MicroRNA-155 promotes glioma cell proliferation via the regulation of MXI1.
Gliomas are the most common and aggressive primary tumors in the central nervous system. Recently, Max interactor-1 (MXI1), an antagonist of c-Myc that is involved in brain tumor progression, has been reported to be deregulated in a variety of tumors including glioma. However, the mechanism of MXI1 deregulation in gliomas remains unclear. In this study, we show that the relative expression level of MXI1 is markedly down-regulated in glioma cell lines. Using integrated bioinformatic analysis and experimental confirmation, we identified several miRNAs by screening a panel of predicted miRNAs that may regulate the MXI1 3'UTR. The strongest inhibitory miRNA, miR-155, can attenuate the activity of a luciferase reporter gene that is fused with the MXI1 3'UTR and decrease the expression levels of MXI1 mRNA and protein in U87 glioma cells. The potential role of miR-155 in promoting glioma cell proliferation by targeting MXI1 was confirmed in various glioma cell lines by rescue experiments using MTT assays, EdU incorporation assay, and cell counting experiments. In addition, we determined that the level of MXI1 mRNA was inversely correlated with the expression of miR-155 in 18 sets of glioblastoma multiforme specimens. These findings reveal for the first time that the targeting of MXI1 by miR-155 may result in a reduction in MXI1 expression and promote glioma cell proliferation; this result suggests a novel function of miR-155 in targeting MXI1 in glioma-genesis.


[Violence against women, family cohesion and drugs].
To evaluate the association between cohesion, adaptability and mental risk in families, physical violence against women and the use of drugs. Data for this paired case-control study was collected in 2004 and 2005 in the city of Joao Pessoa, in Northeastern Brazil. The sample included 260 women, divided into 130 battered individuals and 130 non-battered. The case study group consisted of women who lodged complaints for domestic violence at the Specialist Women's Police Station. The control group was made up of women living in the same neighborhood as those who had made the complaint. Cohesion, adaptability and mental risk were all measured using the "Family Adaptability and Cohesion Evaluation Scales". For the statistical analysis the Chi-square and the Fisher's Exact Tests ere used, at a significance level of 5%. The two groups differed for measures relating to mental risk and cohesion, but had similar results for family adaptability (p=0.0917). The women victims of domestic violence had high (43.1%) and medium (39.2%) mental risk, while the non-victims had only medium risk (55.4%). There was a significant difference in drug use between the two groups, with greater consumption among the families of battered women (90.8%) compared with those of non-battered women (56.9%). The most widely used drug was alcohol, which also represented the highest risk factor for aggression if consumed daily (OR=37.33) or in conjunction with other drugs (OR=29,56). Both the instability caused by a lack of family unity and the use of drugs significantly affect family functioning and may give rise to conflict and domestic violence.


Reproducibility of Frankfort horizontal plane on 3D multi-planar reconstructed MR images.
The purpose of this study was to determine the accuracy and reliability of Frankfort horizontal plane identification using displays of multi-planar reconstructed MRI images, and propose it as a sufficiently stable and standardized reference plane for craniofacial structures. MRI images of 43 subjects were obtained from the longitudinal population based cohort study SHIP-2 using a T1-weighted 3D sequence. Five examiners independently identified the three landmarks that form FH plane. Intra-examiner reproducibility and inter-examiner reliability, correlation coefficients (ICC), coefficient of variability and Bland-Altman plots were obtained for all landmarks coordinates to assess reproducibility. Intra-examiner reproducibility and inter-examiner reliability in terms of location and plane angulation were also assessed. Intra- and inter-examiner reliabilities for X, Y and Z coordinates of all three landmarks were excellent with ICC values ranging from 0.914 to 0.998. Differences among examiners were more in X and Z than in Y dimensions. The Bland-Altman analysis demonstrated excellent intra- as well as inter-examiner agreement between examiners in all coordinates for all landmarks. Intra-examiner reproducibility and inter-examiner reliability of the three landmarks in terms of distance showed mean differences between 1.3 to 2.9 mm, Mean differences in plane angulation were between 1.0° to 1.5° among examiners. This study revealed excellent intra-examiner reproducibility and inter-examiner reliability of Frankfort Horizontal plane through 3D landmark identification in MRI. Sufficiently stable landmark-based reference plane could be used for different treatments and studies.


The Neurological Compromised Spine Due to Ewing Sarcoma. What First: Surgery or Chemotherapy? Therapy, Survival, and Neurological Outcome of 15 Cases With Primary Ewing Sarcoma of the Vertebral Column.
The vertebral column is an infrequent site of primary involvement in Ewing sarcoma. Yet when Ewing sarcoma is found in the spine, the urge for decompression is high because of the often symptomatic compression of neural structures. It is unclear in alleviating a neurological deficit whether chemotherapy is preferred over decompressive laminectomy. To underline, in this case series, the efficiency of initial chemotherapy before upfront surgery in the setting of high-grade spinal cord or cauda equina compression of primary Ewing sarcoma. Fifteen patients with Ewing sarcoma primarily located in the spine were treated at our institution between 1983 and 2015. Localization, neurological deficit expressed as Frankel grade, and outcome expressed as Rankin scale before and after initial chemotherapy, the recurrence rate, and overall survival were evaluated. The multidisciplinary approach of 1 case will be discussed in detail. Nine patients (60%) were female. The age at presentation was 15.0 ± 5.5 years (range: 0.9-22.8 years). Ten patients (67%) were initially treated with chemotherapy, and 1 patient (7%) was treated primarily with radiotherapy followed by chemotherapy. The remaining 4 patients (27%) were initially treated with decompressive surgery. All patients treated primarily nonsurgically improved neurologically at follow-up, showing the importance of chemotherapy as an effective initial treatment option. Adequate and quick decompression of neural structures with similar results can be achieved by chemotherapy and radiotherapy, avoiding the local spill of malignant cells.


Retinal vessel centerline extraction using multiscale matched filters, confidence and edge measures.
Motivated by the goals of improving detection of low-contrast and narrow vessels and eliminating false detections at nonvascular structures, a new technique is presented for extracting vessels in retinal images. The core of the technique is a new likelihood ratio test that combines matched-filter responses, confidence measures and vessel boundary measures. Matched filter responses are derived in scale-space to extract vessels of widely varying widths. A vessel confidence measure is defined as a projection of a vector formed from a normalized pixel neighborhood onto a normalized ideal vessel profile. Vessel boundary measures and associated confidences are computed at potential vessel boundaries. Combined, these responses form a six-dimensional measurement vector at each pixel. A training technique is used to develop a mapping of this vector to a likelihood ratio that measures the "vesselness" at each pixel. Results comparing this vesselness measure to matched filters alone and to measures based on the Hessian of intensities show substantial improvements, both qualitatively and quantitatively. The Hessian can be used in place of the matched filter to obtain similar but less-substantial improvements or to steer the matched filter by preselecting kernel orientations. Finally, the new vesselness likelihood ratio is embedded into a vessel tracing framework, resulting in an efficient and effective vessel centerline extraction algorithm.


Survival and functional independence after implantation of a permanent pacemaker in octogenarians and nonagenarians. A population-based study.
The number of very elderly persons who are candidates for implantation of a permanent pacemaker is increasing, but the effect of cardiac pacing on long-term survival and functional variables has not been determined. To determine long-term survival after implantation of a permanent pacemaker in octogenarians and nonagenarians and to assess functional independence after such implantation. Retrospective, population-based cohort study. Epidemiologic setting from an unselected population. 157 octogenarians and nonagenarians who initially received a pacemaker between 1962 and 1988 and were followed through 1992. Overall mortality rate, functional capabilities, and placement in a nursing home. Observed survival in patients with heart disease was significantly worse than that in age-and sex-matched controls (P < 0.001). Observed survival in community residents without heart disease was similar to that in controls (P > 0.2). Multivariable analysis identified congestive heart failure, chronic obstructive pulmonary disease, old age, syncope, cancer, and atrioventricular block as independent predictors of increased mortality. Symptoms decreased in 118 patients (75%) after pacemaker implantation. After implantation, 70 patients (45%) were permanently placed in nursing homes; this number is similar to the estimated probability of lifetime use of nursing homes from the National Mortality Followback Survey. Dementia developed or worsened in 51 patients (32%), and orthopedic disability occurred in 41 patients (26%). Normal relative survival in octogenarians and nonagenarians without heart disease is reassuring; the poor prognosis in patients with heart disease warrants careful evaluation of the methods and indications for cardiac pacing. Permanent pacing alleviates bradycardia-related symptoms. Placement in a nursing home and development or worsening of cardiac, neurologic, or orthopedic disabilities frequently occur after implantation of a permanent pacemaker in the very elderly.


Acute Effects of Linagliptin on Progenitor Cells, Monocyte Phenotypes, and Soluble Mediators in Type 2 Diabetes.
Circulating cells, including endothelial progenitor cells (EPCs) and monocyte subtypes, are involved in diabetic complications. Modulation of these cells may mediate additional benefits of glucose-lowering medications. We assessed whether the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin acutely modifies EPCs and monocyte subsets in patients with type 2 diabetes. This was a randomized, crossover, placebo-controlled trial. The study was conducted at a tertiary referral diabetes outpatient clinic. Forty-six type 2 diabetes patients with (n = 18) or without (n = 28) chronic kidney disease (CKD) participated in the study. Intervention included a 4-day treatment with linagliptin 5 mg or placebo during two arms separated by a 2-week washout. Before and after each treatment, we determined the levels of circulating progenitor cells (CD34, CD133, KDR) and monocyte subtypes (CD14/CD16, chemokine and scavenger receptors) and the concentrations of soluble mediators. Compared with placebo, linagliptin increased CD34(+)CD133(+) progenitor cells (placebo subtracted effect 40.4 ± 18.7/10(6); P = .036), CD34(+)KDR(+) EPCs (placebo subtracted effect 22.1 ± 10.2/10(6); P = .036), and CX3CR1(bright) monocytes (placebo subtracted effect 1.7 ± 0.8%; P = .032). Linagliptin abated DPP-4 activity by greater than 50%, significantly increased active glucagon-like peptide-1 and stromal cell-derived factor-1α, and reduced monocyte chemotactic protein-1, CCL22, and IL-12. Patients with CKD, as compared with those without, had lower baseline CD133(+) and CD34(+)CD133(+) cells and had borderline reduced CD34(+) and CD34(+)KDR(+) cells. The effects of linagliptin on progenitor cells and monocyte subtypes were similar in patients with or without CKD. Fasting plasma glucose, triglycerides and free fatty acids were unaffected. DPP-4 inhibition with linagliptin acutely increases putative vasculoregenerative and antiinflammatory cells. Direct effects of DPP-4 inhibition may be important to lower vascular risk in diabetes, especially in the presence of CKD.


Biopsy-proven spontaneous regression of a rhabdomyomatous mesenchymal hamartoma.
Rhabdomyomatous mesenchymal hamartoma (RMH) is a rare, benign, congenital tumor of the dermis and subcutaneous tissue comprised of skeletal muscle and adipose and adnexal elements. Although the majority of cases are an incidental finding in otherwise healthy patients, some have been reported in association with other anomalies. We present a full-term boy evaluated on day 2 of life for two lesions located on the midline of the lower back and right buttock that each appeared clinically as an atrophic, pink plaque. Ultrasound of the midline lesion revealed an underlying lipomyelomeningocele with a tethered cord in the spinal canal. Histopathology of the right buttock cutaneous lesion was consistent with a diagnosis of RMH. Surgical excision was performed on the midline intradural lipoma and the lesion on the buttock was monitored clinically. Repeat biopsy of this site at 1 year of age revealed complete spontaneous regression. This case highlights three interesting features: the association with an occult spinal dysraphism lipomyelomeningocele and tethered cord, the clinical presentation of an atrophic plaque as opposed to the more commonly reported raised lesions, and the phenomenon of spontaneous regression of the lesion. Most importantly, this final feature of regression in our patient suggests that, in the absence of symptoms, clinical observation of RMH lesions is warranted for spontaneous regression for 1 to 2 years provided that no functional deficit is noted and that the cutaneous or deeper lesions are not causing a medical problem.


Aesthetic facial surgery of male patients: demographics and market trends.
Evaluation of member survey data from the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS) and the American Society for Aesthetic Plastic Surgery (ASAPS) from 2000 through 2004 reveals several procedure-specific as well as overall trends regarding utilization of aesthetic facial enhancement services. This gender-specific 5-year retrospective review indicates that males undergo significantly fewer procedures than females except for surgical hair restoration and otoplasty. There is a slight general trend toward decreased surgical but increased nonsurgical facial enhancement procedures. On a case per physician basis, AAFPRS physicians performed significantly more procedures for both males and females for every procedure and every year evaluated. Evaluation of age group data indicates that the 40- to 59-year-old age group accounts for the majority of surgical and non surgical facial enhancement requests. Despite anticipated growth of the 60- to 79-year-old age group, the 40- to 59-year-old age group is projected to remain relatively stable. Although continuing to pursue aesthetic facial enhancement services in significant numbers, men still represent a vast untapped market. This study yields important demographic and trend information that has implications for the current and future delivery of aesthetic facial enhancement services.


CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.
Cleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor CBFA1. To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, we studied 26 independent cases of CCD and a total of 16 new mutations were identified in 17 families. The majority of mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations which result in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. We further identified three putative hypomorphic mutations (R391X, T200A and 90insC) which result in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth. Functional studies show that two of the three mutations were hypomorphic in nature and two were associated with significant intrafamilial variable expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data show that variable loss of function due to alterations in the runt and PST domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD and isolated primary dental anomalies.


The serine protease testisin is present on the surface of capacitated stallion spermatozoa and interacts with key zona pellucida binding proteins.
Serine proteases are emerging as important players in the spermatozoon's acquisition of functional competence. This study aimed to characterize the serine protease testisin (PRSS21) in stallion spermatozoa, examining its surface expression, possible origins in the testis and epididymis, and changes in response to capacitation and acrosome reaction, as well as its capacity to form high molecular weight complexes and interact with other proteins. The role of serine proteases in spontaneous capacitation and acrosome reaction of stallion spermatozoa was established using the serine protease inhibitor, AEBSF. Testisin localization, before and after exposure of stallion spermatozoa to capacitating conditions and calcium ionophore, was examined using live cell immunofluorescence and flow cytometry. Immunohistochemistry of testicular and epididymal tissues was used to further dissect the origins of sperm testisin. Testisin's participation in high molecular weight protein complexes and identification of its interacting partner proteins were investigated using Blue Native PAGE, co-immunoprecipitation, and mass spectrometry, with interrogation of protein-protein interaction databases and gene ontology analysis of partner proteins used to further explore the potential roles of the testisin-containing complex in sperm function. Testisin surface expression increased significantly in capacitated spermatozoa (p < 0.001), increased further following acrosome reaction (p < 0.01), and was localized to the equatorial region of the sperm head. Testisin was also detected in luminal fluid within the caput and corpus regions of the epididymis, epididymal spermatozoa, and epididymal epithelial cells. Testisin formed several multiprotein complexes; co-immunoprecipitation revealed interactions of testisin with a multitude of zona pellucida-binding proteins, including ZPBP, ZAN, acrosin, several heat-shock proteins, and components of the TCP1 complex. Testisin appears to form part of the zona pellucida-binding complex in stallion spermatozoa and may be involved in the proteolytic cascade that prepares the sperm surface for interaction with the oocyte.


Assortment and the analysis of natural selection on social traits.
A central problem in evolutionary biology is to determine whether and how social interactions contribute to natural selection. A key method for phenotypic data is social selection analysis, in which fitness effects from social partners contribute to selection only when there is a correlation between the traits of individuals and their social partners (nonrandom phenotypic assortment). However, there are inconsistencies in the use of social selection that center around the measurement of phenotypic assortment. Here, we use data analysis and simulations to resolve these inconsistencies, showing that: (i) not all measures of assortment are suitable for social selection analysis; and (ii) the interpretation of assortment, and how to detect nonrandom assortment, will depend on the scale at which it is measured. We discuss links to kin selection theory and provide a practical guide for the social selection approach.


Access to Obstetric Care and Children's Health, Growth and Cognitive Development in Vietnam: Evidence from Young Lives.
Background The impact of birth with poor access to skilled obstetric care such as home birth on children's long term development is unknown. This study explores the health, growth and cognitive development of children surviving homebirth in the Vietnam Young Lives sample during early childhood. Methods The Young Lives longitudinal cohort study was conducted in Vietnam with 1812 children born in 2001/2 with follow-up at 1, 5, and 8 years. Data were collected on height/weight, health and cognitive development (Peabody Picture Vocabulary test). Statistical models adjusted for sociodemographic and pregnancy-related factors. Results Children surviving homebirth did not have significantly poorer long-term health, greater stunting after adjusting for sociodemographic/pregnancy-related factors. Rural location, lack of household education, ethnic minority status and lower wealth predicted greater stunting and poorer scores on Peabody Vocabulary test. Conclusions Social disadvantage rather than homebirth influenced children's health, growth and development.


Characterization of a membrane-active peptide from the Bordetella pertussis CyaA toxin.
Bordetella pertussis, the pathogenic bacteria responsible for whooping cough, secretes several virulence factors, among which is the adenylate cyclase toxin (CyaA) that plays a crucial role in the early stages of human respiratory tract colonization. CyaA invades target cells by translocating its catalytic domain directly across the plasma membrane and overproduces cAMP, leading to cell death. The molecular process leading to the translocation of the catalytic domain remains largely unknown. We have previously shown that the catalytic domain per se, AC384, encompassing residues 1-384 of CyaA, did not interact with lipid bilayer, whereas a longer polypeptide, AC489, spanning residues 1-489, binds to membranes and permeabilizes vesicles. Moreover, deletion of residues 375-485 within CyaA abrogated the translocation of the catalytic domain into target cells. Here, we further identified within this region a peptidic segment that exhibits membrane interaction properties. A synthetic peptide, P454, corresponding to this sequence (residues 454-485 of CyaA) was characterized by various biophysical approaches. We found that P454 (i) binds to membranes containing anionic lipids, (ii) adopts an α-helical structure oriented in plane with respect to the lipid bilayer, and (iii) permeabilizes vesicles. We propose that the region encompassing the helix 454-485 of CyaA may insert into target cell membrane and induce a local destabilization of the lipid bilayer, thus favoring the translocation of the catalytic domain across the plasma membrane.


Self-Management in Long-Term Prostate Cancer Survivors: A Randomized, Controlled Trial.
This randomized clinical trial compared a personally tailored, automated telephone symptom management intervention to improve self-management among long-term survivors of prostate cancer with usual care enhanced with a nontailored newsletter about symptom management. We hypothesized that intervention-group participants would have more confident symptom self-management and reduced symptom burden. A total of 556 prostate cancer survivors who, more than 1 year after treatment, were experiencing symptom burden were recruited from April 2015 to February 2017 across four Veterans Affairs sites. Participants were randomly assigned to intervention (n = 278) or usual care (n = 278) groups. We compared differences in the primary (symptom burden according to Expanded Prostate Cancer Index Composite-26 [EPIC], confidence in self-management) and secondary outcomes between groups using intent-to-treat analyses. We compared domain-specific changes in symptom burden from baseline to 5 and 12 months among the intervention group according to the primary symptom focus area (urinary, bowel, sexual, general) of participants. Most of the prostate cancer survivors in this study were married (54.3%), were white (69.2%), were retired (62.4%), and underwent radiation therapy (56.7% v 46.2% who underwent surgery), and the mean age was 67 years. There were no baseline differences in urinary, bowel, sexual, or hormonal domain EPIC scores across groups. We observed higher EPIC scores in the intervention arm in all domain areas at 5 months, though differences were not statistically significant. No differences were found in secondary outcomes; however, coping appraisal was higher (2.8 v 2.6; P = .02) in intervention-arm patients at 5 months. In subgroup analyses, intervention participants reported improvement from baseline at 5 and 12 months in their symptom focus area domains. This intervention was well received among veterans who were long-term survivors of prostate cancer. Although overall outcome differences were not observed across groups, the intervention tailored to symptom area of choice may hold promise to improve associated burden.


Trust and Glycemic Control in Black Patients With Diabetic Retinopathy: A Pilot Study.
Diabetic retinopathy (DR) is more prevalent in blacks than whites because, compared to whites, blacks on average have worse glycemic control. Both of these racial disparities reflect differences in sociocultural determinants of health, including physician mistrust. This randomized, controlled 6-month pilot trial compared the efficacy of a culturally tailored behavioral health/ophthalmologic intervention called Collaborative Care for Depression and Diabetic Retinopathy (CC-DDR) to enhanced usual care (EUC) for improving glycemic control in black patients with DR (n = 33). The mean age of participants was 68 years (SD 6.1 years), 76% were women, and the mean A1C was 8.7% (SD 1.5%). At baseline, 14 participants (42%) expressed mistrust about ophthalmologic diagnoses. After 6 months, CC-DDR participants had a clinically meaningful decline in A1C of 0.6% (SD 2.1%), whereas EUC participants had an increase of 0.2% (SD 1.1%) (f[1, 28] = 1.9; P = 0.176). Within CC-DDR, participants with trust had a reduction in A1C (1.4% [SD 2.5%]), whereas participants with mistrust had an increase in A1C (0.44% [SD 0.7%]) (f[1, 11] = 2.11; P = 0.177). EUC participants with trust had a reduction in A1C (0.1% [SD 1.1%]), whereas those with mistrust had an increase in A1C (0.70% [SD 1.1%]) (f[1, 16] = 2.01; P = 0.172). Mistrust adversely affected glycemic control independent of treatment. This finding, coupled with the high rate of mistrust, highlights the need to target mistrust in new interventions to improve glycemic control in black patients with DR.


Comparison of Strain Elastography, Shear Wave Elastography, and Conventional Ultrasound in Diagnosing Thyroid Nodules.
The purpose of this study is to compare the diagnostic performances of strain elastography (SE), shear wave elastography (SWE), and traditional ultrasound (US) features in diagnosing thyroid nodules. This study included 185 adult patients with thyroid nodules who underwent conventional gray-scale US, SE, and SWE. SE was scored using a four-pattern elastographic scoring (ES) system. SWE values were presented as mean SWE values and standard derivation using Young's modules. The optimal cutoff values of the mean SWE values for predicting malignancy were determined using receiver operating characteristic (ROC) curve analysis. We used logistic regression models to test elastography as a novel significant predictor for the diagnosis of malignant nodules. The diagnostic performance of elastography parameters was compared with a traditional trained model. Malignant thyroid nodules were stiffer for SE (ES patterns 1 and 2/3 and 4) and mean SWE values (4/17; 51.0 ± 24.4 kPa) than for benign nodules (114/50; 33.1 ± 25.2 kPa) (P < 0.01). In ROC curve analyses, a mean SWE value of 32 kPa was the optimal cutoff point, with diagnostic performance measures of 81% sensitivity, 65% specificity, a 23% positive predictive value (PPV), and 96% negative predictive value (NPV). In multivariate logistic regression, the mean SWE value (≥32 kPa) was an independent predictor for malignancy (odds ratio: 16.8; 95% confidence interval [CI]: 3.6-78.3). However, after the addition of SE and SWE to traditional US features, the C-statistic was not significantly increased compared to the traditional model (0.88, 95% CI: 0.81-0.94 vs. 0.91, 0.85-0.97, P = 0.4). In this study, we confirmed SWE as an independent predictor for malignant thyroid nodules. However, in comparing the new extended elastography model to our previous prediction model, the new extended model showed no significant difference in the diagnostic performance.


Improvement of 3D protein models using multiple templates guided by single-template model quality assessment.
Modelling the 3D structures of proteins can often be enhanced if more than one fold template is used during the modelling process. However, in many cases, this may also result in poorer model quality for a given target or alignment method. There is a need for modelling protocols that can both consistently and significantly improve 3D models and provide an indication of when models might not benefit from the use of multiple target-template alignments. Here, we investigate the use of both global and local model quality prediction scores produced by ModFOLDclust2, to improve the selection of target-template alignments for the construction of multiple-template models. Additionally, we evaluate clustering the resulting population of multi- and single-template models for the improvement of our IntFOLD-TS tertiary structure prediction method. We find that using accurate local model quality scores to guide alignment selection is the most consistent way to significantly improve models for each of the sequence to structure alignment methods tested. In addition, using accurate global model quality for re-ranking alignments, prior to selection, further improves the majority of multi-template modelling methods tested. Furthermore, subsequent clustering of the resulting population of multiple-template models significantly improves the quality of selected models compared with the previous version of our tertiary structure prediction method, IntFOLD-TS. Source code and binaries can be freely downloaded from http://www.reading.ac.uk/bioinf/downloads/


Transient dynamics between displaced fixed points: an alternate nonlinear dynamical framework for olfaction.
Significant insights into the dynamics of neuronal populations have been gained in the olfactory system where rich spatio-temporal dynamics is observed during, and following, exposure to odours. It is now widely accepted that odour identity is represented in terms of stimulus-specific rate patterning observed in the cells of the antennal lobe (AL). Here we describe a nonlinear dynamical framework inspired by recent experimental findings which provides a compelling account of both the origin and the function of these dynamics. We start by analytically reducing a biologically plausible conductance based model of the AL to a quantitatively equivalent rate model and construct conditions such that the rate dynamics are well described by a single globally stable fixed point (FP). We then describe the AL's response to an odour stimulus as rich transient trajectories between this stable baseline state (the single FP in absence of odour stimulation) and the odour-specific position of the single FP during odour stimulation. We show how this framework can account for three phenomena that are observed experimentally. First, for an inhibitory period often observed immediately after an odour stimulus is removed. Second, for the qualitative differences between the dynamics in the presence and the absence of odour. Lastly, we show how it can account for the invariance of a representation of odour identity to both the duration and intensity of an odour stimulus. We compare and contrast this framework with the currently prevalent nonlinear dynamical framework of 'winnerless competition' which describes AL dynamics in terms of heteroclinic orbits. This article is part of a Special Issue entitled "Neural Coding".


Meanings of existential uncertainty and certainty for people diagnosed with cancer and receiving palliative treatment: a life-world phenomenological study.
Many people around the world are getting cancer and living longer with the disease. Thanks to improved treatment options in healthcare, patients diagnosed with advanced gastrointestinal cancer can increasingly live for longer. Living with cancer creates existential uncertainty, but what does this situation mean for the individual? The purpose of the study is to interpret meanings of existential uncertainty and certainty for people diagnosed with advanced gastrointestinal cancer and receiving palliative treatment. This study is part of a larger project in which 7 men and 7 women aged between 49 and 79 participated in a study of information and communication for people with advanced gastrointestinal cancer. A total of 66 interviews were conducted with participants who were followed up over time. The narrative interviews were transcribed verbatim and the texts were analysed in three steps: naive reading, structural analysis and interpreted whole by utilizing a phenomenological life-world approach. THIS STUDY HAS IDENTIFIED DIFFERENT SPHERES IN WHICH PEOPLE DIAGNOSED WITH ADVANCED GASTROINTESTINAL CANCER VACILLATE BETWEEN EXISTENTIAL UNCERTAINTY AND CERTAINTY: bodily changes, everyday situations, companionship with others, healthcare situations and the natural environment. Existing in the move between existential uncertainty and certainty appears to change people's lives in a decisive manner. The interview transcripts reveal aspects that both create existential certainty and counteract uncertainty. They also reveal that participants appear to start reflecting on how the new and uncertain aspects of their lives will manifest themselves -a new experience that lays the foundation for development of knowledge, personal learning and growth. People diagnosed with advanced gastrointestinal cancer and receiving palliative care expressed thoughts about personal learning initiated by the struggle of living with an uncertain future despite their efforts to live in the present. Their personal learning was experienced through a changed life for themselves and having to confront their own pending death and develop self-insight regarding finality of life. Healthcare professionals can try to support people receiving palliative treatment for cancer by diversifying avenues for their personal growth, thus helping them manage their existential uncertainty and gravitate towards greater existential certainty.


Breastfeeding and risk for fever after immunization.
The objective of this study was to evaluate the effects of breastfeeding on the risk for fever after routine immunizations. A prospective cohort study was conducted at a pediatric vaccination center in Naples, Italy. The mothers of the infants scheduled to receive routine immunizations were instructed on how to measure and record infant temperature on the evening of the vaccination and for the subsequent 3 days. The information about the incidence of fever was obtained by telephone on the third day after vaccination. The relative risk for fever in relation to the type of breastfeeding was estimated in multivariate analyses that adjusted for vaccine dose, maternal education and smoking, and number of other children in the household. A total of 460 infants were recruited, and information on the outcome was obtained for 450 (98%). Fever was reported for 30 (25%), 48 (31%), and 94 (53%) of the infants who were being exclusively breastfed, partially breastfed, or not breastfed at all, respectively (P < .01). The relative risk for fever among infants who were exclusively and partially breastfed was 0.46 (95% confidence interval: 0.33-0.66) and 0.58 (95% confidence interval: 0.44-0.77), respectively. The protection conferred by breastfeeding persisted even when considering the role of several potential confounders. In this study, breastfeeding was associated with a decreased incidence of fever after immunizations.


A systematic review of community-to-facility neonatal referral completion rates in Africa and Asia.
An estimated 2.8 million neonatal deaths occur annually worldwide. The vulnerability of newborns makes the timeliness of seeking and receiving care critical for neonatal survival and prevention of long-term sequelae. To better understand the role active referrals by community health workers play in neonatal careseeking, we synthesize data on referral completion rates for neonates with danger signs predictive of mortality or major morbidity in low- and middle-income countries. A systematic review was conducted in May 2014 of the following databases: Medline-PubMed, Embase, and WHO databases. We also searched grey literature. In addition, an investigator group was established to identify unpublished data on newborn referral and completion rates. Inquiries were made to the network of research groups supported by Save the Children's Saving Newborn Lives project and other relevant research groups. Three Sub-Saharan African and five South Asian studies reported data on community-to-facility referral completion rates. The studies varied on factors such as referral rates, the assessed danger signs, frequency of home visits in the neonatal period, and what was done to facilitate referrals. Neonatal referral completion rates ranged from 34 to 97 %, with the median rate of 74 %. Four studies reported data on the early neonatal period; early neonatal completion rates ranged from 46 to 97 %, with a median of 70 %. The definition of referral completion differed by studies, in aspects such as where the newborns were referred to and what was considered timely completion. Existing literature reports a wide range of neonatal referral completion rates in Sub-Saharan Africa and South Asia following active illness surveillance. Interpreting these referral completion rates is challenging due to the great variation in study design and context. Often, what qualifies as referral and/or referral completion is poorly defined, which makes it difficult to aggregate existing data to draw appropriate conclusions that can inform programs. Further research is necessary to continue highlighting ways for programs, governments, and policymakers to best aid families in low-resource settings in protecting their newborns from major health consequences.


Itopride for gastric volume, gastric emptying and drinking capacity in functional dyspepsia.
To study the effect of itopride on gastric accommodation, gastric emptying and drinking capacity in functional dyspepsia (FD). Randomized controlled trial was conducted to check the effect of itopride on gastric accommodation, gastric emptying, capacity of tolerating nutrient liquid and symptoms of FD. We recruited a total of 31 patients having FD on the basis of ROME III criteria. After randomization, itopride was received by 15 patients while 16 patients received placebo. Gastric accommodation was determined using Gastric Scintigraphy. 13C labeled octanoic breadth test was performed to assess gastric emptying. Capacity of tolerating nutrient liquid drink was checked using satiety drinking capacity test. The intervention group comprised of 150 mg itopride. Patients in both arms were followed for 4 wk. Mean age of the recruited participant 33 years (SD = 7.6) and most of the recruited individuals, i.e., 21 (67.7%) were males. We found that there was no effect of itopride on gastric accommodation as measured at different in volumes in the itopride and control group with the empty stomach (P = 0.14), at 20 min (P = 0.38), 30 min (P = 0.30), 40 min (P = 0.43), 50 min (P = 0.50), 60 min (P = 0.81), 90 min (P = 0.25) and 120 min (P = 0.67). Gastric emptying done on a sub sample (n = 11) showed no significant difference (P = 0.58) between itopride and placebo group. There was no significant improvement in the capacity to tolerate liquid in the itopride group as compared to placebo (P = 0.51). Similarly there was no significant improvement of symptoms as assessed through a composite symptom score (P = 0.74). The change in QT interval in itopride group was not significantly different from placebo (0.10). Our study found no effect of itopride on gastric accommodation, gastric emptying and maximum tolerated volume in patients with FD.


Consumer acceptance of natural sweeteners in protein beverages.
Protein beverage consumption by Americans has increased in recent years. Coupled with this increased consumption is an interest in natural sweeteners. The objective of this study was to evaluate the sensory properties of naturally sweetened ready-to-mix (RTM) whey protein beverages using 3 temporal methods and to formulate a natural noncaloric sweetener blend that could be added to RTM protein beverages to provide sweetness while still appealing in flavor to consumers. Iso-sweet concentrations of sweeteners (sucralose, sucrose, fructose, stevia, monk fruit) in RTM vanilla whey protein beverages (25 g of protein/360 mL of water) were established using magnitude estimation scaling and 2-alternative forced-choice testing. Temporal sensory profiling was then conducted on each beverage by a trained panel using time intensity, temporal dominance of sensations, and temporal check-all-that-apply. These findings were used to formulate natural sweetener blends that closely matched the temporality of sucrose-sweetened RTM vanilla protein beverages for consumer testing. One sugar-free blend (25% stevia/75% monk fruit) and 1 reduced-sugar blend (25% stevia/25% monk fruit/50% fructose) were selected for consumer testing (n = 150 consumers) in addition to 3 control RTM beverages containing sucralose, stevia, or monk fruit. Two distinct consumer clusters were identified. The label-conscious segment of consumers preferred beverages sweetened with natural blends when primed. The flavor-driven segment of consumers conceptually preferred naturally sweetened beverages but preferred sucralose-sweetened beverages when primed. An all-natural label claim was most preferred across all consumers. Application of these findings to commercially produced RTM protein beverages aids in the development of naturally sweetened protein beverages with reduced calories and desirable sensory properties and highlights the importance of label claims to consumers overall but to a label-conscious segment of consumers in particular.


Patterns of pancytopenia patients in a general medical ward and a proposed diagnostic approach.
There has been little systematic study on the clinical spectrum of pancytopenia. This study was done to describe the etiology, presentation and outcome of patients with pancytopenia presenting in a general medical ward. Hundred patients with pancytopenia were included in the study from October 2001 to October 2002. Patients on cancer chemotherapy were excluded. Blood counts, bone marrow examinations and trephine biopsies were performed according to standard methods. In all cases, megaloblastic anemia constituted the largest group (n = 39), and also seen in conjunction with hemolytic anemia and septicemia. Hypersplenism secondary to portal hypertension (cirrhosis) was the second most common diagnosis (n = 19). Aplastic anemia, septicemia and myelodysplasia were other common causes. Two patients were the suspected cases of viral hemorrhagic fever. Thirteen (13%) patients expired. Absolute neutrophil count (ANC) less than 500/microliter was seen in 14 (14%) patients, among which 6 (15.3%) had megaloblastic anemia, 3 (37.5%) had aplastic anemia, and 2 (40%) had myelodysplasia. Eleven patients with platelet counts < or = 10 x 10(9)/L, 6 (54.5%) presented with bleeding; and 2 of these 8 had aplastic anemia and 1 patient with megaloblastic anemia. MCV values > 100 fL and > 110 fL were more frequent in patients with megaloblastic anemia with most prominent anisopoikilocytosis, microcytosis and fragmented RBCs. Macrocytosis was noted in 35 (89.7%) patients with megaloblastic anemia and 12 (63.1%) with hypersplenism, 4 (50%) with aplastic anemia. Hypersegmented neutrophils were noted in the blood films of 36 (92.3%) patients with megaloblastic anemia. Megaloblastic anemia, hypersplenism and aplastic anemia are the common causes of pancytopenia in our study.


Reporting and understanding the safety and adverse effect profile of mobile apps for psychosocial interventions: An update.
Recent years have seen a rapidly increasing trend towards the delivery of health technology through mobile devices. Smartphones and tablet devices are thus becoming increasingly popular for accessing information and a wide range of services, including health care services. Modern mobile apps can be used for a variety of reasons, ranging from education for the patients and assistance to clinicians to delivery of interventions. Mobile phone apps have also been established to benefit patients in a scope of interventions across numerous medical specialties and treatment modalities. Medical apps have their advantages and disadvantages. It is important that clinicians have access to knowledge to make decisions regarding the use of medical apps on the basis of risk-benefit ratio. Mobile apps that deliver psycho social interventions offer unique challenges and opportunities. A number of reviews have highlighted the potential use of such apps. There is a need to describe, report and study their side effects too. The adverse effects associated with these apps can broadly be divided into: (1) those resulting from the security and safety concerns; (2) those arising from the use of a particular psycho social intervention; and (3) those due to the interaction with digital technology. There is a need to refine and reconsider the safety and adverse effects in this area. The safety profile of a mobile PSI app should describe its safety profile in: (1) privacy and security; (2) adverse effects of psychotherapy; and (3) adverse effects unique to the use of apps and the internet. This is, however, a very new area and further research and reporting is required to inform clinical decision making.


Dapsone hypersensitivity syndrome causing disseminated intravascular coagulation.
Dapsone hypersensitivity syndrome is an idiosyncratic reaction to this drug and can present with different clinical manifestations of varying severity. We describe a patient with disseminated intravascular coagulation (DIC) as an adverse reaction to dapsone. To the best of our knowledge, this is the first time it has been described in the literature. She presented with fever, rash and abdominal pain; she also had marked eosinophilia and features suggestive of oxidative haemolysis. Her course was complicated by DIC, splenic infarction and gastrointestinal bleeding. Extensive investigations did not reveal any alternative aetiology. She was initially treated with supportive measures and folic acid; steroids were administered later, following clinical deterioration. There was gradual improvement and the steroids were tapered. The patient recovered fully and remains well; her underlying chronic dermatologic condition is under satisfactory control with other medications.


Challenge studies in anxiety disorders.
In psychiatry, the use of pharmacological challenges in panic disorder is unique in that the clinical phenomenon of central interest (i.e., the panic attack) can be provoked readily and assessed in the clinical laboratory setting. During the past 20 years pharmacological challenge studies have increased our knowledge concerning the neurobiology of panic disorder remarkably and may ultimately result in novel and more causal treatment strategies. Moreover, the differences in sensitivity to certain panicogens such as serotonergic agents, lactate, carbon dioxide and cholecystokinin tetrapeptide are likely to be fruitful in serving as biological markers of subtypes of panic disorders and should be a major focus of research, as the identification of reliable endophenotypes is currently one of the major rate-limiting steps in psychiatric genetic studies.


Olanzapine-induced early cardiovascular effects are mediated by the biological clock and prevented by melatonin.
Second generation antipsychotics (SGA) are associated with adverse cardiometabolic side effects contributing to premature mortality in patients. While mechanisms mediating these cardiometabolic side effects remain poorly understood, three independent studies recently demonstrated that melatonin was protective against cardiometabolic risk in SGA-treated patients. As one of the main target areas of circulating melatonin in the brain is the suprachiasmatic nucleus (SCN), we hypothesized that the SCN is involved in SGA-induced early cardiovascular effects in Wistar rats. We evaluated the acute effects of olanzapine and melatonin in the biological clock, paraventricular nucleus and autonomic nervous system using immunohistochemistry, invasive cardiovascular measurements, and Western blot. Olanzapine induced c-Fos immunoreactivity in the SCN followed by the paraventricular nucleus and dorsal motor nucleus of the vagus indicating a potent induction of parasympathetic tone. The involvement of a SCN-parasympathetic neuronal pathway after olanzapine administration was further documented using cholera toxin-B retrograde tracing and vasoactive intestinal peptide immunohistochemistry. Olanzapine-induced decrease in blood pressure and heart rate confirmed this. Melatonin abolished olanzapine-induced SCN c-Fos immunoreactivity, including the parasympathetic pathway and cardiovascular effects while brain areas associated with olanzapine beneficial effects including the striatum, ventral tegmental area, and nucleus accumbens remained activated. In the SCN, olanzapine phosphorylated the GSK-3β, a regulator of clock activity, which melatonin prevented. Bilateral lesions of the SCN prevented the effects of olanzapine on parasympathetic activity. Collectively, results demonstrate the SCN as a key region mediating the early effects of olanzapine on cardiovascular function and show melatonin has opposing and potentially protective effects warranting additional investigation.


Selective Synthesis of Fe2O3 and Fe3O4 Nanowires Via a Single Precursor: A General Method for Metal Oxide Nanowires.
Hematite (α-Fe2O3) and magnetite (Fe3O4) nanowires with the diameter of about 100 nm and the length of tens of micrometers have been selectively synthesized by a microemulsion-based method in combination of the calcinations under different atmosphere. The effects of the precursors, annealing temperature, and atmosphere on the morphology and the structure of the products have been investigated. Moreover, Co3O4 nanowires have been fabricated to confirm the versatility of the method for metal oxide nanowires.


Body size from birth to middle age and the risk of hip and knee replacement.
Information regarding the effects of body size in childhood and early adulthood on the risk of hip and knee replacement in later life is inconsistent. We aimed to assess their effect, taking into account body mass index (BMI) in middle-age. Prospective cohort (Million Women Study) of 791,034 women with information on birth weight, body size at age 10 and age 20, and current BMI (at mean age 59.5 years) were followed for 6.82 million person-years. Adjusted relative risks (RRs) and absolute risks of hospitalisations for hip or knee replacement surgery for osteoarthritis were estimated. After a mean of 8.6 years follow-up, 17,402 women had a hip replacement and 18,297 a knee replacement. Between the ages of 50 and 79 years, absolute risks for women with current BMIs of <22.5 kg/m(2) and 35 + kg/m(2) were respectively 5.6 and 13.2 % for hip replacement; and 2.6 and 35.1 % for knee replacement. Within each category of current BMI, increasing body size at age 10 and at age 20 had comparatively small effects; there were no significant associations with birth weight. We estimate that 40 % of UK women with a BMI 35 + kg/m(2) have either a hip or knee replacement between the ages of 50-79 years; this compares to just 10 % of UK women with a healthy BMI (<25 kg/m(2)). The effects of body size in childhood and early adulthood on the absolute risks of either a hip or knee replacement are minimal compared to the effect of adiposity in middle age.


Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles.
The aim of this study was to assess the relative efficacy and mechanism of gene transfection by ultrasound (US) destruction of plasmid-bearing microbubbles. Luciferase reporter plasmid was charge-coupled to cationic lipid microbubbles. Rat hindlimb skeletal muscle was exposed to intermittent high-power US during dose-adjusted intra-arterial (IA) or IV administration of plasmid-bearing microbubbles via the carotid artery or jugular vein, respectively. At 4 days, luciferase activity in US-exposed skeletal muscle was 200-fold greater with IA than with IV administration of plasmid-bearing microbubbles, and was similar to transfection achieved by IM injection of plasmid (positive control). No transfection occurred with US and IA injection of plasmid alone. Intravital microscopy of the cremaster muscle in mice following administration of microbubbles and US exposure demonstrated perivascular deposition of fluorescent plasmid, the extent of which was twofold greater for IA compared to IV injection. Electron microscopy demonstrated a greater extent of myocellular microporations in US-exposed muscle after IA injection of microbubbles. We conclude that muscle transfection by US destruction of plasmid-bearing cationic microbubbles is amplified by IA, rather than IV, injection of microbubbles due to greater extravascular deposition of plasmid and to greater extent of myocellular microporation.


Differential validity for cognitive ability tests in employment and educational settings: not much more than range restriction?
The concept of differential validity suggests that cognitive ability tests are associated with varying levels of validity across ethnic groups, such that validity is lower in certain ethnic subgroups than in others. A recent meta-analysis has revived the viability of this concept. Unfortunately, data were not available in this meta-analysis to correct for range restriction within ethnic groups. We reviewed the differential validity literature and conducted 4 studies. In Study 1, we empirically demonstrated that using a cognitive ability test with a common cutoff decreases variance in test scores of Black subgroup samples more than in White samples. In Study 2, we developed a simulation that examined the effects of range restriction on estimates of differential validity. Results demonstrated that different levels of range restriction for subgroups can explain the apparent observed differential validity results in employment and educational settings (but not military settings) when no differential validity exists in the population. In Study 3, we conducted a simulation in which we examined how one corrects for range restriction affects the accuracy of these corrections. Results suggest that the correction approach using a common range restriction ratio for various subgroups may create or perpetuate the illusion of differential validity and that corrections are most accurate when done within each subgroup. Finally, in Study 4, we conducted a simulation in which we assumed differential validity in the population. We found that range restriction artificially increased the size of observed differential validity estimates when the validity of cognitive ability tests was assumed to be higher among Whites. Overall, we suggest that the concept of differential validity may be largely artifactual and current data are not definitive enough to suggest such effects exist.


Field-deployable, high-resolution, time-of-flight aerosol mass spectrometer.
The development of a new high-resolution time-of-flight aerosol mass spectrometer (HR-ToF-AMS) is reported. The high-resolution capabilities of this instrument allow the direct separation of most ions from inorganic and organic species at the same nominal m/z, the quantification of several types of organic fragments (CxHy, CxHyOz, CxHyNp, CxHyOzNp), and the direct identification of organic nitrogen and organosulfur content. This real-time instrument is field-deployable, and its high time resolution (0.5 Hz has been demonstrated) makes it well-suited for studies in which time resolution is critical, such as aircraft studies. The instrument has two ion optical modes: a single-reflection configuration offers higher sensitivity and lower resolving power (up to approximately 2100 at m/z 200), and a two-reflectron configuration yields higher resolving power (up to approximately 4300 at m/z 200) with lower sensitivity. The instrument also allows the determination of the size distributions of all ions. One-minute detection limits for submicrometer aerosol are <0.04 microg m(-3) for all species in the high-sensitivity mode and <0.4 microg m(-3) in the high-resolution mode. Examples of ambient aerosol data are presented from the SOAR-1 study in Riverside, CA, in which the spectra of ambient organic species are dominated by CxHy and CxHyOz fragments, and different organic and inorganic fragments at the same nominal m/z show different size distributions. Data are also presented from the MIRAGE C-130 aircraft study near Mexico City, showing high correlation with independent measurements of surrogate aerosol mass concentration.


Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients.
Infection with high-risk types of human papilloma virus (HPV) is currently the best-established prognostic marker for head and neck squamous cell carcinoma (HNSCC), one of the most common and lethal human malignancies worldwide. Clinical trials have been launched to address the concept of treatment de-escalation for HPV-positive HNSCC with the final aim to reduce treatment related toxicity and debilitating long-term impacts on the quality of life. However, HPV-related tumors are mainly restricted to oropharyngeal SCC (OPSCC) and there is an urgent need to establish reliable biomarkers for all patients at high risk for treatment failure. A patient cohort (n = 295) with mainly non-OPSCC (72.9%) and a low prevalence of HPV16-related tumors (8.8%) was analyzed by MassARRAY to determine a previously established prognostic methylation score (MS). Kaplan-Meier revealed a highly significant correlation between a high MS and a favorable survival for OPSCC (P = 0.0004) and for non-OPSCC (P<0.0001), which was confirmed for all HNSCC by multivariate Cox regression models (HR: 9.67, 95% CI [4.61-20.30], P<0.0001). Next, we established a minimal methylation signature score (MMSS), which consists of ten most informative of the originally 62 CpG units used for the MS. The prognostic value of the MMSS was confirmed by Kaplan-Meier analysis for all HNSCC (P<0.0001) and non-OPSCC (P = 0.0002), and was supported by multivariate Cox regression models for all HNSCC (HR: 2.15, 95% CI [1.36-3.41], P = 0.001). In summary, the MS and the MMSS exhibit an excellent performance as prognosticators for survival, which is not limited by the anatomical site, and both could be implemented in future clinical trials.


Reduction of serum cholesterol and hypercholesterolemic atherosclerosis in rabbits by secoisolariciresinol diglucoside isolated from flaxseed.
Secoisolariciresinol diglucoside (SDG) is a plant lignan isolated from flaxseed. Lignans are platelet-activating factor-receptor antagonists that would inhibit the production of oxygen radicals by polymorphonuclear leukocytes. SDG is an antioxidant. Antioxidants studied thus far are known to reduce hypercholesterolemic atherosclerosis. The objective of this study was to determine the effect of SDG on various blood lipid and aortic tissue oxidative stress parameters and on the development of atherosclerosis in rabbits fed a high-cholesterol diet. Rabbits were assigned to 4 groups: group 1, control; group 2, SDG control (15 mg. kg body wt-1. d-1 PO); group 3, 1% cholesterol diet; and group 4, same as group 3 but with added SDG (15 mg. kg body wt-1. d-1 PO). Blood samples were collected before (time 0) and after 4 and 8 weeks of experimental diets for measurement of serum triglycerides, total cholesterol (TC), and LDL, HDL, and VLDL cholesterol (LDL-C, HDL-C, and VLDL-C). The aorta was removed at the end of the protocol for assessment of atherosclerotic plaques; malondialdehyde, an aortic tissue lipid peroxidation product; and aortic tissue chemiluminescence, a marker for antioxidant reserve. Serum TC, LDL-C, and the ratios LDL-C/HDL-C and TC/HDL-C increased in groups 3 and 4 compared with time 0, the increase being smaller in group 4 than in group 3. Serum HDL-C decreased in group 3 and increased in group 4 compared with time 0, but changes were lower in group 3 than in group 4. SDG reduced TC and LDL-C by 33% and 35%, respectively, at week 8 but increased HDL-C significantly, by>140%, as early as week 4. It also decreased TC/LDL-C and LDL-C/HDL-C ratios by approximately 64%. There was an increase in aortic malondialdehyde and chemiluminescence in group 3, and they were lower in group 4 than in group 3. SDG reduced hypercholesterolemic atherosclerosis by 73%. These results suggest that SDG reduced hypercholesterolemic atherosclerosis and that this effect was associated with a decrease in serum cholesterol, LDL-C, and lipid peroxidation product and an increase in HDL-C and antioxidant reserve.


Cholinesterase inhibitors for Alzheimer's disease.
Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues. To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease. Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated. The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine. The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.


Identification of novel noncoding transcripts in telomerase-negative yeast using RNA-seq.
Telomerase is a ribonucleoprotein that maintains the ends of linear chromosomes in most eukaryotes. Loss of telomerase activity results in shortening of telomeric DNA and eventually a specific G2/M cell-cycle arrest known as senescence. In humans, telomere shortening occurs during aging, while inappropriate activation of telomerase is associated with approximately 90% of cancers. Previous studies have identified several classes of noncoding RNAs (ncRNA) also associated with aging-related senescence and cancer, but whether ncRNAs are also involved in short-telomere-induced senescence in yeast is unknown. Here, we report 112 putative novel lncRNAs in the yeast Saccharomyces cerevisiae, 41 of which are only expressed in telomerase-negative yeast. Expression of approximately half of the lncRNAs is strongly correlated with that of adjacent genes, suggesting this subset may influence transcription of neighboring genes. Our results reveal a new potential mechanism governing adaptive changes in senescing and post-senescent survivor yeast cells.


The Effect of Grandmothers' Presence on the Provision of Multidisciplinary Perinatal Support for Pregnant and Postpartum Women with Psychosocial Problems.
Pregnant and postpartum women with psychosocial problems are prone to face limited or absent perinatal functional support from biological grandmothers due to familial dysfunction. The study aimed to investigate whether the involvement and presence of biological maternal grandmothers providing practical support for their pre/postnatal daughters (ie, pregnant women) during the perinatal period may influence the number of support services provided by multidisciplinary agencies, including child consultation centers and municipal offices. This is a retrospective cohort study based on the medical records of all pregnant women with psychosocial problems that visited, gave birth, and received intervention from the hospital-based child protection unit at the Chiba University Hospital between February 2018 to March 2019. The primary outcome was to identify whether there was a difference in the number of multidisciplinary agencies providing perinatal support between pregnant women with and without the presence of functional support from biological maternal grandmothers during the perinatal period. We identified 114 pregnant and postpartum women with psychosocial problems. Seventy-six of these participants (66.7%) had functional support from their biological maternal grandmothers during the perinatal period, and 38 participants (33.3%) did not. The number of agencies involved with participants who lacked functional support was significantly higher than participants with functional support (t(55.14) = 2.98, p < 0.01). This finding was consistent among pregnant and postpartum primipara participants (n = 70) (t(68) = 3.87, p < 0.001), but not multipara (n = 44). The findings indicate that the presence and functional support of biological maternal grandmothers influence the support that is needed from multidisciplinary perinatal support systems by pregnant and postpartum women with psychosocial problems. Primipara mothers without support from their own mothers may need greater multidisciplinary support.


Complement C4 inhibits systemic autoimmunity through a mechanism independent of complement receptors CR1 and CR2.
The complement system enhances antibody responses to T-dependent antigens, but paradoxically, deficiencies in C1 and C4 are strongly linked to autoantibody production in humans. In mice, disruption of the C1qa gene also results in spontaneous autoimmunity. Moreover, deficiencies in C4 or complement receptors 1 and 2 (CR1/CR2) lead to reduced selection against autoreactive B cells and impaired humoral responses. These observations suggest that C1 and C4 act through CR1/CR2 to enhance humoral immunity and somehow suppress autoimmunity. Here we report high titers of spontaneous antinuclear antibody (ANA) in C4(-/)- mice. This systemic lupus erythematosus-like autoimmunity is highly penetrant; by 10 mo of age, all C4(-)(/)- females and most males produced ANA. In contrast, titers and frequencies of ANA in Cr2(-)(/)- mice, which are deficient in CR1 and CR2, never rose significantly above those in normal controls. Glomerular deposition of immune complexes (ICs), glomerulonephritis, and splenomegaly were observed in C4(-)(/)- but not Cr2(-)(/)- mice. C4(-)(/)-, but not Cr2(-)(/)-, mice accumulate activated T and B cells. Clearance of circulating ICs is impaired in preautoimmune C4(-)(/)-, but not Cr2(-)(/)-, mice. C4 deficiency causes spontaneous, lupus-like autoimmunity through a mechanism that is independent of CR1/CR2.


Metabolic biomarkers of prenatal alcohol exposure in human embryonic stem cell-derived neural lineages.
Fetal alcohol spectrum disorders (FASD) are a leading cause of neurodevelopmental disability. The mechanisms underlying FASD are incompletely understood, and biomarkers to identify those at risk are lacking. Here, we perform metabolomic analysis of embryoid bodies and neural lineages derived from human embryonic stem (hES) cells to identify the neural secretome produced in response to ethanol (EtOH) exposure. WA01 and WA09 hES cells were differentiated into embryoid bodies, neural progenitors, or neurons. Cells along this progression were cultured for 4 days with 0, 0.1, or 0.3% EtOH. Supernatants were subjected to C18 chromatography followed by ESI-QTOF-MS. Features were annotated using public databases, and the identities of 4 putative biomarkers were confirmed with purified standards and comparative MS/MS. EtOH treatment induced statistically significant changes to metabolite abundance in human embryoid bodies (180 features), neural progenitors (76 features), and neurons (42 features). There were no shared significant features between different cell types. Fifteen features showed a dose-response to EtOH. Four chemical identities were confirmed: L-thyroxine, 5'-methylthioadenosine, and the tryptophan metabolites, L-kynurenine and indoleacetaldehyde. One feature with a putative annotation of succinyladenosine was significantly increased in both EtOH treatments. Additional features were selective to EtOH treatment but were not annotated in public databases. EtOH exposure induces statistically significant changes to the metabolome profile of human embryoid bodies, neural progenitors, and neurons. Several of these metabolites are normally present in human serum, suggesting their usefulness as potential serum FASD biomarkers. These findings suggest the biochemical pathways that are affected by EtOH in the developing nervous system and delineate mechanisms of alcohol injury during human development.


Construct validity of the NIH Toolbox Cognition Battery in individuals with stroke.
The National Institutes of Health (NIH) Toolbox (NIHTB) for the Assessment of Behavior and Neurological Function Cognition Battery (NIHTB-CB) provides a brief assessment (approximately 30 min) of key components of cognition. This article examines construct validity to support the clinical utility of the NIHTB-CB in individuals with stroke. A total of 131 individuals with stroke (n = 71 mild stroke; n = 60 moderate/severe stroke) completed the NIHTB-CB. Univariate analyses were conducted to examine the cognitive profiles of the two different stroke groups (mild vs. moderate/severe stroke) on NIHTB-CB measures and composite scores. Pearson correlations were conducted between NIHTB-CB and established measures to examine convergent and discriminant validity. Effect sizes and clinical impairment rates for the different NIHTB-CB measures and composite scores were also examined. Participants experiencing moderate to severe stroke had poorer performance than did individuals with mild stroke on several of the NIHTB cognition measures. Evidence of convergent validity was provided by moderate to strong correlations between the NIHTB measures and the corresponding standard neuropsychological test (Pearson rs ranged from 0.31 to 0.88; median = .60). Evidence of discriminant validity was provided by smaller correlations between different cognitive domains than correlations of measures within the same domain. Effect sizes for composite and subtest scores regarding stroke severity were generally moderate-to-large. In addition, 42% of the sample were exhibiting mild cognitive impairment (i.e., ≥2 low scores on fluid tests). Findings provide support for the construct validity of the NIHTB-CB in individuals with stroke. (PsycINFO Database Record


Potential applications of polymeric microsphere suspension as subcutaneous depot for insulin.
The objective of this investigation was to develop an injectable, depot-forming drug delivery system for insulin based on microparticle technology to maintain constant plasma drug concentrations over prolonged period of time for the effective control blood sugar levels. Formulations were optimized with two well-characterized biodegradable polymers namely, poly(DL-lactide-co-glycolide) and poly-epsilon-caprolactone and evaluated in vitro for physicochemical characteristics, drug release in phosphate buffered saline (pH 7.4), and evaluated in vivo in streptozotocin-induced hypoglycemic rats. With a large volume of internal aqueous phase during w/o/w double emulsion solvent evaporation process and high molecular weight of the polymers used, we could not achieve high drug capture and precise control over subsequent release within the study period of 60 days. However, this investigation revealed that upon subcutaneous injection, the biodegradable depot-forming polymeric microspheres controlled the drug release and plasma sugar levels more efficiently than plain insulin injection. Preliminary pharmacokinetic evaluation exhibited steady plasma insulin concentration during the study period. These formulations, with their reduced frequency of administration and better control over drug disposition, may provide an economic benefit to the user compared with products currently available for diabetes control.


Champions are racers, not pacers: an analysis of qualification patterns of Olympic and IAAF World Championship middle distance runners.
The aim of this study was to analyse qualification patterns in middle distance running and identify whether athletes adopt theoretically optimal tactics, or whether the will to win overrides these. The performances of 295 men and 258 women finalists in the Olympic and IAAF World Championship 800 m and 1500 m events from 1999 to 2017 were analysed across all three rounds of competition. Finishing position, time and ranking amongst all competitors were found for each athlete. Position in the final was correlated with finishing position in the heats and semi-finals (all P < 0.001), but not with finishing times in those rounds. Of the 57 champions, 40 won both their heat and semi-final, even though a lower automatic qualification position would have been sufficient, and only 18 achieved a season's best time in the final. The will to win amongst the eventual champions (and other medallists) suggests predominantly ego oriented behaviour that is encouraged by a performance climate, and which did not appear to differ between men and women. Coaches and athletes are recommended to note that championship-specific physiological and psychological factors are important to develop in training and prior competition to improve both short- and long-term championship strategies.


Adenosine signaling promotes regeneration of pancreatic β cells in vivo.
Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing β cells is still needed. Using a zebrafish model of diabetes, we screened ~7,000 small molecules to identify enhancers of β cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of β cell regeneration was the adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA), which, acting through the adenosine receptor A2aa, increased β cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating β cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in β cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes.


Phase II study of gemcitabine and vinorelbine as second- or third-line therapy in patients with primary refractory or platinum-resistant recurrent ovarian and primary peritoneal cancer by the Korean Cancer Study Group (KCSG)_KCSG GY10-10.
The main aim of this study was to evaluate the antitumor activity and safety of vinorelbine and gemcitabine combination chemotherapy in patients with primary refractory or recurrent platinum-resistant epithelial ovarian and primary peritoneal cancers. Patients with platinum-resistant or primary refractory disease were eligible. Patients were allowed one prior chemotherapy for the treatment of platinum-resistant or refractory disease. Vinorelbine 25mg/m(2), followed by gemcitabine 1000mg/m(2), was administered intravenously on days 1 and 8 every 3weeks. Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 and cancer antigen 125 test (CA-125 criteria) were adopted to classify responses. 44 patients received the median of 4 (range, 1-24) treatments with fifteen (34.1%) receiving six or more cycles. The overall objective response rate was 22.7%. One patient (2.3%) had complete while 9 patients (20.4%) had partial responses with median duration of response of 5.9months. 17 patients (38.6%) had stable disease for a median of 3.3months. Median progression-free survival (PFS) was 3.4months and overall survival (OS) was 14.5months. Four (9.1%) patients were not assessable. Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 22 patients (50.0%). Fifteen patients (34.1%) needed immediate dose reduction. No treatment related death was reported. The combination chemotherapy with gemcitabine and vinorelbine achieved the primary end point of our clinical trial in management of platinum resistant recurrent ovarian cancer. However, further sophisticated dosing and scheduling of combination chemotherapy are needed because of a significant proportion of dose reduction.


Variation in seclusion rates across New Zealand's specialist mental health services: Are sociodemographic and clinical factors influencing this?
Rates of seclusion vary across New Zealand's publicly funded district health board (DHB) adult mental health inpatient services as indicated by national data. Anecdotally, this variation has been attributed to a range of factors directly relating to the people admitted to acute inpatient services. This study examined the extent to which variation in seclusion rates could be explained by the sociodemographic and clinical differences between populations admitted into adult mental health inpatient services. Retrospective data were obtained from the Programme for the Integration of Mental Health Data (PRIMHD). A logistic regression model was fitted to these data, with seclusion (yes/no) as the dependent variable and DHB groups as the independent variable. The DHBs were classified into four groups based on their seclusion rates. The model adjusted for ethnicity, age, number of bed nights, total Health of the Nation Outcome Scales (HoNOS) scores, and compulsory treatment status. Odds ratios remained virtually unchanged after adjustment for sociodemographic and clinical factors. People admitted to DHB Group 4 (highest secluding DHBs) were 11 times more likely to be secluded than people in Group 1 (lowest secluding DHBs), adjusted OR = 11.1, 95% CI [7.5,16.4], P < 0.001. Results indicate DHB variation in seclusion rates cannot be attributed to the sociodemographic and clinical factors of people admitted into DHB adult mental health inpatient services. Instead, this variation may be explained by differences in service delivery models and practice approaches. A model of system improvements aimed at reducing seclusion is discussed.


Diabetes, insulin, and development of acute lung injury.
Recently, many studies have investigated the immunomodulatory effects of insulin and glucose control in critical illness. This review examines evidence regarding the relationship between diabetes and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), reviews studies of lung injury related to glycemic and nonglycemic metabolic features of diabetes, and examines the effect of diabetic therapies. A MEDLINE/PubMed search from inception to August 1, 2008, was conducted using the search terms acute lung injury, acute respiratory distress syndrome, hyperglycemia, diabetes mellitus, insulin, hydroxymethylglutaryl-CoA reductase inhibitors (statins), angiotensin-converting enzyme inhibitor, and peroxisome proliferator-activated receptors, including combinations of these terms. Bibliographies of retrieved articles were manually reviewed. Available studies were critically reviewed, and data were extracted with special attention to the human and animal studies that explored a) diabetes and ALI; b) hyperglycemia and ALI; c) metabolic nonhyperglycemic features of diabetes and ALI; and d) diabetic therapies and ALI. Clinical and experimental data indicate that diabetes is protective against the development of ALI/ARDS. The pathways involved are complex and likely include effects of hyperglycemia on the inflammatory response, metabolic abnormalities in diabetes, and the interactions of therapeutic agents given to diabetic patients. Multidisciplinary, multifaceted studies, involving both animal models and clinical and molecular epidemiology techniques, are essential.


Regulation of lean mass, bone mass, and exercise tolerance by the central melanocortin system.
Signaling via the type 4-melanocortin receptor (MC4R) is an important determinant of body weight in mice and humans, where loss of function mutations lead to significant obesity. Humans with mutations in the MC4R experience an increase in lean mass. However, the simultaneous accrual of fat mass in such individuals may contribute to this effect via mechanical loading. We therefore examined the relationship of fat mass and lean mass in mice lacking the type-4 melanocortin receptor (MC4RKO). We demonstrate that MC4RKO mice display increased lean body mass. Further, this is not dependent on changes in adipose mass, as MC4RKO mice possess more lean body mass than diet-induced obese (DIO) wild type mice with equivalent fat mass. To examine potential sources of the increased lean mass in MC4RKO mice, bone mass and strength were examined in MC4RKO mice. Both parameters increase with age in MC4RKO mice, which likely contributes to increases in lean body mass. We functionally characterized the increased lean mass in MC4RKO mice by examining their capacity for treadmill running. MC4R deficiency results in a decrease in exercise performance. No changes in the ratio of oxidative to glycolytic fibers were seen, however MC4RKO mice demonstrate a significantly reduced heart rate, which may underlie their impaired exercise performance. The reduced exercise capacity we report in the MC4RKO mouse has potential clinical ramifications, as efforts to control body weight in humans with melanocortin deficiency may be ineffective due to poor tolerance for physical activity.


X chromosome inactivation: silencing, topology and reactivation.
To ensure X-linked gene dosage compensation between females (XX) and males (XY), one X chromosome undergoes X chromosome inactivation (XCI) in female cells. This process is tightly regulated throughout development by many different factors, with Xist as a key regulator, encoding a long non-coding RNA, involved in establishment of several layers of repressive epigenetic modifications. Several recent studies on XCI focusing on identification and characterization of Xist RNA-protein interactors, revealed new factors involved in gene silencing, genome topology and nuclear membrane attachment, amongst others. Also, new insights in higher order chromatin organization have been presented, revealing differences between the topological organization of active and inactive X chromosomes (Xa and Xi), with associated differences in gene expression. Finally, further evidence indicates that the inactive state of the Xi can be (partially) reversed, and that this X chromosome reactivation (XCR) might be associated with disease.


Existing Data Sources for Clinical Epidemiology: The PHARMO Database Network.
The PHARMO Database Network provides a unique opportunity to gain insight in the complete patient journey and healthcare in the Netherlands. The PHARMO Database Network is a population-based network of electronic healthcare databases and combines anonymous data from different primary and secondary healthcare settings in the Netherlands. Healthcare settings include general practitioners, out-patient and in-patient pharmacies, hospitals and clinical laboratories. Furthermore, databases are linked with external registries such as the Cancer Registry, Pathology Registry and Perinatal Registry. The different data sources are linked on a patient level through probabilistic linkage based on validated algorithms. The longitudinal and ongoing nature of the PHARMO Database Network system enables to follow up more than 10 million residents of the Netherlands for an average of 12 years. Data collection period, catchment area and overlap between data sources differ. Access to the PHARMO Database Network is, by governance regulations of the data collection, restricted to researchers of the PHARMO Institute and academic affiliates. Each data request is checked against privacy and company policies, and requires approval of the privacy and governance board. The terms and conditions and a data application form are available on the PHARMO website (www.pharmo.com).


Quantum-well enhancement of the Goos-Hänchen shift for p-polarized beams in a two-prism configuration.
It is predicted that the Goos-Hänchen effect can be resonantly enhanced by placing a metallic quantum well (ultrathin film) at the dielectric-vacuum (air) interface. We study the enhancement of the phenomenon, as it appears in frustrated total internal reflection with p-polarized light, both theoretically and numerically. Starting from boundary conditions for the electromagnetic field, which in a self-consistent manner take into account the quantum-well dynamics, we derive new expressions for the amplitude reflection and transmission coefficients of light, and from these the stationary phase approximation to the Goos-Hänchen shifts is obtained. It is shown that large peaks appear in the Goos-Hänchen shift below the critical angle in reflection, and these are located at the minima for the energy reflection coefficient. Both positive and negative shifts may occur, and the number of peaks depends on the gap width. To determine the accuracy of the simple stationary phase approximation, we carry out a rigorous stationary energy-transport calculation of the Goos-Hänchen shift. Although the overall agreement between the two approaches is good, the stationary phase approach mostly overestimates the peak heights. For a Gaussian incident beam, the resonance displacement of the reflected beam can be as large as the Gaussian width parameter. It is suggested that the possible relation between the Goos-Hänchen effect and the optical tunneling phenomenon in the two-prism configuration should be reinvestigated by depositing quantum wells on the glass-vacuum interfaces to obtain a better spatial photon localization.


Introduction of the CIITA gene into tumor cells produces exosomes with enhanced anti-tumor effects.
Exosomes are small membrane vesicles secreted from various types of cells. Tumor-derived exosomes contain MHC class I molecules and tumor-specific antigens, receiving attention as a potential cancer vaccine. For induction of efficient anti-tumor immunity, CD4+ helper T cells are required, which recognize appropriate MHC class II-peptide complexes. In this study, we have established an MHC class II molecule-expressing B16F1 murine melanoma cell line (B16F1- CIITA) by transduction of the CIITA (Class II transactivator) gene. Exosomes from B16-CII cells (CIITA- Exo) contained a high amount of MHC class II as well as a tumor antigen TRP2. When loaded on dendritic cells (DCs), CIITA-Exo induced the increased expression of MHC class II molecules and CD86 than the exosomes from the parental cells (Exo). In vitro assays using co-culture of immunized splenocytes and exosome-loaded DCs demonstrated that CIITA-Exo enhanced the splenocyte proliferation and IL-2 secretion. Consistently, compared to B16-Exo, CIITA-Exo induced the increased mRNA levels of inflammatory cytokines such as TNF-α, chemokine receptor CCR7 and the production of Th1-polarizing cytokine IL-12. A tumor preventive model showed that CIITA-Exo significantly inhibited tumor growth in a dose-dependent manner. Ex vivo assays using immunized mice demonstrated that CIITA-Exo induced a higher amount of Th1-polarized immune responses such as Th1-type IgG2a antibodies and IFN-γ cytokine as well as TRP2-specific CD8+ T cells. A tumor therapeutic model delayed effects of tumor growth by CIITA-Exo. These findings indicate that CIITA-Exo are more efficient as compared to parental Exo to induce anti-tumor immune responses, suggesting a potential role of MHC class II-containing tumor exosomes as an efficient cancer vaccine.


Induction of heme oxygenase 1 by moderately oxidized low-density lipoproteins in human vascular smooth muscle cells: role of mitogen-activated protein kinases and Nrf2.
Oxidized low-density lipoproteins (LDL) play a central role in atherogenesis and induce expression of the antioxidant stress protein heme oxygenase 1 (HO-1). In the present study we investigated induction of HO-1 and adaptive increases in reduced glutathione (GSH) in human aortic smooth muscle cells (SMC) in response to moderately oxidized LDL (moxLDL, 100 microg protein/ml, 24 h), a species containing high levels of lipid hydroperoxides. Expression and activity of HO-1 and GSH levels were elevated to a greater extent by moxLDL than highly oxidized LDL but unaffected by native or acetylated LDL. Inhibitors of protein kinase C (PKC) or mitogen-activated protein kinases (MAPK) p38(MAPK) and MEK or c-jun-NH2-terminal kinase (JNK) significantly attenuated induction of HO-1. Phosphorylation of p38(MAPK), extracellular signal-regulated kinase (ERK1/2), or JNK and nuclear translocation of the transcription factor Nrf2 were enhanced following acute exposure of SMC to moxLDL (100 microg protein/ml, 1-2 h). Pretreatment of SMC with the antioxidant vitamin C (100 microM, 24 h) attenuated the induction of HO-1 by moxLDL. Native and oxidized LDL did not alter basal levels of intracellular ATP, mitochondrial dehydrogenase activity, or expression of the lectin-like oxidized LDL receptor (LOX-1) in SMC. These findings demonstrate for the first time that activation of PKC, p38(MAPK), JNK, ERK1/2, and Nrf2 by oxidized LDL in human SMC leads to HO-1 induction, constituting an adaptive response against oxidative injury that can be ameliorated by vitamin C.


Double covalent coupling method for the fabrication of highly sensitive and reusable electrogenerated chemiluminescence sensors.
A double covalent coupling method for the fabrication of a highly sensitive and reusable electrogenerated chemiluminescence (ECL) chemical sensor for the detection of tertiary amines and ECL aptamer-based (ECL-AB) biosensor for the detection of cocaine is reported. The ECL sensors were constructed by covalent coupling of amino-containing Ru(bpy)(3)(2+) derivatives (Ru1, Ru(bpy)(3)(2+) = tris(2,2'-bipyridyl)ruthenium(II)) or cocaine aptamer-Ru1 to the surface of a paraffin-impregnated graphite electrode that had been covalently modified with a monolayer of 4-aminobenzene sulfonic acid via electrochemical oxidations. ECL performance of the newly developed chemical sensors was evaluated using tri-n-propylamine (TPrA) and metoclopramide (MCP) as model analytes. The sensors exhibited excellent sensitivity, stability, and reproducibility with a detection limit of 30 nM for TPrA and 2.0 nM for MCP, and relative standard deviations (RSDs) of 2.1% over 90 cyclic potential cycles (0 to 1.50 V vs Ag/AgCl) and 2.6% over 45 cycles (0.60 to +1.30 V vs Ag/AgCl) at 400 mV/s for 50 nM TPrA and 200 nM MCP, respectively. For the ECL-AB biosensor, it showed an extremely low detection limit of 10 pM for cocaine, and offered a good selectivity toward cocaine, heroin, and caffeine. This detection limit was about 4-6 orders of magnitude lower than that reported on the basis of alternating current (AC) voltammetry and optical aptamer-based cocaine biosensors. Additionally, the ECL-AB biosensor was highly reusable (RSD = 2.8%, n = 7) and possessed long-term storage stability (96.8% initial ECL recovery over 21 days storage). A binding constant of 4.6 +/- 0.3 x 10(9) M(-1) between cocaine and its aptamer was estimated using an ECL based Langmuir isotherm approach. Wide ranging applications of the presently reported strategy in fabricating various chemical sensors or biosensors are expected.


8-Oxo-7,8-dihydroguanine: links to gene expression, aging, and defense against oxidative stress.
The one-electron oxidation product of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is an abundant lesion in genomic, mitochondrial, and telomeric DNA and RNA. It is considered to be a marker of oxidative stress that preferentially accumulates at the 5' end of guanine strings in the DNA helix, in guanine quadruplexes, and in RNA molecules. 8-OxoG has a lower oxidation potential compared to guanine; thus it is susceptible to oxidation/reduction and, along with its redox products, is traditionally considered to be a major mutagenic DNA base lesion. It does not change the architecture of the DNA double helix and it is specifically recognized and excised by 8-oxoguanine DNA glycosylase (OGG1) during the DNA base excision repair pathway. OGG1 null animals accumulate excess levels of 8-oxoG in their genome, yet they do not have shorter life span nor do they exhibit severe pathological symptoms including tumor formation. In fact they are increasingly resistant to inflammation. Here we address the rarely considered significance of 8-oxoG, such as its optimal levels in DNA and RNA under a given condition, essentiality for normal cellular physiology, evolutionary role, and ability to soften the effects of oxidative stress in DNA, and the harmful consequences of its repair, as well as its importance in transcriptional initiation and chromatin relaxation.