Effects of whole body vibration on strength and functional mobility in multiple sclerosis.
The aim of this study was to examine the effectiveness of regular whole body vibration (WBV) training on lower limb muscle strength and functional mobility in individuals with multiple sclerosis. A single subject experimental design was replicated on three subjects. Phases included a 4-week baseline phase without intervention, 6 weeks of twice weekly WBV intervention on a VibroGym apparatus, and a 4-week baseline phase without intervention. During all phases, strength of the ankle plantarflexors and knee extensors was assessed twice weekly with the Nicholas Manual Muscle tester and functional mobility with the Timed Up and Go test. All subjects improved significantly in plantarflexor strength (p<0.05). One subject improved significantly in knee extensor strength bilaterally and one subject in the weaker leg. Two subjects improved significantly in functional mobility. These improvements in strength and mobility were maintained in the final baseline phase. In conclusion, regular WBV training can improve lower limb strength and mobility in some individuals with multiple sclerosis. Individuals who do not perform any other exercise, are in a moderate stage of disease progression, and have a more intensive exercise protocol in conjunction with WBV seem to benefit most. However, further high-quality studies are needed.


Analysis of microbial communities using culture-dependent and culture-independent approaches in an anaerobic/aerobic SBR reactor.
Comparative analysis of microbial communities in a sequencing batch reactor which performed enhanced biological phosphorus removal (EBPR) was carried out using a cultivation-based technique and 16S rRNA gene clone libraries. A standard PCR protocol and a modified PCR protocol with low PCR cycle was applied to the two clone libraries of the 16S rRNA gene sequences obtained from EBPR sludge, respectively, and the resulting 424 clones were analyzed using restriction fragment length polymorphisms (RFLPs) on 16S rRNA gene inserts. Comparison of two clone libraries showed that the modified PCR protocol decreased the incidence of distinct fragment patterns from about 63% (137 of 217) in the standard PCR method to about 34% (70 of 207) under the modified protocol, suggesting that just a low level of PCR cycling (5 cycles after 15 cycles) can significantly reduce the formation of chimeric DNA in the final PCR products. Phylogenetic analysis of 81 groups with distinct RFLP patterns that were obtained using the modified PCR method revealed that the clones were affiliated with at least 11 phyla or classes of the domain Bacteria. However, the analyses of 327 colonies, which were grouped into just 41 distinct types by RFLP analysis, showed that they could be classified into five major bacterial lineages: alpha, beta, gamma- Proteobacteria, Actinobacteria, and the phylum Bacteroidetes, which indicated that the microbial community yielded from the cultivation-based method was still much simpler than that yielded from the PCR-based molecular method. In this study, the discrepancy observed between the communities obtained from PCR-based and cultivation-based methods seems to result from low culturabilities of bacteria or PCR bias even though modified culture and PCR methods were used. Therefore, continuous development of PCR protocol and cultivation techniques is needed to reduce this discrepancy.


Role of biologics and biosimilars in inflammatory bowel disease: current trends and future perspectives.
Inflammatory bowel disease (IBD) is an idiopathic chronic inflammatory disease of the gastrointestinal system. The spectrum is of predominantly two types, namely, ulcerative colitis and Crohn's disease. The incidence of IBD has been increasing steadily since 1990, and so the number of agents used in their treatment. Biologics that are derived partly or completely from living biological sources such as animals and humans have become widely available, which provide therapeutic benefits to the IBD patients. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab) are approved for use in IBD. Biosimilars of infliximab and adalimumab are also available for the treatment of IBD. This review summarizes the clinical pharmacology, studies leading to their approval, overall indications and their use in IBD, usage in pregnancy and lactation, and the adverse effects of these agents. This review also summarizes the recent advances and future perspectives specific to biologics and biosimilars in IBD.


Impedance matching vertical optical waveguide couplers for dense high index contrast circuits.
We designed and demonstrated a compact, high-index contrast (HIC) vertical waveguide coupler for TE single mode operation with the lowest coupling loss of 0.20 dB +/- 0.05 dB at 1550 nm. Our vertical coupler consists of a pair of vertically overlapping inverse taper structures made of SOI and amorphous silicon. The vertical coupler can suppress power oscillation observed in regular directional couplers and guarantees vertical optical impedance matching with great tolerance for fabrication and refractive index variations of the waveguide materials. The coupler furthermore shows excellent broadband coupling efficiencies between 1460 nm and 1570 nm.


Normal immunofluorescence pattern of skin basement membranes in a family with porencephaly due to COL4A1 G749S mutation.
COL4A1 mutations have been associated with cerebral small-vessel disease, including perinatal intracerebral hemorrhage with consequent porencephaly, microbleeds, and lacunar strokes. Moreover, involvement of multiple organs and tissues like kidney, muscle, and large vessels have been reported. Three related patients with porencephaly bearing the G749S mutation in the COL4A1 gene and one healthy control belonging to the same family underwent skin biopsy. Tissue was examined by means of immunofluorescence microscopy and immunoreactivity for collagen type IV in skin basement membranes was tested. In subjects with COL4A1 mutation, we did not detect significant alterations of immunofluorescence patterns in basal membranes of different skin structures. Heterozygous COL4A1 G749S mutation is associated with a normal immunofluorescence pattern of skin basement membranes. Further studies are needed to clarify the role of possible functional abnormalities of the basement membranes in patients with this mutation.


Contextual modulations of center-surround interactions in motion revealed with the motion aftereffect.
Segregation of objects from their backgrounds is one of vision's most important tasks and one that is accomplished with ease. It is often hypothesized that suppressive center-surround receptive field interactions represent a key neural substrate underlying efficient figure-ground segregation, yet this intuitively appealing hypothesis has received very little experimental support. Using the motion aftereffect as an experimental tool, we explored this hypothesis by examining how surround suppression was affected by contextual manipulations that altered the perceived figure-ground relations but kept local motion signals unchanged. The results demonstrated that surround suppression was strong when the visual context implied a large moving field. On the other hand, when the contextual interpretation was consistent with a smaller moving object, surround suppression was greatly reduced. These findings are consistent with the notion that center-surround interactions play a role in segregating moving objects from backgrounds.


Quality of Quality Measurement: Impact of Risk Adjustment, Hospital Volume, and Hospital Performance.
The validity of basing healthcare reimbursement policy on pay-for-performance is grounded in the accuracy of performance measurement. Monte Carlo simulation was used to examine the accuracy of performance profiling as a function of statistical methodology, case volume, and the extent to which hospital or physician performance deviates from the average. There is extensive variation in the true-positive rate and false discovery rate as a function of model specification, hospital quality, and hospital case volume. Hierarchical and nonhierarchical modeling are both highly accurate at very high case volumes for very low-quality hospitals. At equivalent case volumes and hospital effect sizes, the true-positive rate is higher for nonhierarchical modeling than for hierarchical modeling, but the false discovery rate is generally much lower for hierarchical modeling than for nonhierarchical modeling. At low hospital case volumes (200) that are typical for many procedures, and for hospitals with twice the rate of death or major complications for patients undergoing isolated coronary artery bypass graft surgery at the average hospital, hierarchical modeling missed 90.6% of low-quality hospitals, whereas nonhierarchical modeling missed 65.3%. However, at low case volumes, 38.9% of hospitals classified as low-quality outliers using nonhierarchical modeling were actually average quality, compared to 5.3% using hierarchical modeling. Nonhierarchical modeling frequently misclassified average-quality hospitals as low quality. Hierarchical modeling commonly misclassified low-quality hospitals as average. Assuming that the consequences of misclassifying an average-quality hospital as low quality outweigh the consequences of misclassifying a low-quality hospital as average, hierarchical modeling may be the better choice for quality measurement.


Multiplexed coded illumination for Fourier Ptychography with an LED array microscope.
Fourier Ptychography is a new computational microscopy technique that achieves gigapixel images with both wide field of view and high resolution in both phase and amplitude. The hardware setup involves a simple replacement of the microscope's illumination unit with a programmable LED array, allowing one to flexibly pattern illumination angles without any moving parts. In previous work, a series of low-resolution images was taken by sequentially turning on each single LED in the array, and the data were then combined to recover a bandwidth much higher than the one allowed by the original imaging system. Here, we demonstrate a multiplexed illumination strategy in which multiple randomly selected LEDs are turned on for each image. Since each LED corresponds to a different area of Fourier space, the total number of images can be significantly reduced, without sacrificing image quality. We demonstrate this method experimentally in a modified commercial microscope. Compared to sequential scanning, our multiplexed strategy achieves similar results with approximately an order of magnitude reduction in both acquisition time and data capture requirements.


QTL mapping of flowering and fruiting traits in olive.
One of the challenge fruit growers are facing is to balance between tree production and vegetative growth from year to year. To investigate the existence of genetic determinism for reproductive behaviour in olive tree, we studied an olive segregating population derived from a cross between 'Olivière' and 'Arbequina' cultivars. Our strategy was based on (i) an annual assessment of individual trees yield, and (ii) a decomposition of adult growth units at the crown periphery into quantitative variables related to both flowering and fruiting process in relation to their growth and branching. Genetic models, including the year, genotype effects and their interactions, were built with variance function and correlation structure of residuals when necessary. Among the progeny, trees were either 'ON' or 'OFF' for a given year and patterns of regular vs. irregular bearing were revealed. Genotype effect was significant on yield but not for flowering traits at growth unit (GU) scale, whereas the interaction between genotype and year was significant for both traits. A strong genetic effect was found for all fruiting traits without interaction with the year. Based on the new constructed genetic map, QTLs with small effects were detected, revealing multigenic control of the studied traits. Many were associated to alleles from 'Arbequina'. Genetic correlations were found between Yield and Fruit set at GU scale suggesting a common genetic control, even though QTL co-localisations were in spe`cific years only. Most QTL were associated to flowering traits in specific years, even though reproductive traits at GU scale did not capture the bearing status of the trees in a given year. Results were also interpreted with respect to ontogenetic changes of growth and branching, and an alternative sampling strategy was proposed for capturing tree fruiting behaviour. Regular bearing progenies were identified and could constitute innovative material for selection programs.


Prevention of central venous catheter-related bloodstream infection by use of an antiseptic-impregnated catheter. A randomized, controlled trial.
Bloodstream infection related to short-term use of noncuffed central venous catheters is a common and serious problem. Technologic innovations to reduce the risk for these infections are needed. To determine 1) the efficacy of a novel antiseptic catheter in preventing central venous catheter-related infection, 2) patient tolerance of this catheter, and 3) the sources of bloodstream infection originating from noncuffed, multilumen central venous catheters. Randomized, controlled clinical trial. Medical-surgical intensive care unit of a 450-bed university hospital. 158 adults scheduled to receive a central venous catheter; 403 catheters were studied. Participants received either a standard triple-lumen polyurethane catheter or a catheter that was indistinguishable from the standard catheter and was impregnated with chlorhexidine and silver sulfadiazine. Catheters were studied for colonization and catheter-related bloodstream infection at removal; local and systemic effects of catheters were assessed. The origin of each catheter-associated bloodstream infection was sought by culturing all potential sources (skin, catheter segments, hubs, and infusate) and confirmed by restriction-fragment DNA subtyping. Antiseptic catheters were less likely to be colonized at removal than control catheters (13.5 compared with 24.1 colonized catheters per 100 catheters; relative risk, 0.56 [95% CI, 0.36 to 0.89]; P = 0.005) and were nearly fivefold less likely to produce bloodstream infection (1.0 compared with 4.7 infections per 100 catheters; 1.6 compared with 7.6 infections per 1000 catheter-days; relative risk, 0.21 [CI, 0.03 to 0.95]; P = 0.03). In the control group, 8 catheter-related bloodstream infections were caused by Staphylococcus aureus, gram-negative bacilli, enterococci, or Candida species; no infections with these organisms occurred in the antiseptic catheter group (P = 0.003). No adverse effects from the antiseptic catheter were seen, and none of the 122 isolates obtained from infected catheters in either group showed in vitro resistance to chlorhexidine-silver sulfadiazine. Cost-benefit analysis indicated that the antiseptic catheter should prove cost-beneficial if an institution's rate of catheter-related bacteremia with noncuffed central venous catheters is at least 3 infections per 1000 catheter-days). The chlorhexidine-silver sulfadiazine catheter is well tolerated, reduces the incidence of catheter-related infection, extends the time that noncuffed central venous catheters can be safely left in place for the short term, and should allow cost savings.


Identification of a recombination event narrowing the Lafora disease gene region.
Patients affected with progressive myoclonus epilepsy of the Lafora type present during late adolescence with a characteristic EEG pattern and Lafora bodies seen on skin biopsy. The critical region for the Lafora gene has been localised to chromosome 6q24 flanked by the dinucleotide repeat markers D6S292 and D6S420. This study for linkage of markers from the candidate gene region was performed in a previously unpublished family affected with Lafora disease. EEG and skin biopsy evaluation for Lafora bodies were performed on five of eight family members followed for seizure activity. Haplotype and linkage analysis of DNA from five family members were carried out using the nine dinucleotide repeat markers reported in the common region of homozygosity by Serratosa et al in 1995. The present study of an additional family affected by Lafora disease has narrowed the 17 cM critical region for the Lafora disease gene on chromosome 6q24 to a 4 cM region flanked by markers D6S308 and D6S311.


Attitudes toward vaccination: a survey of Canadian chiropractic students.
Although the Canadian Chiropractic Association and the Canadian Memorial Chiropractic College (CMCC) endorse vaccination, the prevalence of anti-vaccination attitudes among Canadian chiropractors is unknown. This study describes the prevalence of anti-vaccination attitudes among Canadian chiropractic students. An 11-item questionnaire about attitudes toward vaccination was distributed to students enrolled at CMCC during the 1999/2000 academic year. The responses for the 11 items were then summed to arrive at a total score ranging from 0 (most negative attitude toward vaccination) to 22 (most positive attitude toward vaccination). Respondents' perceptions of sources of vaccine information were also investigated. Over 75% of the students (467 of 621) completed the questionnaire. Most students (53.3%) reported that in general they agreed with vaccination. This was especially true among first-year students (60.7%). However, among fourth year students, only 39.5% agreed with vaccination. The proportion of respondents who stated that they were against vaccination in general was 5 (4.5%) of 112 first-year students, 10 (8.3%) of 121 second-year students, 16 (13.9%) of 115 third-year students and 35 (29.4%) of 119 fourth-year students. The mean scores on the questionnaire were progressively lower with each higher year of study at the College. The mean survey scores for each year of study were first year, 15.9 (95% confidence interval [CI] 15.2-16.6); second year, 16.1 (95% CI 15.3-1 7.0); third year, 14.5 (95% CI 13.5-15.4); and fourth year, 12.8 (95% CI 11.7-13.9). The mean scores varied among year of study and were statistically significant using one-way ANOVA (p < 0.0001). Among students who relied primarily on informal sources of vaccine information, such as the chiropractic literature and informal talks at CMCC, anti-vaccination attitudes were more prevalent in later years. Most CMCC students reported pro-vaccination attitudes, but there appeared to be an increase in anti-vaccination attitudes as students progressed through the CMCC program. This pattern was seen almost exclusively among students who relied primarily on informal sources of vaccine information rather than on core CMCC lectures or prior lectures at university.


Convergent validity and stability of secure base script knowledge from young adulthood to midlife.
Attachment theory posits that early experiences with caregivers are made portable across development in the form of mental representations of attachment experiences. These representations, the secure base script included, are thought to be stable across time. Here, we present data from two studies. Study 1 (N = 141) examined the degree of empirical convergence between the two major measures of secure base script knowledge in Study 2, we examined stability of secure base script knowledge from late adolescence to midlife combining data from both a high- and normative-risk cohort (N = 113). Study 1 revealed evidence for convergent validity (r = .50) and Study 2 revealed moderate rank-order stability (r = .43), which was not moderated by cohort risk status. Results support the validity of secure base script knowledge assessments and prediction that attachment representations show moderate stability across early adulthood and into midlife.


Identifying Ingredient Substitutions Using a Knowledge Graph of Food.
People can affect change in their eating patterns by substituting ingredients in recipes. Such substitutions may be motivated by specific goals, like modifying the intake of a specific nutrient or avoiding a particular category of ingredients. Determining how to modify a recipe can be difficult because people need to 1) identify which ingredients can act as valid replacements for the original and 2) figure out whether the substitution is "good" for their particular context, which may consider factors such as allergies, nutritional contents of individual ingredients, and other dietary restrictions. We propose an approach to leverage both explicit semantic information about ingredients, encapsulated in a knowledge graph of food, and implicit semantics, captured through word embeddings, to develop a substitutability heuristic to rank plausible substitute options automatically. Our proposed system also helps determine which ingredient substitution options are "healthy" using nutritional information and food classification constraints. We evaluate our substitutability heuristic, diet-improvement ingredient substitutability heuristic (DIISH), using a dataset of ground-truth substitutions scraped from ingredient substitution guides and user reviews of recipes, demonstrating that our approach can help reduce the human effort required to make recipes more suitable for specific dietary needs.


The Psychology of Schizophrenia: Implications for Biological and Psychotherapeutic Treatments.
The focus on recent advances in the neurobiology of schizophrenia has pushed aside the psychological understanding of the person with schizophrenia for several decades. However, a useful functional psychology of schizophrenia (in distinction to a psychological approach to symptoms) remains clinically important for several reasons: it is a core part of the bio-psycho-social formulation; it helps us understand and connect with persons with schizophrenia; and it provides a framework by which to organize our treatment efforts (both psychotherapeutic and particularly biological), which can improve adherence and outcomes. A coherent psychological model (the deficit model) based on object relations theory best explains all the biological, psychological, clinical, and sociocultural factors relevant to the understanding and treatment of persons with schizophrenia. A better understanding of a coherent psychology of persons with schizophrenia and provision of psychotherapies improves both the biological and psychotherapeutic treatment of persons with schizophrenia.


Mean subaxial space available for the cord index as a novel method of measuring cervical spine geometry to predict the chronic stinger syndrome in American football players.
The chronic stinger syndrome is a distinct entity from acute stingers and has been shown to have its own pathophysiology that, unlike acute stingers, may reflect long-standing geometrical changes of the subaxial spinal canal and chronic irritation/degeneration of the exiting nerve root complex. There is no method available, however, to accurately predict these symptoms in athletes. The mean subaxial cervical space available for the cord (MSCSAC) is a novel alternative to the Torg ratio for predicting neurological symptoms caused by cervical spondylosis in elite athletes. It is the goal of this study to determine critical values for this measurement index and to retrospectively correlate those values to neurological symptoms. Magnetic resonance images obtained in 103 male athletes participating in the 2005 and 2006 National Football League Scouting Combine and a control group of 42 age-matched male nonathletes were retrospectively reviewed. The Torg ratio and SAC values were calculated in triplicate at each cervical level from C3-6 by using lateral radiographs and midsagittal T2-weighted MR images of the cervical spine, respectively. These values were then averaged for each individual to produce mean subaxial cervical Torg ratio (MSCTR) and MSCSAC values. Receiver operating characteristic curves were constructed for each measurement technique and were compared based on their respective area under the curves (AUCs). The MSCSAC difference between athletes with and without chronic stingers was statistically significant (p < 0.01). The difference between athletes with and without chronic stingers compared with controls was also statistically significant (p < 0.001 and p < 0.001, respectively). The AUC for the MSCSAC was 0.813, which was significantly greater than the AUC for both the MSCTR (p = 0.0475) and the individual Torg ratio (p = 0.0277). The MSCTR had the second largest AUC (0.676) and the conventional method of measuring individual Torg ratio values produced the lowest AUC (0.661). It was found that using the MSCSAC with a critical value of 5.0 mm produced a sensitivity of 80% and a negative likelihood ratio of 0.23 for predicting chronic stingers. Lowering the cutoff value to 4.3 mm for the MSCSAC resulted in a possible confirmatory test with a specificity of 96% and a positive likelihood ratio of 13.25. A critical value of 5.0 mm for the MSCSAC provides the clinician with a screening test for chronic stingers and anything < 4.3 mm adds additional confidence as a confirmatory test. These results are approximately 20% more accurate than the classic Torg ratio based on our AUC analysis. It was found that measuring the spinal geometry throughout the length of the subaxial cervical spine produced a more reliable method by which to predict neurological symptoms than the traditional approach of measuring individual levels. This shows that the underlying pathogenesis of the chronic stinger syndrome is best characterized as a process that involves the entire subaxial region uniformly.


Osmotic/ionic status of body fluids in the euryhaline cephalopod suggest possible parallel evolution of osmoregulation.
Acclimation from marine to dilute environments constitutes among the dramatic evolutionary transitions in the history of life. Such adaptations have evolved in multiple lineages, but studies of the blood/hemolymph homeostasis mechanisms are limited to those using evolutionarily advanced Deuterostome (chordates) and Ecdysozoa (crustaceans). Here, we examined hemolymph homeostasis in the advanced Lophotrochozoa/mollusc, the other unexplored taxa, and its possible regulation by the vasopressin/oxytocin superfamily peptides known to be implicated in fluid homeostasis in Chordata and Arthropoda. The hemolymph osmotic and ionic status in the euryhaline cephalopod (Octopus ocellatus) following transfer from 30-ppt normal seawater to 20 ppt salinity indicate hyperosmo- and hyperionoregulatory abilities for more than 1 week, as in crustaceans and teleost fish. While ventilation frequency decreased by 1 day, Na(+)/K(+)-ATPase activity, which has been generally implicated in ion transport, was induced in two of the eight posterior gills after 1 week. In addition, the octopuses were intravenously injected with 1 or 100 ng/g octopressin or cephalotocin, which are Octopus vasopressin/oxytocin orthologs. After 1 day, octopressin, but not cephalotocin, decreased the hemolymph osmolality and Ca concentrations, as well as urinary Na concentrations. These data provide evidence for possible parallel evolution in hyperionoregulatory mechanisms and coordination by conserved peptides.


Clinical characteristics of Acanthamoeba keratitis infections in 28 states, 2008 to 2011.
The aim was to describe a geographically and clinically diverse sample of cases of Acanthamoeba keratitis (AK) and establish the risk factors for poor outcomes among patients with this disease. We conducted a retrospective, population-based case series of 116 patients with AK identified through a national surveillance network. Data were collected via a medical record review by diagnosing ophthalmologists and by phone interviews with patients. Exact logistic regression modeling was used to determine risk factors for poor visual outcomes. Among patients with data available on contact lens use, it was found that 93.3% wore contact lenses. The median time from symptom onset to care seeking was 2 days, whereas the median time from symptom onset to diagnosis was 27 days. Keratoplasty was performed in 27 of 81 patients with available outcome data and was more likely in patients >40 years old [odds ratio (OR) 5.25, 95% confidence interval (CI) 1.49-21.92]. When adjusted for age, the risk factors for keratoplasty included the presence of a ring infiltrate (OR 40.00, 95% CI 3.58-447.0) or any sign of stromal invasion (OR 10.48, 95% CI 2.56-55.09). One-third of patients with available data on best-corrected visual acuity had a best-corrected visual acuity <20/200, with the presence of a ring infiltrate as the only significant predictor of this outcome when adjusted for age (aOR 3.45, 95% CI 1.01-12.31). AK remains challenging to diagnose. Consequently, patients with advanced disease are more likely to have poor outcomes, particularly if they are older. The increasing awareness of AK among general eye care providers may shorten referral times and potentially improve outcomes.


NS2 proteases from hepatitis C virus and related hepaciviruses share composite active sites and previously unrecognized intrinsic proteolytic activities.
Over the recent years, several homologues with varying degrees of genetic relatedness to hepatitis C virus (HCV) have been identified in a wide range of mammalian species. HCV infectious life cycle relies on a first critical proteolytic event of its single polyprotein, which is carried out by nonstructural protein 2 (NS2) and allows replicase assembly and genome replication. In this study, we characterized and evaluated the conservation of the proteolytic mode of action and regulatory mechanisms of NS2 across HCV and animal hepaciviruses. We first demonstrated that NS2 from equine, bat, rodent, New and Old World primate hepaciviruses also are cysteine proteases. Using tagged viral protein precursors and catalytic triad mutants, NS2 of equine NPHV and simian GBV-B, which are the most closely and distantly related viruses to HCV, respectively, were shown to function, like HCV NS2 as dimeric proteases with two composite active sites. Consistent with the reported essential role for NS3 N-terminal domain (NS3N) as HCV NS2 protease cofactor via NS3N key hydrophobic surface patch, we showed by gain/loss of function mutagenesis studies that some heterologous hepacivirus NS3N may act as cofactors for HCV NS2 provided that HCV-like hydrophobic residues are conserved. Unprecedently, however, we also observed efficient intrinsic proteolytic activity of NS2 protease in the absence of NS3 moiety in the context of C-terminal tag fusions via flexible linkers both in transiently transfected cells for all hepaciviruses studied and in the context of HCV dicistronic full-length genomes. These findings suggest that NS3N acts as a regulatory rather than essential cofactor for hepacivirus NS2 protease. Overall, unique features of NS2 including enzymatic function as dimers with two composite active sites and additional NS3-independent proteolytic activity are conserved across hepaciviruses regardless of their genetic distances, highlighting their functional significance in hepacivirus life cycle.


Cardioprotective effect of lycopene against isoproterenol-induced myocardial infarction in rats.
The present study was designed to evaluate the cardioprotective potential of lycopene (LCP) against isoproterenol (ISP)-induced myocardial infarction (MI), by assessing hemodynamic, biochemical and histopathological parameters. Wistar male albino rats were orally administered with LCP (0.5, 1.0 and 1.5 mg/kg) or with vehicle for 30 days, with concurrent subcutaneous injections of ISP (85 mg/kg) on days 28 and 29. ISP significantly (p < 0.05) decreased systolic, diastolic and mean arterial blood pressure (SAP, DAP and MAP, respectively) and heart rate (HR). ISP also decreased contractility (+LVdP/dt), relaxation (-LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP). In addition to functional impairment, ISP also caused a significant (p < 0.05) decrease in antioxidants, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSHPx), glutathione (GSH), cardiac injury marker enzymes, creatine phosphokinase-MB (CK-MB) and lactate dehydrogenase (LDH), as well as induced lipid peroxidation, malonaldialdehyde (MDA) and histopathological alterations in heart. However, pretreatment with LCP significantly (p < 0.05) attenuated ISP-induced cardiac dysfunction as evidenced by improved SAP, DAP, MAP, HR, (±)LVdP/dt and reduced LVEDP. Pretreatment with LCP also significantly (p < 0.05) prevented the depletion of antioxidants (SOD, CAT, GSHPx and GSH), myocyte injury marker enzymes (CK-MB and LDH) and inhibited lipid peroxidation and MDA formation in the heart. Furthermore, reduced necrosis, edema and infiltration of inflammatory cells on histopathological examination also depicted the protective effect of LCP against the deleterious effect of ISP. Based on the results, it is suggested that LCP possesses significant cardioprotective potential and may serve as an adjunct in treatment and prophylaxis of MI.


Prediction of functional outcome in young patients with a recent-onset psychiatric disorder: Beyond the traditional diagnostic classification system.
A critical research goal is to identify modifiable risk factors leading to functional disabilities in young psychiatric patients. The authors developed a multidimensional trans-diagnostic predictive model of functional outcome in patients with the recent-onset of a psychiatric illness. Baseline clinical, psychosis-risk status, cognitive, neurological-soft-signs measures, and dopamine-related-gene polymorphisms (DRD1-rs4532, COMT-rs165599, and DRD4-rs1800955) were collected in 138 young non-psychotic outpatients. 116 individuals underwent follow-up (mean=2.2years, SD=0.9) examination. A binary logistic model was used to predict low-functioning status at follow-up as defined by a score lower than 65 in the social occupational functioning assessment scale. A total of 54% of patients experiences low functioning at follow-up. Attention, Avolition, and Motor-Coordination subscale were significant predictors of low-functioning with an accuracy of 79.7%. A non-significant trend was found for a dopamine-related-gene polymorphism (DRD1-rs4532). The model was independent of psychotic-risk status, DSM-diagnosis, and psychotic conversion. A trans-diagnostic approach taking into account specific neurocognitive, clinical, and neurological information has the potential to identify those individuals with low-functioning independent of DSM diagnosis or the level of psychosis-risk. Specific early interventions targeting modifiable risk factors and emphasize functional recovery in young psychiatric samples, independent of DSM-diagnosis and psychosis-risk, are essential.


Coronary calcium measurement improves prediction of cardiovascular events in asymptomatic patients with type 2 diabetes: the PREDICT study.
The PREDICT Study is a prospective cohort study designed to evaluate coronary artery calcification score (CACS) as a predictor of cardiovascular events in type 2 diabetes (T2DM). A total of 589 patients with no history of cardiovascular disease and with established T2DM had CACS measured, as well as risk factors, including plasma lipoprotein, apolipoprotein, homocysteine and C-reactive protein concentrations, homeostasis model assessment insulin resistance (HOMA-IR), and urine albumin creatinine ratio. Participants were followed for a median of 4 years and first coronary heart disease (CHD) and stroke events were identified as primary endpoints. There were 66 first cardiovascular events (including 10 strokes). CACS was a highly significant, independent predictor of events (P < 0.001), with a doubling in CACS being associated with a 32% increase in risk of events (29% after adjustment). Hazard ratios relative to CACS in the range 0-10 Agatston units (AU) were: CACS 11-100 AU, 5.4 (P = 0.02); 101-400 AU 10.5 (P = 0.001); 401-1000 AU, 11.9 (P = 0.001), and >1000 AU, 19.8 (P < 0.001). Only HOMA-IR predicted primary endpoints independently of CACS (P = 0.01). The areas under the receiver operator characteristic curve for United Kingdom Prospective Diabetes Study (UKPDS) risk engine primary endpoint risk and for UKPDS risk plus CACS were 0.63 and 0.73, respectively (P = 0.03). Measurement of CACS is a powerful predictor of cardiovascular events in asymptomatic patients with T2DM and can further enhance prediction provided by established risk models.


Dynamic virulence: real-time assessment of intracellular pathogenesis links Cryptococcus neoformans phenotype with clinical outcome.
While a myriad of studies have examined host factors that predispose persons to infection with the opportunistic fungal pathogen Cryptococcus neoformans, comparatively little has been done to examine how virulence factor differences among cryptococcal isolates may impact outcome. In the recent report by Alanio et al. (A. Alanio, M. Desnos-Ollivier, and F. Dromer, mBio 2:e00158-11, 2011), novel flow cytometry-based techniques were employed to demonstrate an association between the phenotype of C. neoformans-macrophage interactions, as measured by phagocytosis and intracellular replication, and patient outcomes, as determined by positive cultures on therapy and survival. These experiments establish that the prognosis of patients with cryptococcosis is influenced by the phenotypic properties of the infecting fungal isolate.


Clinical Concept Value Sets and Interoperability in Health Data Analytics.
This paper focuses on value sets as an essential component in the health analytics ecosystem. We discuss shared repositories of reusable value sets and offer recommendations for their further development and adoption. In order to motivate these contributions, we explain how value sets fit into specific analytic tasks and the health analytics landscape more broadly; their growing importance and ubiquity with the advent of Common Data Models, Distributed Research Networks, and the availability of higher order, reusable analytic resources like electronic phenotypes and electronic clinical quality measures; the formidable barriers to value set reuse; and our introduction of a concept-agnostic orientation to vocabulary collections. The costs of ad hoc value set management and the benefits of value set reuse are described or implied throughout. Our standards, infrastructure, and design recommendations are not systematic or comprehensive but invite further work to support value set reuse for health analytics. The views represented in the paper do not necessarily represent the views of the institutions or of all the co-authors.


Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy.
Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.


Religious service attendance and spiritual well-being are differentially associated with risk of major depression.
The complex relationships between religiosity, spirituality and the risk of DSM-IV depression are not well understood. We investigated the independent influence of religious service attendance and two dimensions of spiritual well-being (religious and existential) on the lifetime risk of major depression. Data came from the New England Family Study (NEFS) cohort (n=918, mean age=39 years). Depression according to DSM-IV criteria was ascertained using structured diagnostic interviews. Odds ratios (ORs) for the associations between high, medium and low tertiles of spiritual well-being and for religious service attendance and the lifetime risk of depression were estimated using multiple logistic regression. Religious service attendance was associated with 30% lower odds of depression. In addition, individuals in the top tertile of existential well-being had a 70% lower odds of depression compared to individuals in the bottom tertile. Contrary to our original hypotheses, however, higher levels of religious well-being were associated with 1.5 times higher odds of depression. Religious and existential well-being may be differentially associated with likelihood of depression. Given the complex interactions between religiosity and spirituality dimensions in relation to risk of major depression, the reliance on a single domain measure of religiosity or spirituality (e.g. religious service attendance) in research or clinical settings is discouraged.


Double-blind, placebo-controlled, randomized trial of octreotide in malignant bowel obstruction.
Does octreotide reduce vomiting in cancer-associated bowel obstruction? To evaluate the net effect of adding octreotide or placebo to standardized therapies on the number of days free of vomiting for populations presenting with vomiting and inoperable bowel obstruction secondary to cancer or its treatment. Twelve services enrolled people with advanced cancer presenting with vomiting secondary to bowel obstruction where surgery or anti-cancer therapies were not indicated immediately. In a double-blind study, participants were randomized to placebo or octreotide (600 μg/24 hours by infusion). Both arms received standardized supportive therapy (infusion of ranitidine [200 mg/24 hours], dexamethasone [8 mg/24 hours], and parenteral hydration [10-20 mL/kg/24 hours]). The primary outcome was patient-reported days free of vomiting at 72 hours. In a study that recruited to the numbers identified in its power calculation, 87 participants provided data at 72 hours (45, octreotide arm). Seventeen people (octreotide) and 14 (placebo) were free of vomiting for 72 hours (P = 0.67). Mean days free of vomiting were 1.87 (SD 1.10; octreotide) and 1.69 (SD 1.15; placebo; P = 0.47). An adjusted multivariate regression of the incidence of vomiting over the study showed a reduced number of episodes of vomiting in the octreotide group (incidence rate ratio = 0.40; 95% CI: 0.19-0.86; P = 0.019); however, people in the octreotide arm were 2.02 times more likely to be administered hyoscine butylbromide (P = 0.004), potentially reflecting increased colicky pain. Although there was no reduction in the number of days free of vomiting, the multivariate analysis suggests that further study of somatostatin analogues in this setting is warranted.


Systematic domain-based aggregation of protein structures highlights DNA-, RNA- and other ligand-binding positions.
Domains are fundamental subunits of proteins, and while they play major roles in facilitating protein-DNA, protein-RNA and other protein-ligand interactions, a systematic assessment of their various interaction modes is still lacking. A comprehensive resource identifying positions within domains that tend to interact with nucleic acids, small molecules and other ligands would expand our knowledge of domain functionality as well as aid in detecting ligand-binding sites within structurally uncharacterized proteins. Here, we introduce an approach to identify per-domain-position interaction 'frequencies' by aggregating protein co-complex structures by domain and ascertaining how often residues mapping to each domain position interact with ligands. We perform this domain-based analysis on ∼91000 co-complex structures, and infer positions involved in binding DNA, RNA, peptides, ions or small molecules across 4128 domains, which we refer to collectively as the InteracDome. Cross-validation testing reveals that ligand-binding positions for 2152 domains are highly consistent and can be used to identify residues facilitating interactions in ∼63-69% of human genes. Our resource of domain-inferred ligand-binding sites should be a great aid in understanding disease etiology: whereas these sites are enriched in Mendelian-associated and cancer somatic mutations, they are depleted in polymorphisms observed across healthy populations. The InteracDome is available at http://interacdome.princeton.edu.


OCIAD1 Controls Electron Transport Chain Complex I Activity to Regulate Energy Metabolism in Human Pluripotent Stem Cells.
Pluripotent stem cells (PSCs) derive energy predominantly from glycolysis and not the energy-efficient oxidative phosphorylation (OXPHOS). Differentiation is initiated with energy metabolic shift from glycolysis to OXPHOS. We investigated the role of mitochondrial energy metabolism in human PSCs using molecular, biochemical, genetic, and pharmacological approaches. We show that the carcinoma protein OCIAD1 interacts with and regulates mitochondrial complex I activity. Energy metabolic assays on live pluripotent cells showed that OCIAD1-depleted cells have increased OXPHOS and may be poised for differentiation. OCIAD1 maintains human embryonic stem cells, and its depletion by CRISPR/Cas9-mediated knockout leads to rapid and increased differentiation upon induction, whereas OCIAD1 overexpression has the opposite effect. Pharmacological alteration of complex I activity was able to rescue the defects of OCIAD1 modulation. Thus, hPSCs can exist in energy metabolic substates. OCIAD1 provides a target to screen for additional modulators of mitochondrial activity to promote transient multipotent precursor expansion or enhance differentiation.


Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells.
The histone demethylase LSD1 (KDM1A) demethylates mono- and di-methylated (Me2) lysine (K) 4 on histone H3. High LSD1 expression blocks differentiation and confers a poor prognosis in acute myeloid leukemia (AML). Here, treatment with the novel LSD1 antagonist SP2509 attenuated the binding of LSD1 with the corepressor CoREST, increased the permissive H3K4Me3 mark on the target gene promoters, and increased the levels of p21, p27 and CCAAT/enhancer binding protein α in cultured AML cells. In addition, SP2509 treatment or LSD1 shRNA inhibited the colony growth of AML cells. SP2509 also induced morphological features of differentiation in the cultured and primary AML blasts. SP2509 induced more apoptosis of AML cells expressing mutant NPM1 than mixed-lineage leukemia fusion oncoproteins. Treatment with SP2509 alone significantly improved the survival of immune-depleted mice following tail-vein infusion and engraftment of cultured or primary human AML cells. Co-treatment with pan-HDAC inhibitor (HDI) panobinostat (PS) and SP2509 was synergistically lethal against cultured and primary AML blasts. Compared with each agent alone, co-treatment with SP2509 and PS significantly improved the survival of the mice engrafted with the human AML cells, without exhibiting any toxicity. Collectively, these findings show that the combination of LSD1 antagonist and pan-HDI is a promising therapy warranting further testing against AML.


OSETI with STACEE: a search for nanosecond optical transients from nearby stars.
We have used the Solar Tower Atmospheric Cherenkov Effect Experiment (STACEE) high-energy gamma-ray detector to look for fast blue-green laser pulses from the vicinity of 187 stars. The STACEE detector offers unprecedented light-collecting capability for the detection of nanosecond pulses from such lasers. We estimate STACEE's sensitivity to be approximately 10 photons/m(2) at a wavelength of 420 nm. The stars have been chosen because their characteristics are such that they may harbor habitable planets, and they are relatively close to Earth. Each star was observed for 10 minutes, and we found no evidence for laser pulses in any of the data sets. Key Words: Search for extraterrestrial intelligence-Optical search for extraterrestrial intelligence-Interstellar communication-Laser.


International Spine Radiosurgery Consortium consensus guidelines for target volume definition in spinal stereotactic radiosurgery.
Spinal stereotactic radiosurgery (SRS) is increasingly used to manage spinal metastases. However, target volume definition varies considerably and no consensus target volume guidelines exist. This study proposes consensus target volume definitions using common scenarios in metastatic spine radiosurgery. Seven radiation oncologists and 3 neurological surgeons with spinal radiosurgery expertise independently contoured target and critical normal structures for 10 cases representing common scenarios in metastatic spine radiosurgery. Each set of volumes was imported into the Computational Environment for Radiotherapy Research. Quantitative analysis was performed using an expectation maximization algorithm for Simultaneous Truth and Performance Level Estimation (STAPLE) with kappa statistics calculating agreement between physicians. Optimized confidence level consensus contours were identified using histogram agreement analysis and characterized to create target volume definition guidelines. Mean STAPLE agreement sensitivity and specificity was 0.76 (range, 0.67-0.84) and 0.97 (range, 0.94-0.99), respectively, for gross tumor volume (GTV) and 0.79 (range, 0.66-0.91) and 0.96 (range, 0.92-0.98), respectively, for clinical target volume (CTV). Mean kappa agreement was 0.65 (range, 0.54-0.79) for GTV and 0.64 (range, 0.54-0.82) for CTV (P<.01 for GTV and CTV in all cases). STAPLE histogram agreement analysis identified optimal consensus contours (80% confidence limit). Consensus recommendations include that the CTV should include abnormal marrow signal suspicious for microscopic invasion and an adjacent normal bony expansion to account for subclinical tumor spread in the marrow space. No epidural CTV expansion is recommended without epidural disease, and circumferential CTVs encircling the cord should be used only when the vertebral body, bilateral pedicles/lamina, and spinous process are all involved or there is extensive metastatic disease along the circumference of the epidural space. This report provides consensus guidelines for target volume definition for spinal metastases receiving upfront SRS in common clinical situations.


The correlation between ferritin level and acute phase parameters in rheumatoid arthritis and systemic lupus erythematosus.
In this study, we evaluated the relationship between ferritin levels and disease activation in rheumatoid arthritis (RA) patients. We included 44 patients with RA, 20 patients with systemic lupus erythematosus (SLE), 25 patients with infection, 22 patients with malignancy, and 20 healthy control subjects. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), whole blood count, and serum iron parameters were determined in all cases. The joint findings in RA patients were recorded, and disease activity score (DAS) was calculated. In SLE patients, antinuclear antibody (ANA) and anti-dsDNA titers and C3 and C4 complement levels were determined. SLE disease activity index (SLEDAI) score was calculated. Serum ferritin levels in the RA, SLE, and control groups were lower than those in the infection and malignancy groups (p<0.05). The ferritin levels in the RA group did not differ significantly from the SLE and control groups. In RA patients, serum ferritin level had a positive correlation with ESR, CRP, RF, platelet count, and DAS score and had a negative correlation with hematocrit (all p values <0.05). In SLE patients, on the other hand, serum ferritin had a positive correlation with ANA, anti-dsDNA, and SLEDAI (all p values <0.05). According to DAS, ferritin level in inactive RA patients was lower than that in active RA patients. When transferrin saturation was considered, iron deficiency anemia was a quite frequent finding in both active and inactive RA patients. Interestingly, we observed that ferritin level in RA patients was similar to the control group; however, it was a good parameter of disease activation. This is because a reduction in storage iron and resultant iron deficiency anemia are very common in RA patients.


In vivo reconstitution of active Thogoto virus polymerase: assays for the compatibility with other orthomyxovirus core proteins and template RNAs.
Tick-borne Thogoto virus (THOV), the prototype of a new genus in the Orthomyxoviridae family, contains six single-stranded RNA segments of negative polarity. Four of them encode gene products that correspond to the influenza virus PB1, PB2, PA and NP core proteins. Here we describe an in vivo system in which the expression of a THOV model RNA is driven by THOV core proteins synthesized from cloned cDNAs. Our results demonstrated the biological activity of our cloned genes and showed that the three polymerase subunits and the NP are required for gene expression. For comparison, we also used the in vivo reconstituted systems of the influenza A and B viruses. None of the polymerase or NP proteins was active in a heterologous orthomyxovirus core, indicating a high specificity in core assembly and/or function. Interestingly, the THOV polymerase did not recognize the influenza A virus promoter and vice versa.


Interplay of retinal determination gene network with TGF-β signaling pathway in epithelial-mesenchymal transition.
As a fundamental event in the generation of tissues and organs during embryogenesis, the epithelial-mesenchymal transition (EMT) has also been implicated in cancer progression by its ability to alter the plasticity of epithelial cells to acquire invasive properties. Evidence is mounting that ectopic activation of transforming growth factors β (TGF-β)/bone morphogenetic protein (BMP) superfamily members to enhance tumorigenesis and metastasis. In this respect, the Retinal Determination Gene Network (RDGN), which was identified to govern the normal initiation of the morphogenetic furrow in Drosophila, has now been found to be de-regulated in various types of cancers, and the key members of this network, DACH, SIX, and EYA, have emerged as novel co-regulators of TGF- signaling during EMT. Understanding the molecular mechanism by which RDGN regulates TGF-β/BMP signaling to influence EMT may lead to novel strategies for targeted therapies.


Evaluation of clinical adverse effects and laboratory alterations in patients with acne vulgaris treated with oral isotretinoin.
Oral isotretinoin therapy has completely changed the treatment of acne. The clinical adverse effects of isotretinoin are classified into two groups: mucocutaneous and systemic toxic. Laboratory alterations such as dyslipidemia and increase of hepatic enzymes are reported. To evaluate the tolerability of oral isotretinoin with special attention to lipid metabolism, hepatic function, and clinical adverse reactions. 150 patients clinically diagnosed with acne being treated with oral isotretinoin were included in the study. Clinical and laboratory evaluations were conducted before the start of therapy, one month after, and every three months thereafter until the completion of treatment. Of the 150 patients evaluated, 48% were female and 52%, male. They were aged from 15 to 32 years. The most prevalent mucocutaneous adverse reaction associated with isotretinoin therapy was cheilitis, reported by 94% of the patients. Systemic clinical effects were much less common. Cholesterol, triglyceride, and transaminase levels were assessed and significant changes were not observed during treatment. Patients showed adverse effects compatible to those described in the literature, which are mostly controlled with symptomatic medication. Isotretinoin is a safe drug and adverse and laboratory effects are well tolerated.


Magnetization transfer or spin-lock? An investigation of off-resonance saturation pulse imaging with varying frequency offsets.
To characterize near-resonance saturation pulse MR imaging on a 1.5-T scanner in order to gain insight into underlying mechanisms that alter tissue contrast and to optimize the technique for neuroimaging. Off-resonance saturation pulses were applied to T1-weighted, spin-density-weighted, and T2-weighted sequences at frequency offsets ranging from 50 Hz to 20,000 Hz down field from water resonance. Suppression ratios were determined at each offset for phantom materials (MnCl2 solution, gadopentetate dimeglumine, corn oil, water, and agar), normal brain structures, and a variety of brain lesions. Signal suppression of MnCl2 on T1-weighted images occurred at offsets of less than 2000 Hz even though no macromolecules were present in the solution. Only those phantom materials and tissues with short or intermediate T1 relaxation times and relatively large T1/T2 ratios were sensitive to changing frequency offsets. Suppression of brain increased from approximately 20% at 2000 Hz offset to approximately 45% when the offset was reduced to 300 Hz. In human subjects, the net effect of reducing the frequency offset was to increase T2 contrast on T1-weighted, spin-density-weighted, and T2-weighted images. Distilled water and contrast material did not suppress except at very low offsets ( < 300 Hz). A frequency offset of 300 Hz was optimal for maximizing conspicuity between most contrast-enhancing lesions and adjacent brain while preserving anatomic detail. Suppression of MnCl2 indicates that magnetization transfer is not the sole mechanism of contrast in near-resonance saturation MR imaging. Spin-lock excitation can reasonably explain the behavior of the phantom solutions and the increase in T2 contrast of tissues achieved as the frequency offset is decreased from 2000 Hz to 300 Hz. Below 300 Hz, saturation is presumably caused by spin-tip effects. With our pulse design, an offset of 300 Hz is optimal for many routine clinical imaging examinations.


Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system.
alpha-Synuclein (alpha-Syn) is a 14 kDa protein of unknown function that has been implicated in the pathophysiology of Parkinson's disease (PD). Here, we show that alpha-Syn-/- mice are viable and fertile, exhibit intact brain architecture, and possess a normal complement of dopaminergic cell bodies, fibers, and synapses. Nigrostriatal terminals of alpha-Syn-/- mice display a standard pattern of dopamine (DA) discharge and reuptake in response to simple electrical stimulation. However, they exhibit an increased release with paired stimuli that can be mimicked by elevated Ca2+. Concurrent with the altered DA release, alpha-Syn-/- mice display a reduction in striatal DA and an attenuation of DA-dependent locomotor response to amphetamine. These findings support the hypothesis that alpha-Syn is an essential presynaptic, activity-dependent negative regulator of DA neurotransmission.


Rationale and design of the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnoea--RICCADSA trial.
Obstructive sleep apnoea (OSA) is common in coronary artery disease (CAD) and a possible cause of increased mortality. To date, there is a lack of randomized controlled trials to draw the conclusion that all CAD patients should be investigated for OSA and subsequently be treated with continuous positive airway pressure (CPAP). The Randomized Intervention with CPAP in CAD and OSA (RICCADSA) trial is designed to address if CPAP treatment reduces the combined rate of new revascularization, myocardial infarction, stroke and cardiovascular mortality over a 3-year period in CAD patients with OSA. Secondary outcomes include cardiovascular biomarkers, cardiac function and maximal exercise capacity at 3-month- and 1-year follow-ups. A sample of 400 CAD patients (100 non-sleepy OSA patients randomized to CPAP, 100 to non-CPAP; 100 sleepy OSA patients on CPAP, and 100 CAD patients without OSA) will be included. So far, 240 patients have been enrolled in the trial since December 31, 2005. The RICCADSA trial will contribute to defining the impact of CPAP on prognosis of CAD patients with OSA.


Anti-tumor effect of orally administered spinach glycolipid fraction on implanted cancer cells, colon-26, in mice.
We succeeded in purifying a major glycolipid fraction from a green vegetable, spinach. This fraction consists mainly of three glycolipids: monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG), and sulfoquinovosyl diacylglycerol (SQDG). In a previous study, we found that the glycolipid fraction inhibited DNA polymerase activity, cancer cell growth and tumor growth with subcutaneous injection. We aimed to clarify oral administration of the glycolipid fraction, suppressing colon adenocarcinoma (colon-26) tumor growth in mice. A tumor graft study showed that oral administration of 20 mg/kg glycolipid fraction for 2 weeks induced a 56.1% decrease in the solid tumor volume (P < 0.05) without any side-effects, such as loss of body weight or major organ failure, in mice. The glycolipid fraction induced the suppression of colon-26 tumor growth with inhibition of angiogenesis and the expression of cell proliferation marker proteins such as Ki-67, proliferating cell nuclear antigen (PCNA), and Cyclin E in the tumor tissue. These results suggest that the orally administered glycolipid fraction from spinach could suppress colon tumor growth in mice by inhibiting the activities of neovascularization and cancer cellular proliferation in tumor tissue.


Localized visceral invasion of peritoneal mesothelioma causing intestinal obstruction: a new clinical presentation.
Peritoneal mesothelioma is a surface malignancy involving the serous surfaces of the abdominal cavity. In the case presented here, the disease presented itself in a manner that has not been previously described. The tumor involved the full thickness of the bowel besides the familiar surface spread which is characteristic of the disease. Intestinal obstruction is a rare or late presentation of mesothelioma. It was the presenting symptom in the present case due to the full thickness infiltration of the small bowel by the tumor. The offending segment was resected and the ascites was treated with intraperitoneal chemotherapy. Though the patient at present has progression of disease he enjoys a reasonable quality of life after palliation of the ascites and obstruction.


A novel member of the rho family of small GTP-binding proteins is specifically required for cytokinesis.
Several members of the rho/rac family of small GTP-binding proteins are known to regulate the distribution of the actin cytoskeleton in various subcellular processes. We describe here a novel rac protein, racE, which is specifically required for cytokinesis, an actomyosin-mediated process. The racE gene was isolated in a molecular genetic screen devised to isolate genes required for cytokinesis in Dictyostelium. Phenotypic characterization of racE mutants revealed that racE is not essential for any other cell motility event, including phagocytosis, chemotaxis, capping, or development. Our data provide the first genetic evidence for the essential requirement of a rho-like protein, specifically in cytokinesis, and suggest a role for these proteins in coordinating cytokinesis with the mitotic events of the cell cycle.


Engineered minichromosomes in plants.
Engineered minichromosomes have been produced in several plant species via telomere-mediated chromosomal truncation. This approach bypasses the complications of the epigenetic nature of centromere function in plants, which has to date precluded the production of minichromosomes by the re-introduction of centromere sequences to a plant cell. Genes to be added to a cleaved chromosome are joined together with telomere repeats on one side. When these constructs are introduced into plant cells, the genes are ligated to the broken chromosomes but the telomere repeats will catalyze the formation of a telomere on the other end cutting the chromosome at that point. Telomere-mediated chromosomal truncation is sufficiently efficient that very small chromosomes can be generated consisting of basically the endogenous centromere and the added transgenes. The added transgenes provide a platform onto which it should be possible to assemble a synthetic chromosome to specification. Combining engineered minichromosomes with doubled haploid breeding should greatly expedite the transfer of transgenes to new lines and to test the interaction of transgenes in new background genotypes. Potential basic and applied applications of synthetic chromosomes are discussed.


Avian cerebellar floccular fossa size is not a proxy for flying ability in birds.
Extinct animal behavior has often been inferred from qualitative assessments of relative brain region size in fossil endocranial casts. For instance, flight capability in pterosaurs and early birds has been inferred from the relative size of the cerebellar flocculus, which in life protrudes from the lateral surface of the cerebellum. A primary role of the flocculus is to integrate sensory information about head rotation and translation to stabilize visual gaze via the vestibulo-occular reflex (VOR). Because gaze stabilization is a critical aspect of flight, some authors have suggested that the flocculus is enlarged in flying species. Whether this can be further extended to a floccular expansion in highly maneuverable flying species or floccular reduction in flightless species is unknown. Here, we used micro computed-tomography to reconstruct "virtual" endocranial casts of 60 extant bird species, to extract the same level of anatomical information offered by fossils. Volumes of the floccular fossa and entire brain cavity were measured and these values correlated with four indices of flying behavior. Although a weak positive relationship was found between floccular fossa size and brachial index, no significant relationship was found between floccular fossa size and any other flight mode classification. These findings could be the result of the bony endocranium inaccurately reflecting the size of the neural flocculus, but might also reflect the importance of the flocculus for all modes of locomotion in birds. We therefore conclude that the relative size of the flocculus of endocranial casts is an unreliable predictor of locomotor behavior in extinct birds, and probably also pterosaurs and non-avian dinosaurs.


Effect of salinity on the activity, settling and microbial community of activated sludge in sequencing batch reactors treating synthetic saline wastewater.
The effects of salinity on the activity in nutrient removal, settling and microbial community of activated sludge in sequencing batch reactors (SBRs) treating synthetic saline wastewater were investigated. Two SBRs, one treating synthetic saline wastewater (the N-Reactor, with NaCl addition) and the other treating fresh synthetic wastewater (the C-Reactor, without NaCl addition), were operated for 68 days. Three salinities (in terms of concentrations of NaCl)--10, 20 and 40 g NaCl/l--were examined. The microbial activity described with the specific glucose utilization rate, specific nitritation and nitratation rates, and specific phosphorus release and uptake rates, was inhibited in the N-Reactor, in comparison with that in the C-Reactor, except that the specific nitritation and nitratation rates were improved at the salinity of 10 g NaCl/l. The sludge yield coefficient decreased at salinities of 10 and 20 g NaCl/l but it rose at the salinity of 40 g NaCl/l. The settling of activated sludge flocs, in terms of the sludge volume index (SVI), was improved by adding NaCl. Particularly in the first 5 minutes during the SVI measurement, activated sludge flocs in the N-Reactor settled much faster than those in the C-Reactor. However, the effluent from the N-Reactor contained higher suspended solids than the effluent from the C-Reactor. The microbial diversity decreased with increasing the salinity, and the microbial community structure was greatly influenced by the salinity. Bacteriodetes and Actinobacteria were the dominant phylums detected with molecular fingerprinting techniques.


Designing chitosan-tripolyphosphate microparticles with desired size for specific pharmaceutical or forensic applications.
Chitosan (CS) is a natural cationic polymer obtained by the partial N-deacetylation of chitin. Chitosan microparticles can be prepared by cross-linking with tripolyphosphate (TPP) via the ionic interaction between positively charged amino groups (CS) and negatively charged counter ions (TPP). This can be controlled by the charge density of CS and TPP, which depend on the pH and ionic strength of the solution. The purpose of this study is to investigate the combined effects of three independent variables (pH, ionic strength and CS:TPP ratio) on three important physico-chemical properties (viscosity, zeta potential and particle size) during the preparation of microparticles. CS:TPP microparticles were prepared using experimental design and equations were generated and used to predict relative viscosity, zeta potential and particle size under different conditions. This gives us the ability to design tuneable CS-TPP microparticles with desired size for specific pharmaceutical or forensic applications e.g. latent fingerprint visualisation.


Chromatic pupillometry dissects function of the three different light-sensitive retinal cell populations in RPE65 deficiency.
The aim of the study was to objectively characterize the function of rods, cones, and intrinsic photosensitive retinal ganglion cells (ipRGCs) in patients with RPE65 mutations by using two published protocols for chromatic pupillometry, and to correlate the data with the clinical phenotype. The study group comprised 11 patients with RPE65 mutations, and for control purposes, 32 healthy probands and 2 achromats. A custom-made binocular chromatic pupillometer (Bino I) connected to a ColorDome Ganzfeld stimulator was used to assess changes in pupil diameter in response to red (640 nm) and blue (462 nm) light stimuli. Light intensities, stimulus duration, and background varied depending on the protocol used. Results were compared to the clinical phenotype, that is, visual field (Goldmann perimetry), best corrected visual acuity, and full-field stimulus testing (FST). No significant differences in any of the pupil response parameters were observed in intraday or intervisit variability tests. Pupil responses to rod-weighted stimulation were significantly diminished in all RPE65 patients. Pupil responses to cone-weighted stimuli differed among RPE65 patients and did not always correlate with residual visual field and cone sensitivity loss in FST. Pupil responses to ipRGC-weighted answers were slightly but significantly diminished, and the postillumination pupil response was significantly increased. Chromatic pupillometry represents a highly sensitive and objective test to quantify the function of rods, cones, and ipRGCs in patients with RPE65 mutations.


Can subjective sleep problems detect latent sleep disorders among commercial drivers?
Long-haul truck drivers experience poor sleep health and heightened accident rates, and undiagnosed sleep disorders contribute to these negative outcomes. Subjective sleep disorder screening tools may aid in detecting drivers' sleep disorders. This study sought to evaluate the value of subjective screening methods for detecting latent sleep disorders and identifying truck drivers at-risk for poor sleep health and safety-relevant performance. Using cross-sectional data from 260 long-haul truck drivers, we: 1) used factor analysis to identify possible latent sleep disorders; 2) explored the construct validity of extracted sleep disorder factors by determining their associations with established sleep disorder risk factors and symptoms; and 3) explored the predictive validity of resulting sleep disorder factors by determining their associations with sleep health and safety-relevant performance. Five latent sleep disorder factors were extracted: 1) circadian rhythm sleep disorders; 2) sleep-related breathing disorders; 3) parasomnias; 4) insomnias; 5) and sleep-related movement disorders. Patterns of associations between these factors generally corresponded with known risk factors and symptoms. One or more of the extracted latent sleep disorder factors were significantly associated with all the sleep health and safety outcomes. Using subjective sleep problems to detect latent sleep disorders among long-haul truck drivers may be a timely and effective way to screen this highly mobile occupational segment. This approach should constitute one component of comprehensive efforts to diagnose and treat sleep disorders among commercial transport operators.


Does isotretinoin therapy have any effects on electrocardiography, heart rate and blood pressure?
Isotretinoin therapy is associated with numerous adverse effects of various systems. Although some cases have been reported, cardiac side effects are rare following isotretinoin treatment. To investigate the effects of isotretinoin on the cardiovascular system. Seventy patients with acne vulgaris were enrolled in the study. The patients were treated with a dose of 0.5-1.0 mg/kg per day of isotretinoin. Screening for biochemical and hematologic parameters, heart rate, blood pressure and electrocardiographic parameters were done before treatment and after 3 months of isotretinoin treatment. Heart rate, systolic/diastolic tension and electrocardiographic parameters (P-wave duration and QTc duration) were not statistically different before compared with after treatment. As far as we know, there is no study researching the effect of isotretinoin on P- and QT-wave measurements in the literature. We found that isotretinoin did not affect P- and QT-wave measurement. Further studies with longer periods of follow-up are needed to understand the effect of isotretinoin on the cardiovascular system.


Effects of aphidicolin and/or 2',3'-dideoxythymidine on DNA repair induced in HeLa cells by four types of DNA-damaging agents.
The alkaline sucrose density gradient centrifugation method was modified to permit detection of 1 lesion/10(9) daltons of DNA. With this technique, the involvements of DNA polymerases in DNA repair of damage by dimethyl sulfate, UV irradiation, neocarzinostatin, and bleomycin were studied in HeLa cells with the aid of the DNA polymerase inhibitors aphidicolin and 2',3'-dideoxythymidine. DNA repair after UV-induced damage seemed to involve only polymerase alpha, while repair of damage by the other three agents involved both polymerase alpha and a non-alpha polymerase, probably polymerase beta. But repair after damage by dimethyl sulfate differed from that after damage by neocarzinostatin or bleomycin with respect to the co-operations of polymerase alpha and polymerase beta: in repair of dimethyl sulfate-induced damage, both polymerases operated on the same lesions, whereas after damage by neocarzinostatin or bleomycin, polymerase alpha and polymerase beta functioned independently on different lesions.


Neuroprotective properties of the natural phenolic antioxidants curcumin and naringenin but not quercetin and fisetin in a 6-OHDA model of Parkinson's disease.
Although the cause of dopaminergic cell death in Parkinson's disease (PD) remains unknown, oxidative stress has been strongly implicated. Because of their ability to combat oxidative stress, diet derived phenolic compounds continue to be considered as potential agents for long-term use in PD. This study was aimed at investigating whether the natural phenolic compounds curcumin, naringenin, quercetin, fisetin can be neuroprotective in the 6-OHDA model of PD. Unilateral infusion of 6-OHDA into the medial forebrain bundle produced a significant loss of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) as well as a decreased of dopamine (DA) content in the striata in the vehicle-treated animals. Rats pretreated with curcumin or naringenin showed a clear protection of the number of TH-positive cells in the SN and DA levels in the striata. However, neither pretreatment with quercetin nor fisetin had any effects on TH-positive cells or DA levels. The ability of curcumin and naringenin to exhibit neuroprotection in the 6-OHDA model of PD may be related to their antioxidant capabilities and their capability to penetrate into the brain.


Personality profiles of rural longitudinal integrated clerkship students who choose family medicine.
Physician workforce projections fuel interest in addressing the shortage of family physicians. Copious research has investigated personality as a variable influencing specialty intention. Medical school rural longitudinal integrated clerkships (LICs) nurture interest in family medicine. This study examined whether rural LIC students who intended to and eventually matched into family medicine portrayed a personality trait profile different from rural LIC students who intended or matched to all other specialities. The profiles of four successive cohorts are described in relation to their intended and eventual specialty match. A cross-sectional design sampled 145 third-year students from 2008--2011. A survey measured demographics, temperament and character personality traits, and Other-Oriented Empathy. Multivariate analysis compared family medicine versus all other specialty matches and original specialty intention with eventual match. Match groups did not differ in gender, age, or marital status. Rural LIC students who matched in family medicine had lower levels of Harm Avoidance, higher Reward Dependence, and nonsignificant higher levels of every other personality trait in comparison to other matches. Rural LIC students who intended and matched to family medicine showed the highest levels of Reward Dependence (warm sociability) and Other-Oriented Empathy compared to any other specialty. Lower levels of Harm Avoidance are conducive to less anxiety, more composure and confidence in making decisions, and being relaxed in accepting a degree of risk and uncertainty. Such calm optimism along with higher Reward Dependence showing social warmth and empathy are desirable traits for family physicians regularly confronted with a wide range of presentations from the obvious to complex. Further investigation of what influences sustainability of the intention to enter family medicine may be useful to educators for counseling.


Case Report Stimulant-Induced Atrial Flutter in a Remote Setting.
Atrial flutter and atrial fibrillation are among the most commonly encountered cardiac arrhythmias; however, there is a dearth of clinical trials or case studies regarding its occurrence in the setting of stimulants such as caffeine and nicotine in otherwise healthy young patients. Described here is a case of a 29-year-old physically fit white man without significant past medical history who presented in stable condition complaining only of palpitations. He was found to have atrial flutter without rapid ventricular response on cardiac monitoring, most likely due to concomitant presence of high levels of nicotine and caffeine via chewing tobacco and energy drinks. He was treated conservatively with vagal maneuvers and intravenous fluids with complete resolution of symptoms and electrocardiographic abnormalities within 14 hours. This demonstrates an alternate conservative treatment strategy in appropriately risk stratified patients who present in an austere field setting with limited resources.


Effects of irrigation regimes on fatty acid composition, antioxidant and antifungal properties of volatiles from fruits of Koroneiki cultivar grown under Tunisian conditions.
The olive tree is generally grown under rain-fed conditions. However, since the yield response to irrigation is great, even with low amounts of water, there is increasing interest in irrigated agriculture. The main goal of this study was, therefore, to investigate the effect of irrigation regimes on olive (Olea europaea L., cv. Koroneiki) obtained from an intensively-managed orchard in a semi-arid area with a Mediterranean climate in Tunisia. Different irrigation treatments 50% ETc, 75% ETc and 100% ETc were applied to the olive orchard. Accordingly, the effects of three irrigation regimes on volatile compounds, fatty acid composition and biological activities of Koroneiki cultivar were studied. The total profile of the volatile constituents of all samples revealed the predominance of 3-ethenylpyridine (from 14.9-19.6%), phenylethyl alcool (from 7.8-19.2%) and benzaldehyde (from 9.0 to 13.8%). During watering level treatments studied, the major fatty acids were oleic, palmitic and linoleic. Antioxidant activity of the fresh fruit volatiles cultivated at a watering level of 100% ETc was higher than that obtained under 50 and 75% Etc. The results of antifungal activity showed that the fruits volatiles of the three irrigation treatments had varying degrees of growth inhibition against the microorganisms tested.


Genetic and antigenic analysis of the G attachment protein of bovine respiratory syncytial virus strains.
Antigenic and genetic studies of bovine respiratory syncytial virus (BRSV) were made on isolates obtained from three continents over 27 years. Antigenic variation between eight isolates was initially determined using protein G-specific monoclonal antibodies. Four distinct reaction patterns were observed, two of which corresponded to the previously established subgroups A and AB. A third pattern was produced by five Scandinavian strains and a fourth was observed from a single Dutch isolate. The genetic diversity of 27 strains of BRSV was investigated by comparative nucleotide sequence analysis of a 731 nucleotide fragment in the G protein gene. Nine of the BRSV strains were analysed by direct sequencing of RT-PCR amplicons whereas sequences of 18 BRSV and three human respiratory syncytial virus (HRSV) strains were obtained from GenBank. The analysis revealed similarities of 88-100% among BRSV strains and 38-41% between BRSV and HRSV. A phylogenetic tree created for BRSV revealed two main branches, one of which divided into five further lineages, each representing a geographic cluster. A correlation was evident between the positions of some strains in the phylogenetic tree and their antigenic pattern. For HRSV strains, a genetic similarity of only 62% allowed the distinction of two antigenic subgroups, A and B, a pattern which was not seen for BRSV. This study showed that genetic analysis was an accurate method for discriminating BRSV strains and that these viruses should be regarded as a single genetic and antigenic group, within which variants can be distinguished.


Next-generation sequencing is highly sensitive for the detection of beta-catenin mutations in desmoid-type fibromatoses.
Desmoid-type fibromatoses are locally aggressive and frequently recurrent tumours, and an accurate diagnosis is essential for patient management. The majority of sporadic lesions harbour beta-catenin (CTNNB1) mutations. We used next-generation sequencing to detect CTNNB1 mutations and to compare the sensitivity and specificity of next-generation sequencing with currently employed mutation detection techniques: mutation-specific restriction enzyme digestion and polymerase chain reaction amplification. DNA was extracted from formalin-fixed paraffin-embedded needle biopsy or resection tissue sections from 144 patients with sporadic desmoid-type fibromatoses, four patients with syndrome-related desmoid-type fibromatoses and 11 morphological mimics. Two primer pairs were designed for CTNNB1 mutation hotspots. Using ≥10 ng of DNA, libraries were generated by Fluidigm and sequenced on the Ion Torrent Personal Genome Machine. Next-generation sequencing had a sensitivity of 92.36 % (133/144, 95 % CIs: 86.74 to 96.12 %) and a specificity of 100 % for the detection of CTNNB1 mutations in desmoid-type fibromatoses-like spindle cell lesions. All mutations detected by mutation-specific restriction enzyme digestion were identified by next-generation sequencing. Next-generation sequencing identified additional mutations in 11 tumours that were not detected by mutation-specific restriction enzyme digestion, two of which have not been previously described. Next-generation sequencing is highly sensitive for the detection of CTNNB1 mutations. This multiplex assay has the advantage of detecting additional mutations compared to those detected by mutation-specific restriction enzyme digestion (sensitivity 82.41 %). The technology requires minimal DNA and is time- and cost-efficient.


iEnhancer-ECNN: identifying enhancers and their strength using ensembles of convolutional neural networks.
Enhancers are non-coding DNA fragments which are crucial in gene regulation (e.g. transcription and translation). Having high locational variation and free scattering in 98% of non-encoding genomes, enhancer identification is, therefore, more complicated than other genetic factors. To address this biological issue, several in silico studies have been done to identify and classify enhancer sequences among a myriad of DNA sequences using computational advances. Although recent studies have come up with improved performance, shortfalls in these learning models still remain. To overcome limitations of existing learning models, we introduce iEnhancer-ECNN, an efficient prediction framework using one-hot encoding and k-mers for data transformation and ensembles of convolutional neural networks for model construction, to identify enhancers and classify their strength. The benchmark dataset from Liu et al.'s study was used to develop and evaluate the ensemble models. A comparative analysis between iEnhancer-ECNN and existing state-of-the-art methods was done to fairly assess the model performance. Our experimental results demonstrates that iEnhancer-ECNN has better performance compared to other state-of-the-art methods using the same dataset. The accuracy of the ensemble model for enhancer identification (layer 1) and enhancer classification (layer 2) are 0.769 and 0.678, respectively. Compared to other related studies, improvements in the Area Under the Receiver Operating Characteristic Curve (AUC), sensitivity, and Matthews's correlation coefficient (MCC) of our models are remarkable, especially for the model of layer 2 with about 11.0%, 46.5%, and 65.0%, respectively. iEnhancer-ECNN outperforms other previously proposed methods with significant improvement in most of the evaluation metrics. Strong growths in the MCC of both layers are highly meaningful in assuring the stability of our models.


Implementation of Point-of-Care Diagnostics Leads to Variable Uptake of Syphilis, Anemia and CD4+ T-Cell Count Testing in Rural Maternal and Child Health Clinics.
Anemia, syphilis and HIV are high burden diseases among pregnant women in sub-Saharan Africa. A quasi-experimental study was conducted in four health facilities in Southern Mozambique to evaluate the effect of point-of-care technologies for hemoglobin quantification, syphilis testing and CD4+ T-cell enumeration performed within maternal and child health services on testing and treatment coverage, and assessing acceptability by health workers. Demographic and testing data on women attending first antenatal care services were extracted from existing records, before (2011; n = 865) and after (2012; n = 808) introduction of point-of-care testing. Study outcomes per health facility were compared using z-tests (categorical variables) and Wilcoxon rank-sum test (continuous variables), while inverse variance weights were used to adjust for possible cluster effects in the pooled analysis. A structured acceptability-assessment interview was conducted with health workers before (n = 22) and after (n = 19). After implementation of point-of-care testing, there was no significant change in uptake of overall hemoglobin screening (67.9% to 83.0%; p = 0.229), syphilis screening (80.8% to 87.0%; p = 0.282) and CD4+ T-cell testing (84.9% to 83.5%; p = 0.930). Initiation of antiretroviral therapy for treatment eligible women was similar in the weighted analysis before and after, with variability among the sites. Time from HIV diagnosis to treatment initiation decreased (median of 44 days to 17 days; p<0.0001). A generally good acceptability for point-of-care testing was seen among health workers. Point-of-care CD4+ T-cell enumeration resulted in a decreased time to initiation of antiretroviral therapy among treatment eligible women, without significant increase in testing coverage. Overall hemoglobin and syphilis screening increased. Despite the perception that point-of-care technologies increase access to health services, the variability in results indicate the potential for detrimental effects in some settings. Local context needs to be considered and services restructured to accommodate innovative technologies in order to improve service delivery to expectant mothers.


X-ray Detection of Transient Magnetic Moments Induced by a Spin Current in Cu.
We have used a MHz lock-in x-ray spectromicroscopy technique to directly detect changes in magnetic moment of Cu due to spin injection from an adjacent Co layer. The elemental and chemical specificity of x rays allows us to distinguish two spin current induced effects. We detect the creation of transient magnetic moments of 3×10^{-5}μ_{B} on Cu atoms within the bulk of the 28 nm thick Cu film due to spin accumulation. The moment value is compared to predictions by Mott's two current model. We also observe that the hybridization induced existing magnetic moments at the Cu interface atoms are transiently increased by about 10% or 4×10^{-3}μ_{B} per atom. This reveals the dominance of spin-torque alignment over Joule heat induced disorder of the interfacial Cu moments during current flow.


Flexoelectricity in Bones.
Bones generate electricity under pressure, and this electromechanical behavior is thought to be essential for bone's self-repair and remodeling properties. The origin of this response is attributed to the piezoelectricity of collagen, which is the main structural protein of bones. In theory, however, any material can also generate voltages in response to strain gradients, thanks to the property known as flexoelectricity. In this work, the flexoelectricity of bone and pure bone mineral (hydroxyapatite) are measured and found to be of the same order of magnitude; the quantitative similarity suggests that hydroxyapatite flexoelectricity is the main source of bending-induced polarization in cortical bone. In addition, the measured flexoelectric coefficients are used to calculate the (flexo)electric fields generated by cracks in bone mineral. The results indicate that crack-generated flexoelectricity is theoretically large enough to induce osteocyte apoptosis and thus initiate the crack-healing process, suggesting a central role of flexoelectricity in bone repair and remodeling.


International field test results of the Observable Indicators of Nursing Home Care Quality instrument.
Researchers at the University of Missouri-Columbia developed the Observable Indicators of Nursing Home Care Quality instrument to measure the dimensions of nursing home care quality during a brief on-site visit to a nursing home. The instrument has been translated for use in Iceland and used in Canada. Results of the validity and reliability studies using the instrument in 12 nursing homes in Reykjavik, in a large Veterans Home in Ontario with 14 units tested separately, and in 20 nursing homes in Missouri, are promising. High-content validity was observed in all countries, together with excellent inter-rater reliability and coefficient alpha. Test-retest reliabilities in Iceland and Missouri were good. Results of the international field test of the Observable Indicators of Nursing Home Care Quality instrument points to the usefulness of such an instrument in measuring nursing home care quality following a quick on-site observation in a nursing facility. The instrument should be used as a facility-wide assessment of quality, rather than for individual units within a facility. We strongly recommend its use by practising nurses in nursing homes to assess quality of care and guide efforts to improve care. We recommend its use by researchers and consumers and further testing of the use of the instrument with regulators.


SemiBoost: boosting for semi-supervised learning.
Semi-supervised learning has attracted a significant amount of attention in pattern recognition and machine learning. Most previous studies have focused on designing special algorithms to effectively exploit the unlabeled data in conjunction with labeled data. Our goal is to improve the classification accuracy of any given supervised learning algorithm by using the available unlabeled examples. We call this as the Semi-supervised improvement problem, to distinguish the proposed approach from the existing approaches. We design a metasemi-supervised learning algorithm that wraps around the underlying supervised algorithm and improves its performance using unlabeled data. This problem is particularly important when we need to train a supervised learning algorithm with a limited number of labeled examples and a multitude of unlabeled examples. We present a boosting framework for semi-supervised learning, termed as SemiBoost. The key advantages of the proposed semi-supervised learning approach are: 1) performance improvement of any supervised learning algorithm with a multitude of unlabeled data, 2) efficient computation by the iterative boosting algorithm, and 3) exploiting both manifold and cluster assumption in training classification models. An empirical study on 16 different data sets and text categorization demonstrates that the proposed framework improves the performance of several commonly used supervised learning algorithms, given a large number of unlabeled examples. We also show that the performance of the proposed algorithm, SemiBoost, is comparable to the state-of-the-art semi-supervised learning algorithms.


Hodgkin's disease in children in southern Africa: epidemiological characteristics, morbidity and long-term outcome.
We reviewed 39 children < 15 years of age treated for Hodgkin's disease (HD) from 1973 to 1996. There were seven black, 12 white and 20 coloured children (of mixed ethnic origin). The M:F ratio was 2.9:1 and the median ages 147, 124 and 119 months in white, coloured and black children, respectively. Coloured and black children came mainly from a poor socio-economic background. Cervical lymphadenopathy was present in 74% and systemic symptoms in 51% of cases. Five per cent had clinical stage I, 41% stage II, 28% stage III and 26% stage IV disease. Two children underwent a staging splenectomy. The majority of white children presented with stages I and II and the majority of black and coloured children with stages III and IV HD. Nodular sclerosing (59%), mixed cellularity (40%) and lymphocyte-depleted (43%) were the most common histological subtypes in white, coloured and black children, respectively. Epidemiologically, white children fitted the criteria for HD type I and coloured and black children the criteria for HD type III. Nineteen children were treated with ChlVPP (chlorambucil, vinblastine, prednisone, procarbazine) and 20 with MOPP (mustine, Oncovin, procarbazine, prednisone) and/or ABVD (Adriamycin, bleomycin, vinblastine, DTIC) with involved field radiotherapy to bulky mediastinal disease. The projected 10-year survival after ChlVPP or MOPP/ABVD therapy was similar at 52%. In stages I and II, HD projected survival at 5 and 10 years was 85%, and in stages III and IV it was 82% at 5 and 48% at 10 years. The relapse rate was 47% in stage II, 45% in stage III and 44% in stage IV. Tuberculosis was suspected and treated in five children at the time of, and in seven children (three confirmed) subsequent to, the diagnosis of HD. Varicella developed in six and herpes zoster in five children. Five treatment-related deaths were due to septicaemia following splenectomy (two), marrow failure, corpulmonale and secondary leukaemia.


Improvement in the differentiated hepatic phenotype of immortalized human hepatocytes by adenovirus mediated p21 gene transfer.
The p21 molecule, a potent cyclin dependent kinase inhibitor, regulates the transition from the G1 phase to the S phase of the cell cycle and is involved in terminal cellular differentiation. The overexpression of p21 has been shown to induce differentiation in various cell lines. We have made an effort to establish a reliable human hepatocyte cell line as a source of hepatic function in bioartificial liver (BAL) therapy. In this work, we investigated the effect of p21 on the differential phenotype of simian virus 40 large T antigen (SV40Tag) immortalized human hepatocytic NKNT-3 cells. A recombinant adenoviral vector expressing a p21 gene under control of the cytomegalovirus (CMV) promoter (Ad-p21) was used to efficiently transfer genes into NKNT-3 cells. The morphologic alterations, the cell cycle progression, and the expression of p-450 associated enzymes (CYPs) were carefully examined in NKNT-3 cells that had been infected with Ad-p21. Adenovirus mediated gene delivery of p21 was efficiently achieved in NKNT-3 cells without affecting cellular structure. After Ad-p21 infection, NKNT-3 cells were G0/G1 arrested in cell cycle analysis. NKNT-3 cells that had been infected with Ad-p21 showed differentiated hepatic phenotypes in morphology and improvement in protein expression of CYP 3A4 and CYP 2C9. In the present work, we demonstrate that the exogenous expression of p21 enhances the differential phenotype of immortalized hepatocytic NKNT-3 cells.