Evaluation of global simulations of aerosol particle and cloud condensation nuclei number, with implications for cloud droplet formation.
A total of 16 global chemistry transport models and general circulation models have participated in this study; 14 models have been evaluated with regard to their ability to reproduce the near-surface observed number concentration of aerosol particles and cloud condensation nuclei (CCN), as well as derived cloud droplet number concentration (CDNC). Model results for the period 2011-2015 are compared with aerosol measurements (aerosol particle number, CCN and aerosol particle composition in the submicron fraction) from nine surface stations located in Europe and Japan. The evaluation focuses on the ability of models to simulate the average across time state in diverse environments and on the seasonal and short-term variability in the aerosol properties. There is no single model that systematically performs best across all environments represented by the observations. Models tend to underestimate the observed aerosol particle and CCN number concentrations, with average normalized mean bias (NMB) of all models and for all stations, where data are available, of -24% and -35% for particles with dry diameters > 50 and > 120nm, as well as -36% and -34% for CCN at supersaturations of 0.2% and 1.0%, respectively. However, they seem to behave differently for particles activating at very low supersaturations (< 0.1 %) than at higher ones. A total of 15 models have been used to produce ensemble annual median distributions of relevant parameters. The model diversity (defined as the ratio of standard deviation to mean) is up to about 3 for simulated N3 (number concentration of particles with dry diameters larger than 3 nm) and up to about 1 for simulated CCN in the extra-polar regions. A global mean reduction of a factor of about 2 is found in the model diversity for CCN at a supersaturation of 0.2% (CCN0.2) compared to that for N3, maximizing over regions where new particle formation is important. An additional model has been used to investigate potential causes of model diversity in CCN and bias compared to the observations by performing a perturbed parameter ensemble (PPE) accounting for uncertainties in 26 aerosol-related model input parameters. This PPE suggests that biogenic secondary organic aerosol formation and the hygroscopic properties of the organic material are likely to be the major sources of CCN uncertainty in summer, with dry deposition and cloud processing being dominant in winter. Models capture the relative amplitude of the seasonal variability of the aerosol particle number concentration for all studied particle sizes with available observations (dry diameters larger than 50, 80 and 120 nm). The short-term persistence time (on the order of a few days) of CCN concentrations, which is a measure of aerosol dynamic behavior in the models, is underestimated on average by the models by 40% during winter and 20% in summer. In contrast to the large spread in simulated aerosol particle and CCN number concentrations, the CDNC derived from simulated CCN spectra is less diverse and in better agreement with CDNC estimates consistently derived from the observations (average NMB -13% and -22% for updraft velocities 0.3 and 0.6 ms-1, respectively). In addition, simulated CDNC is in slightly better agreement with observationally derived values at lower than at higher updraft velocities (index of agreement 0.64 vs. 0.65). The reduced spread of CDNC compared to that of CCN is attributed to the sublinear response of CDNC to aerosol particle number variations and the negative correlation between the sensitivities of CDNC to aerosol particle number concentration (∂N d/∂N a) and to updraft velocity (∂N d/∂w). Overall, we find that while CCN is controlled by both aerosol particle number and composition, CDNC is sensitive to CCN at low and moderate CCN concentrations and to the updraft velocity when CCN levels are high. Discrepancies are found in sensitivities ∂N d/∂N a and ∂N d/∂w; models may be predisposed to be too "aerosol sensitive" or "aerosol insensitive" in aerosol-cloud-climate interaction studies, even if they may capture average droplet numbers well. This is a subtle but profound finding that only the sensitivities can clearly reveal and may explain inter-model biases on the aerosol indirect effect.


STOPP/START criteria for potentially inappropriate prescribing in older people: version 2.
Screening tool of older people's prescriptions (STOPP) and screening tool to alert to right treatment (START) criteria were first published in 2008. Due to an expanding therapeutics evidence base, updating of the criteria was required. We reviewed the 2008 STOPP/START criteria to add new evidence-based criteria and remove any obsolete criteria. A thorough literature review was performed to reassess the evidence base of the 2008 criteria and the proposed new criteria. Nineteen experts from 13 European countries reviewed a new draft of STOPP & START criteria including proposed new criteria. These experts were also asked to propose additional criteria they considered important to include in the revised STOPP & START criteria and to highlight any criteria from the 2008 list they considered less important or lacking an evidence base. The revised list of criteria was then validated using the Delphi consensus methodology. The expert panel agreed a final list of 114 criteria after two Delphi validation rounds, i.e. 80 STOPP criteria and 34 START criteria. This represents an overall 31% increase in STOPP/START criteria compared with version 1. Several new STOPP categories were created in version 2, namely antiplatelet/anticoagulant drugs, drugs affecting, or affected by, renal function and drugs that increase anticholinergic burden; new START categories include urogenital system drugs, analgesics and vaccines. STOPP/START version 2 criteria have been expanded and updated for the purpose of minimizing inappropriate prescribing in older people. These criteria are based on an up-to-date literature review and consensus validation among a European panel of experts.


Role of axial ligands in the reactivity of Mn peroxidase from Phanerochaete chrysosporium.
Site-directed mutagenesis was performed on Mn peroxidase (MnP) from the white-rot fungus Phanerochaete chrysosporium to investigate the role of the axial ligand hydrogen-bonding network on heme reactivity. D242 is hydrogen bonded to the proximal His of MnP; in other peroxidases, this conserved Asp, in turn, is hydrogen bonded to a Trp. In MnP and other fungal peroxidases, the Trp is replaced by a Phe (F190). Both residues are thought to have a direct influence on the electronic environment of the catalytic center. To study only the active mutants at D242 and F190, we used degenerate oligonucleotides allowing us to screen all 19 possible amino acid mutants at these positions. Two mutants at D242 passed our screen, D242E and D242S. Both mutations impaired only the functioning of compound II. The reactions of the ferric enzyme with H(2)O(2) were unaffected by the mutations, as were the reactions of compound I with reducing substrates. The D242S and D242E mutations reduced the first-order rate constant for the reaction of MnP compound II with chelated Mn(2+) from 233 s(-1) (wild type) to 154 s(-1) and 107 s(-1), respectively. Three F190 mutants passed our screen, F190V, F190L, and F190W. Similar to mutants at D242, these mutants largely affected the function of compound II. The F190V mutation increased the first-order rate constant for the reduction of compound II by chelated Mn(2+) to 320 s(-1). The F190L mutation decreased this rate to 137 s(-1). The F190W mutant was not very stable, but at pH 6.0, this mutation decreased the rate of compound II reduction by Mn(2+) from 140 s(-1) in the wild type to 36 s(-1). There was no indication that the F190W mutant was capable of forming a protein-centered Trp cation radical. All the mutations altered the midpoint potential of the Fe(3+)/Fe(2+) couple of the enzyme, as calculated from cyclic voltammagrams of the proteins. The values were shifted from -96 mV in the wild-type enzyme to -123 mV in D242S, -162 mV in D242E, -82 mV in F190L, -173 mV in F190V, and -51 mV in F190W. Collectively, these results demonstrate that D242 and F190 in MnP influence the electronic environment around the heme and that the reactions of compound II are far more sensitive to this influence than the reduction of compound I.


Hospital Utilization Among Children With the Highest Annual Inpatient Cost.
Children who experience high health care costs are increasingly enrolled in clinical initiatives to improve their health and contain costs. Hospitalization is a significant cost driver. We describe hospitalization trends for children with highest annual inpatient cost (CHIC) and identify characteristics associated with persistently high inpatient costs in subsequent years. Retrospective study of 265 869 children age 2 to 15 years with ≥1 admission in 2010 to 39 children's hospitals in the Pediatric Health Information System. CHIC were defined as the top 10% of total inpatient costs in 2010 (n = 26 574). Multivariate regression and regression tree modeling were used to distinguish individual characteristics and interactions of characteristics, respectively, associated with persistently high inpatient costs (≥80th percentile in 2011 and/or 2012). The top 10% most expensive children (CHIC) constituted 56.9% ($2.4 billion) of total inpatient costs in 2010. Fifty-eight percent (n = 15 391) of CHIC had no inpatient costs in 2011 to 2012, and 27.0% (n = 7180) experienced persistently high inpatient cost. Respiratory chronic conditions (odds ratio [OR] = 3.0; 95% confidence interval [CI], 2.5-3.5), absence of surgery in 2010 (OR = 2.0; 95% CI, 1.8-2.1), and technological assistance (OR = 1.6; 95% CI, 1.5-1.7) were associated with persistently high inpatient cost. In regression tree modeling, the greatest likelihood of persistence (65.3%) was observed in CHIC with ≥3 hospitalizations in 2010 and a chronic respiratory condition. Most children with high children's hospital inpatient costs in 1 year do not experience hospitalization in subsequent years. Interactions of hospital use and clinical characteristics may be helpful to determine which children will continue to experience high inpatient costs over time.


Barefoot vs common footwear: A systematic review of the kinematic, kinetic and muscle activity differences during walking.
Habitual footwear use has been reported to influence foot structure with an acute exposure being shown to alter foot position and mechanics. The foot is highly specialised thus these changes in structure/position could influence functionality. This review aims to investigate the effect of footwear on gait, specifically focussing on studies that have assessed kinematics, kinetics and muscle activity between walking barefoot and in common footwear. In line with PRISMA and published guidelines, a literature search was completed across six databases comprising Medline, EMBASE, Scopus, AMED, Cochrane Library and Web of Science. Fifteen of 466 articles met the predetermined inclusion criteria and were included in the review. All articles were assessed for methodological quality using a modified assessment tool based on the STROBE statement for reporting observational studies and the CASP appraisal tool. Walking barefoot enables increased forefoot spreading under load and habitual barefoot walkers have anatomically wider feet. Spatial-temporal differences including, reduced step/stride length and increased cadence, are observed when barefoot. Flatter foot placement, increased knee flexion and a reduced peak vertical ground reaction force at initial contact are also reported. Habitual barefoot walkers exhibit lower peak plantar pressures and pressure impulses, whereas peak plantar pressures are increased in the habitually shod wearer walking barefoot. Footwear particularly affects the kinematics and kinetics of gait acutely and chronically. Little research has been completed in older age populations (50+ years) and thus further research is required to better understand the effect of footwear on walking across the lifespan.


Treatment of depressive disorders in primary care--protocol of a multiple treatment systematic review of randomized controlled trials.
Several systematic reviews have summarized the evidence for specific treatments of primary care patients suffering from depression. However, it is not possible to answer the question how the available treatment options compare with each other as review methods differ. We aim to systematically review and compare the available evidence for the effectiveness of pharmacological, psychological, and combined treatments for patients with depressive disorders in primary care. To be included, studies have to be randomized trials comparing antidepressant medication (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), hypericum extracts, other agents) and/or psychological therapies (e.g. interpersonal psychotherapy, cognitive therapy, behavioural therapy, short dynamically-oriented psychotherapy) with another active therapy, placebo or sham intervention, routine care or no treatment in primary care patients in the acute phase of a depressive episode. Main outcome measure is response after completion of acute phase treatment. Eligible studies will be identified from available systematic reviews, from searches in electronic databases (Medline, Embase and Central), trial registers, and citation tracking. Two reviewers will independently extract study data and assess the risk of bias using the Cochrane Collaboration's corresponding tool. Meta-analyses (random effects model, inverse variance weighting) will be performed for direct comparisons of single interventions and for groups of similar interventions (e.g. SSRIs vs. tricyclics) and defined time-windows (up to 3 months and above). If possible, a global analysis of the relative effectiveness of treatments will be estimated from all available direct and indirect evidence that is present in a network of treatments and comparisons. Practitioners do not only want to know whether there is evidence that a specific treatment is more effective than placebo, but also how the treatment options compare to each other. Therefore, we believe that a multiple treatment systematic review of primary-care based randomized controlled trials on the most important therapies against depression is timely.


Effect of progesterone-releasing intravaginal device on reproductive performance of cows with cystic ovarian follicles after puerperium.
The aim of the study was to investigate the influence of cystic ovarian follicles (COFs) occurring after puerperium on fertility and the effect of their treatment with progesterone releasing device on reproductive performance in dairy cows. The study was carried out in 3 herds of Polish Holstein-Friesian cows under herd health program. COFs were diagnosed by ultrasound above 60 days p.p. They were defined as follicular structures with a diameter > 2.5 cm in the absence of a corpus luteum at two repeated examinations at the 14-days interval. On the day of COF diagnosis blood samples were collected to measure progesterone (P4) concentration. On the basis of the wall thickness measurement and progesterone concentration at the first examination, the COFs were differentiated into follicular and luteal cysts. The experimental group consisted of 23 animals with COF. The cows were treated with PRID Delta (Ceva Animal Health, Poland), containing 1.55 g of progesterone, for 7 days. The cows without oestrus signs within 14 days after treatment were re-examinated. If COF persisted, the cows were treated again with PRID Delta. The treatment was repeated maximum three times. Fifteen cows with ovarian cysts were left untreated and served as a control group. The cows with COF were matched to healthy cows without COF. The cows with COF had worse fertility performances compared to cows without COF. There were significant (p⟨0.05) differences in conception rates, number of services per conception and days open between these groups. Compared with non-treated cows with COF, in cows with COF treated with PRID Delta conceptions rates and number of services per conception were similar, but the days open were significantly (p⟨0.05) lower in cows treated than in non-treated (183.3 days vs. 277.6 days). There were no differences in reproductive performances between the follicular and luteal cysts in treated and non-treated cows. In conclusion, the results of our study confirm the negative impact of COF after puerperium on fertility in dairy cows. Furthermore the results indicate the usefulness of PRID Delta for the treatment of COF occurring after the puerperium regardless of cysts type.


Two-way lightwave subcarrier transmission system.
This Letter proposes and demonstrates a two-way lightwave subcarrier transmission system employing interleavers to deliver intensity-modulated CATV/phase-modulated RoF/intensity-remodulated 16-QAM-OFDM signals over two 20 km SMF links. To the best of our knowledge, it is the first time that interleavers have been employed in two-way lightwave subcarrier transmission systems. The downstream light is successfully intensity-remodulated with a 16-QAM-OFDM signal for uplink transmission. We obtained excellent performance from the CNR/CSO/CTB/BER for CATV/RoF/16-QAM-OFDM signal transmissions. The proposed systems offer impressive performance features to deliver hybrid CATV/RoF/16-QAM-OFDM signals.


Gene regulatory networks elucidating huanglongbing disease mechanisms.
Next-generation sequencing was exploited to gain deeper insight into the response to infection by Candidatus liberibacter asiaticus (CaLas), especially the immune disregulation and metabolic dysfunction caused by source-sink disruption. Previous fruit transcriptome data were compared with additional RNA-Seq data in three tissues: immature fruit, and young and mature leaves. Four categories of orchard trees were studied: symptomatic, asymptomatic, apparently healthy, and healthy. Principal component analysis found distinct expression patterns between immature and mature fruits and leaf samples for all four categories of trees. A predicted protein - protein interaction network identified HLB-regulated genes for sugar transporters playing key roles in the overall plant responses. Gene set and pathway enrichment analyses highlight the role of sucrose and starch metabolism in disease symptom development in all tissues. HLB-regulated genes (glucose-phosphate-transporter, invertase, starch-related genes) would likely determine the source-sink relationship disruption. In infected leaves, transcriptomic changes were observed for light reactions genes (downregulation), sucrose metabolism (upregulation), and starch biosynthesis (upregulation). In parallel, symptomatic fruits over-expressed genes involved in photosynthesis, sucrose and raffinose metabolism, and downregulated starch biosynthesis. We visualized gene networks between tissues inducing a source-sink shift. CaLas alters the hormone crosstalk, resulting in weak and ineffective tissue-specific plant immune responses necessary for bacterial clearance. Accordingly, expression of WRKYs (including WRKY70) was higher in fruits than in leaves. Systemic acquired responses were inadequately activated in young leaves, generally considered the sites where most new infections occur.


Comparison of Treatment Goals for Moderate-to-Severe Psoriasis between Korean Dermatologists and the European Consensus Report.
The development of therapies for psoriasis has led to the need for a new strategy to the treatment of patients with moderate-to-severe psoriasis. New consensus guidelines for psoriasis treatment have been developed in some countries, some of which have introduced treatment goals to determine the timing of therapeutic regimens for psoriasis. To investigate the opinions held by Korean dermatologists who specialize in psoriasis about treatment goals, and to compare these with the European consensus. Korean dermatologists who specialize in psoriasis were asked 11 questions about defining the treatment goals for psoriasis. The questionnaire included questions about the factors used to classify the severity of psoriasis, defining the induction and maintenance phases of psoriasis treatment, defining treatment responses during the induction phase, and defining treatment responses during the maintenance phase. The Korean consensus showed responses that were almost similar to the European consensus, even without using the Delphi technique, which uses repeated rounds of questions to reach a consensus. Only one response that related to psoriasis severity in the context of the quality of patients' lives differed from the European consensus. The concept of using treatment goals in the treatment of moderate-to-severe psoriasis can be applied to Korean psoriasis patients. Since a tool for assessing the quality of patients' lives is not commonly used in Korea, the development of a simple, rapidly completed, and region-specific health-related quality of life assessment tool would enable treatment goals to be used in routine clinical practice.


Delayed degradation of chlorophylls and photosynthetic proteins in Arabidopsis autophagy mutants during stress-induced leaf yellowing.
Plant autophagy, one of the essential proteolysis systems, balances proteome and nutrient levels in cells of the whole plant. Autophagy has been studied by analysing Arabidopsis thaliana autophagy-defective atg mutants, but the relationship between autophagy and chlorophyll (Chl) breakdown during stress-induced leaf yellowing remains unclear. During natural senescence or under abiotic-stress conditions, extensive cell death and early yellowing occurs in the leaves of atg mutants. A new finding is revealed that atg5 and atg7 mutants exhibit a functional stay-green phenotype under mild abiotic-stress conditions, but leaf yellowing proceeds normally in wild-type leaves under these conditions. Under mild salt stress, atg5 leaves retained high levels of Chls and all photosystem proteins and maintained a normal chloroplast structure. Furthermore, a double mutant of atg5 and non-functional stay-green nonyellowing1-1 (atg5 nye1-1) showed a much stronger stay-green phenotype than either single mutant. Taking these results together, it is proposed that autophagy functions in the non-selective catabolism of Chls and photosynthetic proteins during stress-induced leaf yellowing, in addition to the selective degradation of Chl-apoprotein complexes in the chloroplasts through the senescence-induced STAY-GREEN1/NYE1 and Chl catabolic enzymes.


Azelaic acid: Properties and mode of action.
Acne is a common skin disorder that can be problematic for adults as well as for adolescents. It has several key pathophysiological features such as follicular hyperkeratosis, elevated Propionibacterium acnes proliferation, and reactive inflammation, all of which should be targeted for an optimal outcome. Azelaic acid (AzA) has profound anti-inflammatory, antioxidative effects, and is bactericidal against a range of Gram-negative and Gram-positive microorganisms as well, including antibiotic-resistant bacterial strains. In addition, AzA's antikeratinizing effects are inhibitory toward comedones. AzA is effective overall in targeting multiple causes of acne and has been proven to be well tolerated in numerous clinical trials.


Sensitivity to change of the Rheumatoid Arthritis Self-Efficacy scale (RASE) and predictors of change in self-efficacy.
Patient education in rheumatoid arthritis (RA) aims to improve health outcomes by prompting people to adopt self-management behaviours. One precursor for initiating behaviour change is self-efficacy (SE), a belief that you can do a task. This study tested the sensitivity to change of a new scale to measure SE for self-management in people with RA, the Rheumatoid Arthritis Self-Efficacy scale (RASE). Exploratory analysis examined potential predictors of change in SE. People with RA at 11 rheumatology centres, who had accepted an education programme as part of clinical care, completed questionnaires at baseline, and two and eight weeks after their programme end. Programmes were not standardized, as this was a pragmatic study in clinical practice. A total of 128 patients participated. After controlling for baseline scores, the RASE showed small but significant improvements in SE from baseline (RASE 107.57, CI 105.42-109.72) to two weeks after programme end (RASE 110.80, CI 108.60-112.99), and eight weeks (RASE 110.62, CI 108.40-112.85, p<0.001). Standardized response means, calculated both by absolute and percentage change, were 0.339 and 0.371 at two weeks after programme end, and 0.321 and 0.352 at eight weeks. Changes in the RASE were associated with behaviour initiation at two and eight weeks (r=0.419, r=0.342, p<0.001). No substantial predictors of change in SE could be identified. The RASE is sensitive to change in a cohort of people with RA in the UK receiving education programmes as routine clinical care. Exploratory analysis did not identify clinical or psychological factors that predict change in SE, suggesting that programmes should not be restricted to particular patients.


Regulation of expression of the rat orthologue of mouse double minute 2 (MDM2) by H(2)O(2)-induced oxidative stress in neonatal rat cardiac myocytes.
The Mdm2 ubiquitin ligase is an important regulator of p53 abundance and p53-dependent apoptosis. Mdm2 expression is frequently regulated by a p53 Mdm2 autoregulatory loop whereby p53 stimulates Mdm2 expression and hence its own degradation. Although extensively studied in cell lines, relatively little is known about Mdm2 expression in heart where oxidative stress (exacerbated during ischemia-reperfusion) is an important pro-apoptotic stimulus. We demonstrate that Mdm2 transcript and protein expression are induced by oxidative stress (0.2 mm H(2)O(2)) in neonatal rat cardiac myocytes. In other cells, constitutive Mdm2 expression is regulated by the P1 promoter (5' to exon 1), with inducible expression regulated by the P2 promoter (in intron 1). In myocytes, H(2)O(2) increased Mdm2 expression from the P2 promoter, which contains two p53-response elements (REs), one AP-1 RE, and two Ets REs. H(2)O(2) did not detectably increase expression of p53 mRNA or protein but did increase expression of several AP-1 transcription factors. H(2)O(2) increased binding of AP-1 proteins (c-Jun, JunB, JunD, c-Fos, FosB, and Fra-1) to an Mdm2 AP-1 oligodeoxynucleotide probe, and chromatin immunoprecipitation assays showed it increased binding of c-Jun or JunB to the P2 AP-1 RE. Finally, antisense oligonucleotide-mediated reduction of H(2)O(2)-induced Mdm2 expression increased caspase 3 activation. Thus, increased Mdm2 expression is associated with transactivation at the P2 AP-1 RE (rather than the p53 or Ets REs), and Mdm2 induction potentially represents a cardioprotective response to oxidative stress.


A serological survey of antibodies to Leptospira species in dogs in South Africa.
Leptospirosis, a disease more common in the tropics, can cause a life-threatening multisystemic syndrome in humans and animals. Immunity, whether natural or vaccine-induced, is serogroup-specific with the infecting serovars varying according to geographical locality. In South Africa, in spite of the fact that the bacterin vaccine for some Leptospira serovars is often used, there is no recent information on the incidence of canine leptospirosis as well as the infecting serovar/s. The aim of this study, which was undertaken on sera collected in 2008 and 2009 from both strays and owned dogs predominantly in the coastal regions of South Africa, was to determine the presence of leptospiral antibodies to 15 serovars known to infect dogs. Of the 530 samples tested, 25 tested positive to 7 different serovars with the microscopic agglutination test (MAT). Nine of the 25 samples tested positive to more than one serovar. The 2 serovars most frequently represented were Canicola, which reacted to 17 sera, and Pyrogenes, which reacted to 10 sera. Currently the only vaccines available in South Africa in different combinations contain serovars Canicola, Icterohaemorrhagiae, Pomona and Grippotyphosa. The results showed that the use of vaccines containing serovar Canicola is still justifiable in certain regions of the country. However, the presence of antibodies to serovar Pyrogenes in several dogs, pending a broader investigation, indicates that this serovar should also be included in the range of Leptospira vaccines for use in South Africa.


The influence of the pituitary tumor transforming gene-1 (PTTG-1) on survival of patients with small cell lung cancer and non-small cell lung cancer.
PTTG-1 (pituitary tumor transforming gene) is a novel oncogene that is overexpressed in tumors, such as pituitary adenoma, breast and gastrointestinal cancers as well as in leukemia. In this study, we examined the role of PTTG-1 expression in lung cancer with regard to histological subtype, the correlation of PTTG-1 to clinical parameters and relation on patients' survival. Expression of PTTG-1 was examined immunohistochemically on formalin-fixed, paraffin-embedded tissue sections of 136 patients with small cell lung cancer (SCLC) and 91 patients with non-small cell lung cancer (NSCLC), retrospectively. The intensity of PTTG-1 expression as well as the proportion of PTTG-1 positive cells within a tumor was used for univariate and multivariate analysis. PTTG-1 expression was observed in 64% of SCLC tumors and in 97.8% of NSCLC tumors. In patients with SCLC, negative or low PTTG-1 expression was associated with a shorter mean survival time compared with patients with strong PTTG-1 expression (265 +/- 18 days vs. 379 +/- 66 days; p = 0.0291). Using the Cox regression model for multivariate analysis, PTTG-1 expression was a significant predictor for survival next to performance status, tumor stage, LDH and hemoglobin. In contrast, in patients with NSCLC an inverse correlation between survival and PTTG-1 expression was seen. Strong PTTG-1 expression was associated with a shorter mean survival of 306 +/- 58 days compared with 463 +/- 55 days for those patients with no or low PTTG-1 intensities (p = 0.0386). Further, PTTG-1 expression was associated with a more aggressive NSCLC phenotype with an advanced pathological stage, extensive lymph node metastases, distant metastases and increased LDH level. Multivariate analysis using Cox regression confirmed the prognostic relevance of PTTG-1 expression next to performance status and tumor stage in patients with NSCLC. Lung cancers belong to the group of tumors expressing PTTG-1. Dependent on the histological subtype of lung cancer, PTTG-1 expression was associated with a better outcome in patients with SCLC and a rather unfavourable outcome for patients with NSCLCs. These results may reflect the varying role of PTTG-1 in the pathophysiology of the different histological subtypes of lung cancer.


Outstanding personalities in German-speaking mycology : Dedicated to Professor Dr. Johannes Müller.
The history of medical and veterinary mycology in general has been reviewed in the excellent monography by G.C. Ainsworth (1905-1998) published in 1986. Here, we will focus on German-speaking mycology and their outstanding personalities. We will start with the early years when medical mycology was in its infancy. Microscopy was a most valuable tool for the identification of fungi followed by cultivation and staining methods. Human pathologies became linked to fungi. After World War I, medical mycology flourished as an integral part of dermatology at universities and in private institutes. The development was interrupted by World War II, which divided Germany. In both parts of Germany, medical mycology had to be re-established. After re-unification the two different medical societies joined together. The development of DMyK (Deutschsprachigen Mykologischen Gesellschaft - Mykologie) is illustrated. Important personalities and some of their achievements are mentioned. Mycology has attracted other fields of medicine including internal medicine, pediatrics, microbiology, and veterinary medicine.


Optimization of Hyperglycemic Induction in Zebrafish and Evaluation of Its Blood Glucose Level and Metabolite Fingerprint Treated with Psychotria malayana Jack Leaf Extract.
A standard protocol to develop type 1 diabetes in zebrafish is still uncertain due to unpredictable factors. In this study, an optimized protocol was developed and used to evaluate the anti-diabetic activity of Psychotria malayana leaf. The aims of this study were to develop a type 1 diabetic adult zebrafish model and to evaluate the anti-diabetic activity of the plant extract on the developed model. The ability of streptozotocin and alloxan at a different dose to elevate the blood glucose levels in zebrafish was evaluated. While the anti-diabetic activity of P. malayana aqueous extract was evaluated through analysis of blood glucose and LC-MS analysis fingerprinting. The results indicated that a single intraperitoneal injection of 300 mg/kg alloxan was the optimal dose to elevate the fasting blood glucose in zebrafish. Furthermore, the plant extract at 1, 2, and 3 g/kg significantly reduced blood glucose levels in the diabetic zebrafish. In addition, LC-MS-based fingerprinting indicated that 3 g/kg plant extract more effective than other doses. Phytosterols, sugar alcohols, sugar acid, free fatty acids, cyclitols, phenolics, and alkaloid were detected in the extract using GC-MS. In conclusion, P. malayana leaf aqueous extract showed anti-diabetic activity on the developed type 1 diabetic zebrafish model.


The electronic structure of vanadium monochloride cation (VCl(+)): tackling the complexities of transition metal species.
Six electronic states (X (4)Σ(-), A (4)Π, B (4)Δ, (2)Φ, (2)Δ, (2)Σ(+)) of the vanadium monochloride cation (VCl(+)) are described using large basis set coupled cluster theory. For the two lowest quartet states (X (4)Σ(-) and A (4)Π), a focal point analysis (FPA) approach was used that conjoined a correlation-consistent family of basis sets up to aug-cc-pwCV5Z-DK with high-order coupled cluster theory through pentuple (CCSDTQP) excitations. FPA adiabatic excitation energies (T0) and spectroscopic constants (re, r0, Be, B0, D¯e, He, ωe, v0, αe, ωexe) were extrapolated to the valence complete basis set Douglas-Kroll (DK) aug-cc-pV∞Z-DK CCSDT level of theory, and additional treatments accounted for higher-order valence electron correlation, core correlation, and spin-orbit coupling. Due to the delicate interplay between dynamical and static electronic correlation, single reference coupled cluster theory is able to provide the correct ground electronic state (X (4)Σ(-)), while multireference configuration interaction theory cannot. Perturbations from the first- and second-order spin orbit coupling of low-lying states with quartet spin multiplicity reveal an immensely complex rotational spectrum relative to the isovalent species VO, VS, and TiCl. Computational data on the doublet manifold suggest that the lowest-lying doublet state ((2)Γ) has a Te of ∼11 200 cm(-1). Overall, this study shows that laboratory and theoretical rotational spectroscopists must work more closely in tandem to better understand the bonding and structure of molecules containing transition metals.


Cerebrospinal fluid shunt placement for pseudotumor cerebri-associated intractable headache: predictors of treatment response and an analysis of long-term outcomes.
Cerebrospinal fluid (CSF) shunts effectively reverse symptoms of pseudotumor cerebri postoperatively, but long-term outcome has not been investigated. Lumboperitoneal (LP) shunts are the mainstay of CSF shunts for pseudotumor cerebri; however, image-guided stereotaxy and neuroendoscopy now allow effective placement of a ventricular catheter without causing ventriculomegaly in these cases. To date it remains unknown if CSF shunts provide long-term relief from pseudotumor cerebri and whether a ventricular shunt is better than an LP shunt. The authors investigated these possibilities. The authors reviewed the records of all shunt placement procedures that were performed for intractable headache due to pseudotumor cerebri at one institution between 1973 and 2003. Using proportional hazards regression analysis, predictors of treatment failure (continued headache despite a properly functioning shunt) were assessed, and shunt revision and complication rates were compared between LP and ventricular (ventriculoperitoneal [VP] or ventriculoatrial [VAT]) shunts. Forty-two patients underwent 115 shunt placement procedures: 79 in which an LP shunt was used and 36 in which a VP or VAT shunt was used. Forty patients (95%) experienced a significant improvement in their headaches immediately after the shunt was inserted. Severe headache recurred despite a properly functioning shunt in eight (19%) and 20 (48%) patients by 12 and 36 months, respectively, after the initial shunt placement surgery. Seventeen patients without papilledema and 19 patients in whom preoperative symptoms had occurred for longer than 2 years experienced recurrent headache, making patients with papilledema or long-term symptoms fivefold (relative risk [RR] 5.2, 95% confidence interval [CI] 1.5-17.8; p < 0.01) or 2.5-fold (RR 2.51, 95% CI 1.01-9.39; p = 0.05) more likely to experience headache recurrence, respectively. In contrast to VP or VAT shunts, LP shunts were associated with a 2.5-fold increased risk of shunt revision (RR 2.5, 95% CI 1.5-4.3; p < 0.001) due to a threefold increased risk of shunt obstruction (RR 3, 95% CI 1.5-5.7; p < 0.005), but there were similar risks between the two types of shunts for overdrainage (RR 2.3, 95% CI 0.8-7.9; p = 0.22), distal catheter migration (RR 2.1, 95% CI 0.3-19.3; p = 0.55), and shunt infection (RR 1.3, 95% CI 0.3-13.2; p = 0.75). Based on their 30-year experience in the treatment of these patients, the authors found that CSF shunts were extremely effective in the acute treatment of pseudotumor cerebri-associated intractable headache, providing long-term relief in the majority of patients. Lack of papilledema and long-standing symptoms were risk factors for treatment failure. The use of ventricular shunts for pseudotumor cerebri was associated with a lower risk of shunt obstruction and revision than the use of LP shunts. Using ventricular shunts in patients with papilledema or symptoms lasting less than 2 years should be considered for those with pseudotumor cerebri-associated intractable headache.


Ultrasound appearance of peripheral nerves in the neck: vagus, hypoglossal and greater auricular.
Information in ultrasonography about reference values of nerves, particularly of those located in the neck is limited. The aim of the study is to demonstrate the feasibility of direct visualization of the vagus, hypoglossal and greater auricular nerves, testing the method on healthy volunteers and estimate the reference values for two perpendicular diameters and cross-sectional area (CSA). A prospective study was carried out on 21 healthy volunteers (12 women and 9 men), recording their demographic characteristics. A 13 MHz transducer was used on a Hitachi EUB-8500 machine. The vagus nerve was measured at the bifurcation of common carotid artery (CCA) and at the intersection of the internal jugular vein with omohyoid muscle. The hypoglossal nerve was identified as it crosses the posterolateral border of the mylohyoid muscle in the submandibular space. The auricular nerve was identified on the superficial surface of the sternocleidomastoid muscle at 1 cm from its posterior margin. The mean CSA on axial scans, nerve width and thickness were determined. The side-to-side and gender differences of the estimated reference values and their correlations with the weight, height, and body mass index (BMI) were evaluated. The mean ultrasound-estimated CSA was measured for the vagus nerve at CCA bifurcation (2.14 ± 0.79 on the left 2.86 ± 1.27 on the right), vagus nerve at the level of omohyoid muscle (2.10 ± 0.06 on the left and 2.43 ± 0.08 on the right), hypoglossal nerve (1.71 ± 0.08 on the left, 1.24 ± 0.06 on the right) and greater auricular nerve (0.90 ± 0.53 on the left and 0.79 ± 0.71 on the right). The vagus nerve was significantly larger on the right side compared to the left side. Larger hypoglossal nerve was observed in men compared to women. Significant correlations were observed between weight and CSA of the greater auricular nerve. Direct visualization of the vagus, greater auricular nerve and hypoglossal nerves is feasible. Reference values for the size of the studied nerves at specific anatomic landmarks were established. Side, gender and body weight differences of the nerves CSA were noted.


Publish or be damned: Individual Funding Requests and the publicity condition.
Many jurisdictions have processes to consider Individual Funding Requests but, with few exceptions, the decisions made with respect to these are not made public. Drawing upon Daniels and Sabin's account of the requirements of procedural justice, Accountability for Reasonableness, this paper considers several arguments for and against publishing individual funding request decisions. After briefly reviewing the case for publicity as a requirement of procedural justice and canvassing several arguments against publicity, we consider whether patient confidentiality justifies suppressing funding decisions. We claim that, with one possible exception, publication of individual funding request decisions does not raise concerns that are different in kind from those that apply to publication of legal judgments relating to healthcare, and that the protections instituted in that setting should be sufficient to allow publication of funding decisions. The discussion concludes with several cautionary notes.


Detection of predation using qPCR: effect of prey quantity, elapsed time, chaser diet, and sample preservation on detectable quantity of prey DNA.
Using quantitative PCR that amplified a prey-specific mtDNA 214 bp amplicon from the COI mitochondrial gene of the Colorado potato beetle, Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae), prey eggs of known age and number were fed to larvae of the generalist predator lady beetle Coleomegilla maculata (De Geer) (Coleoptera: Coccinellidae), to elucidate the effects of time and diet since consumption, number of prey eggs, and methods for sample fixation and preservation, on the quantity of target DNA detected. Signal was strongly attenuated directly after cessation of feeding, even when predators were immediately frozen at -20 degrees C. However, the quantity of target detected was significantly related to the number of eggs consumed and the time elapsed since eating. Decrease in detected prey DNA was consistent with a negative exponential model. The target DNA sequence disappeared from starved predators (quantitative half-life estimate of 59 min) more slowly than those fed potato aphids after consuming the target prey eggs (half-life estimate 16 min), whereas those fed C. maculata eggs as a chaser were intermediate in the rate at which they degraded the target prey DNA sequence. Fixative protocols are of critical importance in proper use of the qPCR technique. Among seven methods tested, storing the predator immediately in 70% ethanol prechilled to -20 degrees C yielded the highest amount of target sequence, 22.8% of that recovered directly from a single intact prey egg. Samples frozen without solvent at -80 degrees C and -20 degrees C yielded only 6.0% and 2.3% of the target DNA respectively, and room temperature ethanol and ethylene glycol-based antifreeze averaged below 1% recovery of target DNA. Nevertheless, target prey was detected in more than 80% of antifreeze-stored predators. Predators killed and held at room temperature for 4 h or 5 days yielded no target prey DNA in 18 of 20 cases. These results emphasize both the value and the complexities of application of the qPCR technique to field predation studies.


Prevalence of Head Injury and Associated Disability in Prison Populations: A Systematic Review.
This review systematically assesses literature on the prevalence of head injury (HI) and associated disability in adults in prison. Searches were carried out using electronic databases (PsycINFO, Cochrane Databases, MEDLINE, EMBASE, Web of Science). Reference lists of 2 meta-analyses were checked for relevant articles. Methods were rated for risk of bias. The 10 studies included report a range in prevalence of HI in prisoners from 25% to 86%. Risk of bias was high overall, probably because a range of HI definitions was used, assessments were often not validated, and samples were not or not evidenced to be representative of the prison population. There was an absence of appropriate population controls from which to compare relative risk of HI in different countries. No study reported the prevalence of disability associated with HI. The wide range in prevalence estimates of HI in prisoners is associated with high risk of bias from study design and methods. Persisting disability associated with HI was not reported and as a result the service need for prisoners with HI is unclear. Future studies should indicate that samples are representative of prison populations, use validated tools and internationally accepted definitions of HI, and link prevalence to persisting disability.


Management of acute postpartum pain in patients maintained on methadone or buprenorphine during pregnancy.
Empirical evidence is needed to guide adequate postpartum pain relief of methadone and buprenorphine stabilized patients. To first determine the adequacy of pain control using non-opioid and opioid medication in participants stabilized on buprenorphine or methadone before a vaginal delivery. Second, to compare the amount of non-opioid and opioid medication needed for adequate pain control for buprenorphine-and methadone-maintained patients during the immediate postpartum period. Pain control adequacy and amount of non-opioid and opioid medication needed in buprenorphine- (n = 8) and methadone-maintained (n = 10) patients over the first five days postpartum were examined. Pain ratings and number of opioid medication doses decreased over time in both medication groups. While the buprenorphine and methadone groups began with similar mean daily ibuprofen (IB) doses, the buprenorphine group decreased its IB use, while the methadone group increased its IB use. Patients treated daily with either buprenorphine or methadone can have adequate pain control postpartum with opioid medication and IB. Pain control is dependent on the opioid-agonist medication in use at delivery, and must be individualized.


Gender-related factors affecting health seeking for neglected tropical diseases: findings from a qualitative study in Ethiopia.
Despite known gender-specific differences in terms of prevalence, transmission and exposure to neglected tropical diseases (NTDs), there is limited discussion of the influence of gender in NTD programmes and interventions. There is a paucity of research on how gender interacts with NTD service provision and uptake. This study, part of broader implementation research in Ethiopia, applied a gender lens to health seeking for five NTDs: lymphatic filariasis, podoconiosis, schistosomiasis, soil-transmitted helminth infection and trachoma. The study was conducted in a district of the Southern Nations, Nationalities, and Peoples' Region of Ethiopia where the five NTDs are prevalent. A qualitative methodology was adopted to explore participants' perspectives and experiences. Data generation methods included 20 interviews and four focus group discussions. Community members, volunteer Health Development Army leaders, Health Extension Workers and a range of health workers at the health post, health centre and hospital level (n = 59) were purposively sampled. Interviews and focus group discussions were audio recorded, transcribed verbatim into English then analysed through open coding, drawing on constant comparative methods. Gender related factors affected care seeking for NTDs and were described as reasons for not seeking care, delayed care seeking and treating NTDs with natural remedies. Women faced additional challenges in seeking health care due to gender inequalities and power dynamics in their domestic partnerships. Participants recommended raising community awareness about NTDs, however this remains problematic due to gender and social norms around appropriate discourse with members of the opposite gender. The findings from this study provide crucial insights into how gender interacts with accessing health services, at different levels of the health system. If we are committed to leaving no one behind and achieving universal health coverage, it is essential to address gender disparities to access and utilisation of interventions delivered by national NTD programmes.


Assessing the value of imperfect biocontainment nationally: rapeseed in the United Kingdom as an exemplar.
Paternal biocontainment methods (PBMs) act by preventing pollen-mediated transgene flow. They are compromised by transgene escape via the crop-maternal line. We therefore assess the efficacy of PBMs for transgenic rapeseed (Brassica napus) biocontainment across the United Kingdom by estimating crop-maternal hybridization with its two progenitor species. We used remote sensing, field surveys, agricultural statistics, and meta-analysis to determine the extent of sympatry between the crop and populations of riparian and weedy B. rapa and B. oleracea. We then estimated the incidence of crop-maternal hybridization across all settings to predict the efficacy of PBMs. Evidence of crop chloroplast capture by the progenitors was expanded to a national scale, revealing that crop-maternal gene flow occurs at widely variable rates and is dependent on both the recipient and setting. We use these data to explore the value that this kind of biocontainment can bring to genetic modification (GM) risk management in terms of reducing the impact that hybrids have on the environment rather than preventing or reducing hybrid abundance per se.


Optical sensor arrays for chemical sensing: the optoelectronic nose.
A comprehensive review is presented on the development and state of the art of colorimetric and fluorometric sensor arrays. Optical arrays based on chemoresponsive colorants (dyes and nanoporous pigments) probe the chemical reactivity of analytes, rather than their physical properties. This provides a high dimensionality to chemical sensing that permits high sensitivity (often down to ppb levels), impressive discrimination among very similar analytes and exquisite fingerprinting of extremely similar mixtures over a wide range of analyte types, both in the gas and liquid phases.


Kinetically-controlled laser-synthesis of colloidal high-entropy alloy nanoparticles.
The single-step incorporation of multiple immiscible elements into colloidal high-entropy alloy (HEA) nanoparticles has manifold technological potential, but it continues to be a challenge for state-of-the-art synthesis methods. Hence, the development of a synthesis approach by which the chemical composition and phase of colloidal HEA nanoparticles can be controlled could lead to a new pool of nanoalloys with unparalleled functionalities. Herein, this study reports the single-step synthesis of colloidal CoCrFeMnNi HEA nanoparticles with targeted equimolar stoichiometry and diameters less than 5 nm by liquid-phase, ultrashort-pulsed laser ablation of the consolidated and heat-treated micropowders of the five constituent metals. Further, the scalability of the process with an unprecedented productivity of 3 grams of colloidal HEA nanoparticles per hour is demonstrated. Electrochemical analysis reveals a unique redox behavior of the particles' surfaces in an alkaline environment and a potential for future application as a heterogeneous catalyst for the oxygen evolution reaction.


Early vs Late Use of Anti-TNFa Therapy in Adult Patients With Crohn Disease: A Systematic Review and Meta-Analysis.
While anti-tumor necrosis factor alpha (anti-TNFa) therapies for Crohn disease (CD) were initially introduced in 1998 for biologic therapies are often introduced after a minimum of 6 years after diagnosis. The benefit of anti-TNFa early in the course of CD is still controversial, with some studies showing better outcomes but others not. To determine whether earlier introduction of anti-TNFa therapy improves efficacy in clinical trials or clinical series, we aimed to perform a meta-analysis comparing early vs late anti-TNFa use in the management of CD. A comprehensive search of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus was conducted from each database's inception to November 3, 2019. We included comparative studies of early vs late use of anti-TNFa therapy in adult patients with CD. Eleven studies were included in the analysis, with a total of 2501 patients. Meta-analysis demonstrated that the early use of anti-TNFa was associated with a statistically significant decrease in the need for surgery (relative risk [RR] = 0.43; 95% confidence interval [CI], 0.26-0.69; I2 = 68%) and disease progression (RR = 0.51; 95% CI, 0.35-0.75; I2 = 61%). Early use also showed an increase in early remission (RR = 1.94; 95% CI, 1.54-2.46; I2 = 0%) and clinical response. There was no statistically significant difference in achieving late remission (RR = 1.39; 95% CI, 0.94-2.05; I2 = 65%) or mucosal healing (RR = 1.10; 95% CI, 0.63-1.91; I2 = 0%). This systematic review suggests that using anti-TNFa earlier in the treatment of CD (within 3 years) may improve clinical outcomes compared to late administration in terms of achieving early clinical remission, clinical response, disease progression, and the need for surgery.


Home treatment of haemarthrosis with recombinant activated factor VII in patients with haemophilia A or B and inhibitors: experience from developing countries.
Home therapy for uncomplicated mild/moderate bleeding can decrease healthcare burden, promote self-esteem, reduce complications, and provide near-normal quality of life. To evaluate recombinant activated factor VII (rFVIIa) as home therapy for joint bleeds in Algeria, Morocco, Oman, Saudi Arabia, and United Arab Emirates. Twenty-seven patients aged more than 2 years with congenital haemophilia and inhibitors were monitored for up to 8 months after a first haemarthrosis episode treated with rFVIIa. Assessments were made by patients/caregivers with a standardized diary. The main measures included home-managed bleeds, haemostasis, and pain relief within 9 h after first injection. Additional analyses included convenience, time to pain resolution, and doses given within 48 h. Of 132 bleeds, 84 (63.6%) were managed at home. Of these, successful haemostasis (partial or complete) was achieved at 9 h in 87.8%, with pain relief for 84.0%. For all treatment settings, successful haemostasis at 9 h was achieved for 86.3% of bleeds, with pain relief achieved for 74.8% of bleeds. Higher initial dosing was associated with fewer injections. Median time to complete haemostasis was 48 h (spontaneous bleeds) and 24 h (traumatic bleeds). Median time to complete pain relief was 24 h for both bleed types. Satisfaction with treatment was high. No safety concerns were reported. Results from this observational study agree with previous data on the safety and efficacy of home treatment with rFVIIa and will help to increase awareness and aggregate experience, fostering confidence in home management of haemophilia patients with inhibitors in developing countries.


Guidelines for multi-model comparisons of the impact of infectious disease interventions.
Despite the increasing popularity of multi-model comparison studies and their ability to inform policy recommendations, clear guidance on how to conduct multi-model comparisons is not available. Herein, we present guidelines to provide a structured approach to comparisons of multiple models of interventions against infectious diseases. The primary target audience for these guidelines are researchers carrying out model comparison studies and policy-makers using model comparison studies to inform policy decisions. The consensus process used for the development of the guidelines included a systematic review of existing model comparison studies on effectiveness and cost-effectiveness of vaccination, a 2-day meeting and guideline development workshop during which mathematical modellers from different disease areas critically discussed and debated the guideline content and wording, and several rounds of comments on sequential versions of the guidelines by all authors. The guidelines provide principles for multi-model comparisons, with specific practice statements on what modellers should do for six domains. The guidelines provide explanation and elaboration of the principles and practice statements as well as some examples to illustrate these. The principles are (1) the policy and research question - the model comparison should address a relevant, clearly defined policy question; (2) model identification and selection - the identification and selection of models for inclusion in the model comparison should be transparent and minimise selection bias; (3) harmonisation - standardisation of input data and outputs should be determined by the research question and value of the effort needed for this step; (4) exploring variability - between- and within-model variability and uncertainty should be explored; (5) presenting and pooling results - results should be presented in an appropriate way to support decision-making; and (6) interpretation - results should be interpreted to inform the policy question. These guidelines should help researchers plan, conduct and report model comparisons of infectious diseases and related interventions in a systematic and structured manner for the purpose of supporting health policy decisions. Adherence to these guidelines will contribute to greater consistency and objectivity in the approach and methods used in multi-model comparisons, and as such improve the quality of modelled evidence for policy.


The relationship between target joints and direct resource use in severe haemophilia.
Target joints are a common complication of severe haemophilia. While factor replacement therapy constitutes the majority of costs in haemophilia, the relationship between target joints and non drug-related direct costs (NDDCs) has not been studied. Data on haemophilia patients without inhibitors was drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the United Kingdom) in which 139 haemophilia specialists provided demographic and clinical information for 1285 adult patients. NDDCs were calculated using publicly available cost data, including 12-month ambulatory and secondary care activity: haematologist and other specialist consultant consultations, medical tests and examinations, bleed-related hospital admissions, and payments to professional care providers. A generalized linear model was developed to investigate the relationship between NDDCs and target joints (areas of chronic synovitis), adjusted for patient covariates. Five hundred and thirteen patients (42% of the sample) had no diagnosed target joints; a total of 1376 target joints (range 1-10) were recorded in the remaining 714 patients. Mean adjusted NDDCs for persons with no target joints were EUR 3134 (standard error (SE) EUR 158); for persons with one or more target joints, mean adjusted NDDCs were EUR 3913 (SE EUR 157; average mean effect EUR 779; p < 0.001). Our analysis suggests that the presence of one or more target joints has a significant impact on NDDCs for patients with severe haemophilia, ceteris paribus. Prevention and management of target joints should be an important consideration of managing haemophilia patients.


The marketplace for new caries management products: dental caries detection and caries management by risk assessment.
The number of new technologies emerging each year in the realm of dental caries management is growing at an exponential rate. Examining the patent literature, one can see that this growth rate will likely continue, with the outcome that dentistry will see an expanded growth in managing dental caries by risk assessment with medicinal therapeutic interventions. Restorative dentistry solutions, treating the results of dental caries, will continue to grow, while technologies to identify the caries process at its earliest stages will soon invade practices everywhere. The most interesting aspect of these changes will be how industry responds to the inexorable, yet slow change in dental professional demand for these new technologies, while trying to be the "first to market" within the various categories of this business opportunity. This paper will take a close look at how businesses with the core competence to be key players in this emerging growth category will assess the marketplace, and match up their business interests with the changing needs of the dental profession. The paper will also address the strategic planning and business processes that the dental industry will undertake to bring new technologies to market, and how these technologies will be positioned to health care professionals and consumers. The results of the key interactions between industry and the dental profession will determine the extent to which dental caries is managed as a disease, in addition to being managed by surgical restorative interventions.


Peculiar galaxies and radio sources.
Pairs of radio sources which are separated by from 2 degrees to 6 degrees on the sky have been investigated. In a number of cases peculiar galaxies have been found approximately midway along a line joining the two radio sources. The central peculiar galaxies belong mainly to a certain class in the recently compiled Atlas of Peculiar Galaxies. Among the radio sources so far associated with the peculiar galaxies are at least five known quasars. These quasars are indicated to be not at cosmological distances (that is, red shifts not caused by expansion of the universe) because the central peculiar galaxies are only at distances of 10 to 100 megaparsecs. The absolute magnitudes of these quasars are indicated to be in the range of brightness of normal galaxies and downward. Some of the radio sources which have been found to be associated with peculiar galaxies are galaxies themselves. It is therefore implied that ejection of material took place within or near the parent peculiar galaxies with speeds between 10(2) and 10(4) kilometers per second. After traveling for times of the order of 10(7) to 10(9) years, the luminous matter (galaxies) and radio sources (plasma) have reached their observed separations from the central peculiar galaxy. The large red shifts measured for the quasars would seem to be either (i) gravitational, (ii) collapse velocities of clouds of material falling toward the center of these compact galaxies, or (iii) some as yet unknown cause.


Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation.
Topical application of nucleic acids offers many potential therapeutic advantages for suppressing genes in the skin, and potentially for systemic gene delivery. However, the epidermal barrier typically precludes entry of gene-suppressing therapy unless the barrier is disrupted. We now show that spherical nucleic acid nanoparticle conjugates (SNA-NCs), gold cores surrounded by a dense shell of highly oriented, covalently immobilized siRNA, freely penetrate almost 100% of keratinocytes in vitro, mouse skin, and human epidermis within hours after application. Significantly, these structures can be delivered in a commercial moisturizer or phosphate-buffered saline, and do not require barrier disruption or transfection agents, such as liposomes, peptides, or viruses. SNA-NCs targeting epidermal growth factor receptor (EGFR), an important gene for epidermal homeostasis, are > 100-fold more potent and suppress longer than siRNA delivered with commercial lipid agents in cultured keratinocytes. Topical delivery of 1.5 uM EGFR siRNA (50 nM SNA-NCs) for 3 wk to hairless mouse skin almost completely abolishes EGFR expression, suppresses downstream ERK phosphorylation, and reduces epidermal thickness by almost 40%. Similarly, EGFR mRNA in human skin equivalents is reduced by 52% after 60 h of treatment with 25 nM EGFR SNA-NCs. Treated skin shows no clinical or histological evidence of toxicity. No cytokine activation in mouse blood or tissue samples is observed, and after 3 wk of topical skin treatment, the SNA structures are virtually undetectable in internal organs. SNA conjugates may be promising agents for personalized, topically delivered gene therapy of cutaneous tumors, skin inflammation, and dominant negative genetic skin disorders.


Use of (7)Be to document soil erosion associated with a short period of extreme rainfall.
Intensification and expansion of agricultural production since the 1970s have increased soil erosion problems in south-central Chile. Quantitative information on soil loss is needed for erosion risk assessment and to establish the effectiveness of improved land management practices. Since information from traditional sources, such as erosion plots, is limited, attention has been directed to the use of environmental radionuclides for documenting erosion rates. Cs-137 has been successfully utilised for this purpose, but only provides information on medium-term erosion rates. There is also a need to document event-related soil erosion. This paper outlines the basis for using (7)Be measurements to document short-term erosion and reports its successful use for quantifying the erosion that occurred within an arable field, as a result of a period of heavy rainfall (400mm in 27 days) occurring in May 2005. The study field had been under a no-till, no-burning system for 18 years, but immediately prior to the period of heavy rainfall the harvest residues were burnt. The erosion recorded therefore reflected both the extreme nature of the rainfall and the effects of the burning in increasing surface runoff and erosion. The sampled area corresponded to that used previously by the authors to document the medium-term erosion rates associated with both conventional tillage and the subsequent switch to a no-till system. Comparisons between the erosion documented for the period of heavy rainfall in 2005 with these medium-term erosion rates permits some tentative conclusions regarding the importance of extreme events and the impact of burning in increasing the erosion associated with the no-till system.


Multinucleated Giant Hemocytes Are Effector Cells in Cell-Mediated Immune Responses of Drosophila.
We identified and characterized a so far unrecognized cell type, dubbed the multinucleated giant hemocyte (MGH), in the ananassae subgroup of Drosophilidae. Here, we describe the functional and ultrastructural characteristics of this novel blood cell type as well as its characterization with a set of discriminative immunological markers. MGHs are encapsulating cells that isolate and kill the parasite without melanization. They share some properties with but differ considerably from lamellocytes, the encapsulating cells of Drosophila melanogaster, the broadly used model organism in studies of innate immunity. MGHs are nonproliferative effector cells that are derived from phagocytic cells of the sessile tissue and the circulation, but do not exhibit phagocytic activity. In contrast to lamellocytes, MGHs are gigantic cells with filamentous projections and contain many nuclei, which are the result of the fusion of several cells. Although the structure of lamellocytes and MGHs differ remarkably, their function in the elimination of parasites is similar, which is potentially the result of the convergent evolution of interactions between hosts and parasites in different geographic regions. MGHs are highly motile and share several features with mammalian multinucleated giant cells, a syncytium of macrophages formed during granulomatous inflammation.


Time series analysis of the impact of oral vaccination on raccoon rabies in West Virginia, 1990-2007.
To assess the potential impact of oral rabies vaccination (ORV) on the occurrence of raccoon rabies in the mid-Atlantic region, temporal and seasonal trends of raccoon rabies cases reported in West Virginia from 1990 to 2007 were identified with both descriptive statistical analysis and exploratory time series analysis. Raccoon rabies cases in the non-ORV region maintain an enzootic pattern and increase over time; a bimodal seasonal pattern is observed with a large peak in April and a smaller peak in August. The results of the model indicate that the effect of the ORV intervention to control raccoon rabies was statistically significant. ORV should be attempted in other enzootic raccoon rabies areas.


Equilibrium Assays Are Required to Accurately Characterize the Activity Profiles of Drugs Modulating Gq-Protein-Coupled Receptors.
This paper discusses the process of determining the activity of candidate molecules targeting Gq-protein activation through G-protein-coupled receptors for possible therapeutic application with two functional assays; calcium release and inositol phosphate metabolism [inositol monophosphate (IP1)]. While both are suitable for detecting ligand activity (screening), differences are seen when these assays are used to quantitatively measure ligand parameters for therapeutic activity. Specifically, responses for Gq-related pathways present different and dissimulating patterns depending on the functional assay used to assess them. To investigate the impact of functional assays on the accuracy of compound pharmacological profiles, five exemplar molecules [partial agonist, antagonist, inverse agonist, positive allosteric modulator (PAM) agonist, and positive β-PAM] targeting either muscarinic M1 or ghrelin receptors were tested using two functional assays (calcium release and IP1) and the results were compared with theoretical pharmacological models. The IP1 assay is an equilibrium assay that is able to determine the correct (i.e., internally consistent) pharmacological profiles of all tested compounds. In contrast, the nonequilibrium nature of calcium assays yields misleading classification of most of the tested compounds. Our study suggests that the use of an equilibrium assay, such as IP1, is mandatory for the optimal use of pharmacological models that can both identify mechanisms of action and also convert descriptive-to-predictive data for therapeutic systems. Such assays allow the identification of consistent and simple scales of activity that can guide medicinal chemistry in lead optimization of candidate molecules for therapeutic use.


Comparison of sensitivity of enzyme immunoassays for toxin A and B in different C. difficile PCR ribotypes.
Enzyme immunoassays (EIAs) for toxins A and B are the most common assays for the diagnosis of Clostridium difficile infection due to their rapidity and ease of use. However, the sensitivity of different kits varies greatly. The predominant PCR ribotypes of C. difficile vary according to the region or country studied, and it was recently reported that the sensitivity of EIAs can be affected by the strain type. The aim of this study was to assess the sensitivity of EIAs in different PCR ribotypes of C. difficile during a period of five years in a Korean hospital. A total of 969 toxigenic C. difficile isolates were recovered from patients with diarrhea in a hospital from 2006 to 2009 (inclusive), and 2011. Overall sensitivities of Tox A/B Quik Chek (TechLab, Blacksburg, VA) and VIDAS C. difficile A & B (bioMérieux, Marcy l'Etoile, France) were 36.4% and 46.3%, respectively. The sensitivities of TOX A/B Quick Chek and VIDAS Clostridium difficile A & B for the five most common ribotypes were as follows: 56.6% and 71.7% for ribotype AB17 (ribotype 018); 48.6% and 54.3% for ribotype aB (ribotype 017); 25.3% and 36.3% for ribotype AB2 (ribotype 014); 13.0% and 24.2% for ribotype AB3; 66.7% and 0% for ribotype AB1 (ribotype 001), respectively. The sensitivity for the predominant ribotype, AB17, was significantly different from those for aB, AB2, AB1, and AB3 using VIDAS Clostridium difficile A & B (p<0.05). These data suggest that the sensitivity of EIA may be affected by the distribution of ribotypes.


Liquid-based porous membranes.
Porous membranes have a long history of research and applications, and their operations have been consolidated for a wide range of uses in the fields of chemical separation, water treatment, food production, catalysis, and energy storage and conversion. Regardless of their significance in the above areas, they still suffer from compromise that arise due to achieving a balance between the selectivity and permeability, fouling issues, and lack of adaptability to meet versatile and aggressive environments. Liquid-based porous membranes have come to the fore as a new alternative to avert these challenges with significant advantages in diffusive, dynamic, antifouling, omniphobic, self-healing, and adaptive properties. Although rapidly progressing, there is a still lack of a comprehensive review that specifically addresses these members of the membrane family, and more importantly, the confusions occurring among myriad liquid-based porous membranes that have impeded their applications in potential uses. With this goal, this tutorial review will give a new unifying view on the state-of-the-art progress of liquid-based porous membranes, including the historical timeline, interfacial behavior, materials design, materials chemistry, mass transport mechanism, fluid behavior, and emerging applications. Anatomizing the basic aspects such as chemical compatibility and mutual interplays between the porous matrix and the infused functional liquid, and the varied transport mechanisms, we hope to dissolve the complexities of liquid-based porous membranes for more audience. Emergent applications such as gas separation, extraction, smart gating systems, multiphase separation, and chemical detection are also touched upon, inspiring frontier researches in interfacial chemistry, material chemistry, fluid mechanics, membrane science, chemical engineering, etc.


Dietary factors that promote or retard inflammation.
Inflammation plays a pivotal role in all stages of atherosclerosis. Cardiovascular risk factors and metabolic syndrome are typified by low-grade inflammation. Intervention trials convincingly demonstrate that weight loss reduces biomarkers of inflammation, such as C-reactive protein (CRP) and interleukin (IL)-6. Limited studies have shown that certain dietary factors; oleic acid, alpha-linolenic acid, and antioxidants RRR-alpha-alpha tocopherol, reduce biomarkers of inflammation. Most of the studies with fish oil supplementation have shown null effects, and conflicting results have been reported with saturated and trans fatty acids, cholesterol, and soy intake. Much further research is needed to define the role of individual dietary factors on the biomarkers of inflammation and the mechanism of the anti-inflammatory effects of weight loss.


Recovery of external anal sphincter contractile function after prolonged vaginal distention or sphincter transection in an animal model.
To estimate the effect of prolonged vaginal distention and anal sphincter transection on contractile properties of the external anal sphincter as a function of time. One hundred thirty-nine young female virginal rats were randomly assigned into four treatment groups (sham, vaginal distention, transection of anal sphincter plus repair, or combined distention and transection plus repair). After 3 days, 3 months, or 6 months, the anal sphincter complex was analyzed for peak force of twitch tension, peak tetanic force, fatigue, and maximal responses to electrical field stimulation. Statistical analysis was performed using analysis of variance (Student-Neuman-Keuls). After 3 days, vaginal balloon distention, anal sphincter transection with repair, and combined distention and transection plus repair resulted in compromise of maximal tetanic contraction and electrical field stimulated force generation. Twitch tension, and resistance to fatigue were also significantly decreased in animals with anal sphincter disruption and repair with and without vaginal distention at 3 days. Contractile function of the external anal sphincter, however, was fully recovered by 3 months and was sustained at 6 months in all treatment groups. The time course of repair was slower in animals with sphincter laceration. Anal sphincter transection with or without antecedent prolonged vaginal distention results in severe compromise of external anal sphincter function in the immediate period after injury. In this animal model, complete recovery of external anal sphincter function occurs 3 months after initial insult.


Neighborhood perceptions and active school commuting in low-income cities.
Few children accumulate the recommended ≥60 minutes of physical activity each day. Active travel to and from school (ATS) is a potential source of increased activity for children, accounting for 22% of total trips and time spent traveling by school-aged children. This study identifies the association of parents' perceptions of the neighborhood, geospatial variables, and demographic characteristics with ATS among students in four low-income, densely populated urban communities with predominantly minority populations. Data were collected in 2009-2010 from households with school-attending children in four low-income New Jersey cities. Multivariate logistic regression analyses (n=765) identified predictors of ATS. Analyses were conducted in 2012. In all, 54% of students actively commuted to school. Students whose parents perceived the neighborhood as very unpleasant for activity were less likely (OR=0.39) to actively commute, as were students living farther from school, with a 6% reduction in ATS for every 0.10 mile increase in distance to school. Perceptions of crime, traffic, and sidewalk conditions were not predictors of ATS. Parents' perceptions of the pleasantness of the neighborhood, independent of the effects of distance from school, may outweigh concerns about crime, traffic, or conditions of sidewalks in predicting active commuting to school in the low-income urban communities studied. Efforts such as cleaning up graffiti, taking care of abandoned buildings, and providing shade trees to improve neighborhood environments are likely to increase ATS, as are efforts that encourage locating schools closer to the populations they serve.


Migration of all-polyethylene compared with metal-backed tibial components in cemented total knee arthroplasty.
Background and purpose - With a rapidly increasing population in need of total knee arthroplasty (TKA), there is renewed interest in cost-saving all-polyethylene designs. Differences between metal-backed and all-polyethylene designs in initial component migration assessed by radiostereometric analysis (RSA), a proven predictor for late aseptic loosening, have been scantily reported. The purpose of this study was to compare implant migration and clinical outcomes of all-polyethylene tibial components versus metal-backed trays of similar geometrical shape. Patients and methods - In this randomized controlled trial, 59 patients received a cemented Triathlon condylar-stabilizing implant (Stryker, Mahwah, NJ, USA) with either an all-polyethylene (n = 29) or a metal-backed tibial component (n = 30). RSA measurements and clinical scores (the Knee Society Score, Forgotten Joint Score, and Knee Osteoarthritis and Injury Outcome Score) were evaluated at baseline and postoperatively at 3, 12, and 24 months. A linear mixed-effects model was used to analyze the repeated measurements. Results - A statistically significant difference in mean migration after 2 years was found in favor of the all-polyethylene group, with a mean maximum total point motion of 0.61 mm (95% CI 0.49-0.74) versus 0.81 mm (95% CI 0.68-0.96) for the cemented group (p = 0.03). However, this difference was smaller and not statistically significant after post hoc adjustment for surgeon effect. Both groups showed comparable improvements on all clinical outcome scores over time. Interpretation - The Triathlon all-polyethylene tibial component showed less migration, suggesting a lower risk of late loosening as compared with its metal-backed counterpart. However, the found surgeon effect warrants further investigation.


The effect of menu labeling with calories and exercise equivalents on food selection and consumption.
Better techniques are needed to help consumers make lower calorie food choices. This pilot study examined the effect of menu labeling with caloric information and exercise equivalents (EE) on food selection. Participants, 62 females, ages 18-34, recruited for this study, ordered a fast food meal with menus that contained the names of the food (Lunch 1 (L1), control meal). One week later (Lunch 2 (L2), experiment meal), participants ordered a meal from one of three menus with the same items as the previous week: no calorie information, calorie information only, or calorie information and EE. There were no absolute differences between groups in calories ordered from L1 to L2. However, it is noteworthy that calorie only and calorie plus exercise equivalents ordered about 16% (206 kcal) and 14% (162 kcal) fewer calories from Lunch 1 to Lunch 2, respectively; whereas, the no information group ordered only 2% (25 kcal) fewer. Menu labeling alone may be insufficient to reduce calories; however, further research is needed in finding the most effective ways of presenting the menu labels for general public.


Modeling and optimization of lipase-catalyzed production of succinic acid ester using central composite design analysis.
Esterification of succinic acid with oleyl alcohol catalyzed by immobilized Candida antarctica lipase B (Novozym 435) was investigated in this study. Response surface methodology (RSM) based on a five-level, four-variable central composite design (CCD) was used to model and analyze the reaction. A total of 21 experiments representing different combinations of the four parameters including temperature (35-65°C), time (30-450 min), enzyme amount (20-400 mg), and alcohol:acid molar ratio (1:1-8:1) were generated. A partial cubic equation could accurately model the response surface with a R(2) of 0.9853. The effect and interactions of the variables on the ester synthesis were also studied. Temperature was found to be the most significant parameter that influenced the succinate ester synthesis. At the optimal conditions of 41.1°C, 272.8 min, 20 mg enzyme amount and 7.8:1 alcohol:acid molar ratio, the esterification percentage was 85.0%. The model can present a rapid means for estimating the conversion yield of succinate ester within the selected ranges.


Clinical Characteristics of Stenotrophomonas maltophilia Bacteremia: A Regional Report and a Review of a Japanese Case Series.
Objective Stenotrophomonas maltophilia is an emerging nosocomial pathogen that causes fatal infections in critically ill or immunocompromised patients. S. maltophilia bacteremia (SMB) is a rare condition, and its clinical characteristics in Japanese settings are not well known. Methods The medical charts of patients with SMB were retrospectively reviewed at two medical facilities (Okayama University Hospital and Tsuyama Chuo Hospital) for seven years. The data were analyzed along with those previously reported from other Japanese facilities. Result A total of 181 patients (110 men and 71 women) were evaluated. The major underlying diseases included hematologic malignancy (36.5%), solid organ malignancy (25.4%), and neutropenia (31.5%). The recent use of carbapenem was seen in 56.9% of the cases in total, and more than one-third of the patients in our hospitals were treated with carbapenem at the onset of SMB. Of 28 (63.6%) of 44 cases treated for S. maltophilia, those who did not survive were more likely to have been treated with broad-spectrum antibiotics. A multivariate analysis revealed that a higher updated Charlson Comorbidity Index [odds ratio (95% confidence interval), 1.75 (1.11-2.75); p=0.015] and intubation [odds ratio (95% confidence interval), 12.6 (1.62-97.9); p=0.016] were associated with mortality in our cases. Pathogens were often resistant to ceftazidime but susceptible to minocycline, trimethoprim/sulfamethoxazole, and fluoroquinolones. The overall mortality rates within 30 and 90 days were 37.5% and 62.5%, respectively. Conclusion The clinical characteristics of SMB in Japanese cases were similar to those reported from other countries. Clinicians should be aware that breakthrough infection by S. maltophilia may occur during administration of carbapenem.


An efficient and accurate solution methodology for bilevel multi-objective programming problems using a hybrid evolutionary-local-search algorithm.
Bilevel optimization problems involve two optimization tasks (upper and lower level), in which every feasible upper level solution must correspond to an optimal solution to a lower level optimization problem. These problems commonly appear in many practical problem solving tasks including optimal control, process optimization, game-playing strategy developments, transportation problems, and others. However, they are commonly converted into a single level optimization problem by using an approximate solution procedure to replace the lower level optimization task. Although there exist a number of theoretical, numerical, and evolutionary optimization studies involving single-objective bilevel programming problems, not many studies look at the context of multiple conflicting objectives in each level of a bilevel programming problem. In this paper, we address certain intricate issues related to solving multi-objective bilevel programming problems, present challenging test problems, and propose a viable and hybrid evolutionary-cum-local-search based algorithm as a solution methodology. The hybrid approach performs better than a number of existing methodologies and scales well up to 40-variable difficult test problems used in this study. The population sizing and termination criteria are made self-adaptive, so that no additional parameters need to be supplied by the user. The study indicates a clear niche of evolutionary algorithms in solving such difficult problems of practical importance compared to their usual solution by a computationally expensive nested procedure. The study opens up many issues related to multi-objective bilevel programming and hopefully this study will motivate EMO and other researchers to pay more attention to this important and difficult problem solving activity.


SOD3 Variant, R213G, Altered SOD3 Function, Leading to ROS-Mediated Inflammation and Damage in Multiple Organs of Premature Aging Mice.
Among the isoforms of superoxide dismutase, SOD3 is uniquely associated with the extracellular matrix (ECM) by virtue of its heparin-binding domain (HBD). Substitution of arginine by glycine at amino acid 213 (R213G) of its HBD was first identified in patients with heart failure, followed by many studies that focused on the role of this variant (SOD3(R213G)) in ischemic heart disease and cardiovascular disease. However, the biological significance of this mutation in a physiological context is largely unknown. As a first step, we generated SOD3(R213G) transgenic mice, in which the variant gene was driven by the β-actin promoter allowing expression in all tissues. Unexpectedly, we found that SOD3(R213G) transgenic mice exhibited premature aging, including hair graying, abnormal gait, and a shortened life span. Specifically, the aged mice showed systemic inflammation and organ degeneration. In addition, aged SOD3(R213G) mice are susceptible to neutrophil-mediated inflammation. Among other functions, the neutrophils of SOD3(R213G) mice produce high amounts of reactive oxygen species, which would normally be controlled by SOD3 in ECM. These findings showed for the first time that arginine 213 in the HBD of SOD3 is critical for maintaining proper organ function through moderating the normal innate immune response, which would otherwise lead to chronic inflammation and degenerative diseases in aged mice. Therefore, patients with this variant may be treated with SOD3 as a therapeutic strategy to prevent or cure these diseases.


What makes an effective executive.
An effective executive does not need to be a leader in the typical sense of the word. Peter Drucker, the author of more than two dozen HBR articles, says some of the best business and nonprofit CEOs he has worked with over his 65-year consulting career were not stereotypical leaders. They ranged from extroverted to nearly reclusive, from easygoing to controlling, from generous to parsimonious. What made them all effective is that they followed the same eight practices: They asked, "What needs to be done?" They also asked, "What is right for the enterprise?" They developed action plans. They took responsibility for decisions. They took responsibility for communicating. They were focused on opportunities rather than problems. They ran productive meetings. And they thought and said "we" rather than "I." The first two practices provided them with the knowledge they needed. The next four helped them convert this knowledge into effective action, for knowledge is useless to executives until it has been translated into deeds. The last two ensured that the whole organization felt responsible and accountable. Effective executives know that they have authority only because they have the trust of the organization. This means they must think of the needs and opportunities of the organization before they think of their own needs and opportunities. The author also suggests a ninth practice that's so important, he elevates it to the level of a rule: Listen first, speak last. The demand for effective executives is much too great to be satisfied by those few people who are simply born to lead. Effectiveness is a discipline. And, like every discipline, it can be learned and must be earned.


Endoscopic treatment of pancreatic calculi.
Chronic pancreatitis is a progressive inflammatory disease that destroys pancreatic parenchyma and alters ductal stricture, leading to ductal destruction and abdominal pain. Pancreatic duct stones (PDSs) are a common complication of chronic pancreatitis that requires treatment to relieve abdominal pain and improve pancreas function. Endoscopic therapy, extracorporeal shock wave lithotripsy (ESWL), and surgery are treatment modalities of PDSs, although lingering controversies have hindered a consensus recommendation. Many comparative studies have reported that surgery is the superior treatment because of reduced duration and frequency of hospitalization, cost, pain relief, and reintervention, while endoscopic therapy is effective and less invasive but cannot be used in all patients. Surgery is the treatment of choice when endoscopic therapy has failed, malignancy is suspected, or duodenal stricture is present. However, in patients with the appropriate indications or at high-risk for surgery, endoscopic therapy in combination with ESWL can be considered a first-line treatment. We expect that the development of advanced endoscopic techniques and equipment will expand the role of endoscopic treatment in PDS removal.


Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice.
Human infection with Mycobacterium tuberculosis can progress to active disease, be contained as latent infection, or be eradicated by the host response. Tuberculosis diagnostics classify a patient into one of these categories. These are not fixed distinct states, but rather are continua along which patients can move, and are affected by HIV infection, immunosuppressive therapies, antituberculosis treatments, and other poorly understood factors. Tuberculosis biomarkers-host or pathogen-specific-provide prognostic information, either for individual patients or study cohorts, about these outcomes. Tuberculosis case detection remains difficult, partly because of inaccurate diagnostic methods. Investments have yielded some progress in development of new diagnostics, although the existing pipeline is limited for tests for sputum-smear-negative cases, childhood tuberculosis, and accurate prediction of reactivation of latent tuberculosis. Despite new, sensitive, automated molecular platforms for detection of tuberculosis and drug resistance, a simple, inexpensive point-of-care test is still not available. The effect of any new tests will depend on the method and extent of their introduction, the strength of the laboratories, and the degree to which access to appropriate therapy follows access to diagnosis. Translation of scientific progress in biomarkers and diagnostics into clinical and public health programmes is possible-with political commitment, increased funding, and engagement of all stakeholders.


Alcohol-related brain damage in humans.
Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.


Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.
Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).


The effect of Am-80, a synthetic retinoid, on spinal cord injury-induced motor dysfunction in rats.
The present study investigated the effect of 4[(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-naphthalenyl)carbamoyl] benzoic acid (Am-80), a synthetic retinoid, on spinal cord injury (SCI) in rats. Treatment with Am-80 (orally and subcutaneously) significantly promoted recovery from SCI-induced motor dysfunction. On day 28 after injury, the lesion cavity was markedly reduced, while the expression of myelin basic protein (MBP; myelin), betaIIItubulin (neuron), and glial fibrillary acidic protein (GFAP; astrocyte) was increased, in comparison with SCI controls. Interestingly, expression of neurotrophin receptor, tyrosine kinase B (TrkB) was over 3-fold higher after Am-80 treatment than in SCI controls. A lot of TrkB-positive cells as well as brain-derived neurotrophic factor (BDNF)-positive ones were observed around the injured site. Am-80 (10 microM) combined with BDNF (100 ng/ml) promoted extensive neurite outgrowth and TrkB gene expression by cultured SH-SY5Y cells, as did all-trans retinoic acid (ATRA). Thymidine incorporation was dramatically suppressed, but there was little effect on cell viability. These findings suggest that Am-80 has the potential to be used for treating neurodegenerative disorders, including SCI. Its efficacy may be partly ascribed to promotion of cell viability and differentiation of neural stem cells through increased TrkB expression.