechanism for the mind-brain interaction using modern physics and some quantum concepts which do not exist in the classical physics. The independent effect of mind on the brain has been one of the challenging issues in the history of science and philosophy. In some recent mind-brain interaction models, the direct influence of mind on matter is either not accepted (as in Stapp's model) or not clear, and there have not been any clear mechanism for it (as in Penrose-Hameroff's model or in Eccles's model). In this manuscript we propose a model and mechanism for mind's effect on the matter using an extended Bohmian quantum mechanics and Avicenna's ideas. We show that mind and mental states can affect brain's activity without any violation of physical laws. This is a mathematical and descriptive model which shows the possibility of providing a causal model for mind's effect on matter. It is shown that this model guarantees the realistic philosophical constraints and respects the laws of nature. In addition, it is shown that it is in agreement with the Libet style experimental results and parapsychological data. To propose this model, we obtained a modified (non-unitary) Schrödinger equation via second quantization method which affects the particle through a modified quantum potential and a new term in the continuity equation. At the second quantized level, which is equivalent to quantum field theory level (QFT), we can use the path integral formalism of Feynman. We show that there are three methods to extend Bohmian QM via path integral formalism, which has different interpretations. By numerical simulation of trajectories in the two-slits experiment, we show their differences and choose one of these methods for our mind-brain model which can be the basis for explaining some phenomena which are not possible to explain in the standard Bohmian QM.


The duration of breastfeeding by HIV-1-infected mothers in developing countries: balancing benefits and risks.
How best to advise mothers infected with human immunodeficiency virus type 1 (HIV-1) in developing countries regarding breastfeeding is an important issue that has generated considerable debate. Previous studies have addressed this problem by means of mathematical models, but without considering the issue of the duration of breastfeeding. A mathematical model was developed to compare the age-specific risks of mother-to-child HIV transmission versus the excess mortality due to not breastfeeding. In this model it is assumed that both the risk of mother-to-child transmission of HIV through breast milk and the relative risk of not breastfeeding do not vary with age. The model indicates that, in HIV-1-seropositive mothers, the decrease in child mortality afforded by breastfeeding may exceed the risk of mother-to-child HIV-1 transmission only during the first 3-7 months of life. Thereafter the risk of HIV-1 transmission probably exceeds the mortality benefit of breastfeeding. Experimental studies of counselling HIV-1-infected mothers to limit their duration of breastfeeding should be considered in the setting of developing countries.


Emerging predictable features of replicated biological invasion fronts.
Biological dispersal shapes species' distribution and affects their coexistence. The spread of organisms governs the dynamics of invasive species, the spread of pathogens, and the shifts in species ranges due to climate or environmental change. Despite its relevance for fundamental ecological processes, however, replicated experimentation on biological dispersal is lacking, and current assessments point at inherent limitations to predictability, even in the simplest ecological settings. In contrast, we show, by replicated experimentation on the spread of the ciliate Tetrahymena sp. in linear landscapes, that information on local unconstrained movement and reproduction allows us to predict reliably the existence and speed of traveling waves of invasion at the macroscopic scale. Furthermore, a theoretical approach introducing demographic stochasticity in the Fisher-Kolmogorov framework of reaction-diffusion processes captures the observed fluctuations in range expansions. Therefore, predictability of the key features of biological dispersal overcomes the inherent biological stochasticity. Our results establish a causal link from the short-term individual level to the long-term, broad-scale population patterns and may be generalized, possibly providing a general predictive framework for biological invasions in natural environments.


Generation of extended plasma channels in air using femtosecond Bessel beams.
Extending the longitudinal range of plasma channels created by ultrashort laser pulses in atmosphere is important in practical applications of laser-induced plasma such as remote spectroscopy and lightning control. Weakly focused femtosecond Gaussian beams that are commonly used for generating plasma channels offer only a limited control of filamentation. Increasing the pulse energy in this case typically results in creation of multiple filaments and does not appreciably extend the longitudinal range of filamentation. Bessel beams with their extended linear foci intuitively appear to be better suited for generation of long plasma channels. We report experimental results on creating extended filaments in air using femtosecond Bessel beams. By probing the linear plasma density along the filament, we show that apertured Bessel beams produce stable single plasma channels that span the entire extent of the linear focus of the beam. We further show that by temporally chirping the pulse, the plasma channel can be longitudinally shifted beyond the linear-focus zone, an important effect that may potentially offer additional means of controlling filament formation.


Evaluation of an educational program on deciphering heterogeneity for medical coverage decisions.
It is increasingly important for decision makers, such as medical and pharmacy managers (or pharmacy therapeutics committee members and staff), to understand the variation and diversity in treatment response as decisions shift from an individual patient perspective to optimizing care for populations of patients. To assess the effectiveness of an instructional program on heterogeneity designed for medical and pharmacy managers. A live educational program was offered to members of the Academy of Managed Care Pharmacy at the fall 2012 educational meeting and also to medical directors and managers attending a national payer roundtable meeting in October 2012. Participants completed a retrospective pretest-posttest assessment of their knowledge, attitudes, and self-efficacy immediately following the program. Participants were offered the opportunity to participate in a follow-up assessment 6 months later. Willing participants for the follow-up assessment were contacted via e-mail and telephone. Rasch rating scale models were used to compare pre- and postscores measuring participants' knowledge about and attitude towards heterogeneity. A total of 49 individuals completed the retrospective pretest-posttest assessment and agreed to be a part of the program evaluation. Fifty percent (n = 25) of participants had heard of the phrase "heterogeneity of treatment effect," and 36 (72%) were familiar with the phrase "individualized treatment effect" prior to the live program. Participants reported a significant improvement in knowledge of heterogeneity (P less than 0.01) and attitudes about heterogeneity (P less than 0.01) immediately after attending the program. At the time of the educational program, participants had either never considered heterogeneity (26%) or reported not knowing (28%) whether their organizations considered it when determining basic coverage. Participants were more likely to report "sometimes" considering heterogeneity for determining necessity for individual appeals, prior authorization, tier placement for pharmaceutical therapies, and other types of medical management. At the 6-month follow-up, 21 of the 49 willing participants (43% response rate) completed the evaluation; participants continued to have a good understanding of heterogeneity, but there was no significant difference in attitudes towards heterogeneity between pre- and 6-month follow-up. A live educational program was effective in improving participants' immediate knowledge and attitudes regarding the topic of heterogeneity. Participating managed care pharmacists and medical managers indicated that heterogeneity of treatment effect was likely to be used in determining prior authorizations and determining necessity.


Dynein Binding of Competitive Regulators Dynactin and NudE Involves Novel Interplay between Phosphorylation Site and Disordered Spliced Linkers.
Dynactin and NudE/Nudel are prominent regulators of cytoplasmic dynein motility and cargo-binding activities. Both interact with the intrinsically disordered N-terminal domain of dynein intermediate chain (IC), which also contains phosphorylation sites that apparently regulate these interactions. Nuclear magnetic resonance and isothermal calorimetry studies demonstrate that the Ser84 phosphorylation site identified in cells is in a disordered linker distant from the N-terminal helix that contains both the dynactin- and the Nudel-binding interfaces. Structural studies of a phosphomimetic Ser84Asp imply that phosphorylation stabilizes an electrostatic cluster that docks the disordered linker containing Ser84 against the N-terminal helix, resulting in a conformation that blocks access of IC to dynactin, but not to NudE/Nudel. Formation of this cluster is dependent on the length and sequence of the disordered linkers. This model explains the selective binding of mammalian IC to dynactin versus NudE/Nudel and why this selection is specific for IC-2C and not the IC-1A isoform.


The effect of deprivation and HbA1c on admission to hospital for diabetic ketoacidosis in type 1 diabetes.
Diabetic ketoacidosis is a potentially life-threatening complication of diabetes and has a strong relationship with HbA(1c). We examined how socioeconomic group affects the likelihood of admission to hospital for diabetic ketoacidosis. The Scottish Care Information - Diabetes Collaboration (SCI-DC), a dynamic national register of all cases of diagnosed diabetes in Scotland, was linked to national data on hospital admissions. We identified 24,750 people with type 1 diabetes between January 2005 and December 2007. We assessed the relationship between HbA(1c) and quintiles of deprivation with hospital admissions for diabetic ketoacidosis in people with type 1 diabetes adjusting for patient characteristics. We identified 23,479 people with type 1 diabetes who had complete recording of covariates. Deprivation had a substantial effect on odds of admission to hospital for diabetic ketoacidosis (OR 4.51, 95% CI 3.73, 5.46 in the most deprived quintile compared with the least deprived). This effect persisted after the inclusion of HbA(1c) and other risk factors (OR 2.81, 95% CI 2.32, 3.39). Men had a reduced risk of admission to hospital for diabetic ketoacidosis (OR 0.71, 95% CI 0.63, 0.79) and those with a history of smoking had increased odds of admission to hospital for diabetic ketoacidosis by a factor of 1.55 (95% CI 1.36, 1.78). Women, smokers, those with high HbA(1c) and those living in more deprived areas have an increased risk of admission to hospital for diabetic ketoacidosis. The effect of deprivation was present even after inclusion of other risk factors. This work highlights that those in poorer areas of the community with high HbA(1c) represent a group who might be usefully supported to try to reduce hospital admissions.


Hypofractionated Radiotherapy for Localized Prostate Cancer: When and for Whom?
To summarize recent evidence concerning the use of moderately hypofractionated external beam radiotherapy, defined as 2.4-3.4 Gy per fraction, and ultrahypofractionated external beam radiotherapy (also known as stereotactic body radiotherapy [SBRT]), defined as at least 5 Gy per fraction, in men with localized prostate cancer. Taken together, a number of recently completed randomized trials show that moderately hypofractionated radiotherapy confers similar biochemical control compared to conventionally fractionated radiotherapy without increasing late toxicity. These effects appear to extend across all baseline clinical risk groups. Several single-arm phase II studies, as well as a recently published large-scale randomized trial comparing SBRT with conventional fractionation, show very promising biochemical control and favorable acute and late treatment-related morbidity with the use of SBRT in predominantly low- and intermediate-risk prostate cancer. As it is associated with similar prostate cancer control and toxicity while improving patient convenience and reducing cost, moderate hypofractionation is a preferred alternative to conventional fractionation in a majority of men with localized prostate cancer choosing radiotherapy as their primary treatment modality. To date, studies conducted largely in low- and intermediate-risk prostate cancer report encouraging oncologic outcomes and acceptable toxicity with SBRT. Mature results of phase III trials evaluating five-fraction SBRT regimens are eagerly awaited.


Order through destruction: how ER-associated protein degradation contributes to organelle homeostasis.
The endoplasmic reticulum (ER) is a large, dynamic, and multifunctional organelle. ER protein homeostasis is essential for the coordination of its diverse functions and depends on ER-associated protein degradation (ERAD). The latter process selects target proteins in the lumen and membrane of the ER, promotes their ubiquitination, and facilitates their delivery into the cytosol for degradation by the proteasome. Originally characterized for a role in the degradation of misfolded proteins and rate-limiting enzymes of sterol biosynthesis, the many branches of ERAD now appear to control the levels of a wider range of substrates and influence more broadly the organization and functions of the ER, as well as its interactions with adjacent organelles. Here, we discuss recent mechanistic advances in our understanding of ERAD and of its consequences for the regulation of ER functions.


Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles.
1-Methyl-3-phenyl-3-pyrrolines are structural analogues of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and like MPTP are selective substrates of monoamine oxidase B (MAO-B). As part of an ongoing investigation into the substrate properties of various 1-methyl-3-phenyl-3-pyrrolinyl derivatives, it is shown in the present study that their respective MAO-B catalyzed oxidation products act as reversible competitive inhibitors of the enzyme. The most potent inhibitor among the oxidation products considered was 1-methyl-3-(4-trifluoromethylphenyl)pyrrole with an enzyme-inhibitor dissociation constant (K(i) value) of 1.30 microM. The least potent inhibitor was found to be 1-methyl-3-phenylpyrrole with a K(i) value of 118 microM. The results of an SAR study established that the potency of MAO-B inhibition by the 1-methyl-3-phenylpyrrolyl derivatives examined here is dependent on the Taft steric parameter (E(s)) and Swain-Lupton electronic constant (F) of the substituents attached to C-4 of the phenyl ring. Electron-withdrawing substituents with a large degree of steric bulkiness appear to enhance inhibition potency. Potency was also found to vary with the substituents at C-3, again with E(s) and F being the principal substituent descriptors.


Understanding extranuclear (nongenomic) androgen signaling: what a frog oocyte can tell us about human biology.
Steroids are key factors in a myriad of mammalian biological systems, including the brain, kidney, heart, bones, and gonads. While alternative potential steroid receptors have been described, the majority of biologically relevant steroid responses appear to be mediated by classical steroid receptors that are located in all parts of the cell, from the plasma membrane to the nucleus. Interestingly, these classical steroid receptors modulate different signals depending upon their location. For example, receptors in the plasma membrane interact with membrane signaling molecules, including G proteins and kinases. In contrast, receptors in the nucleus interact with nuclear signaling molecules, including transcriptional co-regulators. These extranuclear and intranuclear signals function together in an integrated fashion to regulate important biological functions. While most studies on extranuclear steroid signaling have focused on estrogens, recent work has demonstrated that nongenomic androgen signaling is equally important and that these two steroids modulate similar signaling pathways. In fact, by taking advantage of a simple model system whereby a physiologically relevant androgen-mediated process is regulated completely independent of transcription (Xenopus laevis oocyte maturation), many novel and conserved concepts in nongenomic steroid signaling have been uncovered and characterized.


Resonator with reduced sample heating and increased homogeneity for solid-state NMR.
In the application of solid-state NMR to many systems, the presence of radiofrequency (rf) electric fields inside classical solenoidal coils causes heating of lossy samples. In particular, this is critical for proteins in ionic buffers. Rf sample heating increases proportional to frequency which may result in the need to reduce the rf pulse power to prevent partial or total sample deterioration. In the present paper, we propose a multifrequency-tunable NMR resonator where the sample is electrically shielded from the NMR coil by a conductive sheet that increases the magneto-electric ratio. Expressions for the B1 efficiency as function of magnetic and electric filling factors are derived that allow a direct comparison of different resonators. Rf efficiency, homogeneity, signal-to-noise, and rf sample heating are compared. NMR spectra at 700MHz on ethylene glycol, glycine, and a model protein were acquired to compare the resonators under realistic experimental conditions.


Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock.
Nonselective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with fewer adverse effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury. Mouse hippocampal cells were subjected to oxygen-glucose deprivation (0% O2, glucose-free and serum-free medium, 18 hours) and reoxygenation (21% O2, normal culture media, 4 hours) with/without VPA (4 mmol/L) or ACY-1083 (30 nmol/L, 300 nmol/L). Cell viability was measured by methylthiazolyl tetrazolium assay. Expression of hypoxia-inducible factor-1α, heat shock protein 70, and effectors in the phosphoinositide-3 kinase/mammalian target of rapamycin pathway were measured by Western blot analysis. Additionally, swine were subjected to combined traumatic brain injury and hemorrhagic shock and randomized to three treatment groups (n = 5/group): (i) normal saline (NS; 3× hemorrhage volume); (ii) NS + VPA (NS; 3× hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3× hemorrhage volume, ACY-1083; 30 mg/kg). After 6 hours, brain tissue was harvested to assess lesion size and brain swelling. Significant improvement in cell viability was seen with both HDAC inhibitors in the in vitro study. ACY-1083 suppressed hypoxia-inducible factor-1α expression and up-regulated phosphorylated mammalian target of rapamycin and heat shock protein 70 in a dose-dependent manner. Lesion size and brain swelling in animals treated with pharmacologic agents (VPA and ACY-1083) were both smaller than in the NS group. No differences were observed between the VPA and ACY-1083 treatment groups. In conclusion, selective inhibition of HDAC6 is as neuroprotective as nonselective HDAC inhibition in large animal models of traumatic brain injury and hemorrhagic shock.


An evaluation of the EGS4 and CYLTRAN Monte Carlo codes with regard to boundary beta-ray dosimetry by comparison with experimental beta-ray dose backscatter factors.
Beta-ray dose backscatter factors or dose ratios at planar soft-tissue boundaries were calculated using the EGS4/RESTA and CYLTRAN (version 2.1) Monte Carlo codes and these data were compared with experimental results. Since the beta-ray source was 32P, this work addressed the transport of, and energy deposition by, electrons less energetic than 2 MeV. In particular, the simulations targeted the codes' performances with regard to the transport of low energy electrons across material boundaries and the backscattering of low energy electrons. In general, backscatter factors calculated at 7.25 mg/cm2 from several soft-tissue interfaces agreed with experimental values to within about five percent. CYLTRAN was also used to calculate the variation of backscatter factor with distance from aluminum/soft-tissue and air/soft-tissue interfaces and was found to reproduce the shapes of experimental backscatter factor depth profiles.


Progesterone receptor variant increases ovarian cancer risk in BRCA1 and BRCA2 mutation carriers who were never exposed to oral contraceptives.
Oral contraceptives have been shown to be protective against hereditary ovarian cancer. The variant progesterone receptor allele named PROGINS is characterized by an Alu insertion into intron G and two additional mutations in exons 4 and 5. The PROGINS allele codes for a progesterone receptor with increased stability and increased hormone-induced transcriptional activity. We studied the role of the PROGINS allele as a modifying gene in hereditary breast and ovarian cancer. The study included 195 BRCA1 and BRCA2 carriers with a prior diagnosis of ovarian cancer, 392 carriers with a diagnosis of breast cancer and 249 carriers with neither cancer. Fifty-eight women had both forms of cancer. Five hundred and ninety-five women had a BRCA1 mutation and 183 women had a BRCA2 mutation. Overall, there was no association between disease status and the presence of the PROGINS allele. Information on oral contraception use was available for 663 of the 778 carriers of BRCA1 or BRCA2 mutations. Among the 449 subjects with a history of oral contraceptive use (74 cases and 365 controls), no modifying effect of PROGINS was observed [odds ratio (OR) 0.8; 95% confidence interval (CI) 0.5-1.3]. Among the 214 carriers with no past exposure to oral contraceptives, the presence of one or more PROGINS alleles was associated with an OR of 2.4 for ovarian cancer, compared to women without ovarian cancer and with no PROGINS allele (P = 0.004; 95% CI 1.4-4.3). The association was present after adjustment for ethnic group and for year of birth.


Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome.
Platelet integrity and function critically depend on lipid composition. However, the lipid inventory in platelets was hitherto not quantified. Here, we examined the lipidome of murine platelets using lipid-category tailored protocols on a quantitative lipidomics platform. We could show that the platelet lipidome comprises almost 400 lipid species and covers a concentration range of 7 orders of magnitude. A systematic comparison of the lipidomics network in resting and activated murine platelets, validated in human platelets, revealed that <20% of the platelet lipidome is changed upon activation, involving mainly lipids containing arachidonic acid. Sphingomyelin phosphodiesterase-1 (Smpd1) deficiency resulted in a very specific modulation of the platelet lipidome with an order of magnitude upregulation of lysosphingomyelin (SPC), and subsequent modification of platelet activation and thrombus formation. In conclusion, this first comprehensive quantitative lipidomic analysis of platelets sheds light on novel mechanisms important for platelet function, and has therefore the potential to open novel diagnostic and therapeutic opportunities.


Enhancing Diversity in Undergraduate Science: Self-Efficacy Drives Performance Gains with Active Learning.
Efforts to retain underrepresented minority (URM) students in science, technology, engineering, and mathematics (STEM) have shown only limited success in higher education, due in part to a persistent achievement gap between students from historically underrepresented and well-represented backgrounds. To test the hypothesis that active learning disproportionately benefits URM students, we quantified the effects of traditional versus active learning on student academic performance, science self-efficacy, and sense of social belonging in a large (more than 250 students) introductory STEM course. A transition to active learning closed the gap in learning gains between non-URM and URM students and led to an increase in science self-efficacy for all students. Sense of social belonging also increased significantly with active learning, but only for non-URM students. Through structural equation modeling, we demonstrate that, for URM students, the increase in self-efficacy mediated the positive effect of active-learning pedagogy on two metrics of student performance. Our results add to a growing body of research that supports varied and inclusive teaching as one pathway to a diversified STEM workforce.


Proton computed tomography using a 1D silicon diode array.
Proton radiography (PR) and proton computed tomography (PCT) can be used to measure proton stopping power directly. However, practical and cost effective proton imaging detectors are not widely available. In this study, the authors investigated the feasibility of proton imaging using a silicon diode array. A one-dimensional silicon diode detector array (1DSDA) was aligned with the central axis (CAX) of the proton beam. Polymethyl methacrylate (PMMA) slabs were used to find the correspondence between the water equivalent thickness (WET) and 1DSDA channel number. Two-dimensional proton radiographs were obtained by translation and rotation of a phantom relative to CAX while the proton nozzle and 1DSDA were kept stationary. A PCT image of one slice of the phantom was reconstructed using filtered backprojection. PR and PCT images of the PMMA cube were successfully acquired using the 1DSDA. The WET of the phantom was measured using PR data. The resolution and maximum error in WET measurement are 2.0 and 1.5 mm, respectively. Structures down to 2.0 mm in size could be resolved completely. Reconstruction of a PCT image showed very good agreement with simulation. Limitations in spatial resolution are attributed to limited spatial sampling, beam collimation, and proton scatter. The results demonstrate the feasibility of using silicon diode arrays for proton imaging. Such a device can potentially offer fast image acquisition and high spatial and energy resolution for PR and PCT.


Characterizing mental healthcare service teams.
Describing profiles for professional psychiatric service categories in Ribeirão Preto. This was an exploratory study of 8 services (3 hospitals and 5 extra-hospital facilities). Data was collected using questionnaires and semi-structured interviews with professionals who worked for all these services. 74 % of the professionals working for the eight services investigated took part in the study. Doctors and nurses predominated in the hospitals and multidisciplinary teams in extra-hospital facilities. Ages ranged from 24 to 68, females predominating (73 %). 127 (88 %) of the 144 subjects in this study had received specific education after graduating in their respective areas but only 48.5 % had studied mental health. Doctors (42/44) and nurses (36/42) predominated in the teams; 121 (83 %) earned over R$ 1,000 per month as their salary. The teams mainly consisted of doctors and nurses, although it was considered that other professionals were important in constituting such teams. One of the main problems hampering reform in the psychiatric field is how services are provided for the population. No country has been able to make the necessary reforms for overcoming all the barriers. The service network studied met the minimum prerequisites for providing psychiatric care for the community.


Effect of an iPod video intervention on consent to donate organs: a randomized trial.
The gap between the supply of organs available for transplantation and demand is growing, especially among ethnic groups. To evaluate the effect of a video designed to address concerns of ethnic groups about organ donation. Cluster randomized, controlled trial. Randomization was performed by using a random-number table with centralized allocation concealment. Participants and investigators assessing outcomes were not blinded to group assignment. (ClinicalTrials.gov registration number: NCT00870506) Twelve branches of the Ohio Bureau of Motor Vehicles in northeastern Ohio. 952 participants aged 15 to 66 years. Video (intervention; n = 443) or usual Bureau of Motor Vehicles license practices (control; n = 509). The primary outcome was the proportion of participants who provided consent for organ donation on a newly acquired driver's license, learner's permit, or state identification card. Secondary outcomes included willingness to make a living kidney donation to a family member in need and personal beliefs about donation. More participants who viewed the video consented to donate organs than control participants (84% vs. 72%; difference, 12 percentage points [95% CI, 6 to 17 percentage points]). The video was effective among black participants (76% vs. 54%; difference, 22 percentage points [CI, 9 to 35 percentage points]) and white participants (88% vs. 77%; difference, 11 percentage points [CI, 5 to 15 percentage points]). At the end of the trial, fewer intervention than control participants reported having insufficient information about organ donation (34% vs. 44%; difference, -10 percentage points [CI, -16 to -4 percentage points]), wanting to be buried with all of their organs (14% vs. 25%; difference, -11 percentage points [CI, -16 to -6 percentage points]), and having conflicts with organ donation (7% vs. 11%; difference, -4 percentage points [CI, -8 to -2 percentage points]). How the observed increases in consent to donate organs might translate into a greater organ supply in the region is unclear. Exposure to a brief video addressing concerns that ethnic groups have about organ donation just before obtaining a license, permit, or identification card increased consent to donate organs among white and black participants. National Institutes of Health and the Robert Wood Johnson Foundation.


Different perceptions of disease severity and self care between patients with cystic fibrosis, their close companions, and physician.
An investigation was carried out to determine whether patients with cystic fibrosis, their close companions, and physician perceived the severity of the disease and the level of patient self care similarly. Sixty adults with cystic fibrosis (16-44 years), their close companion, and physician independently completed scales measuring their perceptions of disease severity and patient self care on three occasions over a two year period. Percentage predicted forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), Shwachman score, and weight for height were recorded following each assessment. Patients and close companions considered the disease to be less severe than their physician. Fifty patients (83%) rated their health as "above/well above average", and 49 (82%) close companions rated the patient's health in the same way, but only 21 (35%) patients were considered by their physician to have mild disease. Differences also emerged in the estimation of patient self care; 48 close companions (80%) rated patients as "very good" or "excellent" in their self care, compared with 26 (44%) of the patients themselves. Only nine patients (15%) were considered to achieve this level of self care by their physician. Over the two year period the physician's ratings of severity increased in accordance with the decline in lung function. Patients' perceptions remained unchanged. From the physician's view-point, patients and close companions underestimate the severity of cystic fibrosis and overestimate patient self care. Patients' perceptions remain constant over time even when their health is clinically deteriorating.


Differential localization of vacuolar H+-ATPases containing a1, a2, a3, or a4 (ATP6V0A1-4) subunit isoforms along the nephron.
Vacuolar H(+)-ATPase are multi-subunit containing pumps important for several processes along the nephron such as receptor mediated endocytosis, acidification of intracellular organelles, bicarbonate reabsorption and secretion, and H(+)- extrusion. Mutations in the human a4 (ATP6V0A4) subunit cause distal renal tubular acidosis (dRTA). There are 4 known isoforms of the 'a' subunit (a1-a4). Here we investigated the expression and localization of all four isoforms in mouse kidney. Real-time PCR detected mRNAs encoding all four 'a' isoforms in mouse kidney with a relative abundance in the following order: a4>a2=a1>a3. Immunolocalization demonstrated expression of all 'a' subunits in the proximal tubule and in the intercalated cells of the collecting system. In intercalated cells a1 and a4 isoforms appeared on both the apical and basolateral side and were expressed in all subtypes of intercalated cells. In contrast, a2, and a3 were only found in the apical membrane. a1 and a4 were colocalized in the same cells with AE1 or pendrin, whereas a2 was only found in AE1 positive cells but absent from pendrin expressing intercalated cells. These results suggest that vacuolar H(+)-ATPases containing different 'a' isoforms may serve specific and distinct functions and may help explaining why loss of the a4 isoform causes only dRTA without an apparent defect in the proximal tubule.


The relationship between socioeconomic status, ethnicity, and cigarette smoking in urban adolescents.
This study examined the relationship between community-level and school-level socioeconomic status indicators and current cigarette smoking among urban adolescents, and examined whether the socioeconomic status-cigarette smoking relationship was similar for African Americans and Whites. Participants were 3,813 seventh-graders recruited in a large school system in the United States. Independent variables included median income and mean education within zip codes of participants' residence, percentage of participants receiving lunch at reduced or no cost at school level, and ethnicity. The dependent variable was current smoking status (never smoked vs smoking one or more cigarettes per month). Whites were significantly more likely than African Americans to smoke cigarettes. There was a main effect of education and lunch at reduced or no cost on cigarette smoking. Mean education by zip code was inversely associated with cigarette smoking, and lunch at reduced or no cost was directly associated with cigarette smoking. There was a significant interaction between income and ethnicity. Median income by zip code was directly associated with cigarette smoking among African Americans. Our findings suggest that smoking prevention efforts in this population should take both socioeconomic status and ethnicity into account.


Controlling resonance energy transfer in nanostructure emitters by positioning near a mirror.
The ability to control light-matter interactions in quantum objects opens up many avenues for new applications. We look at this issue within a fully quantized framework using a fundamental theory to describe mirror-assisted resonance energy transfer (RET) in nanostructures. The process of RET communicates electronic excitation between suitably disposed donor and acceptor particles in close proximity, activated by the initial excitation of the donor. Here, we demonstrate that the energy transfer rate can be significantly controlled by careful positioning of the RET emitters near a mirror. The results deliver equations that elicit new insights into the associated modification of virtual photon behavior, based on the quantum nature of light. In particular, our results indicate that energy transfer efficiency in nanostructures can be explicitly expedited or suppressed by a suitably positioned neighboring mirror, depending on the relative spacing and the dimensionality of the nanostructure. Interestingly, the resonance energy transfer between emitters is observed to "switch off" abruptly under suitable conditions of the RET system. This allows one to quantitatively control RET systems in a new way.


Companions through cancer: the care given by informal carers in cancer contexts.
This paper explores the care-giving experiences of informal carers in cancer contexts, drawing on both quantitative and qualitative data generated in a 3 year study in the UK on the psychosocial needs of cancer patients and their main carers. The study adopted a sociological approach to psychosocial needs, in contrast to dominant psychological and psychiatric perspectives on such needs in psycho-oncology. Data collection methods involved a descriptive cross-sectional survey of carers (an achieved sample of 262 respondents, with similar numbers of male and female carers) followed by in-depth guided interviews with a sub-sample of surveyed carers (n = 32). Key findings are presented in three sections: (i) the characteristics of the survey and interview samples; (ii) the examination of the care work undertaken by informal carers; and (iii), the exploration of the emotion work undertaken by informal carers. CARE WORK FINDINGS: additional care work demands were an important feature of informal carers' experiences, although this varied with the stage of the patient's disease and with the presence of either co-morbidity in patients or morbidity in carers. Specific groups of carers expressed the need for help with particular practical tasks and with the personal effects of the burden of care work. EMOTION WORK FINDINGS: carers of either gender worked hard to manage the emotions of the patient as well as their own feeling states, and these aspects of emotion work were intimately connected. Carers felt that they had to be, and often wanted to be, strong' and 'positive', and to try to maximise the sense of 'life carrying on as normal'. In doing this emotion work, carers, especially spousal carers, often symbolically shared in the illness and presented the struggle with cancer as a joint one. A concluding section considers the significance of our findings for cancer service provision.


Efficiency of Human Epiphyseal Chondrocytes with Differential Replication Numbers for Cellular Therapy Products.
The cell-based therapy for cartilage or bone requires a large number of cells; serial passages of chondrocytes are, therefore, needed. However, fates of expanded chondrocytes from extra fingers remain unclarified. The chondrocytes from human epiphyses morphologically changed from small polygonal cells to bipolar elongated spindle cells and to large polygonal cells with degeneration at early passages. Gene of type II collagen was expressed in the cells only at a primary culture (Passage 0) and Passage 1 (P1) cells. The nodules by implantation of P0 to P8 cells were composed of cartilage and perichondrium. The cartilage consisted of chondrocytes with round nuclei and type II collagen-positive matrix, and the perichondrium consisted of spindle cells with type I collage-positive matrix. The cartilage and perichondrium developed to bone with marrow cavity through enchondral ossification. Chondrogenesis and osteogenesis by epiphyseal chondrocytes depended on replication number in culture. It is noteworthy to take population doubling level in correlation with pharmaceutical efficacy into consideration when we use chondrocytes for cell-based therapies.


Resequencing of the common marmoset genome improves genome assemblies and gene-coding sequence analysis.
The first draft of the common marmoset (Callithrix jacchus) genome was published by the Marmoset Genome Sequencing and Analysis Consortium. The draft was based on whole-genome shotgun sequencing, and the current assembly version is Callithrix_jacches-3.2.1, but there still exist 187,214 undetermined gap regions and supercontigs and relatively short contigs that are unmapped to chromosomes in the draft genome. We performed resequencing and assembly of the genome of common marmoset by deep sequencing with high-throughput sequencing technology. Several different sequence runs using Illumina sequencing platforms were executed, and 181 Gbp of high-quality bases including mate-pairs with long insert lengths of 3, 8, 20, and 40 Kbp were obtained, that is, approximately 60× coverage. The resequencing significantly improved the MGSAC draft genome sequence. The N50 of the contigs, which is a statistical measure used to evaluate assembly quality, doubled. As a result, 51% of the contigs (total length: 299 Mbp) that were unmapped to chromosomes in the MGSAC draft were merged with chromosomal contigs, and the improved genome sequence helped to detect 5,288 new genes that are homologous to human cDNAs and the gaps in 5,187 transcripts of the Ensembl gene annotations were completely filled.


Mode-locking of a terahertz laser by direct phase synchronization.
A novel scheme to achieve mode-locking of a multimode laser is demonstrated. Traditional methods to produce ultrashort laser pulses are based on modulating the cavity gain or losses at the cavity roundtrip frequency, favoring the pulsed emission. Here, we rather directly act on the phases of the modes, resulting in constructive interference for the appropriated phase relationship. This was performed on a terahertz quantum cascade laser by multimode injection seeding with an external terahertz pulse, resulting in phase mode-locked terahertz laser pulses of 9 ps duration, characterized unambiguously in the time domain.


European Society for Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for the Evaluation and Treatment of Gastrointestinal and Nutritional Complications in Children With Neurological Impairment.
Feeding difficulties are frequent in children with neurological impairments and can be associated with undernutrition, growth failure, micronutrients deficiencies, osteopenia, and nutritional comorbidities. Gastrointestinal problems including gastroesophageal reflux disease, constipation, and dysphagia are also frequent in this population and affect quality of life and nutritional status. There is currently a lack of a systematic approach to the care of these patients. With this report, European Society of Gastroenterology, Hepatology and Nutrition aims to develop uniform guidelines for the management of the gastroenterological and nutritional problems in children with neurological impairment. Thirty-one clinical questions addressing the diagnosis, treatment, and prognosis of common gastrointestinal and nutritional problems in neurological impaired children were formulated. Questions aimed to assess the nutritional management including nutritional status, identifying undernutrition, monitoring nutritional status, and defining nutritional requirements; to classify gastrointestinal issues including oropharyngeal dysfunctions, motor and sensory function, gastroesophageal reflux disease, and constipation; to evaluate the indications for nutritional rehabilitation including enteral feeding and percutaneous gastrostomy/jejunostomy; to define indications for surgical interventions (eg, Nissen Fundoplication, esophagogastric disconnection); and finally to consider ethical issues related to digestive and nutritional problems in the severely neurologically impaired children. A systematic literature search was performed from 1980 to October 2015 using MEDLINE. The approach of the Grading of Recommendations Assessment, Development, and Evaluation was applied to evaluate the outcomes. During 2 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation using the nominal voting technique. Expert opinion was applied to support the recommendations where no randomized controlled trials were available.


Long-term effects of oral contraceptives on ovarian cancer risk.
Several epidemiologic studies have reported a protective effect of oral contraceptives (OCs) on ovarian cancer. However, there remain open issues, including better quantification of time-related factors such as time since last use, age at first use and time since first use. We performed a collaborative reanalysis of 6 case-control studies conducted between 1978 and 1999 in the United Kingdom, Greece and Italy, including a total of 2,768 incident, histologically confirmed cases of epithelial ovarian cancer and 6,274 hospital controls under age 70 years. A reduced risk of ovarian cancer was found for ever- compared to never-users [odds ratio (OR) = 0.66, 95% confidence interval (CI) 0.56-0.79], and a stronger reduction was observed for women who had used OCs for > or =5 years (OR = 0.50, 95% CI 0.33-0.76) compared to those who had used them for <5 years. The protective effect of OCs on ovarian cancer was consistent across strata of age, parity, menopausal status and family history of breast or ovarian cancer. After allowance for duration of use, no other time factor was related to ovarian cancer risk: the reduced risk was similar for women who stopped OC use > or =20 years before compared to <10 years; likewise, no significant modification of risk reduction was observed for age at first OC use and time since first OC use. The present analysis indicates that, after taking into account duration of OC use, the OC protection from ovarian cancer persists for a long time after stopping use.