Potential for a web-based management information system to improve malaria control: An exploratory study in the Lahat District, South Sumatra Province, Indonesia.
A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia. An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office. The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting. The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.


National Trauma Institute prospective evaluation of the ventilator bundle in trauma patients: does it really work?
Since its introduction by the Institute for Healthcare Improvement, the ventilator bundle (VB) has been credited with a reduction in ventilator-associated pneumonia (VAP). The VB consists of stress ulcer prophylaxis, deep venous thrombosis prophylaxis, head-of-bed elevation, and daily sedation vacation with weaning assessment. While there is little compelling evidence that the VB is effective, it has been widely accepted. The Centers for Medical and Medicaid Services has suggested that VAP should be a "never event" and may reduce payment to providers. To provide evidence of its efficacy, the National Trauma Institute organized a prospective multi-institutional trial to evaluate the utility of the VB. This prospective observational multi-institutional study included six Level I trauma centers. Entry criteria required at least 2 days of mechanical ventilation of trauma patients in an intensive care unit (ICU). Patients were followed up daily in the ICU until the development of VAP, ICU discharge, or death. Compliance for each VB component was recorded daily, along with patient risk factors and injury specifics. Primary outcomes were VAP and death. VB compliance was analyzed as a time-dependent covariate using Cox regression as it relates to outcomes. A total 630 patients were enrolled; 72% were male, predominately with blunt injury; and mean age, Injury Severity Score (ISS), and 24-hour Glasgow Coma Scale (GCS) score were 47, 24, and 8.7, respectively. VAP occurred in 36%; mortality was 15%. Logistic regression identified male sex and pulmonary contusion as independent predictors of VAP and age, ISS, and 24-hour Acute Physiology and Chronic Health Evaluation as independent predictors of death. Cox regression analysis demonstrated that the VB, as a time-dependent covariate, was not associated with VAP prevention. In trauma patients, VAP is independently associated with male sex and chest injury severity and not the VB. While quality improvement activities should continue efforts toward VAP prevention, the Institute for Healthcare Improvement VB is not the answer. Financial penalties for VAP and VB noncompliance are not warranted. Therapeutic study, level III.


Plasticity of animal genome architecture unmasked by rapid evolution of a pelagic tunicate.
Genomes of animals as different as sponges and humans show conservation of global architecture. Here we show that multiple genomic features including transposon diversity, developmental gene repertoire, physical gene order, and intron-exon organization are shattered in the tunicate Oikopleura, belonging to the sister group of vertebrates and retaining chordate morphology. Ancestral architecture of animal genomes can be deeply modified and may therefore be largely nonadaptive. This rapidly evolving animal lineage thus offers unique perspectives on the level of genome plasticity. It also illuminates issues as fundamental as the mechanisms of intron gain.


Theoretical investigation on nonlinear optical effects in laser trapping of dielectric nanoparticles with ultrafast pulsed excitation.
The use of low-power high-repetition-rate ultrafast pulsed excitation in stable optical trapping of dielectric nanoparticles has been demonstrated in the recent past; the high peak power of each pulse leads to instantaneous trapping of a nanoparticle with fast inertial response and the high repetition-rate ensures repetitive trapping by successive pulses However, with such high peak power pulsed excitation under a tight focusing condition, nonlinear optical effects on trapping efficiency also become significant and cannot be ignored. Thus, in addition to the above mentioned repetitive instantaneous trapping, trapping efficiency under pulsed excitation is also influenced by the optical Kerr effect, which we theoretically investigate here. Using dipole approximation we show that with an increase in laser power the radial component of the trapping potential becomes progressively more stable but the axial component is dramatically modulated due to increased Kerr nonlinearity. We justify that the relevant parameter to quantify the trapping efficiency is not the absolute depth of the highly asymmetric axial trapping potential but the height of the potential barrier along the beam propagation direction. We also discuss the optimal excitation parameters leading to the most stable dipole trap. Our results show excellent agreement with previous experiments.


The metabolic syndrome and retinal microvascular signs in a Japanese population: the Funagata study.
To determine the relationship of metabolic syndrome and its components with retinopathy and other retinal microvascular signs in a Japanese population. The Funagata study recruited 1961 (53.3% of eligible) Japanese aged 35 or older. The metabolic syndrome was diagnosed primarily using definitions of the International Diabetes Federation. Retinopathy and retinal microvascular signs were assessed from fundus photographs. Retinal arteriolar and venular diameters were measured using a computer-assisted programme. Data were available for analysis in 1638 persons for retinopathy and retinal microvascular signs and 921 persons for retinal vessel diameters. Various components of the metabolic syndrome were associated with retinal microvascular signs: a larger waist circumference was associated with wider venular diameter and retinopathy lesions; a higher blood pressure level was associated with focal arteriolar narrowing, arteriovenous nicking, enhanced arteriolar wall reflex and narrower arteriolar diameter; and a higher triglyceride level was associated with enhanced arteriolar wall reflex. Overall, persons with the metabolic syndrome were more likely to have retinopathy (odds ratio 1.64, 95% CI: 1.02 to 2.64) and wider venular diameter 4.69 microm (95% CI: 1.20 to 8.19 microm) than persons without the metabolic syndrome. We report associations of metabolic syndrome components with retinopathy and wider venular diameter in Japanese adults. These data suggest that metabolic abnormalities, indicated by metabolic syndrome components, are associated with microvascular changes in the retina. There was no synergistic effect of the metabolic syndrome on retinal microvascular changes beyond its individual components.


Interferon regulatory factor 7 is negatively regulated by the Epstein-Barr virus immediate-early gene, BZLF-1.
Virus infection stimulates potent antiviral responses; specifically, Epstein-Barr virus (EBV) infection induces and activates interferon regulatory factor 7 (IRF-7), which is essential for production of alpha/beta interferons (IFN-alpha/beta) and upregulates expression of Tap-2. Here we present evidence that during cytolytic viral replication the immediate-early EBV protein BZLF-1 counteracts effects of IRF-7 that are central to host antiviral responses. We initiated these studies by examining IRF-7 protein expression in vivo in lesions of hairy leukoplakia (HLP) in which there is abundant EBV replication but the expected inflammatory infiltrate is absent. This absence might predict that factors involved in the antiviral response are absent or inactive. First, we detected significant levels of IRF-7 in the nucleus, as well as in the cytoplasm, of cells in HLP lesions. IRF-7 activity in cell lines during cytolytic viral replication was examined by assay of the IRF-7-responsive promoters, IFN-alpha4, IFN-beta, and Tap-2, as well as of an IFN-stimulated response element (ISRE)-containing reporter construct. These reporter constructs showed consistent reduction of activity during lytic replication. Both endogenous and transiently expressed IRF-7 and EBV BZLF-1 proteins physically associate in cell culture, although BZLF-1 had no effect on the nuclear localization of IRF-7. However, IRF-7-dependent activity of the IFN-alpha4, IFN-beta, and Tap-2 promoters, as well as an ISRE promoter construct, was inhibited by BZLF-1. This inhibition occurred in the absence of other EBV proteins and was independent of IFN signaling. Expression of BZLF-1 also inhibited activation of IRF-7 by double-stranded RNA, as well as the activity of a constitutively active mutant form of IRF-7. Negative regulation of IRF-7 by BZLF-1 required the activation domain but not the DNA-binding domain of BZLF-1. Thus, EBV may subvert cellular antiviral responses and immune detection by blocking the activation of IFN-alpha4, IFN-beta, and Tap-2 by IRF-7 through the medium of BZLF-1 as a negative regulator.


'Autism and the good life': a new approach to the study of well-being.
Medical, psychological, educational and social interventions to modify the behaviour of autistic people are only justified if they confer benefit on those people. However, it is not clear how 'benefit' should be understood. Most such interventions are justified by referring to the prospect that they will effect lasting improvements in the well-being and happiness of autistic people, so they can lead good lives. What does a good life for an autistic person consist in? Can we assume that his or her well-being is substantively the same as the well-being of non-autistic individuals? In this paper, we argue that, as it stands, the current approach to the study of well-being is for the most part unable to answer these questions. In particular, much effort is needed in order to improve the epistemology of well-being, especially so if we wish this epistemology to be 'autism-sensitive'. Towards the end of the paper, we sketch a new, autism-sensitive approach and apply it in order to begin answering our initial questions.


Brain death and organ donation in a neurosurgical unit: audit of recent practice.
To assess the potential for increasing the yield of donors by comparing the current pattern of brain death and organ donation in a neurosurgical unit with that reported in 1981 and with a recent national audit. Retrospective review of all deaths for 1986, 1987, and 1988 and prospective data for 1989. A regional neurosurgical unit serving 2.7 million population. Of 553 deaths, 35% (191) patients died while on a ventilator and 17% (92) after discontinuation of ventilation. Medical contraindications to donation were found in 23% (32) of 141 patients tested for brain death, in 38% (19) of 50 patients who died while being ventilated who were not tested, and in 12% (11) of 92 patients no longer being ventilated. Consent for donation was sought in 88% (96) of 109 medically suitable brain dead patients and granted in 70% (67) of these. Half those with permission for multiorgan donation had only the kidneys removed. More organs may be lost owing to transplant team logistics than by failure to seek consent from relatives of brain dead patients. The estimated size of the pool of potential donors depends on what types of patients might be considered. Ensuring that all who die while being ventilated are tested for brain death and considering the potential for donation before withdrawing ventilation could yield more donors. Ventilating more patients who are hopelessly brain damaged to secure more donors raises ethical and economic issues.


XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G.
Impaired protein homeostasis induced by endoplasmic reticulum dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore endoplasmic reticulum function impaired by stress, the unfolded protein response is activated. A key unfolded protein response prosurvival pathway is controlled by the endoplasmic reticulum stress sensor (inositol-requiring enzyme-1), XBP1 (downstream X-box-binding protein-1), and O-GlcNAc (O-linked β-N-acetylglucosamine) modification of proteins (O-GlcNAcylation). Stroke impairs endoplasmic reticulum function, which activates unfolded protein response. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Mice with Xbp1 loss and gain of function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Deletion of Xbp1 worsened outcome after transient and permanent middle cerebral artery occlusion. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1 dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacological increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Our study indicates a critical role for the IRE1/XBP1 unfolded protein response branch in stroke outcome. O-GlcNAcylation is a prosurvival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting prosurvival pathways to counterbalance the age-related decline in the brain's self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains.


Metabolic factors and risk of thyroid cancer in the Metabolic syndrome and Cancer project (Me-Can).
To investigate metabolic factors and their possible impact on risk of thyroid cancer. A prospective cohort study was conducted based on seven population-based cohorts in Norway, Austria, and Sweden, in the Metabolic syndrome and Cancer project (Me-Can). Altogether 578,700 men and women with a mean age of 44.0 years at baseline were followed for on average 12.0 years. Relative risk of incident thyroid cancer was assessed by levels of BMI, blood pressure, and blood levels of glucose, cholesterol, triglycerides, and by a combined metabolic syndrome (MetS) score. Risk estimates were investigated for quintiles, and a z score distribution of exposures was analyzed using Cox proportional hazards regression. During follow-up, 255 women and 133 men were diagnosed with thyroid cancer. In women, there was an inverse association between glucose and thyroid cancer risk, with adjusted RR: 95% CI was 0.61 (0.41-0.90), p trend = 0.02 in the fifth versus the first quintile, and a positive association between BMI and thyroid cancer risk with a significant trend over quintiles. There was no association between the other metabolic factors, single or combined (Met-S), and thyroid cancer. In women, BMI was positively, while blood glucose levels were inversely, associated with thyroid cancer.


Microbial existence in controlled habitats and their resistance to space conditions.
The National Research Council (NRC) has recently recognized the International Space Station (ISS) as uniquely suitable for furthering the study of microbial species in closed habitats. Answering the NRC's call for the study, in particular, of uncommon microbial species in the ISS, and/or of those that have significantly increased or decreased in number, space microbiologists have begun capitalizing on the maturity, speed, and cost-effectiveness of molecular/genomic microbiological technologies to elucidate changes in microbial populations in the ISS and other closed habitats. Since investigators can only collect samples infrequently from the ISS itself due to logistical reasons, Earth analogs, such as spacecraft-assembly clean rooms, are used and extensively characterized for the presence of microbes. Microbiologists identify the predominant, problematic, and extremophilic microbial species in these closed habitats and use the ISS as a testbed to study their resistance to extreme extraterrestrial environmental conditions. Investigators monitor the microbes exposed to the real space conditions in order to track their genomic changes in response to the selective pressures present in outer space (external to the ISS) and the spaceflight (in the interior of the ISS). In this review, we discussed the presence of microbes in space research-related closed habitats and the resistance of some microbial species to the extreme environmental conditions of space.


Coherent X-Ray Diffraction Imaging of Chloroplasts from Cyanidioschyzon merolae by Using X-Ray Free Electron Laser.
Coherent X-ray diffraction imaging (CXDI) is a lens-less technique for visualizing the structures of non-crystalline particles with the dimensions of submicrometer to micrometer at a resolution of several tens of nanometers. We conducted cryogenic CXDI experiments at 66 K to visualize the internal structures of frozen-hydrated chloroplasts of Cyanidioschyzon merolae using X-ray free electron laser (XFEL) as a coherent X-ray source. Chloroplast dispersed specimen disks at a number density of 7/(10×10 µm(2)) were flash-cooled with liquid ethane without staining, sectioning or chemical labeling. Chloroplasts are destroyed at atomic level immediately after the diffraction by XFEL pulses. Thus, diffraction patterns with a good signal-to-noise ratio from single chloroplasts were selected from many diffraction patterns collected through scanning specimen disks to provide fresh specimens into the irradiation area. The electron density maps of single chloroplasts projected along the direction of the incident X-ray beam were reconstructed by using the iterative phase-retrieval method and multivariate analyses. The electron density map at a resolution of 70 nm appeared as a C-shape. In addition, the fluorescence image of proteins stained with Flamingo™ dye also appeared as a C-shape as did the autofluorescence from Chl. The similar images suggest that the thylakoid membranes with an abundance of proteins distribute along the outer membranes of chloroplasts. To confirm the present results statistically, a number of projection structures must be accumulated through high-throughput data collection in the near future. Based on the results, we discuss the feasibility of XFEL-CXDI experiments in the structural analyses of cellular organelles.


A case-cohort study of diet and risk of benign proliferative epithelial disorders of the breast (Canada).
A case-cohort analysis of the association between diet and risk of benign proliferative epithelial disorders (BPED) of the breast was undertaken within a cohort of 56,537 women who were enrolled in the Canadian National Breast Screening Study (NBSS) and who completed a self-administered dietary questionnaire. (The NBSS is a randomized controlled trial of screening for breast cancer in women aged 40 to 59 years.) BPED are thought to have premalignant potential. Specific hypotheses were that risk of BPED would increase with increasing energy-adjusted fat intake and decrease with increasing energy-adjusted vitamin A and fiber intake. Additionally, we explored the association between calcium intake and risk of BPED. During the active follow-up phase of the NBSS, 657 women in the dietary cohort were diagnosed with biopsy-confirmed incident BPED. For comparative purposes, a subcohort consisting of a random sample of 5,581 women was selected from the full dietary cohort. After exclusions for various reasons, the analyses were based on 545 cases and 4,921 non-cases. Overall, the results were almost uniformly null, and provided little support for the study hypotheses. Rate ratios (95 percent confidence intervals [CI]) for the highest cf the lowest quintile levels for total fat, retinol, beta-carotene, fiber, and calcium were 0.88 (CI = 0.65-1.20), 0.97 (CI = 0.71-1.31), 0.94 (CI = 0.70-1.27), 1.11 (CI = 0.82-1.50), and 0.81 (CI = 0.60-1.07), respectively. There were too few cases of atypical BPED for meaningful analysis, but results for those whose BPED showed no atypia were similar to the overall results. Further analyses conducted separately in the screened and control arms of the NBSS also failed to provide strong support for dietary associations, as did those conducted separately for screen-detected and interval-detected BPED.


Mapping longitudinal development of local cortical gyrification in infants from birth to 2 years of age.
Human cortical folding is believed to correlate with cognitive functions. This likely correlation may have something to do with why abnormalities of cortical folding have been found in many neurodevelopmental disorders. However, little is known about how cortical gyrification, the cortical folding process, develops in the first 2 years of life, a period of dynamic and regionally heterogeneous cortex growth. In this article, we show how we developed a novel infant-specific method for mapping longitudinal development of local cortical gyrification in infants. By using this method, via 219 longitudinal 3T magnetic resonance imaging scans from 73 healthy infants, we systemically and quantitatively characterized for the first time the longitudinal cortical global gyrification index (GI) and local GI (LGI) development in the first 2 years of life. We found that the cortical GI had age-related and marked development, with 16.1% increase in the first year and 6.6% increase in the second year. We also found marked and regionally heterogeneous cortical LGI development in the first 2 years of life, with the high-growth regions located in the association cortex, whereas the low-growth regions located in sensorimotor, auditory, and visual cortices. Meanwhile, we also showed that LGI growth in most cortical regions was positively correlated with the brain volume growth, which is particularly significant in the prefrontal cortex in the first year. In addition, we observed gender differences in both cortical GIs and LGIs in the first 2 years, with the males having larger GIs than females at 2 years of age. This study provides valuable information on normal cortical folding development in infancy and early childhood.


Predictors for DSM-5 nonsuicidal self-injury in female adolescent inpatients: The role of childhood maltreatment, alexithymia, and dissociation.
The purpose of this study was to examine the relationship between various adverse childhood experiences, alexithymia, and dissociation in predicting nonsuicidal self-injury (NSSI) in an inpatient sample of female adolescents. Seventy-two adolescents (aged 14-18 years) with NSSI disorder (n=46) or mental disorders without NSSI (n=26) completed diagnostic interviews and self-report measures to assess NSSI disorder according to the DSM-5 criteria, childhood maltreatment, alexithymia, and dissociation. Alexithymia and dissociation were highly prevalent in both study groups. Multivariate logistic regression analyses indicated that only alexithymia was a significant predictor for NSSI, whereas childhood maltreatment and dissociation had no predictive influence. The association between alexithymia and NSSI emphasizes the significance of emotion regulation training for female adolescents with NSSI. Efforts to reduce NSSI behavior should therefore foster skills to heighten the perception and recognition of one's own emotions.


Iron status and its relations with oxidative damage and bone loss during long-duration space flight on the International Space Station.
Increases in stored iron and dietary intake of iron during space flight have raised concern about the risk of excess iron and oxidative damage, particularly in bone. The objectives of this study were to perform a comprehensive assessment of iron status in men and women before, during, and after long-duration space flight and to quantify the association of iron status with oxidative damage and bone loss. Fasting blood and 24-h urine samples were collected from 23 crew members before, during, and after missions lasting 50 to 247 d to the International Space Station. Serum ferritin and body iron increased early in flight, and transferrin and transferrin receptors decreased later, which indicated that early increases in body iron stores occurred through the mobilization of iron to storage tissues. Acute phase proteins indicated no evidence of an inflammatory response during flight. Serum ferritin was positively correlated with the oxidative damage markers 8-hydroxy-2'-deoxyguanosine (r = 0.53, P < 0.001) and prostaglandin F2α (r = 0.26, P < 0.001), and the greater the area under the curve for ferritin during flight, the greater the decrease in bone mineral density in the total hip (P = 0.031), trochanter (P = 0.006), hip neck (P = 0.044), and pelvis (P = 0.049) after flight. Increased iron stores may be a risk factor for oxidative damage and bone resorption.


Molecular genetic analysis of the V kappa Ser group associated with two mouse light chain genetic markers. Complementary DNA cloning and southern hybridization analysis.
Previous studies (21) have shown that two mouse kappa light (L) chain variable (V) region polymorphisms, the IB-peptide and Efla markers, reflect expression of a characteristic group of V kappa regions, called V kappa Ser, by some inbred strains and not others. Expression of V kappa Ser is controlled by a locus on chromosome 6, the chromosome that contains the kappa locus. To further characterize this V kappa group and begin to analyze the basis for its strain-specific expression, full-length complementary DNA (cDNA) copies were produced of L chain mRNA from the M75 myeloma that had been induced in the C.C58 strain of mice, and which produces a V kappa Ser L chain. The C.C58 strain is congenic with BALB/cAn, differing in the region of chromosome 6 that controls expression of the V kappa polymorphisms and the Lyt-2 and Lyt-3 T cell alloantigens. The complete nucleotide sequence of this cloned cDNA was determined and compared with the nucleotide sequences the most closely related BALB/c myeloma L chains known. Results indicated significant differences throughout the variable region, but particularly toward the 5' portion of the sequence. A probe corresponding to 200 bp of the 5' end of the cloned V kappa Ser cDNA was used in Southern hybridizations of restriction digests of liver DNA from a number of inbred, recombinant, and recombinant inbred strains. Under stringent hybridization conditions, one strongly-hybridizing fragment was observed in Bam HI, Hind III, and Eco RI digests, and based on the size of the fragments, strains could be organized into two groups. The presence of strongly hybridizing Bam HI, Hind III, and Eco RI fragments of 3.2, 2.8, and 2.1 kb, respectively, was found to correlate completely with expression by the strain of the IB-peptide and Efla markers. All nonexpressor strains yielded hybridizing fragments of 7.8, 8.4, and 2.8 kb, respectively. Possible explanations for strain-specific expression of V kappa Ser-associated phenotypic markers are discussed.


Waveguides in single-crystal lithium niobate thin film by proton exchange.
The proton exchanged (PE) planar and channel waveguides in a 500 nm thick single-crystal lithium niobate thin film (lithium niobate on insulator, LNOI) were studied. The mature PE technique and strong confinement of light in the LN single-crystal thin film were used. The single mode and cut-off conditions of the channel waveguides were obtained by finite difference simulation. The results showed that the single mode channel waveguide would form if the width of the PE region was between 0.75 μm and 2.1 μm in the β(4) phase. The channel waveguide in LNOI had a much smaller mode size than that in the bulk material due to the high-refractive-index contrast. The mode size reached as small as 0.6 μm(2). in simulation. In the experiment, the refractive index and phase transition after PE in LNOI were analyzed using the prism coupling method and X-ray diffraction. Three different width waveguides (5 μm, 7 μm and 11 μm) were optically characterized. Near-field intensity distribution showed that their mode sizes were 3.3 μm(2).,5 μm(2). and 7 μm(2). The propagation losses were evaluated to be about 16 dB/cm, 12 dB/cm and 11 dB/cm, respectively. The results indicate that PE is a promising method for building more complicated photonic integrated circuits in single-crystal LN thin film.


Stability and Change in Men's Intimate Partner Violence and Substance Use in Early Adulthood.
Despite substantial evidence of the role of substance use in intimate partner violence (IPV), little is known about the impact of substance use on stability and change in the experience of IPV as both a perpetrator and a victim. Using an ethnically diverse sample of 232 men in early adulthood (mean age = 29.1, SD = 0.91), this study defined typologies of IPV based on men's reports of both perpetration and victimization; examined the potential impact of substance use, including alcohol and marijuana use, on IPV typologies over two measurement occasions; and quantified stability and change in these typologies over time. Patterns of IPV were characterized by three classes at each time point: no IPV, psychological aggression, and physical aggression. Men's regular marijuana use was associated with physical aggression contemporaneously and prospectively. Partner's problem alcohol use was associated with psychological aggression contemporaneously, suggesting that women's problem alcohol use could be a risk factor for their own and their partner's IPV perpetration. IPV appeared to remain somewhat stable over time with 67% of men remaining in the same IPV class. Among those who did transition from one typology to another, it was most often to a less severe IPV typology. Regular marijuana users were more likely to be in the physical aggression typology rather than the no IPV typology, with a higher probability of transitioning to a more severe IPV typology than nonusers. The present study has implications for prevention and intervention efforts by its ability to identify men who are at greatest risk for continued or increased violence and underscores that men's marijuana use may exacerbate IPV.


Examination of Antibody Responses as a Measure of Exposure to Malaria in the Indigenous Batwa and Their Non-Indigenous Neighbors in Southwestern Uganda.
Understanding variations in malaria transmission and exposure is critical to identify populations at risk and enable better targeting of interventions. The indigenous Batwa of southwestern Uganda have a disproportionate burden of malaria infection compared with their non-indigenous neighbors. To better understand the individual- and community-level determinants of malaria exposure, a seroepidemiological study was conducted in 10 local council cells in Kanungu District, Uganda, in April 2014. The Batwa had twice the odds of being seropositive to two Plasmodium falciparum-specific antigens, apical membrane antigen-1 and merozoite surface protein-119, compared with the non-indigenous Bakiga (odds ratio = 2.08, 95% confidence interval = 1.51-2.88). This trend was found irrespective of altitude level and after controlling for cell location. Seroconversion rates in the Batwa were more than twice those observed in the Bakiga. For the Batwa, multiple factors may be associated with higher exposure to malaria and antibody levels relative to their non-indigenous neighbors.


Chapter 19. In vitro studies of phenol coupling enzymes involved in vancomycin biosynthesis.
Oxidative phenol cross-linking reactions play a key role in the biosynthesis of glycopeptide antibiotics such as vancomycin. The vancomycin aglycone contains three cross-links between aromatic amino acid side-chains, which stabilize the folded backbone conformation required for binding to the target D-Ala-D-Ala dipeptide. At least the first cross-link is introduced into a peptide precursor whilst it is still bound as a thioester to a peptide carrier protein (PCP) domain (also called a thiolation domain) within the nonribosomal peptide synthetase. We described here methods for the solid-phase synthesis of peptides and their coupling to PCP domains, which may be useful for in vitro studies of cross-linking and related tailoring reactions during nonribosomal glycopeptide antibiotic biosynthesis.


Anomalous metallic-like transport of Co-Pd ferromagnetic nanoparticles cross-linked with π-conjugated molecules having a rotational degree of freedom.
We investigated the electron transport in Co-Pd ferromagnetic nanoparticles (Co 16%) cross-linked with oligo(phenyleneethynylene)diethanethiolate, which consists of three rotary phenylene moieties bridged by two acetylene groups, or icosane-1,20-dithiol, which consists of one alkane chain. Although the nanoparticles cross-linked with the alkane dithiols (the latter) have extremely high electrical resistance in electron transport, the resistance of the nanoparticles cross-linked with the conjugated molecules (the former) demonstrates a linear temperature dependence from room temperature to ca. 20 K; below that temperature, it has a weak temperature-dependent residual contribution with a resistance minimum around 7 K. Computational simulations suggest that the apparent metallic-like temperature dependence at high temperatures can be explained in terms of the rotational degree of freedom of the linker molecule. The rotational motion of the constituent phenylene groups, which hinders π-conjugation along the linker molecule, becomes less excited as the temperature is lowered. The successive development of a ballistic transport path through the π-conjugated linker molecule with decreasing temperature yields the metallic-like temperature dependence observed for the bridged nanoparticles. The low-temperature resistance behaviour with a minimum is a consequence of carrier scattering by the localized Co spins of Co-Pd nanoparticles randomly ordered in a ferromagnetic state that develops below the temperature of the resistance minimum.


Verlukast (MK-0679) conjugation with glutathione by rat liver and kidney cytosols and excretion in the bile.
Verlukast (MK-0679) is a potent leukotriene D4 antagonist that was under development for the treatment of bronchial asthma. A previously uncharacterized metabolite of verlukast was formed in incubations using rat liver cytosol fortified with glutathione (GSH). The metabolite was detected by HPLC and characterized by UV spectroscopy (photodiode array detection after HPLC) and capillary HPLC continuous flow-liquid secondary-ion mass spectrometry. After a large-scale incubation and isolation, it was further characterized by 500 MHz proton NMR. The metabolite is a 1,4-Michael addition product in which GSH has added to position 12 of the styryl quinoline double bond of verlukast. There is no apparent stereoselectivity because a mixture of the two possible isomers, in equal amounts, was observed by NMR. Although there was spontaneous chemical addition of GSH to verlukast (0.18 nmol/min), the reaction was shown to be enzyme-catalyzed in studies using three different preparations of rat liver cytosol at pH 7.4. Using Lineweaver-Burk analysis of experiments in which the effect of verlukast concentration on the rate of conjugation was studied, the apparent KM and Vmax were determined to be 107 +/- 22 microM (SD, N=3) and 0.66 +/- 0.21 nmol/min/mg protein, respectively. In similar studies with GSH as the variable substrate, the apparent KM and Vmax were 2.32 +/- 0.68 mM and 0.69 +/- 0.14 nmol/min/mg protein, respectively. Incubations with kidney cytosol produced the GSH, cysteinylglycine, and cysteine conjugates of verlukast. In bile collected from rats dosed intravenously with 50 mg/kg of verlukast, approximately 80% of the dose was recovered up to 4 hr postdose. The GSH conjugate accounted for 16.5% of the dose. The cysteinylglycine, cysteine, and N-acetylcysteine conjugates were observed and together accounted for 7.5%. Verlukast accounted for 14.5%, and the remainder of the metabolites (40.5%) were oxidation or acyl glucuronide metabolites.


Adult major affective disorder after prenatal exposure to an influenza epidemic.
We have previously reported an increase in schizophrenia diagnoses in a population exposed during the second trimester to the 1957 influenza epidemic. These basic findings together with a fair number of replications have been interpreted as supporting a neurodevelopmental contribution to the origins of schizophrenia. Recent neuroimaging findings suggest that affective illness may also have a neurodevelopmental origin. We examined the hypothesis that exposure to an influenza epidemic during the second trimester would increase the risk for adult major affective disorder. The subjects had been exposed as fetuses to the type A2/Singapore influenza epidemic in greater Helsinki, Finland. Control subjects were born in the 6 years before the epidemic. We found a significant (P < .001) increase in the proportion of hospital diagnoses for major affective disorder for individuals exposed to the influenza epidemic during their second trimester of fetal development compared with control subjects (13% vs 2%). This second-trimester effect seems somewhat stronger in men (16% vs 2%) (P < .001), although the rates of major affective disorder in women (8% vs 3%) (P > .05) were similar. The second-trimester effect remained when we estimated population-based rates (2.1 vs 0.6 per 1000) (P < .05) of major affective disorder. Additional analyses revealed that the increase of major affective disorder among subjects in the index group who were exposed during the second trimester was due to a significant (P < .002) elevation of unipolar forms, although a similar though not significant (P > .05) elevation was observed for the bipolar forms of major affective disorder. These data are consistent with the hypothesis concerning the possible neurodevelopmental contribution to the origins of some forms of major affective disorder, especially unipolar depressive disorder. These encouraging findings, if replicated, may suggest that some mental disorders may stem, in part, from a disturbance in the development of the fetal brain during the second trimester.


The Wnt/Ca2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes.
Tunneling nanotubes (TNTs) are actin-based transient tubular connections that allow direct communication between distant cells. TNTs play an important role in several physiological (development, immunity, and tissue regeneration) and pathological (cancer, neurodegeneration, and pathogens transmission) processes. Here, we report that the Wnt/Ca2+ pathway, an intracellular cascade that is involved in actin cytoskeleton remodeling, has a role in TNT formation and TNT-mediated transfer of cargoes. Specifically, we found that Ca2+ /calmodulin-dependent protein kinase II (CaMKII), a transducer of the Wnt/Ca2+ pathway, regulates TNTs in a neuronal cell line and in primary neurons. We identified the β isoform of CaMKII as a key molecule in modulating TNT formation and transfer, showing that this depends on the actin-binding activity of the protein. Finally, we found that the transfer of vesicles and aggregated α-synuclein between primary neurons can be regulated by the activation of the Wnt/Ca2+ pathway. Our findings suggest that Wnt/Ca2+ pathway could be a novel promising target for therapies designed to impair TNT-mediated propagation of pathogens.


A mark of disease: how mRNA modifications shape genetic and acquired pathologies.
RNA modifications have recently emerged as a widespread and complex facet of gene expression regulation. Counting more than 170 distinct chemical modifications with far-reaching implications for RNA fate, they are collectively referred to as the epitranscriptome. These modifications can occur in all RNA species, including messenger RNAs (mRNAs) and noncoding RNAs (ncRNAs). In mRNAs the deposition, removal, and recognition of chemical marks by writers, erasers and readers influence their structure, localization, stability, and translation. In turn, this modulates key molecular and cellular processes such as RNA metabolism, cell cycle, apoptosis, and others. Unsurprisingly, given their relevance for cellular and organismal functions, alterations of epitranscriptomic marks have been observed in a broad range of human diseases, including cancer, neurological and metabolic disorders. Here, we will review the major types of mRNA modifications and editing processes in conjunction with the enzymes involved in their metabolism and describe their impact on human diseases. We present the current knowledge in an updated catalog. We will also discuss the emerging evidence on the crosstalk of epitranscriptomic marks and what this interplay could imply for the dynamics of mRNA modifications. Understanding how this complex regulatory layer can affect the course of human pathologies will ultimately lead to its exploitation toward novel epitranscriptomic therapeutic strategies.


A new solution path algorithm in support vector regression.
In this paper, regularization path algorithms were proposed as a novel approach to the model selection problem by exploring the path of possibly all solutions with respect to some regularization hyperparameter in an efficient way. This approach was later extended to a support vector regression (SVR) model called epsilon-SVR. However, the method requires that the error parameter epsilon be set a priori. This is only possible if the desired accuracy of the approximation can be specified in advance. In this paper, we analyze the solution space for epsilon-SVR and propose a new solution path algorithm, called epsilon-path algorithm, which traces the solution path with respect to the hyperparameter epsilon rather than lambda. Although both two solution path algorithms possess the desirable piecewise linearity property, our epsilon-path algorithm overcomes some limitations of the original lambda-path algorithm and has more advantages. It is thus more appealing for practical use.


Decreased systemic formation of prostaglandin E and prostacyclin, and unchanged thromboxane formation, in alcoholics during withdrawal as estimated from metabolites in urine.
1. The rates of secretion into the circulation of prostaglandin E, prostacyclin, and thromboxane A2 were estimated in male alcoholics on the third day of withdrawal and in control subjects by measuring appropriate metabolites in urine. 2. Urinary levels of tetranor-5,11-diketo-7 alpha-hydroxyprostane-1,16-dioic acid (the major urinary metabolite of prostaglandins E1 and E2), of 2,3-dinor-6-keto-prostaglandin F1 alpha (the major urinary metabolite of prostacyclin) and of 6-keto-prostaglandin F1 alpha (the stable hydrolysis product of prostacyclin) were significantly different from the normal subjects in the alcoholic group. In contrast, 2,3-dinor-thromboxane B2 (the major urinary metabolite of thromboxane A2) and thromboxane B2 (the stable hydrolysis product of thromboxane A2) were not significantly different between the groups. 3. These data suggest that the ratio of the vasodilator prostanoids prostaglandin E and prostacyclin and the vasoconstrictor prostanoid thromboxane A2 is lower than in normal subjects, in alcoholics during withdrawal. This may be one causal factor for the higher incidence of hypertension observed in withdrawing alcoholics compared with control subjects.


Progressive Low-Grade Glioma: Assessment of Prognostic Importance of Histologic Reassessment and MRI Findings.
In patients with progressive low-grade glioma (LGG), the presence of new magnetic resonance imaging (MRI) enhancement is commonly used as an indicator of malignant degeneration, but its accuracy in this setting is uncertain. We characterize the ability of new MRI enhancement to serve as a surrogate for histologic grade in patients with progressive LGG, and to explore the prognostic value of new MRI enhancement, pathologic grade, and extent of resection. Patients at our institution with World Health Organization grade II glioma diagnosed between 1994 and 2010 and who underwent repeat biopsy or resection at progression were retrospectively reviewed (n = 108). The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were characterized. A multivariable proportional hazards model was used to test associations with overall survival (OS), and Kaplan-Meier curves were constructed to compare OS between patient subsets. The positive predictive value, negative predictive value, sensitivity, and specificity of new MRI enhancement were 82%, 77%, 92%, and 57%, respectively. In patients without malignant degeneration, new MRI enhancement was associated with inferior median OS (92.5 months vs. not reached; P = 0.03). In patients with malignant degeneration, gross or near total resection was associated with improved median OS (58.8 vs. 28.8 months; P = 0.02). In patients with progressive LGG, new MRI enhancement and pathologic grade were discordant in greater than 20% of cases. Pathologic confirmation of grade should therefore be attempted, when safe, to dictate management. Beyond functioning as a surrogate for pathologic grade, new MRI enhancement may predict for worse outcomes, a concept that merits prospective investigation.


Molecular mechanism of anti-prostate cancer activity of Scutellaria baicalensis extract.
Scutellaria baicalensis is a widely used Chinese herbal medicine historically used in antiinflammatory and anticancer therapy. The goals of the study were to 1) determine its in vitro and in vivo anti-prostate cancer activity, 2) investigate its molecular mechanism directed at cell proliferation control including cyclooxygenase-2(COX-2) prostaglandin E2 (PGE2) and cyclins/cdks pathways, and 3) compare it with those of PC-SPES (PC stands for prostate cancer and spes is Latin for hope), a former herbal mixture for prostate cancer treatment of which S. baicalensis is a major constituent. Two human prostate cancer cell lines (LNCaP, androgen dependent, and PC-3, androgen independent) were assessed for growth inhibition. S. baicalensis exerted dose- and time-dependent increased growth inhibition in both cell lines. However, the PC-3 cells IC50 (50% growth inhibition concentration) were slightly more sensitive than LNCaP cells (IC50=0.15 mg/ml), although the former is androgen independent. S. baicalensis was more effective in inhibition of cell growth compared with PC-SPES (IC50=0.38 mg/ml for PC-3 cells). Significant reduction of PGE2 synthesis in both cells after treatment with S. baicalensis resulted from direct inhibition of COX-2 activity rather than COX-2 protein suppression. S. baicalensis also inhibited prostate-specific antigen production in LNCaP cells. Finally, S. baicalensis suppressed expression of cyclin D1 in LNCaP cells, resulting in a G1 phase arrest, while inhibiting cdk1 expression and kinase activity in PC-3 cells, ultimately leading to a G2/M cell cycle arrest. Animal studies showed a 50% reduction in tumor volume after a 7-wk treatment period. This study demonstrated that S. baicalensis may be a novel anticancer agent for the treatment of prostate cancer.


Resin-bonded restorations: a strategy for managing anterior tooth loss in adolescence.
In children or adolescents with anterior tooth loss, space closure with the patient's own teeth should be considered as the first choice to avoid lifelong restorative needs. Thorough diagnostics and treatment planning are required when autotransplantation or orthodontic space closure is considered. If these options are not indicated and a single tooth implant restoration is considered, implant placement should be postponed until adulthood, particularly in young women and in patients with hyperdivergent skeletal growth pattern. A ceramic resin-bonded fixed dental prosthesis with 1 retainer is an excellent treatment solution for the interim period; it may also serve as a long-term restoration, providing that sound enamel structure is present, sufficient framework dimensions have been provided, adhesive cementation techniques have been meticulously applied, and functional contacts of the cantilever pontic avoided. In contrast, a resin-bonded fixed dental prosthesis with a metal framework and retentive preparation is indicated if the palatal enamel structure is compromised, interocclusal clearance is limited, splinting (such as after orthodontic treatment) is required, or more than 1 tooth has to be replaced.


Nurses who work outside nursing.
The desire to care for people, a family history of professional health care work, and security in career choice are documented reasons for entering nursing. Reasons for leaving include workload, unsafe work environments and harassment. The relationship between these factors and the time nurses spend in the profession has not been explored. This paper reports a study with people who have left nursing, to investigate why they became a nurse, how long they stayed in nursing, and their reasons for leaving. A questionnaire was mailed to Registered Nurses currently working outside nursing, seeking respondents' reasons for entering and leaving nursing, and perceptions of the skills gained from nursing and the ease of adjustment to working in a non-nursing environment. Data analysis included descriptive statistics, exploratory and confirmatory factor analysis, correlational analysis and linear and multiple regression analysis. A model incorporating the factors 'altruistic reasons', 'default choice' and 'stepping stone' explained 36.2% of the variance in reasons for becoming a nurse. A model incorporating the factors 'legal and employer', 'external values and beliefs about nursing', 'professional practice', 'work life/home life' and 'contract requirements' explained 55.4% of the variance in reasons for leaving nursing. Forty-eight per cent of the variance in tenure in nursing practice was explained through personal characteristics of nurses (36%), reasons for becoming a nurse (7%) and reasons for leaving (6%). The reasons why nurses entered or left the profession were varied and complex. While personal characteristics accounted for a large component of tenure in nursing, those managing the nursing workforce should consider professional practice issues and the balance between work life and home life.


The distribution of mitochondrial DNA haplogroup H in southern Iberia indicates ancient human genetic exchanges along the western edge of the Mediterranean.
The structure of haplogroup H reveals significant differences between the western and eastern edges of the Mediterranean, as well as between the northern and southern regions. Human populations along the westernmost Mediterranean coasts, which were settled by individuals from two continents separated by a relatively narrow body of water, show the highest frequencies of mitochondrial haplogroup H. These characteristics permit the analysis of ancient migrations between both shores, which may have occurred via primitive sea crafts and early seafaring. We collected a sample of 750 autochthonous people from the southern Iberian Peninsula (Andalusians from Huelva and Granada provinces). We performed a high-resolution analysis of haplogroup H by control region sequencing and coding SNP screening of the 337 individuals harboring this maternal marker. Our results were compared with those of a wide panel of populations, including individuals from Iberia, the Maghreb, and other regions around the Mediterranean, collected from the literature. Both Andalusian subpopulations showed a typical western European profile for the internal composition of clade H, but eastern Andalusians from Granada also revealed interesting traces from the eastern Mediterranean. The basal nodes of the most frequent H sub-haplogroups, H1 and H3, harbored many individuals of Iberian and Maghrebian origins. Derived haplotypes were found in both regions; haplotypes were shared far more frequently between Andalusia and Morocco than between Andalusia and the rest of the Maghreb. These and previous results indicate intense, ancient and sustained contact among populations on both sides of the Mediterranean. Our genetic data on mtDNA diversity, combined with corresponding archaeological similarities, provide support for arguments favoring prehistoric bonds with a genetic legacy traceable in extant populations. Furthermore, the results presented here indicate that the Strait of Gibraltar and the adjacent Alboran Sea, which have often been assumed to be an insurmountable geographic barrier in prehistory, served as a frequently traveled route between continents.


Quantitative gait analysis under dual-task in older people with mild cognitive impairment: a reliability study.
Reliability of quantitative gait assessment while dual-tasking (walking while doing a secondary task such as talking) in people with cognitive impairment is unknown. Dual-tasking gait assessment is becoming highly important for mobility research with older adults since better reflects their performance in the basic activities of daily living. Our purpose was to establish the test-retest reliability of assessing quantitative gait variables using an electronic walkway in older adults with mild cognitive impairment (MCI) under single and dual-task conditions. The gait performance of 11 elderly individuals with MCI was evaluated using an electronic walkway (GAITRite System) in two sessions, one week apart. Six gait parameters (gait velocity, step length, stride length, step time, stride time, and double support time) were assessed under two conditions: single-task (sG: usual walking) and dual-task (dG: counting backwards from 100 while walking). Test-retest reliability was determined using intra-class correlation coefficient (ICC). Gait variability was measured using coefficient of variation (CoV). Eleven participants (average age = 76.6 years, SD = 7.3) were assessed. They were high functioning (Clinical Dementia Rating Score = 0.5) with a mean Mini-Mental Status Exam (MMSE) score of 28 (SD = 1.56), and a mean Montreal Cognitive Assessment (MoCA) score of 22.8 (SD = 1.23). Under dual-task conditions, mean gait velocity (GV) decreased significantly (sGV = 119.11 +/- 20.20 cm/s; dGV = 110.88 +/- 19.76 cm/s; p = 0.005). Additionally, under dual-task conditions, higher gait variability was found on stride time, step time, and double support time. Test-retest reliability was high (ICC>0.85) for the six parameters evaluated under both conditions. In older people with MCI, variability of time-related gait parameters increased with dual-tasking suggesting cognitive control of gait performance. Assessment of quantitative gait variables using an electronic walkway is highly reliable under single and dual-task conditions. The presence of cognitive impairment did not preclude performance of dual-tasking in our sample supporting that this methodology can be reliably used in cognitive impaired older individuals.


Familial risk and ADHD-specific neural activity revealed by case-control, discordant twin pair design.
Individuals with ADHD, as well as their family members who do not meet clinical criteria, have shown deficits in executive function. However, it remains unclear whether underlying neural alterations are familial or ADHD-specific. To investigate this issue, neural activation underlying executive function was assessed using functional magnetic resonance imaging during performance of a Stroop task in three groups of individuals: 20 young adults who were diagnosed with ADHD in childhood, their 20 dizygotic co-twins without ADHD in childhood, and 20 unrelated controls selected from dizygotic twin pairs in which neither twin had ADHD in childhood (total n=60). Implicating the frontoparietal network as a location of effects specific to ADHD, activation in the superior frontal (Brodmann's Area - BA 6) and parietal regions (BA 40) was significantly reduced in twins with childhood ADHD compared to both their control co-twins and unrelated control twins. Consistent with familial influences, activity in the anterior cingulate and insula was significantly reduced in both the twins with ADHD and their co-twins compared to the unrelated controls. These results show that both ADHD-specific and familial influences related to an ADHD diagnosis impact neural systems underlying executive function.


Daily expression of clock genes in whole blood cells in healthy subjects and a patient with circadian rhythm sleep disorder.
In recent years, circadian rhythm sleep disorders in humans have been increasing. Clinical features characteristic of this disorder are well known, but the specific causes remain unknown. However, various derangements of circadian expression of the clock gene are a probable cause of this disease. We have attempted to elucidate the relationship between the expression of the clock genes in whole blood cells and the clinical features characteristic of this disorder. In this study, we indicate the daily expression of clock genes period (Per) 1, 2, 3, Bmal1, and Clock in whole blood cells in 12 healthy male subjects. The peak phase of Per1, Per2, and Per3 appeared in the early morning, whereas that of Bmal1 and Clock appeared in the midnight hours. Furthermore, in one patient case with circadian rhythm sleep disorder, we observed variations of the peak phase in clock genes by treatments such as light therapy, exercise therapy, and medicinal therapy. This study suggested that the monitoring of human clock genes in whole blood cells, which may be functionally important for the molecular control of the circadian pacemaker as well as in suprachiasmatic nucleus, might be useful to evaluate internal synchronization.


Self-Serving Altruism? The Lure of Unethical Actions that Benefit Others.
In three experiments, we propose and find that individuals cheat more when others can benefit from their cheating and when the number of beneficiaries of wrongdoing increases. Our results indicate that people use moral flexibility to justify their self-interested actions when such actions benefit others in addition to the self. Namely, our findings suggest that when people's dishonesty would benefit others, they are more likely to view dishonesty as morally acceptable and thus feel less guilty about benefiting from cheating. We discuss the implications of these results for collaborations in the social realm.


A receptor for the selective uptake and degradation of proteins by lysosomes.
Multiple pathways of protein degradation operate within cells. A selective protein import pathway exists for the uptake and degradation of particular cytosolic proteins by lysosomes. Here, the lysosomal membrane glycoprotein LGP96 was identified as a receptor for the selective import and degradation of proteins within lysosomes. Specific substrates of this proteolytic pathway bound to the cytosolic tail of a 96-kilodalton lysosomal membrane protein in two different binding assays. Overexpression of human LGP96 in Chinese hamster ovary cells increased the activity of the selective lysosomal proteolytic pathway in vivo and in vitro.


Autophagy within the antigen donor cell facilitates efficient antigen cross-priming of virus-specific CD8+ T cells.
Cross-presentation of cell-associated antigen is important in the priming of CD8(+) T-cell responses to proteins that are not expressed by antigen-presenting cells (APCs). In vivo, dendritic cells are the main cross-presenting APC, and much is known regarding their ability to capture and process cell-associated antigen. In contrast, little is known about the way death effector pathways influence the efficiency of cross-priming. Here, we compared two important mechanisms of programmed cell death: classical apoptosis, as it occurs in wild-type (WT) fibroblasts, and caspase-independent cell death, which occurs with increased features of autophagy in Bax/Bak(-/-) fibroblasts. We assessed virally infected WT and Bax/Bak(-/-) fibroblasts as a source of cell-associated antigen. We found that immunization with cells undergoing autophagy before cell death was superior in facilitating the cross-priming of antigen-specific CD8(+) T cells. Strikingly, silencing of Atg5 expression inhibited priming. We interpret this to be a novel form of 'immunogenic death' with the enhanced priming efficiency being a result of persistent MHC I cross-presentation and the induction of type I interferons. These results offer the first molecular evidence that catabolic pathways, including autophagy, influence the efficiency of cross-priming. We predict that targeting the autophagy cascade may provide a therapeutic strategy for achieving robust cross-priming of viral and tumor-specific CD8(+) T cells.


Facile synthesis of 3D N-doped porous carbon nanosheets as highly active electrocatalysts toward the reduction of hydrogen peroxide.
Constructing three-dimensional (3D) conductive frameworks with high specific surface areas and porous structures is indispensable for their applications as electrocatalysts. In this work, we illustrate for the first time that 3D N-doped porous carbon nanosheets (3D-NS), which are synthesized via a facile one-pot pyrolysis reaction using glucose and melamine as raw materials, can serve as high performance and green electrocatalysts for the reduction of H2O2. Moreover, a series of 3D-NS samples with a controllable content of nitrogen were obtained by adjusting the calcination temperature. From our research, the 3D-NS obtained at 900 °C possessed high specific surface areas, porous structures, proper dosages of N atoms, suitable degrees of graphitization and defects. Furthermore, we also illustrate their application in H2O2 electrochemical sensing in physiological environments. Under optimum conditions, the 3D-NS-based sensor displays a wide linear scope in the range of 0.5-14 000 μM and a low detection limit of 0.18 μM (S/N = 3). Therefore, with desirable selectivity, stability and anti-interference performance, the proposed sensor can be feasibly applied to detect H2O2 in human serum samples.


Regional chemotherapy for colorectal liver metastases: a phase II evaluation of targeted hepatic arterial 5-fluorouracil for colorectal liver metastases.
The results of systemic chemotherapy in patients with liver metastases from colorectal cancer remain dismal. Regional chemotherapy has been advocated as a method of improving the delivery of cytotoxic drugs to tumour, while minimizing systemic toxicity. The use of vasoactive agents to redistribute arterial blood flow towards tumour, and of biodegradable microspheres to slow tumour blood flow, have also been suggested as methods of further improving tumour exposure to drug. We present 21 patients who received intrahepatic arterial chemotherapy for colorectal liver metastases. Combined treatment (angiotensin II, albumin microspheres and 5-fluorouracil) was administered 4-6 weekly, and bolus 5-fluorouracil was given in the intervening weeks. Toxicity was minimal. Responses were seen in seven patients. Fewer than half of the deaths were from liver metastases; a quarter of the patients died from non-cancer-related causes. Survival was prolonged in the treated group compared with historical controls. These results suggest that this regimen has activity in patients with colorectal liver metastases.


Local Diffusion Homogeneity Provides Supplementary Information in T2DM-Related WM Microstructural Abnormality Detection.
Objectives: We aimed to investigate whether an inter-voxel diffusivity metric (local diffusion homogeneity, LDH), can provide supplementary information to traditional intra-voxel metrics (i.e., fractional anisotropy, FA) in white matter (WM) abnormality detection for type 2 diabetes mellitus (T2DM). Methods: Diffusion tensor imaging was acquired from 34 T2DM patients and 32 healthy controls. Voxel-based group-difference comparisons based on LDH and FA, as well as the association between the diffusion metrics and T2DM risk factors [i.e., body mass index (BMI) and systolic blood pressure (SBP)], were conducted, with age, gender and education level controlled. Results: Compared to the controls, T2DM patients had higher LDH in the pons and left temporal pole, as well as lower FA in the left superior corona radiation (p < 0.05, corrected). In T2DM, there were several overlapping WM areas associated with BMI as revealed by both LDH and FA, including right temporal lobe and left inferior parietal lobe; but the unique areas revealed only by using LDH included left inferior temporal lobe, right supramarginal gyrus, left pre- and post-central gyrus (at the semiovale center), and right superior radiation. Overlapping WM areas that associated with SBP were found with both LDH and FA, including right temporal pole, bilateral orbitofrontal area (rectus gyrus), the media cingulum bundle, and the right cerebellum crus I. However, the unique areas revealed only by LDH included right inferior temporal lobe, right inferior occipital lobe, and splenium of corpus callosum. Conclusion: Inter- and intra-voxel diffusivity metrics may have different sensitivity in the detection of T2DM-related WM abnormality. We suggested that LDH could provide supplementary information and reveal additional underlying brain changes due to diabetes.


Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801.
Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 μg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner.


Viral adaptation to immune selection pressure by HLA class I-restricted CTL responses targeting epitopes in HIV frameshift sequences.
CD8+ cytotoxic T lymphocyte (CTL)-mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q<0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03-restricted +2 frame-encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.


Human resources for health strategies adopted by providers in resource-limited settings to sustain long-term delivery of ART: a mixed-methods study from Uganda.
Human resources for health (HRH) constraints are a major barrier to the sustainability of antiretroviral therapy (ART) scale-up programs in Sub-Saharan Africa. Many prior approaches to HRH constraints have taken a top-down trend of generalized global strategies and policy guidelines. The objective of the study was to examine the human resources for health strategies adopted by front-line providers in Uganda to sustain ART delivery beyond the initial ART scale-up phase between 2004 and 2009. A two-phase mixed-methods approach was adopted. In the first phase, a survey of a nationally representative sample of health facilities (n = 195) across Uganda was conducted. The second phase involved in-depth interviews (n = 36) with ART clinic managers and staff of 6 of the 195 health facilities purposively selected from the first study phase. Quantitative data was analysed based on descriptive statistics, and qualitative data was analysed by coding and thematic analysis. The identified strategies were categorized into five themes: (1) providing monetary and non-monetary incentives to health workers on busy ART clinic days; (2) workload reduction through spacing ART clinic appointments; (3) adopting training workshops in ART management as a motivation strategy for health workers; (4) adopting non-physician-centred staffing models; and (5) devising ART program leadership styles that enhanced health worker commitment. Facility-level strategies for responding to HRH constraints are feasible and can contribute to efforts to increase country ownership of HIV programs in resource-limited settings. Consideration of the human resources for health strategies identified in the study by ART program planners and managers could enhance the long-term sustainment of ART programs by providers in resource-limited settings.


Bullying in schools: the state of knowledge and effective interventions.
During the school years, bullying is one of the most common expressions of violence in the peer context. Research on bullying started more than forty years ago, when the phenomenon was defined as 'aggressive, intentional acts carried out by a group or an individual repeatedly and over time against a victim who cannot easily defend him- or herself'. Three criteria are relevant in order to define aggressive behaviour as bullying: (1) repetition, (2) intentionality and (3) an imbalance of power. Given these characteristics, bullying is often defined as systematic abuse of power by peers. It is recognised globally as a complex and serious problem. In the present paper, we discuss the prevalence, age and gender differences, and various types of bullying, as well as why it happens and how long it lasts, starting from the large surveys carried out in western countries and to a lower extent in low- and middle-income countries. The prevalence rates vary widely across studies; therefore, specific attention will be devoted to the definition, time reference period and frequency criterion. We will also focus on risk factors as well as short- and long-term outcomes of bullying and victimisation. Finally, a section will be dedicated to review what is known about effective prevention of bullying.


Epidemiology and predictors of short-term mortality in symptomatic venous thromboembolism.
The epidemiology of symptomatic venous thromboembolism (VTE) in Taiwan has not been well investigated. The aim of this study was to report on the epidemiology and short-term prognosis of symptomatic VTE. This nationwide population-based cohort study used the Taiwanese National Health Insurance claims databases to identify adults older than 18 years of age with symptomatic VTE diagnosed in 2002. We investigated the clinical features of VTE and determined independent risk factors of 1-month mortality. A total of 2,774 patients were identified with a mean age of 62.8 years and the female-to-male ratio was 1.15:1. The crude incidence of symptomatic VTE was 16.5 per 100,000 persons, which steadily increased with age, ranging from 4 per 100,000 in patients <40 years old to 108 per 100,000 in patients ≥ 80 years. We observed no seasonal and meteorological variations in the incidence of VTE. The overall 1-month mortality rate was 8.8%, with 7.1% in deep venous thrombosis and 12.9% in pulmonary embolism. Multivariate analysis demonstrated that pulmonary embolism, cancer, neurologic disease with extremity paresis or paralysis, older age, longer hospital stay, and major abdominal and thoracic surgery in the 3 months preceding VTE were independent predictors of 1-month death. Although the incidence of VTE was lower in Taiwanese populations than in Western ones, short-term mortality rates were high in specific populations. These findings suggest optimal treatment is needed in higher-risk patients.


Functional multidrug resistance phenotype associated with combined overexpression of Pgp/MDR1 and MRP together with 1-beta-D-arabinofuranosylcytosine sensitivity may predict clinical response in acute myeloid leukemia.
Overexpression of P-glycoprotein (Pgp) or MDR1 mRNA has been shown to be a negative prognostic factor for clinical outcome in acute myeloid leukemia (AML). However, resistance to chemotherapy also occurs in the absence of Pgp overexpression. Therefore, besides Pgp expression, we have assessed the expression of MRP, a novel drug transporter gene, along with the functional multidrug-resistant (MDR) phenotype of leukemic cells. These MDR parameters are correlated with clinical outcome in individual patients. We found functional changes in fresh leukemic cells from de novo or relapsed patients similar to those reported for tumor cell lines with the MDR phenotype. These changes were reduced drug accumulation as assessed with radiolabeled doxorubicin (factor 1.6), daunomycin (factor 1.13), and vincristine (factor 1.6) in patients who were refractory to the combination treatment of 1-beta-D-arabinofuranosylcytosine (ara-C) and daunomycin or mitoxantrone as opposed to patients who had complete responses. Also, the intracellular distribution of doxorubicin fluorescence (nuclear/cytoplasmic ratio), as assessed with laser scan microscopy, was reduced 1.4-fold in blasts from refractory patients. Based on historically known clinical response to single-agent daunomycin or ara-C in the group of responding de novo AML patients, we have set a threshold level such that a defined part of the samples that had the highest drug accumulation or nuclear to cytoplasmic ratios were above this threshold value. This allowed discrimination between patients responding to daunomycin from those who were refractory to this drug. By using this threshold level, in the refractory group clinical resistance corresponded with high sensitivity with a resistant phenotype. A similar threshold was set for the data of the in vitro ara-C sensitivity test. By combining both assays for all individual patients, clinical refractoriness as well as sensitivity could be predicted with high accuracy. There appeared to be no stringent relationship between the functional MDR phenotype with expression of either Pgp (fluorescence-activated cell sorting analysis) or MRP mRNA (RNase protection). However, by combining both parameters the functional MDR phenotype correlated with the overexpression of either one or both of the parameters in 94% of the samples studied. It is concluded that this combined overexpression in conjunction with functional changes for MDR drugs and ara-C reveal a correlation of MDR phenotype with clinical resistance to combination chemotherapy in AML patients and hereby may adequately predict clinical MDR in individual AML patients.


Chronic diseases in male veterans with multiple sclerosis.
Chronic disease risk may be high in people with multiple sclerosis (MS). Our objective was to identify chronic health conditions that may disproportionately affect male veterans with MS. We collected primary survey data for male veterans with MS (n = 1,142) in 2003 and 2004 and compared the data with 2003 Behavioral Risk Factor Surveillance System secondary data for comparison groups without MS (veteran population, n = 31,500; general population = 68,357). We compared disease prevalence by group and identified variables associated with chronic diseases in male veterans with MS. Overall, veterans with MS had a high prevalence of hypercholesterolemia (49%), hypertension (47%), diabetes (16%), coronary heart disease (11%), and stroke (7%). Overall and for the subset of people aged 50 years or older, diabetes, hypertension, hypercholesterolemia, coronary heart disease, and stroke were significantly more prevalent among male veterans with MS than among the general population. Diabetes, hypertension, hypercholesterolemia, and stroke were more prevalent overall among male veterans with MS than among the general veteran population; however, except for stroke, differences were not significant for the group aged 50 or older. Explanatory variables (eg, age, education, race) and dynamic associations between conditions (higher odds for each when ≥ 1 of the other conditions were present) for chronic disease in men with MS were similar to findings in the general population literature for select conditions. These findings raise awareness of chronic disease in a veteran cohort and help bridge a gap in the literature on chronic disease epidemiology in men with MS. We identified chronic disease priorities that may benefit from focused interventions to reduce disparities.


When does combining markers improve classification performance and what are implications for practice?
When an existing standard marker does not have sufficient classification accuracy on its own, new markers are sought with the goal of yielding a combination with better performance. The primary criterion for selecting new markers is that they have good performance on their own and preferably be uncorrelated with the standard. Most often linear combinations are considered. In this paper, we investigate the increment in performance that is possible by combining a novel continuous marker with a moderately performing standard continuous marker under a variety of biologically motivated models for their joint distribution. We find that an uncorrelated continuous marker with moderate performance on its own usually yields only minimally improved performance. We identify other settings that lead to large improvements, including a novel marker that has very poor performance on its own but is highly correlated with the standard and a novel marker with poor to moderate performance that is highly correlated with the standard but only in one class category. These results suggest changing current strategies for identifying markers to be included in panels for possible combination. Using simulated and real datasets, we examine the merits of a broadened strategy that selects panels of markers as candidates on the basis of their joint performance with existing markers, compared with the standard strategy that selects markers on the basis of their marginal performance. We find that a broadened strategy can be fruitful but necessitates using studies with large numbers of subjects.


Purification and properties of (S)-tetrahydroprotoberberine oxidase from suspension-cultured cells of Berberis wilsoniae.
A novel oxidase, catalyzing in the presence of oxygen the removal of four hydrogen atoms from a number of tetrahydroprotoberberines with simultaneous production of 1 mol H2O2 and H2O each, has been discovered and purified to homogeneity from Berberis wilsoniae cell cultures. This enzyme, (S)-tetrahydroprotoberberine oxidase, exhibited strict specificity for the (S)-enantiomer of tetrahydroprotoberberines and 1-benzylisoquinoline alkaloids, a pH optimum at 8.9, a molecular mass of 105 kDa and consisted of two subunits each of 53 kDa and covalently bound flavin. The Km values for (S)-scoulerine and (S)-norreticuline were 25 microM and 150 microM respectively. Concentration of the end-products, either protoberberines or H2O2, greater than 0.5 mM caused severe enzyme inhibition. This catalyst was responsible for the conversion of (S)-tetrahydrocolumbamine to the key intermediate, columbamine, in the metabolic pathway leading to berberine, jatrorrhizine and palmatine.


A framework for health numeracy: how patients use quantitative skills in health care.
Our objective of this study is to develop a conceptual framework for the construct of health numeracy based on patient perceptions, using a cross-sectional, qualitative design. Interested participants (n=59) meeting eligibility criteria (age 40-74, English speaking) were assigned to one of six focus groups stratified by gender and educational level (low, medium, high). Fifty-three percent were male, and 47% were female. Sixty-one percent were white non-Hispanic, and 39% were of minority race or ethnicity. Participants were randomly selected from three primary care sites associated with an academic medical center. Focus group discussions were held in May 2004 and focused on how numbers are used in the health care setting. Data were presented from clinical trials to further explore how quantitative information is used in health communication and decision making. Focus groups were audio and videotaped; verbatim transcripts were prepared and analyzed. A framework of health numeracy was developed to reflect the themes that emerged. Three broad conceptual domains for health numeracy were identified: primary numeric skills, applied health numeracy, and interpretive health numeracy. Across domains, results suggested that numeracy contains an emotional component, with both positive and negative affect reflected in patient numeracy statements. We conclude that health numeracy is a multifaceted construct that includes applied and interpretive components and is influenced by patient affect.


Automatic processing of political preferences in the human brain.
Individual political preferences as expressed, for instance, in votes or donations are fundamental to democratic societies. However, the relevance of deliberative processing for political preferences has been highly debated, putting automatic processes in the focus of attention. Based on this notion, the present study tested whether brain responses reflect participants' preferences for politicians and their associated political parties in the absence of explicit deliberation and attention. Participants were instructed to perform a demanding visual fixation task while their brain responses were measured using fMRI. Occasionally, task-irrelevant images of German politicians from two major competing parties were presented in the background while the distraction task was continued. Subsequent to scanning, participants' political preferences for these politicians and their affiliated parties were obtained. Brain responses in distinct brain areas predicted automatic political preferences at the different levels of abstraction: activation in the ventral striatum was positively correlated with preference ranks for unattended politicians, whereas participants' preferences for the affiliated political parties were reflected in activity in the insula and the cingulate cortex. Using an additional donation task, we showed that the automatic preference-related processing in the brain extended to real-world behavior that involved actual financial loss to participants. Together, these findings indicate that brain responses triggered by unattended and task-irrelevant political images reflect individual political preferences at different levels of abstraction.


Age-related macular degeneration: A two-level model hypothesis.
Age-related diseases, including age-related macular degeneration (AMD), are of growing importance in a world where population ageing has become a dominant global trend. Although a wide variety of risk factors for AMD have been identified, age itself remains by far the most important risk factor, making it an urgent priority to understand the connections between underlying ageing mechanisms and pathophysiology of AMD. Ageing is both multicausal and variable, so that differences between individuals in biological ageing processes are the focus of a growing number of pathophysiological studies seeking to explain how ageing contributes to chronic, age-related conditions. The aim of this review is to integrate the available knowledge on the pathophysiology of AMD within the framework of the biology of ageing. One highly significant feature of biological ageing is systemic inflammation, which arises as a second-level response to a first level of molecular damage involving oxidative stress, mutations etc. Combining these insights, the various co-existing pathophysiological explanations in AMD arrange themselves according to a two-level hypothesis. Accordingly, we describe how AMD can be considered the consequence of age-related random accumulation of molecular damage at the ocular level and the subsequent systemic inflammatory host response thereof. We summarize evidence and provide original data to enlighten where evidence is lacking. Finally, we discuss how this two-level hypothesis provides a foundation for thoughts and future studies in prevention, prognosis, and intervention.


Pharmacodynamics and pharmacokinetics of oral topotecan in patients with advanced solid tumours and impaired renal function.
The aim of the study was to determine the effect of renal impairment and prior platinum-based chemotherapy on the toxicity and pharmacokinetics of oral topotecan and to identify recommended doses for patients with renal impairment or prior platinum-based (PB) chemotherapy. A multicentre phase I toxicity and pharmacokinetic study of oral topotecan was conducted in patients with advanced solid tumours. Patients were grouped by normal renal function with limited or prior PB chemotherapy or impaired renal function (mild [creatinine clearance (CLcr) = 50-79 ml min(-1) ], moderate [CLcr = 30-49 ml min(-1) ], severe [CLcr <30 ml min(-1) ]). Fifty-nine patients were evaluable. Topotecan lactone and total topotecan area under the concentration-time curve (AUC) was significantly increased in patients with moderate and severe renal impairment (109% and 174%, respectively, topotecan lactone and 148% and 298%, respectively, total topotecan). Asian patients (23 in total) had higher AUCs than non-Asian patients with the same degree of renal impairment. Thirteen dose-limiting toxicities (DLTs) were observed, which were mostly haematological. The maximum tolerated dose (MTD) was 2.3 mg m(-2) day(-1) , given on days 1 to 5 in a 21 day cycle, for patients with prior PB chemotherapy or mild renal impairment, and 1.2 mg m(-2) day(-1) for patients with moderate renal impairment (suggested dose 1.9 mg m(-2) day(-1) for non-Asians). Due to incomplete enrolment of patients with severe renal impairment, the MTD was determined as ≥ 0.6 mg m(-2) day(-1) in this cohort. Oral topotecan dose adjustments are not required in patients with prior PB chemotherapy or mildly impaired renal function, but reduced doses are required for patients with moderate or severe renal impairment.


Explanations of illness experiences among community mental health patients: an argument for the use of an ethnographic interview method in routine clinical care.
Cultural variations in perceptions of mental distress are important issues for healthcare. They can affect communication between patients and professionals and may be a root cause for misdiagnosis, patient disengagement, and disparities in access, outcomes and overall experiences of treatment by patients. Taking into account patients' explanatory models (EMs) of mental distress is fundamental to patient-centred care, and improved outcomes. This paper reports on the outcomes from the Cultural Consultation Service, commissioned in an inner-city London borough. We used a narrative-based ethnographic method of assessment, in which community mental health patients referred for a cultural consultation were interviewed using Barts Explanatory Model Inventory and Checklist (BEMI) to assess the EMs of their mental distress. Patients mainly attributed the causes and consequences of their mental distress to emotional and psychological factors, which were inextricably linked to existing social concerns and interpersonal issues. Desired solutions mainly focused on treatment, social, and systemic interventions. We found that using BEMI could contribute to a comprehensive assessment in routine care and can be used by professionals within a short timeframe and with minimal training. Ethnographic assessment method captures patients' EMs and illness experiences, opening the way for patient-centred interventions and potentially better outcomes and experiences.


Formation and stabilization of pores in bilayer membranes by peptide-like amphiphilic polymers.
We study pore formation in models of lipid bilayer membranes interacting with amphiphilic copolymers mimicking anti-microbial peptides using Monte Carlo simulations and we rationalize our results by a simple brush-model for the fluid membrane. In our study a weak tension on the membrane is required to observe pore-formation induced by the adsorption of flexible amphiphilic copolymers. The copolymers enhance the pore stability by decreasing the line tension due to weak adsorption along the rim of the pore. Pore formation is enhanced with increasing length of copolymers or stronger stretching of the membrane. Both solvent and copolymer permeability increase as the pore becomes stable. Pore-formation proceeds via a meta-stable pore-state according to a discontinuous phase transition scenario which lead to finite pore-sizes at once. Our generic model of copolymer-induced pore-formation does not require high polymer concentration at the pores nor any self-organization of the copolymers to open the pore.


Membrane flow during pinocytosis. A stereologic analysis.
HRP has been used as a cytochemical marker for a sterelogic analysis of pinocytic vesicles and secondary lysosomes in cultivated macrophages and L cells. Evidence is presented that the diaminobenzidine technique (a) detects all vaculoes containing encyme and (b) distinguishes between incoming pinocytic vesicles and those which have fused with pre-existing lysosomes to form secondary lososomes. The HRP reactive pinocytic vesicle spaces fills completely within 5 min after exposure to enzyme, while the secondary lysosome compartment is saturated in 45--60 min. The size distribution of sectioned (profile) vaculoe diameters was measured at equilibrium and converted to actual (spherical) dimensions using a technique modified from Dr. S. D. Wicksell. The most important findings in this study have to do with the rate at which pinocytosed fluid and surface membrane move into the cell and on their subsequent fate. Each minute macrophages form at least 125 pinocytic vesicles having a fractional vol of 0.43% of the cell's volume and a fractional area of 3.1% of the cell's surface area. The fractional volume and surface area flux rates for L cells were 0.05% and 0.8% per minute respectively. Macrophages and L cells thus interiorize the equivalent of their cell surface area every 33 and 125 min. During a 3-period, the size of the secondary lysosome compartment remains constant and represents 2.5% of the cell volume and 18% of the surface area. Each hour, therefore, the volume and surface area of incoming vesicles is 10 times greater than the dimensions of the secondary lysosomes in both macrophages and L cells. This implies a rapid reduction in vesicle size during the formation of the secondary lysosome and the egress of pinocytosed fluid from the vacuole and the cell. In addition, we postulate that membrane components of the vacuole are subsequently recycled back to the cell surface.


Guillain-Barré syndrome as a cause of acute flaccid paralysis in Iraqi children: a result of 15 years of nation-wide study.
Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis (AFP) in the post-poliomyelitis eradication era. This is the first study done to identify the epidemiology, clinical features, and outcome of GBS in Iraqi children over 15 years. The surveillance database about AFP cases < 15 years reported during January 1997-December 2011 was used. GBS represented 52.5% of AFP cases, with an incidence of 1.33 case/100,000 population < 15 years/year. There was a higher incidence in the Southern provinces, age group 1-4 years, males, and outside the capital city of province, with no significant seasonal variations (p = .22). Survival probability after the 1 year of onset for those with respiratory muscle involvement was .76 (95% CI: .60-.86), versus .97 (95% Cl: .96-.98) for those who did not develop it (p < .001); and .97 (95% CI: .96-.98) for those living inside the capital city, versus .94 (.93-.95) for those living outside (p = .001). Cumulative incidence of residual paralysis for patients living inside the capital city was .21 (95% CI: .18-.24), versus .27 (95% CI: .25-.29) for those living outside (p < .001). The incidence, age and gender distribution, and seasonality of GBS among Iraqi children is similar to those reported from other previous studies. It is the most important cause of AFP, especially in those between the age of 1 to 4 years living in rural areas.


Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.


Extracellular regulation of type IIa receptor protein tyrosine phosphatases: mechanistic insights from structural analyses.
The receptor protein tyrosine phosphatases (RPTPs) exhibit a wide repertoire of cellular signalling functions. In particular, type IIa RPTP family members have recently been highlighted as hubs for extracellular interactions in neurons, regulating neuronal extension and guidance, as well as synaptic organisation. In this review, we will discuss the recent progress of structural biology investigations into the architecture of type IIa RPTP ectodomains and their interactions with extracellular ligands. Structural insights, in combination with biophysical and cellular studies, allow us to begin to piece together molecular mechanisms for the transduction and integration of type IIa RPTP signals and to propose hypotheses for future experimental validation.


Rejuvenating Bi(d)ology.
The BH3-only Bid protein is a critical sentinel of cellular stress in the liver and the hematopoietic system. Bid's initial 'claim to fame' came from its ability-as a caspase-truncated product-to trigger the mitochondrial apoptotic program following death receptor activation. Today we know that Bid can response to multiple types of proteases, which are activated under different conditions such as T-cell activation, ischemical reperfusion injury and lysosomal injury. Activation of the mitochondrial apoptotic program by Bid-via its recently identified receptor mitochondrial carrier homolog 2-involves multiple mechanisms, including release of cytochrome c and second mitochondria-derived activator of caspase (Smac), alteration of mitochondrial cristae organization, generation of reactive oxygen species and engagement of the permeability transition pore. Bid is also emerging-in its full-length form-as a pivotal sentinel of DNA damage in the bone marrow regulated by the ataxia telangiectasia mutated (ATM)/ataxia telangiectasia and Rad3-related (ATR) kinases. The ATM/ATR-Bid pathway is critically involved in preserving the quiescence and survival of hematopoietic stem cells both in the absence and presence of external stress, and a large part of this review will be dedicated to recent advances in this area of research.