Understanding Heterosis, Genetic Effects, and Genome Wide Associations for Forage Quantity and Quality Traits in Multi-Cut Pearl Millet.
Pearl millet is an important food and fodder crop cultivated in the arid and semi-arid regions of Africa and Asia, and is now expanding to other regions for forage purpose. This study was conducted to better understand the forage quantity and quality traits to enhance the feed value of this crop. Two sets of pearl millet hybrids (80 single cross hybrids in Set-I and 50 top cross hybrids in Set-II) along with their parents evaluated multi-locationally for the forage-linked traits under multi-cut (two cuts) system revealed significant variability for the forage traits in the hybrids and parents. The mean better parent heterosis (BPH) for total dry forage yield (TDFY) was 136% across all the single cross hybrids and 57% across all the top cross hybrids. The mean BPH for in vitro organic matter digestibility (IVOMD) varied from -11 to 7% in the single cross hybrids and -13 to 11% in the top cross hybrids across cuts. The findings of TDFY and IVOMD heterosis in these sets indicated the potential of improvement of the hybrid cultivars for forage quantity and quality in forage pearl millet. The parental lines single cross parent (SCP)-L02, SCP-L06, and top cross parent (TCP)-T08 found superior in the forage quantity and quality traits can be utilized in the future breeding programs. Most of the forage traits were found to be controlled by using the non-additive gene action. A diverse panel of 105 forage-type hybrid parents (Set-III) genotyped following genotyping by sequencing (GBS) and phenotyped for crude protein (CP) and IVOMD under multi-cuts for 2 years identified one stable significant single nucleotide polymorphism (SNP) on LG4 for CP, and nine SNPs for IVOMD distributed across all the linkage groups except on LG2. The identified loci, once validated, then could be used for the forage quality traits improvement in pearl millet through marker-assisted selection.


Bounding the causal effect of unemployment on mental health: Nonparametric evidence from four countries.
An important, yet unsettled, question in public health policy is the extent to which unemployment causally impacts mental health. The recent literature yields varying findings, which are likely due to differences in data, methods, samples, and institutional settings. Taking a more general approach, we provide comparable evidence for four countries with different institutional settings-Australia, Germany, the UK, and the United States-using a nonparametric bounds analysis. Relying on fairly weak and partially testable assumptions, our paper shows that unemployment has a significant negative effect on mental health in all countries. Our results rule out effects larger than a quarter of a standard deviation for Germany and half a standard deviation for the Anglo-Saxon countries. The effect is significant for both men and women and materialises already for short periods of unemployment. Public policy should hence focus on early prevention of mental health problems among the unemployed.


Comparing Properties of Concrete Containing Electric Arc Furnace Slag and Granulated Blast Furnace Slag.
For sustainable development in the construction industry, blast furnace slag has been used as a substitute for cement in concrete. In contrast, steel-making slag, the second largest by-product in the steel industry, is mostly used as a filler material in embankment construction. This is because steel-making slag has relatively low hydraulicity and a problem with volumetric expansion. However, as the quenching process of slag has improved recently and the steel making process is specifically separated, the properties of steel-making slag has also improved. In this context, there is a need to find a method for recycling steel-making slag as a more highly valued material, such as its potential use as an admixture in concrete. Therefore, in order to confirm the possibility of using electric arc furnace (EAF) oxidizing slag as a binder, a comparative assessment of the mechanical properties of concrete containing electric arc furnace oxidizing slag, steel-making slag, and granulated blast furnace (GBF) slag was performed. The initial and final setting, shrinkage, compressive and split-cylinder tensile strength of the slag concretes were measured. It was found that replacing cement with EAF oxidizing slag delayed the hydration reaction at early ages, with no significant problems in setting time, shrinkage or strength development found.


[Relapsing viral hepatitis type A complicated with renal failure].
We report the case of a 42-year old male with an episode of relapsing hepatitis A of cholestatic pattern, which clinic course was complicated by fever, anemia and renal failure, requiring hemodialysis. The occurrence of cryglobulins and diminished complement levels was detected. A kidney biopsy was performed showing evidence of thrombotic microangiopathy. The patient had a good therapeutic response to corticosteroids, although he developed recurrence of fever and a palpable purpuric rush over his lower extremities when dose was reduced. A skin biopsy found leukocytoclastic vasculitis. Symptoms and physical findings improved when therapy with cycloposphamide was started and the dose of corticosteroids was increased. Hepatitis A virus infection usually has a benign course, although complications may occasionally develop. The relapsing form can be seen in 3-20% of the case; it can appear with a cholestatic pattern and most of the time it has a mild clinic development. Unlike hepatitis B, extra-hepatic manifestations are unusual in hepatitis A, and renal manifestations are even more infrequent. Acute renal failure (ARF) in non-fulminating hepatitis A has been reported only occasionally and its etiology remains unclear. Several hypotheses have been proposed, including renal toxicity due to hyperuricemia or increased bilirrubin, cryoglobulinemia, alterations in the renal blood flow due to endotoxemia or peripheral immune complex-mediated damage when hypocomplementemia is found. Kidney biopsy showed evidence of thrombotic microangiopathy, which raised the hypothesis of a Hemolytic Uremic Syndrome (HUS). An association with HUS has been described in a patient with surface antigen for hepatitis B (HBsAg) and anomalies in the hepatic biochemical tests, but as far as we know this is the first case of relapsing hepatitis A associated with a confirmed microangiopathic renal involvement.


The relation between different dimensions of alcohol consumption and burden of disease: an overview.
As part of a larger study to estimate the global burden of disease and injury attributable to alcohol: to evaluate the evidence for a causal impact of average volume of alcohol consumption and pattern of drinking on diseases and injuries; to quantify relationships identified as causal based on published meta-analyses; to separate the impact on mortality versus morbidity where possible; and to assess the impact of the quality of alcohol on burden of disease. Systematic literature reviews were used to identify alcohol-related diseases, birth complications and injuries using standard epidemiological criteria to determine causality. The extent of the risk relations was taken from meta-analyses. Evidence of a causal impact of average volume of alcohol consumption was found for the following major diseases: tuberculosis, mouth, nasopharynx, other pharynx and oropharynx cancer, oesophageal cancer, colon and rectum cancer, liver cancer, female breast cancer, diabetes mellitus, alcohol use disorders, unipolar depressive disorders, epilepsy, hypertensive heart disease, ischaemic heart disease (IHD), ischaemic and haemorrhagic stroke, conduction disorders and other dysrhythmias, lower respiratory infections (pneumonia), cirrhosis of the liver, preterm birth complications and fetal alcohol syndrome. Dose-response relationships could be quantified for all disease categories except for depressive disorders, with the relative risk increasing with increased level of alcohol consumption for most diseases. Both average volume and drinking pattern were linked causally to IHD, fetal alcohol syndrome and unintentional and intentional injuries. For IHD, ischaemic stroke and diabetes mellitus beneficial effects were observed for patterns of light to moderate drinking without heavy drinking occasions (as defined by 60+ g pure alcohol per day). For several disease and injury categories, the effects were stronger on mortality compared to morbidity. There was insufficient evidence to establish whether quality of alcohol had a major impact on disease burden. Overall, these findings indicate that alcohol impacts many disease outcomes causally, both chronic and acute, and injuries. In addition, a pattern of heavy episodic drinking increases risk for some disease and all injury outcomes. Future studies need to address a number of methodological issues, especially the differential role of average volume versus drinking pattern, in order to obtain more accurate risk estimates and to understand more clearly the nature of alcohol-disease relationships.


Influenza A virus nucleoprotein induces apoptosis in human airway epithelial cells: implications of a novel interaction between nucleoprotein and host protein Clusterin.
Apoptosis induction is an antiviral host response, however, influenza A virus (IAV) infection promotes host cell death. The nucleoprotein (NP) of IAV is known to contribute to viral pathogenesis, but its role in virus-induced host cell death was hitherto unknown. We observed that NP contributes to IAV infection induced cell death and heterologous expression of NP alone can induce apoptosis in human airway epithelial cells. The apoptotic effect of IAV NP was significant when compared with other known proapoptotic proteins of IAV. The cell death induced by IAV NP was executed through the intrinsic apoptosis pathway. We screened host cellular factors for those that may be targeted by NP for inducing apoptosis and identified human antiapoptotic protein Clusterin (CLU) as a novel interacting partner. The interaction between IAV NP and CLU was highly conserved and mediated through β-chain of the CLU protein. Also CLU was found to interact specifically with IAV NP and not with any other known apoptosis modulatory protein of IAV. CLU prevents induction of the intrinsic apoptosis pathway by binding to Bax and inhibiting its movement into the mitochondria. We found that the expression of IAV NP reduced the association between CLU and Bax in mammalian cells. Further, we observed that CLU overexpression attenuated NP-induced cell death and had a negative effect on IAV replication. Collectively, these findings indicate a new function for IAV NP in inducing host cell death and suggest a role for the host antiapoptotic protein CLU in this process.


Psychological therapies for preventing seasonal affective disorder.
Seasonal affective disorder (SAD) is a seasonal pattern of recurrent major depressive episodes that most commonly occurs during autumn or winter and remits in spring. The prevalence of SAD ranges from 1.5% to 9%, depending on latitude. The predictable seasonal aspect of SAD provides a promising opportunity for prevention. This is one of four reviews on the efficacy and safety of interventions to prevent SAD; we focus on psychological therapies as preventive interventions. To assess the efficacy and safety of psychological therapies (in comparison with no treatment, other types of psychological therapy, second-generation antidepressants (SGAs), light therapy, melatonin or agomelatine or lifestyle interventions) in preventing SAD and improving patient-centred outcomes among adults with a history of SAD. We conducted a search of the Cochrane Depression, Anxiety and Neurosis Review Group Specialised Register (CCDANCTR) to 11 August 2015. The CCDANCTR contains reports of relevant randomised controlled trials from EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date) and the Cochrane Central Register of Controlled Trials (CENTRAL). Furthermore, we searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge, The Cochrane Library and the Allied and Complementary Medicine Database (AMED) (to 26 May 2014). We conducted a grey literature search (e.g. in clinical trial registries) and handsearched the reference lists of all included studies and pertinent review articles. To examine efficacy, we planned to include randomised controlled trials on adults with a history of winter-type SAD who were free of symptoms at the beginning of the study. To examine adverse events, we intended to include non-randomised studies. We planned to include studies that compared psychological therapy versus any other type of psychological therapy, placebo, light therapy, SGAs, melatonin, agomelatine or lifestyle changes. We also intended to compare psychological therapy in combination with any of the comparator interventions listed above versus the same comparator intervention as monotherapy. Two review authors screened abstracts and full-text publications against the inclusion criteria. Two review authors planned to independently extract data and assess risk of bias. We planned to pool data for meta-analysis when participant groups were similar and when studies assessed the same treatments versus the same comparator and provided similar definitions of outcome measures over a similar duration of treatment; however, we included no studies. We identified 2986 citations through electronic searches and reviews of reference lists after de-duplication of search results. We excluded 2895 records during title and abstract review and assessed 91 articles at full-text review for eligibility. We found no controlled studies on use of psychological therapy to prevent SAD and improve patient-centred outcomes in adults with a history of SAD. Presently, there is no methodologically sound evidence available to indicate whether psychological therapy is or is not an effective intervention for prevention of SAD and improvement of patient-centred outcomes among adults with a history of SAD. Randomised controlled trials are needed to compare different types of psychological therapies and to compare psychological therapies versus placebo, light therapy, SGAs, melatonin, agomelatine or lifestyle changes for prevention of new depressive episodes in patients with a history of winter-type SAD.


Mixing-demixing transition in polymer-grafted spherical nanoparticles.
Polymer-grafted nanoparticles (PGNPs) can provide property profiles that cannot be obtained individually by polymers or nanoparticles (NPs). Here, we have studied the mixing-demixing transition of symmetric copolymer melts of polymer-grafted spherical nanoparticles by means of coarse-grained molecular dynamics simulation and a theoretical mean-field model. We find that a larger size of NPs leads to higher stability for a given number of grafted chains and chain lengths, reaching a point where demixing is not possible. Most importantly, the increase in the number of grafted chains, Ng, can initially favour the phase separation of PGNPs, but a further increase can lead to more difficult demixing. The reason is the increasing impact of an effective core that forms as the grafting density of the tethered polymer chains around the NPs increases. The range and exact values of Ng where this change in behaviour takes place depend on the NP size and the chain length of the grafted polymer chains. Our study elucidates the phase behaviour of PGNPs and in particular the influence of the grafting density on the phase behaviour of the systems, anticipating that it will open new doors in the understanding of these systems with implications in materials science and medicine.


Multilocus Variable Number of Tandem Repeat Analysis Reveals Multiple Introductions in Spain of Xanthomonas arboricola pv. pruni, the Causal Agent of Bacterial Spot Disease of Stone Fruits and Almond.
Xanthomonas arboricola pv. pruni is the causal agent of the bacterial spot disease of stone fruits, almond and some ornamental Prunus species. In Spain it was first detected in 2002 and since then, several outbreaks have occurred in different regions affecting mainly Japanese plum, peach and almond, both in commercial orchards and nurseries. As the origin of the introduction(s) was unknown, we have assessed the genetic diversity of 239 X. arboricola pv. pruni strains collected from 11 Spanish provinces from 2002 to 2013 and 25 reference strains from international collections. We have developed an optimized multilocus variable number of tandem repeat analysis (MLVA) scheme targeting 18 microsatellites and five minisatellites. A high discriminatory power was achieved since almost 50% of the Spanish strains were distinguishable, confirming the usefulness of this genotyping technique at small spatio-temporal scales. Spanish strains grouped in 18 genetic clusters (conservatively delineated so that each cluster contained haplotype networks linked by up to quadruple-locus variations). Furthermore, pairwise comparisons among populations from different provinces showed a strong genetic differentiation. Our results suggest multiple introductions of this pathogen in Spain and redistribution through contaminated nursery propagative plant material.


The MIRECC version of the Global Assessment of Functioning scale: reliability and validity.
This study examined the reliability and convergent, discriminant, and predictive validity of the Mental Illness Research, Education, and Clinical Center (MIRECC) version of the Global Assessment of Functioning (GAF) scale. The MIRECC GAF measures occupational functioning, social functioning, and symptom severity on three subscales. MIRECC GAF ratings were obtained for 398 individuals with schizophrenia or schizoaffective disorder who were receiving treatment at three Veterans Affairs mental health clinics. Assessments were completed by using the Positive and Negative Syndrome Scale and the Quality of Life Interview at baseline and nine months later. All three MIRECC GAF subscales exhibited very high levels of reliability. The occupational and symptom subscales showed good convergent and discriminant validity. The social subscale was related to measures of social functioning and, to a greater degree, symptom severity. The occupational and social subscales significantly predicted their respective domains at the nine-month follow-up. The symptom subscale predicted negative symptoms at follow-up; however, it did not predict positive symptoms or cognitive disorientation. Instead, the social subscale was predictive of cognitive disorientation at follow-up. When the standard GAF was routinely administered by clinicians, scores demonstrated little validity. The three MIRECC GAF subscales can be scored reliably, and they have good concurrent and predictive validity. Further work is needed on brief measures of patient functioning, especially measures of social functioning.


Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands.
People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up. An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio (ICER, costs in €/quality-adjusted life year (QALY)) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2-3 and dual DAA for genotype 1-4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake. In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses. HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID.


The efficacy of repeated radiofrequency medial branch neurotomy for lumbar facet syndrome.
Radiofrequency (RF) medial branch neurotomy is an effective management of lumbar facet syndrome. However, pain may recur after period of time. When pain recurs, it can be repeated, but the successful outcome and duration of relief from repeated procedures are not clearly known. The objective of this study was to determine the success rate and duration of pain relief from repeated radiofrequency medial branch neurotomy for lumbar facet syndrome. A retrospective review of medical records was done on 60 consecutive patients, from March of 2006 to February of 2009, who had an initial successful RF neurotomy but subsequently underwent repeated procedures due to recurrence of pain. All procedures were done in carefully selected patients after at least two responsive medial branch nerve blocks. C-arm fluoroscopic guide, impedance, sensory and motor threshold monitoring tools were used for the precise placement of electrodes. Responses of repeated procedures were compared with initial radiofrequency neurotomy for success rates and duration of pain relief. There were 48 females and 12 males. Mean age was 52.4 years (range, 26-83). RF medial branch neurotomy was done on one side in 38 and both sides in 22 patients, each covering at least three segments. Average visual analog scale at last procedure was 6.8. Twelve patients had previous lumbar operations, including 4 patients with instrumentations. Fifty-five patients had two procedures and five patients had three procedures. Mean duration of successful pain relief (> 50% of previous pain for at least 3 months period) after initial radiofrequency neurotomy was 10.9 months (range, 3-28) in 51 (85%) patients. From repeated procedures, successful pain relief was seen in 50 (91%) patients with average duration of 10.2 months (range, 3-24). Five patients had third procedure, which was successful in 4 (80%) patients with mean duration of 9.8 months (range, 5-16). This was not statistically different from initial results. There were no permanent neurological complications from the procedures. Results of this study indicate that the frequency of success and durations of relief from repeated RF medial branch neurotomy for lumbar facet syndrome are similar to initial results that provided relatively prolonged period of pain relief without major side effects. Each procedure seems to provide successful pain relief for about 10 months in more than 85% of carefully selected patients when properly done.


Healthcare-provider perceptions of barriers to oxygen therapy for paediatric patients in three government-funded eastern Ugandan hospitals; a qualitative study.
This study aimed to assess on-the-ground barriers to the provision of oxygen therapy for paediatric patients in three government-funded Eastern Ugandan district general hospitals (DGHs). Site visits to DGHs during March 2017 involved semi-structured interviews with medical officers, clinical officers, paediatric nurses and non-clinical staff (n = 29). MAXQDA qualitative data software was used to assist with response analysis. The healthcare professionals reported that erratic electricity supplies, few and/or malfunctioning oxygen cylinders and concentrators, limited or no access to pulse oximetry, inadequate staffing and lack of continued professional training were key barriers to the delivery of oxygen therapy. Local populations were reportedly fearful of oxygen therapy and reluctant to consent for oxygen therapy to be administered to their children. According to healthcare providers in three Eastern Ugandan DGHs, numerous barriers exist to oxygen therapy for paediatric patients. Healthcare professionals reported lack of facilities and training to effectively deliver oxygen therapy. Quality improvement work prioritising oxygen therapy in government-funded district general hospitals should focus on oxygen supply and delivery issues on a site-specific level and sensitizing communities to the potential benefits of oxygen.


Cognitive-behavior therapy singly and combined with medication for persistent insomnia: Impact on psychological and daytime functioning.
While impairment of daytime functioning due to poor sleep is often the main determinant for seeking treatment, few studies have examined the clinical impact of insomnia therapies on daytime outcomes. The main objective of this study was to evaluate the impact of cognitive-behavior therapy (CBT), alone and combined with medication, on various indices of daytime and psychological functioning. Participants were 160 individuals with chronic insomnia who received CBT alone or CBT plus medication (zolpidem) for an initial six-week therapy, followed by an extended six-month therapy. Participants treated with CBT initially received maintenance CBT or no additional treatment and those treated with combined therapy initially continued with CBT plus intermittent medication (prn) or CBT without medication (taper). Measures of anxiety and depressive symptoms, fatigue, quality of life, and perceived impact of sleep difficulties on various indices of daytime functioning were completed at baseline, after each treatment stage, and at six-month follow-up. Following acute treatment, significant improvements of fatigue, quality of life (mental component), anxiety, and depression were obtained in the CBT alone condition but not in the combined CBT plus medication condition. Following extended treatment, further improvements were noted for the subgroup receiving extended CBT relative to that with no additional treatment, and for the subgroup receiving CBT and intermittent medication relative to that with CBT but no medication. Improvements were well maintained at the 6-month follow-up. These findings indicate that insomnia-specific therapy is effective at improving daytime and psychological functioning in the short term, and that maintenance therapy produces an added value to optimize long-term outcomes. www.clinicaltrials.gov (#NCT 00042146).


Social networks and links to isolation and loneliness among elderly HCBS clients.
The purpose of this study was to explore the network types of HCBS clients based on the structural characteristics of their social networks. We also examined how the network types were associated with social isolation, relationship quality and loneliness. Forty personal interviews were carried out with HCBS clients to assess the structure of their social networks as indicated by frequency of contact with children, friends, family and participation in religious and community organizations. Hierarchical cluster analysis was conducted to identify network types. Four network types were found including: family (n = 16), diverse (n = 8), restricted (n = 8) and religious (n = 7). Family members comprised almost half of participants' social networks, and friends comprised less than one-third. Clients embedded in family, diverse and religious networks had significantly more positive relationships than clients embedded in restricted networks. Clients embedded in restricted networks had significantly higher social isolation scores and were lonelier than clients in diverse and family networks. The findings suggest that HCBS clients' isolation and loneliness are linked to the types of social networks in which they are embedded. The findings also suggest that clients embedded in restricted networks are at high risk for negative outcomes.


High resolution genomic analysis of 18q- using oligo-microarray comparative genomic hybridization (aCGH).
The advent of oligonucleotide array comparative genomic hybridization (aCGH) has revolutionized diagnosis of chromosome abnormalities in the genetics clinic. This new technology also has valuable potential as a research tool to investigate larger genomic rearrangements that are typically diagnosed via routine karyotype. aCGH was used as a tool for the high-resolution analysis of chromosome content in individuals with known deletions of chromosome 18. The aim of this study was to clarify the precise location of the breakpoints as well as to determine the presence of occult translocations creating additional deletions and duplications. One hundred eighty-nine DNA samples from individuals with 18q deletions were analyzed. No breakpoint clusters were identified, as no more than two individuals had breakpoints within 2 kb of each other. Only two regions of 18q were never found to be haploid, suggesting the existence of haplolethal genes in those regions. Of the individuals with only a chromosome 18 abnormality, 17% (n = 29) had interstitial deletions. Six percent (n = 11) had a region of duplication immediately proximal to the deletion. Eight percent (n = 15) had more complex rearrangements with captured (non-18q) telomeres thus creating a trisomic region. The 15 captured telomeres originated from a limited number of other telomeres (4q, 10q, 17p, 18p, 20q, and Xq). These data were converted into a format for ease of viewing and analysis by creating custom tracks for the UCSC Genome Browser. Taken together, these findings confirm a higher level of variability and genomic complexity surrounding deletions of 18q than has previously been appreciated.


Gene expression profiling of early-phase Sjögren's syndrome in C57BL/6.NOD-Aec1Aec2 mice identifies focal adhesion maturation associated with infiltrating leukocytes.
Despite considerable efforts, the molecular and cellular events in lacrimal gland tissues initiating inflammatory responses leading to keratoconjunctivitis sicca (KCS), autoimmunity, and Sjögren's syndrome (SjS) have yet to be defined. To determine whether altered glandular homeostasis occurs before the onset of autoimmunity, a temporal transcriptome study was carried out in an animal model of primary SjS. Using oligonucleotide microarrays, gene expression profiles were generated for lacrimal glands of C57BL/6.NOD-Aec1Aec2 mice 4 to 20 weeks of age. Pairwise analyses identified genes differentially expressed, relative to their 4-week expression, during the development of SjS-like disease. Statistical analyses defined differentially and coordinately expressed gene sets. The PANTHER (Protein ANalysis THrough Evolutionary Relationships) classification system was used to define annotated biological processes or functions. Temporal transcript expression profiles of C57BL/6.NOD-Aec1Aec2 lacrimal glands before, or concomitant with, the first appearance of inflammatory cells revealed a highly restricted subset of differentially expressed genes encoding interactive extracellular matrix proteins, fibronectin, integrins, and syndecans. In contrast, genes encoding interepithelial junctional complex proteins defined alterations in tight junctions (TJ), adherens, desmosomes, and gap junctions, suggesting perturbations in the permeability of the paracellular spaces between epithelial barriers. Correlating with this were gene sets defining focal adhesion (FA) maturation and Ras/Raf-Mek/Erk signal transduction. Immunohistochemically, FAs were associated with infiltrating leukocytes and not with lacrimal epithelial cells. For the first time, FA maturations are implicated as initial biomarkers of impending autoimmunity in lacrimal glands of SjS-prone mice. Changes in TJ complex genes support an increased movement of cells through paracellular spaces.


Cardiology patient simulator and computer-assisted instruction technologies in bedside teaching.
The design and uses of an innovative technology-based approach which addresses critical problems with bedside teaching during ward rounds in the current health care situation are described. A cardiology patient simulator (HARVEY) and an accompanying computer-based interactive laserdisk system provide medical students, house officers and other health professionals with the opportunity to encounter a wide variety of clinical problems for learning and assessment. A group of cardiologists and medical educators from a consortium of US medical schools has guided the development and formal assessment of the entire system over the past 10 years. The system and simulator can be configured and programmed to provide appropriate heart sounds, laboratory data, and test results upon request; hands-on experience to practise examination skills is also available. The system, whole or in part, can be used in a variety of instructional modes from self-instruction to demonstration teaching, and from self-assessment to the final clinical examination. The system's effectiveness for teaching medical clerks is summarized, as is its use in providing continuing education for primary care doctors in rural practice.


Synthesis modulation as a tool to increase the catalytic activity of metal-organic frameworks: the unique case of UiO-66(Zr).
The catalytic activity of the zirconium terephthalate UiO-66(Zr) can be drastically increased by using a modulation approach. The combined use of trifluoroacetic acid and HCl during the synthesis results in a highly crystalline material, with partial substitution of terephthalates by trifluoroacetate. Thermal activation of the material leads not only to dehydroxylation of the hexanuclear Zr cluster but also to post-synthetic removal of the trifluoroacetate groups, resulting in a more open framework with a large number of open sites. Consequently, the material is a highly active catalyst for several Lewis acid catalyzed reactions.


Patient confidence regarding secondary lifestyle modification and knowledge of 'heart attack' symptoms following percutaneous revascularisation in Japan: a cross-sectional study.
To assess patient perspectives on secondary lifestyle modification and knowledge of 'heart attack' after percutaneous coronary intervention (PCI) for coronary artery disease (CAD). Observational cross-sectional study. A single university-based hospital centre in Japan. In total, 236 consecutive patients with CAD who underwent PCI completed a questionnaire (age, 67.4±10.1 years; women, 14.8%; elective PCI, 75.4%). The survey questionnaire included questions related to confidence levels about (1) lifestyle modification at the time of discharge and (2) appropriate recognition of heart attack symptoms and reactions to these symptoms on a four-point Likert scale (1=not confident to 4=completely confident). The primary outcome assessed was the patients' confidence level regarding lifestyle modification and the recognition of heart attack symptoms. Overall, patients had a high level of confidence (confident or completely confident,>75%) about smoking cessation, alcohol restriction and medication adherence. However, they had a relatively low level of confidence (<50%) about the maintenance of blood pressure control, healthy diet, body weight and routine exercise (≥3 times/week). After adjustment, male sex (OR 3.61, 95% CI 1.11 to 11.8) and lower educational level (OR 3.25; 95% CI 1.70 to 6.23) were identified as factors associated with lower confidence levels. In terms of confidence in the recognition of heart attack, almost all respondents answered 'yes' to the item 'I should go to the hospital as soon as possible when I have a heart attack'; however, only 28% of the responders were confident in their ability to distinguish between heart attack symptoms and other conditions. There were substantial disparities in the confidence levels associated with lifestyle modification and recognition/response to heart attack. These gaps need to be studied further and disseminated to improve cardiovascular care.


Low Variability in Synthetic Monolayer MoS2 Devices.
Despite much interest in applications of two-dimensional (2D) fabrics such as MoS2, to date most studies have focused on single or few devices. Here we examine the variability of hundreds of transistors from monolayer MoS2 synthesized by chemical vapor deposition. Ultraclean fabrication yields low surface roughness of ∼3 Å and surprisingly low variability of key device parameters, considering the atomically thin nature of the material. Threshold voltage variation and very low hysteresis suggest variations in charge density and traps as low as ∼1011 cm-2. Three extraction methods (field-effect, Y-function, and effective mobility) independently reveal mobility from 30 to 45 cm2/V/s (10th to 90th percentile; highest value ∼48 cm2/V/s) across areas >1 cm2. Electrical properties are remarkably immune to the presence of bilayer regions, which cause only small conduction band offsets (∼55 meV) measured by scanning Kelvin probe microscopy, an order of magnitude lower than energy variations in Si films of comparable thickness. Data are also used as inputs to Monte Carlo circuit simulations to understand the effects of material variability on circuit variation. These advances address key missing steps required to scale 2D semiconductors into functional systems.


How countries can reduce child stunting at scale: lessons from exemplar countries.
Child stunting and linear growth faltering have declined over the past few decades and several countries have made exemplary progress. To synthesize findings from mixed methods studies of exemplar countries to provide guidance on how to accelerate reduction in child stunting. We did a qualitative and quantitative synthesis of findings from existing literature and 5 exemplar country studies (Nepal, Ethiopia, Peru, Kyrgyz Republic, Senegal). Methodology included 4 broad research activities: 1) a series of descriptive analyses of cross-sectional data from demographic and health surveys and multiple indicator cluster surveys; 2) multivariable analysis of quantitative drivers of change in linear growth; 3) interviews and focus groups with national experts and community stakeholders and mothers; and 4) a review of policy and program evolution related to nutrition. Several countries have dramatically reduced child stunting prevalence, with or without closing geographical, economic, and other population inequalities. Countries made progress through interventions from within and outside the health sector, and despite significant heterogeneity and differences in context, contributions were comparable from health and nutrition sectors (40% of change) and other sectors (50%), previously called nutrition-specific and -sensitive strategies. Improvements in maternal education, maternal nutrition, maternal and newborn care, and reductions in fertility/reduced interpregnancy intervals were strong contributors to change. A roadmap to reducing child stunting at scale includes several steps related to diagnostics, stakeholder consultations, and implementing direct and indirect nutrition interventions related to the health sector and nonhealth sector . Our results show that child stunting reduction is possible even in diverse and challenging contexts. We propose that our framework of organizing nutrition interventions as direct/indirect and inside/outside the health sector should be considered when mapping causal pathways of child stunting and planning interventions and strategies to accelerate stunting reduction to achieve the 2030 Sustainable Development Goals.


Antihypertensive drugs metabolism: an update to pharmacokinetic profiles and computational approaches.
Drug discovery and development is a high-risk enterprise that requires significant investments in capital, time and scientific expertise. The studies of xenobiotic metabolism remain as one of the main topics in the research and development of drugs, cosmetics and nutritional supplements. Antihypertensive drugs are used for the treatment of high blood pressure, which is one the most frequent symptoms of the patients that undergo cardiovascular diseases such as myocardial infraction and strokes. In current cardiovascular disease pharmacology, four drug clusters - Angiotensin Converting Enzyme Inhibitors, Beta-Blockers, Calcium Channel Blockers and Diuretics - cover the major therapeutic characteristics of the most antihypertensive drugs. The pharmacokinetic and specifically the metabolic profile of the antihypertensive agents are intensively studied because of the broad inter-individual variability on plasma concentrations and the diversity on the efficacy response especially due to the P450 dependent metabolic status they present. Several computational methods have been developed with the aim to: (i) model and better understand the human drug metabolism; and (ii) enhance the experimental investigation of the metabolism of small xenobiotic molecules. The main predictive tools these methods employ are rule-based approaches, quantitative structure metabolism/activity relationships and docking approaches. This review paper provides detailed metabolic profiles of the major clusters of antihypertensive agents, including their metabolites and their metabolizing enzymes, and it also provides specific information concerning the computational approaches that have been used to predict the metabolic profile of several antihypertensive drugs.


Does the route of immunoglobin replacement therapy impact quality of life and satisfaction in patients with primary immunodeficiency? Insights from the French cohort "Visages".
IgG replacement therapy (IgRT) in primary immunodeficiencies (PID) is a lifelong treatment which may be administered intravenously (IVIg) or subcutaneously (SCIg), at hospital or at home. The objective of the VISAGE study was to investigate if route and/or place for IgRT impact patients' satisfaction regarding IgRT and quality of life (QoL) in real-life conditions. The study enrolled PID patients at least 15 years old receiving IgRT for at least 3 months. Satisfaction and QoL were evaluated at enrollment and over a 12-month follow-up period by Life Quality Index (LQI) which measures 3 dimensions of satisfaction: treatment interference, therapy related problems and therapy settings (factors I, II and III) and SF-36 v2 questionnaire. The study included 116 PID patients (mean age 42 ± 18 years, 44 % males, 58 % with scholar or professional occupation) receiving IgRT for a mean of 8.5 ± 8.4 years. At enrollment they were receiving either home-based SCIg (51 %), hospital-based IVIg (40 %) or home-based IVIg (9 %). Patients exhibited a high degree of satisfaction regarding IgRT whatever the route and place for administration. LQI factor I was higher for home-based SCIg (86 ± 2) than for hospital-based IVIg (81 ± 3) and home-based IVIg (73 ± 5; p = 0.02 versus home-based SCIg); no difference was found for LQI factor II; LQI factor III was higher for home-based SCIg (92 ± 2) than for hospital-based IVIg (87 ± 5) and hospital-based IVIg (82 ± 3; p = 0.005 versus home-based SCIg). By contrast, every dimension of QoL was impaired. Over the follow-up period, 10 patients switched from hospital-based IVIg to home-based SCIg and improved LQI factor I (p = 0.004) and factor III (p = 0.02), while no change was noticed in LQI factors II and QoL. Meanwhile, no change in satisfaction or QoL was found in patients with stable route of IgRT. When asked on their preferred place of treatment all but one patient with home-based treatment would choose to be treated at home and 29 % of patients treated at hospital would prefer home-based IgRT. PID patients expressed a high degree of satisfaction regarding IgRT, contrasting with impaired QoL. In real-life conditions awareness of patient's expectations regarding the route or place of IgRT may be associated with further improvement of satisfaction.


Multicenter prospective randomized study of single-incision mini-sling vs tension-free vaginal tape-obturator in management of female stress urinary incontinence: a minimum of 1-year follow-up.
To compare an adjustable anchored single incision mini-sling (SIMS-Ajust) vs tension-free vaginal tape-obturator (TVT-O) in the management of female stress urinary incontinence (SUI) with a minimum of 1-year follow-up. We conducted a multicenter prospective randomized control trial (RCT) performed in 6 United Kingdom centers in the period between October 2009 and October 2011. Women were randomized to either SIMS-Ajust (C. R. Bard) performed under local anesthesia or TVT-O (Ethicon Inc.) performed under general anesthesia. Women completed validated symptom-severity and quality of life (QOL) questionnaires preoperatively and at 1 year. In addition, women completed the Patient Global Impression of Improvement (PGI-I) and underwent the Cough Stress Test (CST) at 1 year. The primary outcome at 12 months was the patient-reported success rate. Secondary outcomes included objective cure, reoperation rate, impact on women's urinary symptoms, QOL, and sexual function. Data was analyzed using SPSS-19 with significance level set at 5%. One hundred thirty-seven women were randomized into 2 groups: the SIMS-Ajust group (n = 69) and the TVT-O group (n = 68). At 1 year, there were no significant differences in the patient-reported success rate (odds ratio [OR] 0.895, 95% confidence interval [CI] 0.344-2.330, P = 1.000), objectives success rate (OR 0.929, 95% CI 0.382-2.258, P = 1.00), and reoperation rates (OR 0.591, 95% CI 0.136-2.576, P = .721) between the SIMS-Ajust and the TVT-O groups, respectively. A comparable number of women reported cure/improvement of urgency (P = .658), significant improvement in QOL (P = .190), and sexual function (P = .699) in both groups. Adjustable-anchored SIMS (Ajust) is associated with comparable patient-reported and objective success rates when compared to standard midurethral sling (SMUS, TVT-O) at a minimum of 1-year follow-up. The results should be interpreted with caution due to the relatively small cohort size. Long-term follow-up of this RCT is required to ascertain the durability of these results.


Rapid variance components-based method for whole-genome association analysis.
The variance component tests used in genome-wide association studies (GWAS) including large sample sizes become computationally exhaustive when the number of genetic markers is over a few hundred thousand. We present an extremely fast variance components-based two-step method, GRAMMAR-Gamma, developed as an analytical approximation within a framework of the score test approach. Using simulated and real human GWAS data sets, we show that this method provides unbiased estimates of the SNP effect and has a power close to that of the likelihood ratio test-based method. The computational complexity of our method is close to its theoretical minimum, that is, to the complexity of the analysis that ignores genetic structure. The running time of our method linearly depends on sample size, whereas this dependency is quadratic for other existing methods. Simulations suggest that GRAMMAR-Gamma may be used for association testing in whole-genome resequencing studies of large human cohorts.


The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit.
Among the nearly 50 disease mutations in the gene for the catalytic subunit of human DNA polymerase gamma, POLG, the A467T substitution is the most common and has been found in 0.6% of the Belgian population. The A467T mutation is associated with a wide range of mitochondrial disorders, including Alpers syndrome, juvenile spinocerebellar ataxia-epilepsy syndrome, and progressive external ophthalmoplegia, each with vastly different clinical presentations, tissue specificities, and ages of onset. The A467T mutant enzyme possesses only 4% of wild-type DNA polymerase activity, and the catalytic defect is manifest primarily through a 6-fold reduction in kcat with minimal effect on exonuclease function. Human DNA polymerase gamma (pol gamma) requires association of a 55-kDa accessory subunit for enhanced DNA binding and highly processive DNA synthesis. However, the A467T mutant enzyme failed to interact with and was not stimulated by the accessory subunit, as judged by processivity, heat inactivation, and N-ethylmaleimide protection assays in vitro. Thermolysin digestion and immunoprecipitation experiments further indicate weak association of the subunits for A467T pol gamma. This is the first example of a mutation in POLG that disrupts physical association of the pol gamma subunits. We propose that reduced polymerase activity and loss of accessory subunit interaction are responsible for the depletion and deletion of mitochondrial DNA observed in patients with this POLG mutation.


Fetal MRI: An approach to practice: A review.
MRI has been increasingly used for detailed visualization of the fetus in utero as well as pregnancy structures. Yet, the familiarity of radiologists and clinicians with fetal MRI is still limited. This article provides a practical approach to fetal MR imaging. Fetal MRI is an interactive scanning of the moving fetus owed to the use of fast sequences. Single-shot fast spin-echo (SSFSE) T2-weighted imaging is a standard sequence. T1-weighted sequences are primarily used to demonstrate fat, calcification and hemorrhage. Balanced steady-state free-precession (SSFP), are beneficial in demonstrating fetal structures as the heart and vessels. Diffusion weighted imaging (DWI), MR spectroscopy (MRS), and diffusion tensor imaging (DTI) have potential applications in fetal imaging. Knowing the developing fetal MR anatomy is essential to detect abnormalities. MR evaluation of the developing fetal brain should include recognition of the multilayered-appearance of the cerebral parenchyma, knowledge of the timing of sulci appearance, myelination and changes in ventricular size. With advanced gestation, fetal organs as lungs and kidneys show significant changes in volume and T2-signal. Through a systematic approach, the normal anatomy of the developing fetus is shown to contrast with a wide spectrum of fetal disorders. The abnormalities displayed are graded in severity from simple common lesions to more complex rare cases. Complete fetal MRI is fulfilled by careful evaluation of the placenta, umbilical cord and amniotic cavity. Accurate interpretation of fetal MRI can provide valuable information that helps prenatal counseling, facilitate management decisions, guide therapy, and support research studies.


A scoping review of Indigenous suicide prevention in circumpolar regions.
Suicide is a serious public health challenge in circumpolar regions, especially among Indigenous youth. Indigenous communities, government agencies and health care providers are making concerted efforts to reduce the burden of suicide and strengthen protective factors for individuals, families and communities. The persistence of suicide has made it clear that more needs to be done. Our aim was to undertake a scoping review of the peer-reviewed literature on suicide prevention and interventions in Indigenous communities across the circumpolar north. Our objective was to determine the extent and types of interventions that have been reported during past decade. We want to use this knowledge to support community initiative and inform intervention development and evaluation. We conducted a scoping review of online databases to identify studies published between 2004 and 2014. We included articles that described interventions in differentiated circumpolar Indigenous populations and provided evaluation data. We retained grey literature publications for comparative reference. Our search identified 95 articles that focused on suicide in distinct circumpolar Indigenous populations; 19 articles discussed specific suicide-related interventions and 7 of these described program evaluation methods and results in detail. The majority of publications on specific interventions were found in North American countries. The majority of prevention or intervention documentation was found in supporting grey literature sources. Despite widespread concern about suicide in the circumpolar world and active community efforts to promote resilience and mental well-being, we found few recorded programs or initiatives documented in the peer-reviewed literature, and even fewer focusing specifically on youth intervention. The interventions described in the studies we found had diverse program designs and content, and used varied evaluation methods and outcomes. The studies we included consistently reported that it was important to use community-based and culturally guided interventions and evaluations. This article summarizes the current climate of Indigenous circumpolar suicide research in the context of intervention and highlights how intervention-based outcomes have largely remained outside of peer-reviewed sources in this region of the world.


Insulin in type 2 diabetes: a useful alternative despite limited assessment based on surrogate endpoints.
(1) There are few clinical trials comparing combination therapy with a sulphonylurea and metformin after oral antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of insulin therapy in patients in whom oral antidiabetic therapy fails is based solely on surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose glucose levels were no longer controlled by a sulphonylurea, the addition of metformin or a daily injection of insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However, metformin caused less weight gain. (4) There are no randomised controlled trials comparing the addition of insulin versus a sulphonylurea when ongoing metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus metformin, adding a daily insulin injection is more effective in lowering HbA1c levels than the addition of acarbose and as effective as adding a glitazone. The adjunction of insulin appears to have a better risk-benefit balance than an oral three-drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral antidiabetic to ongoing insulin therapy reduces HbA1c levels in patients with type 2 diabetes. The addition of metformin is also beneficial in terms of body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with metformin, have compared the addition of a bedtime injection of insulin isophane versus replacement of the oral antidiabetics by several daily insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less weight gain when the oral antidiabetics were continued and a single insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea, metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of insulin isophane. (9) Insulin isophane is the first-choice insulin for combination therapy with an oral antidiabetic. In comparative trials, when combined with an oral antidiabetic, insulin glargine was no more effective than insulin isophane in terms of HbA1c levels or weight gain. Insulin glargine seems to provoke less hypoglycaemia but, in the absence of adequate follow-up, its long-term adverse effects are not known. (10) When a bedtime insulin injection plus an oral antidiabetic fail to control hyperglycaemia, indirect comparisons support the use of several daily insulin injections plus metformin, or three injections of an ultrarapid insulin analogue plus a sulphonylurea.


Clients' perceptions of discharge housing decisions after stroke rehabilitation.
The purpose of this research was to examine the perceptions of older persons with stroke concerning the discharge housing decisions made during their rehabilitation program. The research explored clients' locus of control, their perceptions of the role of the rehabilitation team and their family in the decision, and their perceptions of their activities of daily living skills. Sixty-two subjects with stroke completed four measures: (a) the Functional Independence Measure (FIM), (b) a housing information questionnaire, (c) a semistructured interview, and (d) the Bialer Locus of Control Scale. Rehabilitation team members also completed the FIM and housing information questionnaire for each subject. These instruments were used to collect data relating to clients' perceptions of their functional status, discharge from the hospital, housing options available, and locus of control. Despite the team or family opinions on discharge housing, subjects saw housing decisions as primarily their own. The majority of subjects were reluctant to consider alternatives to returning home, even though they have self-care deficits and frequently reported that the presence of a spouse and family members were important to support their return home. Subjects generally seemed unaware of the influence of team and family opinions and the impact of their functional status on their discharge housing. Subjects' locus of control seemed unrelated to satisfaction with the discharge decision process. Clients who have had a stroke could use assistance to determine housing that is appropriate for their living skills. Discussions with clinicians concerning accommodation options may lead to a smoother transition from the hospital to longer term housing for clients after stroke.


The impact of visceral adipose tissue as best predictor for difficult colonoscopy and the clinical utility of a long small-caliber scope as rescue.
There have been many reports about a variety of factors associated with incomplete colonoscopy or difficult colonoscopy with long cecal intubation time (CIT). The aim of this retrospective study was to analyze the factors related to difficult colonoscopy under conscious sedation and demonstrate the clinical utility of a small-caliber scope as rescue by using the data from a large number of subjects who underwent health check-ups. Consecutive 1036 cases over a 12-month period (April 2015 to March 2016) were enrolled and 619 subjects were divided into two groups: Easy colonoscopy (CS) Group (CIT ≤ 10 min); Difficult CS Group (CIT > 10 min or incomplete colonoscopy by a standard scope). The two groups were compared by subjects and colonoscopy characteristics with univariate analysis followed by multivariate logistic regression analysis. Reasons for incomplete colonoscopy were also assessed. Cecal intubation rate increased from 97.9% to 99.9% (1007/1008) by the rescue scope. Main reasons for incomplete colonoscopy were tortuosity in the left hemicolon (38%), redundancy in the right hemicolon (29%), pain (19%) and fixation (14%). Moreover, 95% (20/21) of rescue colonoscopies were completed without additional sedation. Higher BMI (21 kg/m2 ≤ BMI) and intermediate visceral adipose tissue (VAT) (75 cm2 ≤ VAT < 150 cm2) were significantly associated with easy CS (80.7% vs 19.3%, P = 0.004; 56.3% vs 43.7%, P = 0.001) by univariate analysis. Age, gender, and VAT, not BMI, were independently associated with difficult colonoscopy by multivariate analysis (OR (95% CI), P: 0.964 (0.942, 0.985), 0.001; 1.845 (1.101, 3.091), 0.020; 2.347 (1.395, 3.951), 0.001). Subgroup analysis by gender also showed VAT as the best predictor for both genders. Difficult colonoscopy was significantly associated with advancing age, female gender and, lower (< 75 cm2) or higher (150 cm2 ≤) VAT. These subjects may benefit from having complete and more comfortable colonoscopy examinations by using the small-caliber scope rather than the standard scope.


Multiplication of tobacco mosaic virus in tobacco leaf disks is inhibited by (2'-5) oligoadenylate.
The oligonucleotide (2'-5') oligoadenylate that is induced in interferon-treated animal cells protects plant tissue from infection by the tobacco mosaic virus. This inhibition of virus multiplication was obtained at concentrations comparable to those affecting protein synthesis and antiviral activities in animal cells. After treatment with (2'-5') oligoadenylate, the multiplicability of tobacco mosaic virus was reduced by 80 to 90 percent as measured by enzyme-linked immunosorbent assay. These results, along with the observation that human interferon protects tobacco tissue from infection by tobacco mosaic virus, indicate that plants and animals may have a common pathway for virus resistance.


Effects of PEMF on patients with osteoarthritis: Results of a prospective, placebo-controlled, double-blind study.
This study aimed to evaluate effects of pulsed electromagnetic fields (PEMF) in a double blind study on patients with knee joint osteoarthritis. The MAGCELL ARTHRO electrode-less therapy delivered a sinusoidal magnetic field, varying in frequency between 4 and 12 Hz. In 1 cm tissue depth, magnetic flux density was 105 mT. A total of n = 57 patients were randomly assigned to the verum, PEMF or placebo group (placebo device). Their average age was 61.6 ± 12.0 years. According to American College of Rheumatology criteria the osteoarthritis level was 2.8 ± 0.8. Treatment was performed twice a day for 5 min over a period of 18 days. Treatment with the MAGCELL device versus control (sham exposed) showed a highly significant reduction in pain (P < 0.001), a significant reduction in stiffness (P = 0.032) and a significant reduction in disability in daily activities (P = 0.005) according to the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scales-with a good overall treatment tolerance. In the placebo group there was no evidence of a significant change between the initial and final examination in any of the three above-mentioned WOMAC scales. Results of this partly randomized placebo-controlled double-blind study show clinically at any rate, that use of PEMF lead to highly significant better results in the treatment group compared to the placebo group with regard to the total WOMAC global score and especially for visual analogue scale. Patient assessment of the "effectiveness" was rated in 29.5% as very good and good in 27.3% compared to 0.0% and 15.4% in controls. This therapy is thus a useful complementary treatment option with no side effects.


Cannabinoids in Pain Management and Palliative Medicine.
There are conflicting interpretations of the evidence regarding the efficacy, tolerability, and safety of cannabinoids in pain management and palliative medicine. We conducted a systematic review (SR) of systematic reviews of randomized controlled trials (RCT) and prospective long-term observational studies of the use of cannabinoids in pain management and palliative medicine. Pertinent publications from January 2009 to January 2017 were retrieved by a selective search in the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and Medline. The methodological quality of the SRs was assessed with the AMSTAR instrument, and the clinical relevance of quantitative data syntheses was assessed according to the standards of the Cochrane Collaboration. Of the 750 publications identified, 11 SRs met the inclusion criteria; 3 of them were of high and 8 of moderate methodological quality. 2 prospective long-term observational studies with medical cannabis and 1 with tetrahydrocannabinol/cannabidiol spray (THC/CBD spray) were also analyzed. There is limited evidence for a benefit of THC/CBD spray in the treatment of neuropathic pain. There is inadequate evidence for any benefit of cannabinoids (dronabinol, nabilone, medical cannabis, or THC/CBD spray) to treat cancer pain, pain of rheumatic or gastrointestinal origin, or anorexia in cancer or AIDS. Treatment with cannabis-based medicines is associated with central nervous and psychiatric side effects. The public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.


Metabolism and disposition of 3,6-dibutanoylmorphine in rat brain.
In previous studies from this laboratory it was found that dibutanoylmorphine (DBM) was more potent than morphine as an analgesic in rats and that it was less active than acetyl esters of morphine on behaviour. As DBM is a morphine prodrug, the aim of this work was to determine if rat brain homogenates were capable of deacylating DBM and monobutanoylmorphine (MBM) and to determine relative proportions of parent drug to metabolites in the brain in vivo. In 10% (w/v) brain homogenates, DBM was eliminated with a half-life of about 70 min (corrected for dilution), while MBM was eliminated 10 times as quickly. DBM and its metabolites were found in both blood and brain as early as 1 min after i.v. administration of DBM. After 5 min, the predominant form in blood was MBM and in brain it was DBM. Thus, rat brain possesses the capacity to metabolize DBM by deesterification and the parent drug, MBM, and morphine were found in blood and brain in vivo.


Exposure of human primary colon carcinoma cells to anti-Fas interactions influences the emergence of pre-existing Fas-resistant metastatic subpopulations.
Fas, an important death receptor-mediated signaling pathway, has been shown to be down-regulated during human colon tumorigenesis; however, how alterations in Fas expression influence the metastatic process remains unresolved. In mouse models, loss of Fas function was found to be both necessary and sufficient for tumor progression. In this study, we investigated the link between functional Fas status and malignant phenotype using a matched pair of naturally occurring primary (Fas-sensitive) and metastatic (Fas-resistant) human colon carcinoma cell lines in both in vitro and in vivo (xenograft) settings. Metastatic sublines were produced in vitro from the primary tumor cell line by functional elimination of Fas-responsive cells. Conversely, sublines derived from the primary tumor in vivo at distal metastatic sites were Fas-resistant. In contrast, simply disrupting the Fas pathway by molecular-based strategies in the Fas-sensitive primary tumor failed to achieve the same metastatic outcome. Interestingly, both in vitro- and in vivo-produced sublines resembled the naturally occurring metastatic population, based on functional and morphologic studies and genome-scale gene expression profiling. Overall, using this human colon carcinoma model, we: 1) showed that loss of Fas function was linked to, but alone was insufficient for, acquisition of a detectable metastatic phenotype; 2) demonstrated that metastatic subpopulations pre-existed within the heterogeneous primary tumor, and that anti-Fas interactions served as a selective pressure for their outgrowth; and 3) identified a large set of differentially expressed genes distinguishing the primary from metastatic malignant phenotypes. Thus, Fas-based interactions may represent a novel mechanism for the biologic or immunologic selection of certain types of Fas-resistant neoplastic clones with enhanced metastatic ability.


Developmental expression of SRC-related tyrosine kinases in the mouse testis.
An increase in protein tyrosine phosphorylation occurs during sperm capacitation in numerous species. The involvement of Src-related tyrosine kinases in this phenomenon has been demonstrated using different inhibitors specifically targeting this family of enzymes. In mammals, this group of nonreceptor tyrosine kinases is made up of 8 members with similar SRC homology domain 3 (SH3) and SH2 domains. Although some members of this group of enzymes can compensate for one another, showing some redundancy, each is unique and may perform specific functions during male germ cell development. To further characterize the importance of Src-related tyrosine kinases in the events leading to proper sperm formation, and because no inhibitor affecting a single gene product exists, expression of Src, Yes1, Fyn, Lyn, Lck, Hck, Blk, and Fgr was assessed by real-time polymerase chain reaction in developing mouse testes and in enriched populations of mouse spermatogenic cells, revealing distinct expression profiles for each kinase during testis development and in isolated male germ cells. Immunolocalization of SRC, LYN, and HCK in adult mouse testes as well as in mature spermatozoa further confirmed differential localization of these kinases during spermatogenesis. Although mRNA levels of these latter kinases were higher in spermatogonia and spermatocytes than in spermatids, protein levels were highest in spermatids, suggesting delayed transcript translation. Taken together, these results clearly show an uneven expression of each kinase in different spermatogenic cells, indicating that each member may play a different role during spermatogenesis, in addition to highlighting the complexity of Src-related kinase expression regulation in male germ cells. Furthermore, differential localization of these tyrosine kinases in mature spermatozoa also suggests a specific role for each member in sperm function and integrity.


Antibiotic prescription strategies and adverse outcome for uncomplicated lower respiratory tract infections: prospective cough complication cohort (3C) study.
Objective To assess the impact on adverse outcomes of different antibiotic prescribing strategies for lower respiratory tract infections in people aged 16 years or more.Design Prospective cohort study.Setting UK general practice.Participants 28 883 patients with lower respiratory tract infection; symptoms, signs, and antibiotic prescribing strategies were recorded at the index consultation.Main outcome measures The main outcomes were reconsultation with symptoms of lower respiratory tract infection in the 30 days after the index consultation, hospital admission, or death. Multivariable analysis controlled for an extensive list of variables related to the propensity to prescribe antibiotics and for clustering by doctor.Results Of the 28 883 participants, 104 (0.4%) were referred to hospital for radiographic investigation or admission, or both on the day of the index consultation, or were admitted with cancer. Of the remaining 28 779, subsequent hospital admission or death occurred in 26/7332 (0.3%) after no antibiotic prescription, 156/17 628 (0.9%) after prescription for immediate antibiotics, and 14/3819 (0.4%) after a prescription for delayed antibiotics. Multivariable analysis documented no reduction in hospital admission and death after immediate antibiotics (multivariable risk ratio 1.06, 95% confidence interval 0.63 to 1.81, P=0.84) and a non-significant reduction with delayed antibiotics (0.81, 0.41 to 1.64, P=0.61). Reconsultation for new, worsening, or non-resolving symptoms was common (1443/7332 (19.7%), 4455/17 628 (25.3%), and 538/3819 (14.1%), respectively) and was significantly reduced by delayed antibiotics (multivariable risk ratio 0.64, 0.57 to 0.72, P<0.001) but not by immediate antibiotics (0.98, 0.90 to 1.07, P=0.66).Conclusion Prescribing immediate antibiotics may not reduce subsequent hospital admission or death for young people and adults with uncomplicated lower respiratory tract infection, and such events are uncommon. If clinicians are considering antibiotics, a delayed prescription may be preferable since it is associated with a reduced number of reconsultations for worsening illness.


Creation of human tumour cells with defined genetic elements.
During malignant transformation, cancer cells acquire genetic mutations that override the normal mechanisms controlling cellular proliferation. Primary rodent cells are efficiently converted into tumorigenic cells by the coexpression of cooperating oncogenes. However, similar experiments with human cells have consistently failed to yield tumorigenic transformants, indicating a fundamental difference in the biology of human and rodent cells. The few reported successes in the creation of human tumour cells have depended on the use of chemical or physical agents to achieve immortalization, the selection of rare, spontaneously arising immortalized cells, or the use of an entire viral genome. We show here that the ectopic expression of the telomerase catalytic subunit (hTERT) in combination with two oncogenes (the simian virus 40 large-T oncoprotein and an oncogenic allele of H-ras) results in direct tumorigenic conversion of normal human epithelial and fibroblast cells. These results demonstrate that disruption of the intracellular pathways regulated by large-T, oncogenic ras and telomerase suffices to create a human tumor cell.


Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Screening and Decolonization to Reduce Surgical Site Infection in Elective Total Joint Arthroplasty.
Deep infection after elective total joint arthroplasty remains a devastating complication. Preoperative nasal swab screening for Staphylococcus aureus colonization and subsequent treatment of colonized patients is one proposed method to identify at-risk patients and decrease surgical site infections (SSIs). The purpose of this study was to determine whether a preoperative staphylococcus screening and treatment program would decrease the incidence of SSI in elective joint arthroplasty patients. Since January 2009, a total of 9690 patients having an elective joint arthroplasty were screened before surgery for Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) with nares swabs. All patients with positive nare colonization for MSSA and MRSA were treated with mupirocin and chlorhexidine gluconate showers for 5 days before surgery. MRSA patients received vancomycin preoperatively and were placed in contact isolation. All elective arthroplasty patients used chlorhexidine gluconate antiseptic cloths the evening prior and the day of surgery. Perioperative infection rates were compared from 1 year before implementation to 5 years after implementation of this screening protocol. SSI rates have decreased from 1.11% (prescreening) to 0.34% (nasal screening; P < .05) after initiation of the process. Staphylococcus was identified in 66.7% of the SSI infections before nasal screening and in 33.3% of the SSI after routine screening (P > .05). The addition of MRSA and/or MSSA nares screening along with a perioperative decolonization protocol has resulted in a decreased SSI rate by 69%.


(Not) getting political: indigenous women and preventing mother-to-child transmission of HIV in West Papua.
This paper builds on critiques that call for a more nuanced and contextualised understanding of conditions that affect HIV prevention by looking at West Papuan women's experiences of prevention of mother-to-child transmission services. Drawing on qualitative, ethnographic research with indigenous women and health workers, the paper demonstrates that women experience poor-quality HIV education and counselling, and that indigenous practices and concerns are largely not addressed by HIV services. We attribute this to a combination of national anti-indigenous and anti-separatist political concerns with donor-led interventions that result in limited localisation and reduced effectiveness of HIV prevention measures. In West Papua, services are needed that enhance cooperation and shared commitment, and that acknowledge and work to overcome existing inequalities, ethnic tensions and discrimination in the health system. Beyond Indonesia, donor-led HIV programmes and interventions need to balance avoidance of politically sensitive issues with complicity in perpetuating health inequalities. Translating global health interventions and donor priorities into locally compelling HIV prevention activities involves more than navigating local cultural and religious beliefs. Programme development and implementation strategies that entail confronting structural questions as well as social hierarchies, cleavages and silences are needed to render more effective services; strategies that are inherently political.


The late positive potential predicts subsequent interference with target processing.
The current study investigated the association between neural engagement with task-irrelevant images and subsequent interference with target processing using the Emotional Interrupt paradigm [Mitchell, D., Richell, R., Leonard, A., & Blair, R. Emotion at the expense of cognition: Psychopathic individuals outperform controls on an operant response task. Journal of Abnormal Psychology, 115, 559, 2006]. Consistent with previous studies, PCA-derived factors corresponding to the early posterior negativity, P300, and late positive potential (LPP) were enhanced for emotional (i.e., both unpleasant and pleasant) compared with neutral distracters, and the P300 elicited by targets was smaller following emotional compared with neutral pictures. In addition, RTs were increased to targets that followed emotional pictures. Within-subject analyses demonstrated that slow trials were characterized by a smaller P300 and were preceded by pictures with a larger LPP. Additionally, between-subject analyses indicate that individuals with a larger LPP also demonstrated slower RTs to targets and reduced target-elicited P300s. All results were specific to the LPP and were not observed for either the early posterior negativity or the P300 elicited by task-irrelevant pictures. By relating the LPP to subsequent behavioral and ERP interference in both within- and between-subject analyses, the current study provides direct support for the notion that LPP indexes attentional engagement with visual stimuli that is uniquely associated with subsequent interference in terms of both RT slowing and P300 reduction to targets.


Synaesthesia: learned or lost?
The question why synaesthesia, an atypical binding within or between modalities, occurs is both enduring and important. Two explanations have been provided: (1) a congenital explanation: we are all born as synaesthetes but most of us subsequently lose the experience due to brain development; (2) a learning explanation: synaesthesia is related to some learning process during childhood. Three recent studies provide conflicting support for these explanations. Two studies supported the idea that synaesthesia is learned by showing that the frequency of everyday language implicitly modulates the synaesthetic experience. Another study argued that synaesthesia reflects basic, innate magnitude representations. In this paper we reassess these points of view, and show that it is possible for both to be valid. These findings are integrated into an interactive specialization account of development in order to explain the neuronal mechanism underlying synaesthesia.


Delayed functional maturation of natural regulatory T cells in the medulla of postnatal thymus: role of TSLP.
Generation of functional (CD4+)(CD8-)CD25+ regulatory T cells (Treg) in the murine thymus depends on FoxP3. Removal of the thymus from neonatal mice has been shown to result in a multiple organ autoimmune disease phenotype that can be prevented by introducing the FoxP3+ Treg population to the animal. It has therefore, been proposed that functional FoxP3+ Treg cells are not made in the neonatal thymus; however, it remains unclear when and where functional (FoxP3+)(CD4+)(CD8-)CD25+ thymocytes are generated in postnatal thymus. We report that neither FoxP3 mRNA nor protein is expressed in (CD4+)(CD8-)CD25+, or (CD4+)(CD8-)CD25- thymocytes until 3-4 days post birth, despite the presence of mature (CD4+)(CD8-)CD25+/- thymocytes in the thymus by 1-2 days after birth. (FoxP3-)(CD4+)(CD8-)CD25+ thymocytes from day 2 newborn mice show no Treg activity. Interestingly, we are able to detect low numbers of FoxP3+ thymocytes dispersed throughout the medullary region of the thymus as early as 3-4 days post birth. Expression of FoxP3 is induced in embryonic day 17 fetal thymus organ culture (FTOC) after 4-6 days of in vitro culture. Treatment of FTOCs with thymic stromal derived lymphopoietin (TSLP) enhanced expression of FoxP3, and blocking the TSLP receptor reduces FoxP3 expression in FTOC. Furthermore, TSLP stimulates FoxP3 expression in purified (CD4+)CD8- thymocytes, but not in (CD4+)CD8+, (CD4-)CD8+ and (CD4-)CD8- thymocytes. Expression of FoxP3 or Treg maturation is ontogenically distinct and kinetically delayed from the generation of (CD4+)(CD8-)CD25+ or (CD4+)(CD8-)CD25- thymocytes in the postnatal thymus. TSLP produced from medullary thymic epithelia cells (mTEC) contributes to the expression of FoxP3 and the maturation of natural regulatory T cells. Overall, these results suggest that the development of Treg cells requires paracrine signaling during late stages of thymocyte maturation that is distinct from signaling during positive or negative selection.


Expression of AXL receptor tyrosine kinase relates to monocyte dysfunction and severity of cirrhosis.
Infectious complications in patients with cirrhosis frequently initiate episodes of decompensation and substantially contribute to the high mortality. Mechanisms of the underlying immuneparesis remain underexplored. TAM receptors (TYRO3/AXL/MERTK) are important inhibitors of innate immune responses. To understand the pathophysiology of immuneparesis in cirrhosis, we detailed TAM receptor expression in relation to monocyte function and disease severity prior to the onset of acute decompensation. TNF-α/IL-6 responses to lipopolysaccharide were attenuated in monocytes from patients with cirrhosis (n = 96) compared with controls (n = 27) and decreased in parallel with disease severity. Concurrently, an AXL-expressing (AXL+) monocyte population expanded. AXL+ cells (CD14+CD16highHLA-DRhigh) were characterised by attenuated TNF-α/IL-6 responses and T cell activation but enhanced efferocytosis and preserved phagocytosis of Escherichia coli Their expansion correlated with disease severity, complications, infection, and 1-yr mortality. AXL+ monocytes were generated in response to microbial products and efferocytosis in vitro. AXL kinase inhibition and down-regulation reversed attenuated monocyte inflammatory responses in cirrhosis ex vivo. AXL may thus serve as prognostic marker and deserves evaluation as immunotherapeutic target in cirrhosis.


Probing absolute spin polarization at the nanoscale.
Probing absolute values of spin polarization at the nanoscale offers insight into the fundamental mechanisms of spin-dependent transport. Employing the Zeeman splitting in superconducting tips (Meservey-Tedrow-Fulde effect), we introduce a novel spin-polarized scanning tunneling microscopy that combines the probing capability of the absolute values of spin polarization with precise control at the atomic scale. We utilize our novel approach to measure the locally resolved spin polarization of magnetic Co nanoislands on Cu(111). We find that the spin polarization is enhanced by 65% when increasing the width of the tunnel barrier by only 2.3 Å due to the different decay of the electron orbitals into vacuum.


Grapes on steroids. Brassinosteroids are involved in grape berry ripening.
Fruit ripening is a unique plant developmental process with direct implications for our food supply, nutrition, and health. In contrast to climacteric fruit, where ethylene is pivotal, the hormonal control of ripening in nonclimacteric fruit, such as grape (Vitis vinifera), is poorly understood. Brassinosteroids (BRs) are steroidal hormones, essential for normal plant growth and development but not previously implicated in the ripening of nonclimacteric fruit. Here we show that increases in endogenous BR levels, but not indole-3-acetic acid (IAA) or GA levels, are associated with ripening in grapes. Putative grape homologs of genes encoding BR biosynthesis enzymes (BRASSINOSTEROID-6-OXIDASE and DWARF1) and the BR receptor (BRASSINOSTEROID INSENSITIVE 1) were isolated, and the function of the grape BRASSINOSTEROID-6-OXIDASE gene was confirmed by transgenic complementation of the tomato (Lycopersicon esculentum) extreme dwarf (dx/dx) mutant. Expression analysis of these genes during berry development revealed transcript accumulation patterns that were consistent with a dramatic increase in endogenous BR levels observed at the onset of fruit ripening. Furthermore, we show that application of BRs to grape berries significantly promoted ripening, while brassinazole, an inhibitor of BR biosynthesis, significantly delayed fruit ripening. These results provide evidence that changes in endogenous BR levels influence this key developmental process. This may provide a significant insight into the mechanism controlling ripening in grapes, which has direct implications for the logistics of grape production and down-stream processing.


Systemic and ocular immune responses in cattle following intranasal vaccination with precipitated or partially solubilized recombinant Moraxella bovis cytotoxin adjuvanted with polyacrylic acid.
OBJECTIVE To evaluate changes in systemic and ocular antibody responses of steers following intranasal vaccination with precipitated or partially solubilized recombinant Moraxella bovis cytotoxin (MbxA). ANIMALS 13 Angus steers with ages ranging from 318 to 389 days and weights ranging from 352 to 437 kg. PROCEDURES Steers were assigned to receive 500 μg of a precipitated (MbxA-P; n = 5) or partially solubilized (MbxA-S; 5) recombinant MbxA subunit adjuvanted with polyacrylic acid. A control group (n = 3) received the adjuvant alone. Each steer received the assigned treatment (1 mL/nostril) on days 0 and 28. Serum and tear samples were collected on days 0 (before vaccination), 14, 28, 42, and 55. Changes in MbxA-neutralizing antibody titers and MbxA-specific IgG concentrations in serum and tears and changes in MbxA-specific IgA concentrations in tears were measured. RESULTS Mean fold changes in MbxA-specific IgG concentration in serum and tears and MbxA-neutralizing antibody titer in tears for the MbxA-P group were significantly greater than those for the MbxA-S and control groups. Mean serum MbxA-neutralizing antibody titer did not differ among the 3 groups. Although the mean fold change in tear MbxA-specific IgA concentration differed significantly among the groups in the overall analysis, post hoc comparisons failed to identify any significant pairwise differences. CONCLUSIONS AND CLINICAL RELEVANCE Systemic and ocular immune responses induced by intranasal administration of the MbxA-P vaccine were superior to those induced by the MbxA-S vaccine. Additional research is necessary to determine whether the MbxA-P vaccine can prevent naturally occurring infectious bovine keratoconjunctivitis.


Sensorimotor disturbances in neck disorders affecting postural stability, head and eye movement control.
The receptors in the cervical spine have important connections to the vestibular and visual apparatus as well as several areas of the central nervous system. Dysfunction of the cervical receptors in neck disorders can alter afferent input subsequently changing the integration, timing and tuning of sensorimotor control. Measurable changes in cervical joint position sense, eye movement control and postural stability and reports of dizziness and unsteadiness by patients with neck disorders can be related to such alterations to sensorimotor control. It is advocated that assessment and management of abnormal cervical somatosensory input and sensorimotor control in neck pain patients is as important as considering lower limb proprioceptive retraining following an ankle or knee injury. Afferent information from the cervical receptors can be altered via a number of mechanisms such as trauma, functional impairment of the receptors, changes in muscle spindle sensitivity and the vast effects of pain at many levels of the nervous system. Recommendations for clinical assessment and management of such sensorimotor control disturbances in neck disorders are presented based on the evidence available to date.


Developmental dissociation between the maturation of procedural memory and declarative memory.
Declarative memory and procedural memory are known to be two fundamentally different kinds of memory that are dissociable in their psychological characteristics and measurement (explicit vs. implicit) and in the neural systems that subserve each kind of memory. Declarative memory abilities are known to improve from childhood through young adulthood, but the developmental maturation of procedural memory is largely unknown. We compared 10-year-old children and young adults on measures of declarative memory and working memory capacity and on four measures of procedural memory that have been strongly dissociated from declarative memory (mirror tracing, rotary pursuit, probabilistic classification, and artificial grammar). Children had lesser declarative memory ability and lesser working memory capacity than adults, but children exhibited learning equivalent to adults on all four measures of procedural memory. Therefore, declarative memory and procedural memory are developmentally dissociable, with procedural memory being adult-like by age 10years and declarative memory continuing to mature into young adulthood.


Dose optimization with first-order total-variation minimization for dense angularly sampled and sparse intensity modulated radiation therapy (DASSIM-RT).
A new treatment scheme coined as dense angularly sampled and sparse intensity modulated radiation therapy (DASSIM-RT) has recently been proposed to bridge the gap between IMRT and VMAT. By increasing the angular sampling of radiation beams while eliminating dispensable segments of the incident fields, DASSIM-RT is capable of providing improved conformity in dose distributions while maintaining high delivery efficiency. The fact that DASSIM-RT utilizes a large number of incident beams represents a major computational challenge for the clinical applications of this powerful treatment scheme. The purpose of this work is to provide a practical solution to the DASSIM-RT inverse planning problem. The inverse planning problem is formulated as a fluence-map optimization problem with total-variation (TV) minimization. A newly released L1-solver, template for first-order conic solver (TFOCS), was adopted in this work. TFOCS achieves faster convergence with less memory usage as compared with conventional quadratic programming (QP) for the TV form through the effective use of conic forms, dual-variable updates, and optimal first-order approaches. As such, it is tailored to specifically address the computational challenges of large-scale optimization in DASSIM-RT inverse planning. Two clinical cases (a prostate and a head and neck case) are used to evaluate the effectiveness and efficiency of the proposed planning technique. DASSIM-RT plans with 15 and 30 beams are compared with conventional IMRT plans with 7 beams in terms of plan quality and delivery efficiency, which are quantified by conformation number (CN), the total number of segments and modulation index, respectively. For optimization efficiency, the QP-based approach was compared with the proposed algorithm for the DASSIM-RT plans with 15 beams for both cases. Plan quality improves with an increasing number of incident beams, while the total number of segments is maintained to be about the same in both cases. For the prostate patient, the conformation number to the target was 0.7509, 0.7565, and 0.7611 with 80 segments for IMRT with 7 beams, and DASSIM-RT with 15 and 30 beams, respectively. For the head and neck (HN) patient with a complicated target shape, conformation numbers of the three treatment plans were 0.7554, 0.7758, and 0.7819 with 75 segments for all beam configurations. With respect to the dose sparing to the critical structures, the organs such as the femoral heads in the prostate case and the brainstem and spinal cord in the HN case were better protected with DASSIM-RT. For both cases, the delivery efficiency has been greatly improved as the beam angular sampling increases with the similar or better conformal dose distribution. Compared with conventional quadratic programming approaches, first-order TFOCS-based optimization achieves far faster convergence and smaller memory requirements in DASSIM-RT. The new optimization algorithm TFOCS provides a practical and timely solution to the DASSIM-RT or other inverse planning problem requiring large memory space. The new treatment scheme is shown to outperform conventional IMRT in terms of dose conformity to both the targetand the critical structures, while maintaining high delivery efficiency.


T antigen and p53 in pre- and post-crisis simian virus 40-transformed human cell lines.
Infection of normal human diploid fibroblasts (HF) with the DNA tumor virus simian virus 40 (SV) leads to an extension of lifespan and concomitant increase in the levels of the viral large tumor antigen (T antigen) and the cellular protein p53. The intracellular localization of T antigen and p53 was mostly nuclear in both SVpre-crisis and SVpost-crisis cells, however certain population doubling (PD) of the SVpre-crisis cells exhibited some cytoplasmic staining. The DNA content of SVpre-crisis cells shifted to tetraploidy and the SVpost-crisis cells were near-tetraploid. Quantitation of T antigen and p53 in single cells by flow cytometry demonstrated that for all antibodies tested the levels of T antigen were higher in the SVpre-crisis HF than in the SVpost-crisis. The quantity of p53 increased with increasing age of SVpre-crisis HF, and the levels of p53 were higher in the SVpost-crisis HF populations. Immunoprecipitation of p53, T antigen and complexes demonstrated that all p53 was bound to T antigen in SVpre-crisis HF and SVpost-crisis HF. The SVpre-crisis HF cells showed that 33% of all T antigen was bound to p53, while 67% was free, and the SVpost-crisis HF exhibited 50% free T antigen and 50% bound to p53. The half-life of p53 was similar in all SVpre-crisis HF; however, the half-life was 2-3 times greater in SVpost-crisis HF than in SVpre-crisis HF. These results suggest that the interaction of DNA (ploidy), T antigen, p53 and complexes may be involved in formation of a stable SV40-transformed human cell line.


Biodegradation of polyvinyl alcohol by different dominant degrading bacterial strains in a baffled anaerobic bioreactor.
Polyvinyl alcohol (PVA) is the main pollutant in printing and dyeing wastewaters. This pollutant exhibits great demand, poor biodegradability and refractory degradation. In this study, PVA wastewater treatment experiments were conducted in a stably operating baffled anaerobic bioreactor (ABR) by using simulated PVA wastewater. The PVA degradation pathway and mechanism of the mixed dominant PVA-degrading bacterial strains were identified through the analysis of their degradation products. From the results, we inferred that PVA was degraded in a stepwise process under the synergistic action of different extracellular and intracellular enzymes produced by the mixed dominant PVA-degrading bacterial strains. In this process, PVA was first degraded into ketones, fatty acids and alcohols. It was then regenerated into acetic acid, hydrogen and carbon dioxide. Finally, these substances could be further utilized by methanogens. PVA was thus degraded completely. This study may serve as a reference for future works on the degradation of PVA in the ecological environment. It may also guide the sustainable development of PVA.


Influence of a hyperlipidic diet on the composition of the non-membrane lipid pool of red blood cells of male and female rats.
Background and objectives. Red blood cells (RBC) are continuously exposed to oxidative agents, affecting their membrane lipid function. However, the amount of lipid in RBCs is higher than the lipids of the cell membrane, and includes triacylglycerols, which are no membrane components. We assumed that the extra lipids originated from lipoproteins attached to the cell surface, and we intended to analyse whether the size and composition of this lipid pool were affected by sex or diet. Experimental design. Adult male and female Wistar rats were fed control or cafeteria diets. Packed blood cells and plasma lipids were extracted and analysed for fatty acids by methylation and GC-MS, taking care of not extracting membrane lipids. Results. The absence of ω3-PUFA in RBC extracts (but not in plasma) suggest that the lipids extracted were essentially those in the postulated lipid surface pool and not those in cell membrane. In cells' extracts, there was a marked depletion of PUFA (and, in general, of insaturation). Fatty acid patterns were similar for all groups studied, with limited effects of sex and no effects of diet in RBC (but not in plasma) fatty acids. Presence of trans fatty acids was small but higher in RBC lipids, and could not be justified by dietary sources. Conclusions. The presence of a small layer of lipid on the RBC surface may limit oxidative damage to the cell outer structures, and help explain its role in the transport of lipophilic compounds. However, there may be other, so far uncovered, additional functions for this lipid pool.