Illegal trade in wild cats and its link to Chinese-led development in Central and South America.
Seizures of hundreds of jaguar heads and canines in Central and South America from 2014 to 2018 resulted in worldwide media coverage suggesting that wildlife traffickers are trading jaguar body parts as substitutes for tiger parts to satisfy the demand for traditional Asian medicine. We compiled a data set of >1000 seized wild cats (jaguar [Panthera onca], puma [Puma concolor], and ocelot [Leopardus pardalis]) from 19 Central and South American countries and China. We ran generalized additive mixed models to detect trends in wild-cat seizures from 2012 to 2018 and assess the effects of socioeconomic factors of source countries and between those countries and China on the number of wild cats seized. Jaguar seizures increased over time, and most of the seized jaguar pieces were canines (1991 of 2117). Around 34% (32 of 93) of the jaguar-part seizure reports were linked with China, and these seizures contained 14-fold more individuals than those intended for domestic markets. Source countries with relatively high levels of corruption and Chinese private investment and low income per capita had 10-50 times more jaguar seizures than the remaining sampled countries. The number of Chinese residents in Central and South America was not significantly related to the number of jaguars seized. No socioeconomic factors influenced the seizures of puma and ocelots. Legal market chains may provide structure for the illegal chain; thus, the influx of illegal jaguar products is potentially a side effect of the economic partnership between Central and South American countries and China. Poverty and high levels of corruption in the source countries may motivate local people to engage in illegal activities and contribute to the growth of this trade. Supply-side interventions to curb this threat to Neotropical wild cats may include improved training for officials and promotion of governance and the value of protecting these animals to local people.


The effect of breed-specific dog legislation on hospital treated dog bites in Odense, Denmark-A time series intervention study.
As dog bite injuries are a considerable problem in modern society, in order to reduce such injuries, breed-specific legislation has been introduced in a number of countries. Whilst many studies have shown a lack of effect with such legislation, the commonly used methodology is known to be flawed. Therefore, the aim of this study is to investigate the effect of the Danish breed-specific legislation on the number of dog bite injuries using more credible methods. A time series intervention method was used on a detailed dataset from Odense University Hospital, Denmark, regarding dog bite injuries presented to the emergency department. The results indicate that banning certain breeds has a highly limited effect on the overall levels of dog bite injuries, and that an enforcement of the usage of muzzle and leash in public places for these breeds also has a limited effect. Despite using more credible and sound methods, this study supports previous studies showing that breed-specific legislation seems to have no effect on dog bite injuries. In order to minimise dog bite injuries in the future, it would seem that other interventions or non-breed-specific legislation should be considered as the primary option.


Control of thumb force using surface functional electrical stimulation and muscle load sharing.
Stroke survivors often have difficulties in manipulating objects with their affected hand. Thumb control plays an important role in object manipulation. Surface functional electrical stimulation (FES) can assist movement. We aim to control the 2D thumb force by predicting the sum of individual muscle forces, described by a sigmoidal muscle recruitment curve and a single force direction. Five able bodied subjects and five stroke subjects were strapped in a custom built setup. The forces perpendicular to the thumb in response to FES applied to three thumb muscles were measured. We evaluated the feasibility of using recruitment curve based force vector maps in predicting output forces. In addition, we developed a closed loop force controller. Load sharing between the three muscles was used to solve the redundancy problem having three actuators to control forces in two dimensions. The thumb force was controlled towards target forces of 0.5 N and 1.0 N in multiple directions within the individual's thumb work space. Hereby, the possibilities to use these force vector maps and the load sharing approach in feed forward and feedback force control were explored. The force vector prediction of the obtained model had small RMS errors with respect to the actual measured force vectors (0.22 ± 0.17 N for the healthy subjects; 0.17 ± 0.13 N for the stroke subjects). The stroke subjects showed a limited work range due to limited force production of the individual muscles. Performance of feed forward control without feedback, was better in healthy subjects than in stroke subjects. However, when feedback control was added performances were similar between the two groups. Feedback force control lead, especially for the stroke subjects, to a reduction in stationary errors, which improved performance. Thumb muscle responses to FES can be described by a single force direction and a sigmoidal recruitment curve. Force in desired direction can be generated through load sharing among redundant muscles. The force vector maps are subject specific and also suitable in feedforward and feedback control taking the individual's available workspace into account. With feedback, more accurate control of muscle force can be achieved.


Planning performance in schizophrenia patients: a meta-analysis of the influence of task difficulty and clinical and sociodemographic variables.
Despite a large body of research on planning performance in adult schizophrenia patients, results of individual studies are equivocal, suggesting either no, moderate or severe planning deficits. This meta-analysis therefore aimed to quantify planning deficits in schizophrenia and to examine potential sources of the heterogeneity seen in the literature. The meta-analysis comprised outcomes of planning accuracy of 1377 schizophrenia patients and 1477 healthy controls from 31 different studies which assessed planning performance using tower tasks such as the Tower of London, the Tower of Hanoi and the Stockings of Cambridge. A meta-regression analysis was applied to assess the influence of potential moderator variables (i.e. sociodemographic and clinical variables as well as task difficulty). The findings indeed demonstrated a planning deficit in schizophrenia patients (mean effect size: ; 95% confidence interval 0.56-0.78) that was moderated by task difficulty in terms of the minimum number of moves required for a solution. The results did not reveal any significant relationship between the extent of planning deficits and sociodemographic or clinical variables. The current results provide first meta-analytic evidence for the commonly assumed impairments of planning performance in schizophrenia. Deficits are more likely to become manifest in problem items with higher demands on planning ahead, which may at least partly explain the heterogeneity of previous findings. As only a small fraction of studies reported coherent information on sample characteristics, future meta-analyses would benefit from more systematic reports on those variables.


Observational study of clinical characteristics of dome-shaped macula in Chinese Han with high myopia at Zhongshan Ophthalmic Centre.
To evaluate the prevalence of dome-shaped macula (DSM) in highly myopic eyes among Chinese Han and to detect the correlation with myopic maculopathy and macular complications. A total of 736 Chinese Han patients (1384 eyes) with high myopia (refractive error≤6.0 diopters or axial length ≥26.5 mm) are reviewed based on information entered into a high-myopia database at Zhongshan Ophthalmic Centre. Subfoveal choroidal thickness (SFCT) and parafoveal choroidal thickness (PFCT) are measured. The prevalence of DSM in patients with myopic maculopathy is categorised from C0 to C4. Clinical features, including macular complications, SFCT and PFCT, are compared between myopic eyes with and without DSM. Among the 1384 eyes, 149 (10.77%) show DSM. In highly myopic eyes without macular complications, the best corrected visual acuity is significantly worse in patients with DSM (p=0.002), and the ratio between subfoveal and parafoveal choroidal thickness (S/PCT) is significantly elevated in patients with DSM (p=0.021). The proportion of foveal schisis (17.24% vs 62.86%) is much lower in eyes with DSM compared with those without DSM. However, the proportions of extrafoveal schisis (39.66% vs 5.37%), foveal serous retinal detachment (SRD) (5.17% vs 0) and epiretinal membrane (ERM) (24.14% vs 10.74%) are much higher in eyes with DSM. The proportion of DSM was lower in C0 and C1, but higher proportion of DSM was found in C3 and C4. DSM is found in 10.77% of highly myopic eyes among Chinese Han. DSM might be a protective mechanism for foveal schisis and a risk factor for extrafoveal schisis, SRD and ERM.


Echigo-1: a panencephalopathic strain of Creutzfeldt-Jakob disease. II. Ultrastructural studies in hamsters.
In this and a companion paper we present immunohistochemical and ultrastructural data on hamsters infected with the Echigo-1 strain of Creutzfeldt-Jakob disease. Ultrastructurally, two types of vacuoles were readily discriminated in the brain: the grey matter vacuoles of spongiform change and intramyelin vacuoles. The vacuoles were always membrane-bound; the membranes were single or double. The axons were entirely missing from the plane of the sections or, if visible, were shrunken and attached to the innermost layer of the myelin. It was noteworthy that some vacuoles indented cell bodies or processes and thus were reminiscent of the intraneuronal vacuoles typical for natural scrapie, BSE and CWD in ungulates and cervids but not of the vacuoles encountered in rodent models of scrapie and CJD. We also noticed vacuoles distending myelinated fibres in which the axons had become dystrophic. Some axons underwent Wallerian degeneration while others met the criteria for dystrophic neuritis. Both alterations existed in the same areas. Typical dystrophic neurites contained abnormal subcellular organelles, mainly electron-dense lysosomal inclusions. Other neurites contained numerous multi-vesicular bodies and autophagic vacuoles. Nuclear paracrystalline rod-like inclusions were occasionally visible in neurons while other inclusions comprised spiroplasma-like inclusions in synaptic boutons. The robust cellular reactions consisted of reactive astrocytes and macrophages filled with cellular debris. It is of note that complex autophagic vacuoles were observed in the cytoplasm of neurons.


Effect of milk thistle on the pharmacokinetics of darunavir-ritonavir in HIV-infected patients.
The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.


Endogenous NO levels regulate nodule functioning: potential role of cGMP in nodule functioning?
Nitric oxide is a small gaseous signaling molecule which functions in the regulation of plant development and responses to biotic and abiotic stresses. Recently, we have shown that nitric oxide is required for development of functional nodules. Here, we show that inhibition of nitric oxide synthase enzymatic activity (using N(ω)-nitro-L-arginine) reduces nitric oxide content in soybean root nodules and this is coupled by reduction of endogenous cyclic guanosine monophosphate content in the nodules. We postulate that the regulation of soybean nodule development by nitric oxide is transduced via cyclic guanosine monophosphate through activation of nitric oxide-responsive soluble guanylate cyclase. Furthermore, we hypothesize that this signaling cascade is mediated via modulation of the activities of antioxidant metabolic pathways.


Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine.
For several decades, serum levels of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury, including a wide range of etiologies from viral hepatitis to fatty liver. The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes, coronary heart disease, atherothrombotic risk profile, and overall risk of metabolic disease. Therefore, it is plausible to suggest that aminotransferases are surrogate biomarkers of "liver metabolic functioning" beyond the classical concept of liver cellular damage, as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function. In this study, we summarize the background information and recent findings on the biological role of ALT and AST, and review the knowledge gained from the application of genome-wide approaches and "omics" technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions. Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes, which suggest that regulation of aminotransferase activity is a complex and highly regulated trait. Finally, links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.


The Role of Simultaneous Integrated Boost in Locally Advanced Rectal Cancer Patients with Positive Lateral Pelvic Lymph Nodes.
Aims: Between 11 to 14% of patients with locally advanced rectal cancer (LARC) have positive lateral pelvic lymph nodes (LPLN) at diagnosis, related to a worse prognosis with a 5-year survival rate between 30 to 40%. The best treatment choice for this group of patients is still a challenge. The optimal radiotherapy (RT) dose for LPLN patients has been investigated. Methods: We retrospectively collected data from LARC patients with LPLN at the primary staging MRI, treated in our center from March 2003 to December 2020. Patients underwent a neoadjuvant concomitant chemo-radiotherapy (CRT) treatment on the primary tumor (T), mesorectum, and pelvic nodes, associated with a fluoride-based chemotherapy. The total reached dose was 45 Gy at 1.8 Gy/fr on the elective sites and 55 Gy at 2.2 Gy/fr on the disease and mesorectum. Patients were divided in two groups based on whether they received a simultaneous integrated RT boost on the LPLN or not. Overall Survival (OS), Disease Free Survival (DFS), Metastasis Free Survival (MFS), and Local Control (LC) were evaluated in the whole group and then compared between the two groups. Results: A total of 176 patients were evaluated: 82 were included in the RT boost group and 94 in the non-RT boost group. The median follow-up period was 57.8 months. All the clinical endpoint (OS, DFS, MFS, LC), resulted were affected by the simultaneous integrated boost on LPLN with a survival rate of 84.7%, 79.5%, 84.1%, and 92%, respectively, in the entire population. From the comparison of the two groups, there was a statistical significance towards the RT boost group with a p < 0.006, 0.030, 0.042, 0.026, respectively. Conclusions: Concomitant radiotherapy boost on positive LPLN has shown to be beneficial on the survival outcomes (OS, DFS, MFR, and LC) in patients with LARC and LPLN. This analysis demonstrates that a higher dose of radiotherapy on positive pelvic lymph nodes led not only to a higher local control but also to a better survival rate. These results, if validated by future prospective studies, can bring a valid alternative to the surgery dissection without the important side effects and permanent disabilities observed during the years.


Geographic variation in maternal investment: acidity affects egg size and fecundity in Rana arvalis.
Environmental-stress-mediated geographic variation in reproductive parameters has been little studied in natural vertebrate populations outside the context of climatic variation. Based on life-history theory, an increase in the degree of environmental stress experienced by a population should lead to (1) a shift in reproductive allocation from fecundity to offspring quality, (2) stronger trade-offs between reproductive parameters, and (3) changes in the relationship between female phenotype and maternal investment. To test these predictions, we investigated geographic variation in maternal investment of moor frogs (Rana arvalis) in relation to breeding site acidity (pH 4-8). We found that mean egg size increased and clutch size and total reproductive output (TRO) decreased with increasing acidity among 19 Swedish moor frog populations. Tests for variation and co-variation in maternal investment and female size and age in 233 females from a subset of four acid origin (AO) and four neutral origin (NO) populations revealed that clutch size and TRO increased with female size in both acid and neutral environments. However, in AO populations, egg size also increased with female size, and clutch size and TRO with female age, whereas in NO populations, egg size increased with female age. The strength of the egg-size-clutch-size tradeoff tended to be stronger in AO than in NO females as expected if the former experience stronger environmental constraints. All in all, these results suggest that environmental acidification selects for investment in larger eggs at a cost to fecundity, imposes negative effects on reproductive output, and alters the relationship between female phenotype and maternal investment.


Efficacy of switching to entecavir monotherapy in Japanese lamivudine-pretreated patients.
To assess the efficacy of switching Japanese chronic hepatitis B patients from lamivudine monotherapy to entecavir 0.5 mg/day. A retrospective analysis was conducted on 134 patients switched to entecavir between September 2006 and February 2008 for 6 months or more. Patients were divided into three groups based on viral load at entecavir switching point (baseline < 2.6, 2.6-5.0 and > 5.0 log(10) copies/mL). At baseline, detection of lamivudine-resistant virus was highest in patients with higher hepatitis B virus (HBV) DNA (76% vs 23% in > or = 2.6 and < 2.6 log(10) copies/mL, respectively), and in patients with longest previous exposure to lamivudine (52%, 28% and 24% for > 3 years, 1-3 years and < 1 year, respectively). Two years after entecavir switching, HBV DNA suppression to less than 2.6 log(10) copies/mL was achieved in 100% (32/32), 92% (12/13) and 44% (4/9) of patients in the less than 2.6, 2.6-5.0 and more than 5.0 log(10) copies/mL baseline groups, respectively. Alanine aminotransferase (ALT) normalization occurred in 76-96% and 90-100% of patients following 1 and 2 years of entecavir treatment, respectively. One patient (2.6-5.0 log(10) copies/mL) with lamivudine-resistant mutants at baseline developed entecavir resistance at week 48 during follow up. Switching to entecavir 0.5 mg/day achieves or maintains undetectable HBV DNA levels and ALT normalization over 2 years, especially in patients with viral load less than 5.0 log(10) copies/mL.


Evolutionary Study of Protein Short Tandem Repeats in Protein Families.
Tandem repeats in proteins are patterns of residues repeated directly adjacent to each other. The evolution of these repeats can be assessed by using groups of homologous sequences, which can help pointing to events of unit duplication or deletion. High pressure in a protein family for variation of a given type of repeat might point to their function. Here, we propose the analysis of protein families to calculate protein short tandem repeats (pSTRs) in each protein sequence and assess their variability within the family in terms of number of units. To facilitate this analysis, we developed the pSTR tool, a method to analyze the evolution of protein short tandem repeats in a given protein family by pairwise comparisons between evolutionarily related protein sequences. We evaluated pSTR unit number variation in protein families of 12 complete metazoan proteomes. We hypothesize that families with more dynamic ensembles of repeats could reflect particular roles of these repeats in processes that require more adaptability.


Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity.
Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.


Exophytic Adiposis Dolorosa (Dercum's Disease) of the Thigh: A Case Report.
Adiposis dolorosa or Dercum's disease is a rare lipomatous disorder characterized by painful lipomas. In this article, we report a case of rather large exophytic adiposis dolorosa causing difficulties with ambulation, and our surgical management of the disorder. To our knowledge, this is the first reported case of a large exophytic adiposis dolorosa of the upper medial thigh causing problems with mobility. This is also the first reported case of the use of a delayed split-thickness skin graft (STSG) after interval use of wound vacuum-assisted closure (VAC) following dermolipectomy. A 77-year-old female presented with a chronic mass on the medial aspect of her right thigh for over 40-50 years. She had noticed a recent rapid increase in size, causing some discomfort and interference with mobility and activities of daily living. The patient underwent an MRI with finding consistent with adiposis dolorosa. She underwent dermolipectomy and reconstruction of the resulting defect with a combination of partial primary closure, wound VAC, and delayed closure using STSG. Dermolipectomy with interval application of a wound VAC combined with delayed reconstruction with STSG is a feasible option for patients with large lesions of the extremity that causes difficulty with mobility and activities of daily living.


Which kindergarten children are at greatest risk for attention-deficit/hyperactivity and conduct disorder symptomatology as adolescents?
We sought to identify which kindergarten children are simultaneously at risk of moderate or severe symptomatology in both attention-deficit/hyperactivity disorder (ADHD) and conduct disorder (CD) as adolescents. These risk factor estimates have not been previously available. We conducted multinomial logistic regression analyses of multiinformant ratings by the end of middle school of a population-based, longitudinal sample of children followed from kindergarten to eighth grade (N = 7,456). Kindergarten children from low SES households, those raised by mothers with depressive symptoms or experiencing emotional problems or substance abuse, or those who were punished by spanking were significantly more likely to later display severe levels of ADHD-CD symptomatology in eighth grade. Kindergarten children frequently engaging in ADHD-CD-type behaviors were more likely to later experience both moderate (covariate adjusted OR = 2.37) and severe (covariate adjusted OR = 3.63) ADHD-CD symptomatology. Low academic achievement uniquely increased the risk of both moderate and severe symptomatology (adjusted OR range = 1.7 to 2.24). The results should guide early screening and school-based intervention efforts for ADHD-CD. Reducing children's risk for adolescent ADHD-CD symptomatology may require remediating low behavioral and academic functioning by the end of kindergarten. When these 2 modifiable factors occur together they increase kindergarten children's odds of experiencing severe ADHD-CD symptomatology in eighth grade by a multiplicative factor of 8.1.


Hypoxia-induced PIM kinase and laminin-activated integrin α6 mediate resistance to PI3K inhibitors in bone-metastatic CRPC.
Bone-metastatic castration-resistant prostate cancer (CRPC) is lethal due to inherent resistance to androgen deprivation therapy, chemotherapy, and targeted therapies. Despite the fact that a majority of CRPC patients (approximately 70%) harbor a constitutively active PI3K survival pathway, targeting the PI3K/mTOR pathway has failed to increase overall survival in clinical trials. Here, we identified two separate and independent survival pathways induced by the bone tumor microenvironment that are hyperactivated in CRPC and confer resistance to PI3K inhibitors. The first pathway involves integrin α6β1-mediated adhesion to laminin and the second involves hypoxia-induced expression of PIM kinases. In vitro and in vivo models demonstrate that these pathways transduce parallel but independent signals that promote survival by reducing oxidative stress and preventing cell death. We further demonstrate that both pathways drive resistance to PI3K inhibitors in PTEN-negative tumors. These results provide preclinical evidence that combined inhibition of integrin α6β1 and PIM kinase in CRPC is required to overcome tumor microenvironment-mediated resistance to PI3K inhibitors in PTEN-negative tumors within the hypoxic and laminin-rich bone microenvironment.


Late promoter selection in the baculovirus gp64 envelope fusion protein gene.
The upstream promoter region of the Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV) gp64 gene contains five copies of TAAG, the conserved sequence found at the transcriptional initiation sites of almost all baculovirus late genes. In AcMNPV-infected Sf9 cells, late transcription initiation is detected from only two upstream TAAG sites and not from three downstream TAAG sites. To examine several models for preferential TAAG site utilization, we constructed a series of recombinant AcMNPV baculoviruses that contain promoter region sequences from the gp64 gene fused to a chloramphenicol acetyl transferase reporter gene. Promoter-reporter constructs were inserted in the polyhedrin locus. To test a scanning model in which TAAG sites are sequentially selected according to their location in the region, we generated recombinant viruses in which the highly transcribed sites were inactivated by point mutations. Transcription from the mutant promoter constructs was compared qualitatively and quantitatively to transcription from the wild-type gp64 promoter. Inactivation of the upstream TAAG sites did not result in increased transcription from the downstream TAAG sites, suggesting that immediate context, rather than position, determines promoter utilization. To test this hypothesis, we made a series of minimal promoter constructs containing decreasing quantities of the sequences immediately flanking one of the active gp64 TAAG sites. Reporter constructs containing a gp64 TAAG site and > or = 12 bp of flanking sequence on both sides were transcribed at near wild-type levels. Constructs with less flanking sequence (9 or 6 bp of flanking sequence) were accurately transcribed, but at substantially lower levels, and transcription was not detected from constructs containing only 3 bp of flanking sequence. These results suggest that nucleotides immediately flanking the TAAG site (4-6 bp) are necessary for basal promoter activity while additional flanking sequences (> or = 12 bp) are required for late promoter activation and regulation. To further examine late promoter selection, we constructed recombinant AcMNPV baculoviruses that contain heterologous late promoters from the gp64 gene of the related virus Orgyia pseudotsugata MNPV (OpMNPV). TAAG sites that serve as functional late promoters in OpMNPV were found to mediate transcription initiation at only basal levels in the context of the AcMNPV genome, suggesting that late promoter activation may be virus specific within the family Baculoviridae.


Developmental Trajectories and Reference Percentiles for the 6-Minute Walk Test for Children With Cerebral Palsy.
The purposes of this study were to document longitudinal developmental trajectories in 6-minute walk test (6MWT) distances and to develop age-specific reference percentiles for children across different Gross Motor Function Classification System (GMFCS) levels. A TOTAL OF: 456 children with cerebral palsy ages 3 to 12 years of, GMFCS levels I to III participated. Children's motor function was classified on the GMFCS, and children completed the 6MWT 2 to 5 times in 2 years. Longitudinal developmental trajectories support that 6MWT distances increase with age followed by a tapering, as children approach their functional limit relative to their GMFCS level. Reference percentile graphs were created to monitor change over time. The 6MWT longitudinal developmental trajectories, reference percentiles, and interpretation of percentile change should assist collaborative and proactive intervention planning relative to functional walking capacity for children with cerebral palsy.


What to say to persons with HIV disease.
I believe that the circumstances in which one learns of being infected with human immunodeficiency virus (HIV) can form a pattern that may either hasten or postpone the physical and psychologic progress of HIV to full-blown AIDS. The experience of learning about one's seropositivity from one's physician sets the stage for the patient to determine who else needs to be told. This paper discusses the steps in communicating the diagnosis of seropositivity.


Biochemical correlates of morphine withdrawal. 1. Characterization in the adrenal medulla and locus ceruleus.
Adrenal catecholamines and their synthesizing enzymes were monitored during morphine treatment and after naloxone-precipitated morphine withdrawal in the rat. At 2 and 6 hr of withdrawal epinephrine content was reduced to approximately 50 and 45% of control. Five days after withdrawal a significant overshoot in adrenal epinephrine concentration was observed. Morphine treatment increased adrenal tyrosine hydroxylase activity to 160% of control. Precipitation of withdrawal with naloxone further increased adrenal tyrosine hydroxylase activity to 240% of control after 1 day; the enzyme activity returned to control values at day 7. Similar effects, but of lesser magnitude, were observed with locus ceruleus tyrosine hydroxylase activity. No increase in adrenal dopamine-beta-hydroxylase activity was seen until day 3 of withdrawal and this activity peaked at 5 days to 160% of control values. Adrenal phenylethanolamine-N-methyltransferase activity was unchanged during the time course studied. Splanchnicotomy caused depletion of adrenal epinephrine to 60% of control. Morphine withdrawal in these animals caused a further (23%) decrease in epinephrine content. These data show that epinephrine is selectively released from the adrenal medulla during naloxone-precipitated morphine withdrawal in the rat and that this release has both a direct and a centrally mediated component. The possible mechanisms underlying these biochemical changes are discussed.


Design of multi-functional 2D open-shell organic networks with mechanically controllable properties.
Triarylmethyls (TAMs) are prominent highly attractive open shell organic molecular building blocks for materials science, having been used in breakthrough syntheses of organic magnetic polymers and metal organic frameworks. With their radical π-conjugated nature and a proven capacity to possess high stability via suitable chemical design, TAMs display a variety of desirable characteristics which can be exploited for a wide range of applications. Due to their particular molecular and electronic structure, the spin localization in TAMs almost entirely depends on the dihedral angles of their three aryl rings with respect to the central methyl carbon atom plane, which opens up the possibility of controlling their fundamental properties by twisting the three aryl rings. Aryl ring twist angles can be tuned to a single value by specific chemical functionalisation but controlling them by external means in organic materials or devices represents a challenging task which has not yet been experimentally achieved. Herein, through rational chemical design we propose two 2D covalent organic frameworks (2D-COFs) based on specific TAM building blocks. By employing ab initio computational modeling we demonstrate that it is possible to externally manipulate the aryl ring twist angles in these 2D-linked TAM frameworks by external mechanical means. Furthermore, we show this structural manipulation allows for finely tuning the most important characteristics of these materials such as spin localization, optical electronic transitions and magnetic interactions. Due to the enormous technological potential offered by this new class of material and the fact that our work is guided by real advances in organic materials synthesis, we believe that our predictions will inspire the experimental realization of radical-2D-COFs with externally controllable characteristics.


Comparative Evaluation of Marginal Adaptation and Fracture Strength of Different Ceramic Inlays Produced by CEREC Omnicam and Heat-Pressed Technique.
The aim of this in vitro study was to evaluate marginal adaptation and fracture strength of inlays produced by CEREC Omnicam using different types of blocs and heat-pressed technique. Methods: Seventy-five extracted human mandibular molars were divided randomly into 5 groups (n=15). 60 molars in four groups received MOD inlay preparations. Experimental groups were CO: Intact teeth, EC: IPS e.max CAD and CEREC, LU: Lava Ultimate and CEREC, EL: IPS Empress CAD and CEREC, EP: IPS Empress Esthetic ingots and heat-pressed technique. Marginal gap measurements were taken with a stereomicroscope. Restorations were cemented with Variolink N and stored in distilled water at 37°C for 24 hours. All samples were subjected to thermocycling. The fracture strength of specimens was determined at a 0.5 mm/min crosshead speed until fracture. Fracture modes were determined. Statistical analyses were performed using one-way analysis of variance for fracture strength data and Kruskal-Wallis for marginal gap data (p=0.05). The mean marginal gap size of EC, LU, EL, and EP were 33.54 µm, 33.77 µm, 34.23 µm, and 85.34 µm, respectively. EP had statistically higher values than other groups. The fracture strength values were significantly higher in the intact teeth group (3959,00 ± 1279,79 N) than those of restored groups EC (2408,00 ± 607,97 N), LU (2206,73 ± 675,16), EL (2573.27 ± 644,73) ve EP (2879,53 ± 897,30). Inlays fabricated using CEREC Omnicam demonstrated better marginal adaptation than inlays produced with heat-pressed technique, whereas fracture strength values of inlays fabricated with different type of blocks using CEREC Omnicam exhibited similarity to those fabricated with heat-pressed technique.


Dietary phytochemical index and the risk of breast cancer: a case control study in a population of Iranian women.
In this study we assessed the dietary phytochemical index in relation to the risk of breast cancer in women. This case-control study was conducted on 100 incident breast cancer cases and 175 healthy controls. Data regarding socio-demographic factors, medical history, medications, and anthropometric measurements were collected. Dietary data were obtained using a validated food frequency questionnaire and a energy-adjusted dietary phytochemical index (PI) was calculated. The odds ratios of breast cancer were assessed across energy- adjusted PI quartile categories. The mean age of participants was 46.2±8.9 and 45.9±9.4 years in cases and controls, respectively. The mean PI across quartile categories was 13.9±2.6, 21.1±1.8, 26.7±2.1, 41.6±10.2 in the first, second, third and fourth quartiles, respectively. After adjustment for all potential confounders, the risk of breast cancer in the forth quartile of dietary PI was significantly decreased (OR=0.08, 95%CI=0.01-0.84). Higher intake of phytochemical-rich foods is associated with lower risk of breast cancer.


Medical procedures in children using a conceptual framework that keeps a focus on human dimensions of care - a discussion paper.
Purpose: Children's perspectives in the context of health service delivery have historically been seen as unimportant. They have been viewed as unintelligent, unable to effectively share or tell of their experiences or fully participate in their care, potentially resulting in a sense of dehumanisation. Method: The present paper illustrates children's experiences when undergoing medical procedures, using application of the eight dimensions of humanised care theoretical framework. Results: Findings from six published papers were reflectively interrogated to identify implicit findings related to the dimensions of humanised care. These implicit findings show ways of caring for childrenwhichcan lead to enhanced human sensitivity in care or conversely where the dimensions of being human are obscured to greater or lesser degrees and can result in forms of dehumanisation. Conclusions: Inadvertent dehumanising features of practice can be mediated by encouraging the inclusion of children's own lifeworld perspective and make room for their voices in both care and research. In this way the present well documented power imbalance could be addressed. Adding the value of the theoretical framework highlights areas of need for young children to be cared for as human beings.


[Clinical case of the month. Disseminated fusariosis in a immunocompromised patient].
Fusarium spp are ubiquitous soil saprophytes and occasional plant pathogens. Fusariosis in humans is usually limited to superficial mycoses. We report the case of a disseminated fungal infection due to Fusarium spp in an immunosuppressed patient suffering from acute lymphoblastic leukemia. This report and review of the recent literature suggest that Fusarium spp are emerging fungal pathogens in immunosuppressed patients.


Confidence in Ability to Communicate With Sexual Partners About PrEP Among Black Cisgender Women.
This study explored the factors associated with Black women's confidence in their ability to engage male sexual partners in discussions about PrEP. Communication about PrEP with male partners is an important, yet minimally explored, outcome in PrEP research among Black women in heterosexual partnerships. Among 315 respondents, results show significant differences in anticipated stigma and interest in PrEP between a binary outcome variable being confident and not-confident discussing PrEP with sexual partners. Further, factors such as employment, worrying about HIV infection, interest in taking oral PrEP, subjective norms, injunctive norms, and descriptive norms were associated with Black women's higher odds of confidence in their ability to engage sexual partners about PrEP. Conversely, PrEP disapproval and stigma resulted in lower odds of Black women's confidence in their ability to engage sexual partners about PrEP. Results indicate the need for continued investigation of confidence and, relatedly, communication about PrEP among heterosexual couples and communitylevel interventions normalizing PrEP discussions and uptake.


Continuous visual information may be important after all: a failure to replicate Thomson (1983).
The purpose of the two experiments reported here was to replicate previous research (Thomson, 1983) which suggests that visual information useful in the control of movement persists for up to 8 s after visual occlusion. Contrary to other findings (Thomson, 1980, 1983), little evidence was found for an 8-s visual representation of the environmental layout, indicating there is no substitute for continuous visual information in the control of movement. Methodological and statistical problems with Thomson's work are discussed.


Harmonic holography: a new holographic principle.
The process of second harmonic generation (SHG) has a unique property of forming a sharp optical contrast between noncentrosymmetric crystalline materials and other types of material, which is a highly valuable asset for contrast microscopy. The coherent signal obtained through SHG also allows for the recording of holograms at high spatial and temporal resolution, enabling whole-field four-dimensional microscopy for highly dynamic microsystems and nanosystems. Here we describe a new holographic principle, harmonic holography (H(2)), which records holograms between independently generated second harmonic signals and reference. We experimentally demonstrate this technique with digital holographic recording of second harmonic signals upconverted from an ensemble of second harmonic generating nanocrystal clusters under femtosecond laser excitation. Our results show that harmonic holography is uniquely suited for ultrafast four-dimensional contrast microscopy.


The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids.
Our research goal is to better understand the mechanisms controlling the initiation and progression of thyroid diseases. One such disease, papillary thyroid carcinoma (PTC), is the leading endocrine malignancy in the United States. Recently, a family of related fusion proteins, RET/PTC1-5, has been implicated in the early stages of PTC. Although all five members of this family have the c-RET proto-oncogene kinase domain in their COOH terminus, little is known about how these genes alter follicular cell biology. Consequently, to answer questions related to the mechanism of the RET/PTC fusion protein action, we have devised a molecular genetic strategy to study PTC using a mouse model of thyroid disease. A new member of this fusion oncogene family, RET/PTC3, which has been implicated in more cases of solid tumor carcinoma (79%) than PTC1 or PTC2 and predominates (80%) in radiation-induced thyroid cancer of children, was investigated in our study. We have generated transgenic mice expressing human RET/PTC3 exclusively in the thyroid. These mice develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. This new transgenic line will be useful in deciphering the molecular and biological mechanisms that cause PTC and histological variations in humans.


Tamoxifen suppresses histologic progression to atypia and DCIS in MCFIOAT xenografts, a model of early human breast cancer.
We evaluated the effects of tamoxifen on the growth and progression of MCFIOAT xenografts, an estrogen responsive model of human breast tumor progression, in which cells are injected orthotopically into the mammary fat pad of female nude mice. At 10 weeks following implantation, histologic sections of each graft were evaluated microscopically for histologic lesions analogous to human breast tumor progression, graded as simple hyperplasia, complex hyperplasia, atypical hyperplasia, ductal carcinoma in situ and invasive carcinoma. Three out of five xenografts in (endocrine intact) control animals progressed to atypical hyperplasia, one progressed to ductal carcinoma in situ and one to invasive carcinoma. The latter two control grafts also contained foci of putative precursor lesions (i.e. atypical hyperplasia and in situ carcinoma, respectively). Tamoxifen supplemented xenografts (N= 17) were uniformly smaller than controls, but contained invasive carcinoma in a similar proportion (4/17, 24%). However, none of these grafts exhibited ductal carcinoma in situ and only one contained atypical hyperplasia. Most grafts in tamoxifen supplemented animals (10/17, including all four with carcinomas) showed complex hyperplasia, which typically dominated the graft. We conclude that tamoxifen selectively inhibits the appearance or growth of preinvasive index lesions. Development of malignancy in the absence of such precursors, though, implies selection for alternative histogenetic pathways as a result of endocrine manipulation.


Early detection of fetal cardiac abnormalities: how effective is it and how should we manage these patients?
Congenital heart defects (CHDs), the most commonly occurring congenital malformations, cause significant mortality and morbidity. With the recognition of early markers for CHD and the development of better ultrasound resolution, interest has turned toward performing a screening anomaly scan, including the heart, together with the nuchal scan. It is also possible, with adequate skill and training, to competently perform an echocardiogram <16 weeks' gestation. This article reviews the detection of major CHD in the first trimester and early second trimester including specific markers that help to identify high-risk groups for early fetal echocardiography (EFEC). CHD detection during first-trimester screening is low (2.3-56%) depending on the center's experience and the population studied. An increased nuchal translucency, abnormal ductus venosus flow, and tricuspid regurgitation in the first trimester are associated with an increased CHD risk and can be used together to identify high-risk fetuses for EFEC. EFEC requires skilled scanning and the expertise of a fetal echocardiographer. In high-risk populations, it is 78.5% sensitive with a 74.5% concordance between the EFEC and the mid-gestational echocardiogram. The availability of qualified personnel and diagnostic accuracy are prerequisites before EFEC can be introduced into management protocols. The limitations of EFEC should be recognized, and a later confirmatory echocardiogram is recommended.


A role for interleukin-12 in the regulation of T cell plasma membrane compartmentation.
The immunological synapse initiates the clustering and stabilization of the T cell receptor by the formation of a large lipid microdomain that accumulates (e.g. CD4/CD8) and segregates (e.g. CD45 and LFA-1) some proteins of the T cell plasma membrane. This work shows that a fraction of transmembrane glycoproteins CD26 and CD45 (the R0 isoform in particular) is present in the rafts of fresh and activated human T lymphocytes. CD26 is proposed as the costimulator of TCR-dependent activation, and CD45 is essential to the T cell activation process because it dephosphorylates at least the inhibitory site of Src kinases. These findings support a more complex model of compartmentation, depending on the stage of T cell maturation and post-transcriptional and post-translational regulation. In addition, interleukin 12 (IL-12; inducer of TH1 responses) drives CD26 and CD45R0 to particular microdomains, thereby involving interleukins in the rules governing raft inclusion or exclusion. The physical association of CD26 and CD45R0 has long been reported. The results presented in this work fit a model in which IL-12 up-regulates a certain type of CD26 expression that interacts on the cell surface with CD45R0, near but outside of the raft core. The use of antisense oligonucleotides for the CD26 mRNAs demonstrated that both events (enhanced by IL-12), CD26-CD45R0 association and membrane compartment redistribution, are related. Thus, CD26 could be part of a shuttling mechanism for CD45 that regulates membrane tyrosine-phosphatase activities, e.g. to control IL-12 receptor-dependent signal transduction.


[CBO guideline 'Breast cancer: screening and diagnosis'].
New developments in the diagnostic procedures for women with an increased risk for, or symptoms related to breast cancer led to development of new guidelines by a working group under the auspices of the Dutch Institute for Health Care Improvement, the Organisation of Comprehensive Cancer Centres and the National Breast Group of the Netherlands. Based on the best available evidence this working group formulated recommendations on the following topics: indications for screening within the population screening programme, screening outside the population screening programme, the diagnostic procedures of symptomatic and asymptomatic lesions in the breast and the organisation of the diagnostic work-up of patients with breast symptoms. The most important recommendations in the guidelines are: individual screening is recommended to certain groups of women who do not participate in the population screening programme, based on their risk profiles; available evidence does not support the extension of the population screening programme to women 40-49 years of age; diagnosis and treatment have to take place in a structured context, the so-called breast team; to guarantee optimal diagnostic procedures a multidisciplinary clinic is mandatory; the diagnostic work-up of breast abnormalities is based on the triple assessment: physical examination, imaging by mammography and/or ultrasound and needle biopsy. For quality-controlled implementation of this guideline, uniform prospective registration of patients, diagnosis and treatment related data is an important condition.


The nervous system effects of occupational exposure on workers in a South African manganese smelter.
Five hundred and nine production workers at a manganese (Mn) smelting works comprising eight production facilities and 67 external controls were studied cross-sectionally for Mn related neuroehavioural effects. Exposure measures from personal sampling included Mn in inhalable dust as cumulative exposure indices (CEI) and average intensity (INT). Biological exposure and biological effect measures included blood (MnB), urine (MnU) manganese and serum prolactin. Endpoints included items from the Swedish nervous system questionnaire (Q16), World Health Organisation neurobehavioural core test battery (WHO NCTB), Swedish performance evaluation system (SPES), Luria-Nebraska (LN), and Danish product development (DPD) test batteries, and a brief clinical examination. Potential confounders and effect modifiers included age, educational level, alcohol and tobacco consumption, neurotoxic exposures in previous work, past medical history, previous head injury and home language. Associations were evaluated by multiple linear and logistic regression modelling. Modelling assumptions were tested. Average exposure intensity across all jobs ranged from near 0 (0.06 microg/m3) for external controls to 5.08 mg/m3 for inhalable Mn, and was greater than the ACGIH TLV for 69% of subjects. Results from the large number of tests performed resolved into three groups. Group 1 shows differences between external unexposed referents and all the exposed and/or differences between internal low exposed referents and the rest of the exposed but no further exposure-response relationships. It includes the Santa Ana, Benton and digit-span tests from the WHO NCTB; the hand tapping and endurance tapping tests from the SPES; Luria-Nebraska item 2L; questionnaire items tired, depressed, irritated, having to take notes in order to remember things, and subjects' perception that they had sex less often than normal; a test of clinical abnormality; and increased sway under two conditions (eyes open without foot insulation, eyes open with foot insulation). Group 2 shows the presence of a more substantive exposure-response relationship. It consists of only two tests: and includes the WHO digit-symbol test (although the major impact is at low exposure and therefore counterintuitive, arguably placing this test in group 3) and the LN item 1R which has a step to a poorer score at high exposure. Group 3 contains the overwhelming majority of test results (almost all the questionnaire items, almost all the DPD tests including tremor, sway and diadochokinesia, and serum prolactin) which were either null or counterintuitive (did not make sense). The CEI was the strongest predictor of test abnormalities, except for the clinical test which was more strongly associated with blood manganese. Despite a comprehensive range of endpoints, and levels of exposure ranging from environmental to industrial, this large study of Mn workers found little convincing evidence for a continuum of effects, contributing further questions to current debates about the adequacy of the current ACGIH TLV.


Pre-operative antimicrobial prophylaxis of infection.
Thoughtful and rational antimicrobial prophylaxis in surgical patients is an important and valued part of patient management, and is best defined as the prevention of postoperative morbidity due to infection. Firm indications for prophylaxis include procedures associated with a high incidence of postoperative infection, those associated with a low incidence of serious sepsis, and low risk procedures in compromised patients.


Kinetics of tamoxifen inhibition of aryl hydrocarbon hydroxylase activity of intestinal and hepatic microsomes from male rats.
The in vitro effects of tamoxifen on microsomal aryl hydrocarbon hydroxylase (AHH) activity from male rat liver and intestinal mucosa were examined. Tamoxifen inhibited microsomal activity from both liver and intestinal mucosa. Tamoxifen was a much more potent inhibitor of hepatic AHH activity as compared to its effects on intestinal AHH activity. At 0.50 mM, tamoxifen inhibited approximately 92% of AHH activity and only 7% of the intestinal activity. Kinetic studies demonstrated that the inhibition of hepatic AHH activity by tamoxifen at concentrations of 0.10 mM or less was non-competitive. However, the same tamoxifen concentrations gave an uncompetitive inhibition when intestinal microsomal AHH activity was studied. The data indicates that AHH inhibition by tamoxifen is both tissue and concentration dependent.


Optimising rigid motion compensation for small animal brain PET imaging.
Motion compensation (MC) in PET brain imaging of awake small animals is attracting increased attention in preclinical studies since it avoids the confounding effects of anaesthesia and enables behavioural tests during the scan. A popular MC technique is to use multiple external cameras to track the motion of the animal's head, which is assumed to be represented by the motion of a marker attached to its forehead. In this study we have explored several methods to improve the experimental setup and the reconstruction procedures of this method: optimising the camera-marker separation; improving the temporal synchronisation between the motion tracker measurements and the list-mode stream; post-acquisition smoothing and interpolation of the motion data; and list-mode reconstruction with appropriately selected subsets. These techniques have been tested and verified on measurements of a moving resolution phantom and brain scans of an awake rat. The proposed techniques improved the reconstructed spatial resolution of the phantom by 27% and of the rat brain by 14%. We suggest a set of optimal parameter values to use for awake animal PET studies and discuss the relative significance of each parameter choice.


Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial.
EMPEROR-Preserved is an ongoing trial evaluating the effect of empagliflozin in patients with heart failure with preserved ejection fraction (HFpEF). This report describes the baseline characteristics of the EMPEROR-Preserved cohort and compares them with patients enrolled in prior HFpEF trials. EMPEROR-Preserved is a phase III randomized, international, double-blind, parallel-group, placebo-controlled trial in which 5988 symptomatic HFpEF patients [left ventricular ejection fraction (LVEF) >40%] with and without type 2 diabetes mellitus (T2DM) have been enrolled. Patients were required to have elevated N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations (i.e. >300 pg/mL in patients without and >900 pg/mL in patients with atrial fibrillation) along with evidence of structural changes in the heart or documented history of heart failure hospitalization. Among patients enrolled from various regions (45% Europe, 11% Asia, 25% Latin America, 12% North America), the mean age was 72 ± 9 years, 45% were women. Almost all patients had New York Heart Association class II or III symptoms (99.6%), and 23% had prior heart failure hospitalization within 12 months. Thirty-three percent of the patients had baseline LVEF of 41-50%. The mean LVEF (54 ± 9%) was slightly lower while the median NT-proBNP [974 (499-1731) pg/mL] was higher compared with previous HFpEF trials. Presence of comorbidities such as diabetes (49%) and chronic kidney disease (50%) were common. The majority of the patients were on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (80%) and beta-blockers (86%), and 37% of patients were on mineralocorticoid receptor antagonists. When compared with prior trials in HFpEF, the EMPEROR-Preserved cohort has a somewhat higher burden of comorbidities, lower LVEF, higher median NT-proBNP and greater use of mineralocorticoid receptor antagonists at baseline. Results of the EMPEROR-Preserved trial will be available in 2021.


Epidermal cell differentiation in cotton mediated by the homeodomain leucine zipper gene, GhHD-1.
Gossypium hirsutum L. (cotton) fibres are specialized trichomes a few centimetres in length that grow from the seed coat. Few genes directly involved in the differentiation of these epidermal cells have been identified. These include GhMYB25-like and GhMYB25, two related MYB transcription factors that regulate fibre cell initiation and expansion. We have also identified a putative homeodomain leucine zipper (HD-ZIP) transcription factor, GhHD-1, expressed in trichomes and early fibres that might play a role in cotton fibre initiation. Here, we characterize GhHD-1 homoeologues from tetraploid G. hirsutum and show, using reporter constructs and quantitative real-time PCR (qRT-PCR), that they are expressed predominantly in epidermal tissues during early fibre development, and in other tissues bearing epidermal trichomes. Silencing of GhHD-1 reduced trichome formation and delayed the timing of fibre initiation. Constitutive overexpression of GhHD-1 increased the number of fibres initiating on the seed, but did not affect leaf trichomes. Expression of GhHD-1 in cotton silenced for different fibre MYBs suggest that in ovules it acts downstream of GhMYB25-like, but is unaffected in GhMYB25- or GhMYB109-silenced plants. Microarray analysis of silencing and overexpression lines of GhHD-1 indicated that it potentially regulates the levels of ethylene and reactive oxidation species (ROS) through a WRKY transcription factor and calcium-signalling pathway genes to activate downstream genes necessary for cell expansion and elongation.


Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatment in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed cross-sectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p < 0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p < 0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.


Heritability of fat distributions in male mice from the founder strains of the Diversity Outbred mouse population.
Specific fat distributions are risk factors for complex diseases, including coronary heart disease and obstructive sleep apnea. To demonstrate the utility of high-diversity mouse models for elucidating genetic associations, we describe the phenotyping and heritability of fat distributions within the five classical inbred and three wild-derived founder mouse strains of the Collaborative Cross and Diversity Outbred mice. Measurements of subcutaneous and internal fat volumes in the abdomen, thorax and neck, and fat volumes in the tongue and pericardium were obtained using magnetic resonance imaging in male mice from the A/J (n = 12), C57BL/6J (n = 17), 129S1/SvlmJ (n = 12), NOD/LtJ (n = 14), NZO/HILtJ (n = 12), CAST/EiJ (n = 14), PWK/PhJ (n = 12), and WSB/EiJ (n = 15) strains. Phenotypes were compared across strains using analysis of variance and heritability estimated as the proportion of phenotypic variability attributable to strain. Heritability ranged from 44 to 91% across traits, including >70% heritability of tongue fat. A majority of heritability estimates remained significant controlling for body weight, suggesting genetic influences independent of general obesity. Principal components analysis supports genetic influences on overall obesity and specific to increased pericardial and intra-neck fat. Thus, among the founder strains of the Collaborative Cross and Diversity Outbred mice, we observed significant heritability of subcutaneous and internal fat volumes in the neck, thorax and abdomen, pericardial fat volume and tongue fat volume, consistent with genetic architecture playing an important role in explaining trait variability. Findings pave the way for studies utilizing high-diversity mouse models to identify genes affecting fat distributions and, in turn, influencing risk for associated complex disorders.


Biomarkers of acute kidney injury.
The diagnosis of acute kidney injury (AKI) is usually based on measurements of blood urea nitrogen (BUN) and serum creatinine. BUN and serum creatinine are not very sensitive or specific for the diagnosis of AKI because they are affected by many renal and nonrenal factors that are independent of kidney injury or kidney function. Biomarkers of AKI that are made predominantly by the injured kidney have been discovered in preclinical studies. In clinical studies of patients with AKI, some of these biomarkers (eg, interleukin-18, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1) have been shown to increase in the urine before the increase in serum creatinine. These early biomarkers of AKI are being tested in different types of AKI and in larger clinical studies. Biomarkers of AKI may also predict long-term kidney outcomes and mortality.


Vibration sensing using a tapered bend-insensitive fiber based Mach-Zehnder interferometer.
In this study, a novel fiber-optic sensor consisting of a tapered bend-insensitive fiber based Mach-Zehnder interferometer is presented to realize damped and continuous vibration measurement. The double cladding structure and the central coating region of the in-fiber interferometer ensure an enhanced mechanical strength, reduced external disturbance, and a more uniform spectrum. A damped vibration frequency range of 29-60 Hz as well as continuous vibration disturbances ranging from 1 Hz up to 500 kHz are successfully demonstrated.


Preservation and Modification of Culture in Family Socialization: Development of Parenting Measures for Korean Immigrant Families.
This study aims to describe the family socialization beliefs and practices of Korean immigrant parents through testing psychometric properties of several newly developed items and scales to assess the major components of the Korean traditional concept of family socialization, ga-jung-kyo-yuk. These new measures were examined for validity and reliability. The findings show that Korean immigrant parents largely preserve their traditional and core parenting values, while also showing meaningful, yet not very dramatic, signs of adopting new cultural traits. The results also suggest that the acculturative process may not be simply bilinear but may generate a new, unique and blended value and behavior set from the two (or more) cultures involved. Culturally appropriate practice requires not only further validation of existing knowledge with minority groups, but the development of a theoretical framework of family socialization that recognizes the cultural uniqueness of immigrant families.


Nitroprusside and ketanserin in the treatment of postoperative hypertension following coronary artery bypass grafting: a haemodynamic and ventilatory comparison.
Postoperative hypertension following coronary artery bypass grafting is usually treated with vasodilating agents like nitroprusside. In recent studies ketanserin, a 5-hydroxytryptamine type 2 antagonist, appeared to be effective in the treatment of this clinical syndrome. In 20 patients, divided into two comparable groups, nitroprusside and ketanserin were compared with respect to their haemodynamic and ventilatory profiles. The study showed that both agents were equally effective in decreasing the raised systolic blood pressure, but that ketanserin was more advantageous with respect to the absence of reflex tachycardia and the unchanged shunt fraction.


Optical color image encryption by wavelength multiplexing and lensless Fresnel transform holograms.
We propose what we believe is a new method for color image encryption by use of wavelength multiplexing based on lensless Fresnel transform holograms. An image is separated into three channels: red, green, and blue, and each channel is independently encrypted. The system parameters of Fresnel transforms and random phase masks in each channel are keys in image encryption and decryption. An optical color image coding configuration with multichannel implementation and an optoelectronic color image encryption architecture with single-channel implementation are presented. The keys can be added by iteratively employing the Fresnel transforms. Computer simulations are given to prove the possibility of the proposed idea.


Wider implications of video-assisted thoracic surgery versus open approach for lung metastasectomy.
Lung metastasectomy is considered a safe and potentially curative procedure despite there is not a strong evidence that metastasectomy prolongs long-term survival in patients with lung metastases. Moreover, the debate is open regarding the best approach for lung metastasectomy, video-assisted thoracic surgery versus open approach. A systematic review of literature to clarify what is the best approach to prolong survival in patients with lung metastases was performed. Our study confirms that overall survival is equivalent for video-assisted thoracic surgery and thoracotomy, therefore the 'gold standard' surgical treatment for lung metastases remains a point of debate. The choice of the surgical approach still depends more on the single center or surgeon practice than on strong scientific evidence. A prospective randomized trial could clarify the question.


Surgical treatment of post-traumatic pseudoaneurysm and arteriovenous fistula due to gunshot injury.
Posttraumatic pseudoaneurysm and arteriovenous fistula are rarely observed. Because of the imminent clinical course, early operation is usually indicated. In this study, we present a case of pseudoaneurysm in the left superficial femoral artery and arteriovenous fistula between the left superficial femoral artery and vein in the left thigh, as a result of a gunshot injury. Magnetic resonance angiography and color Doppler ultrasound were used for diagnosis. The patient underwent a successful aneurysmectomy, saphenous vein interposition and venous repair and was discharged on the eighth postoperative day.


MRS in relation to hippocampal volume in the oldest old.
The MRS brain metabolite ratio N-acetylaspartate (NAA)/myo-inositol (mI) is reported to be decreased in AD. MRS was used to study medial temporal and parietal regions in 60 cognitively healthy subjects older than 85 years. Subjects with small hippocampal volumes, a putative risk factor for dementia, had significantly lower NAA/mI in parietal and temporal lobes compared with other subjects. Neuropsychological tests and APOE genotype did not correlate with MRS ratios. MRS measures are candidate biomarkers for dementia risk.


Trait-mediated effects on flowers: artificial spiders deceive pollinators and decrease plant fitness.
Although predators can affect foraging behaviors of floral visitors, rarely is it known if these top-down effects of predators may cascade to plant fitness through trait-mediated interactions. In this study we manipulated artificial crab spiders on flowers of Rubus rosifolius to test the effects of predation risk on flower-visiting insects and strength of trait-mediated indirect effects to plant fitness. In addition, we tested which predator traits (e.g., forelimbs, abdomen) are recognized and avoided by pollinators. Total visitation rate was higher for control flowers than for flowers with an artificial crab spider. In addition, flowers with a sphere (simulating a spider abdomen) were more frequently visited than those with forelimbs or the entire spider model. Furthermore, the presence of artificial spiders decreased individual seed set by 42% and fruit biomass by 50%. Our findings indicate that pollinators, mostly bees, recognize and avoid flowers with predation risk; forelimbs seem to be the predator trait recognized and avoided by hymenopterans. Additionally, predator avoidance by pollinators resulted in pollen limitation, thereby affecting some components of plant fitness (fruit biomass and seed number). Because most pollinator species that recognized predation risk visited many other plant species, trait-mediated indirect effects of spiders cascading down to plant fitness may be a common phenomenon in the Atlantic rainforest ecosystem.


Multi-probe in situ hybridization to whole mount Arabidopsis seedlings.
In situ RNA-RNA hybridization (ISH) is a molecular method for localization of gene transcripts at the cellular level and is widely used to provide spatial and temporal information regarding gene expression. However, standard protocols are complex and laborious to implement, restricting analysis to one or a few genes at any one time, each one observed on separate ISH preparations. Multi-probe whole-mount in situ hybridization is a powerful technique to compare the expression patterns of two or more genes simultaneously in the same tissue or organ. We describe for the first time in plants, the detection of three different mRNAs in a single fixed whole mount Arabidopsis seedling. A combination of bright fluorescent secondary antibodies was used for the detection of riboprobes differentially labeled by digoxigenin, biotin and fluorescein. The 3-D detection of each of the multiple fluorescent hybridization signals or in combination was obtained through confocal laser-scanning microscopy. The reliability of the method was tested in the root, using the PINFORMED (PIN) genes with non-overlapping temporal and spatial expression patterns. In the shoot, a class-I KNOTTED -like homeobox gene from Arabidopsis (KNAT1) with expression restricted to the shoot apical meristem was used in combination with ELONGATOR3 (ELO3) gene. In addition, the expression patterns of ELONGATOR complex gene (ELO2, ELO3) and HISTONE MONOUBIQUITINATION1 (HUB1) genes were analyzed in both shoot and root and a partial overlapping was observed. The whole procedure takes only 6 days.


Guideline for prevention of nosocomial pneumonia. Centers for Disease Control and Prevention.
Pneumonia is the second most common nosocomial infection in the United States and is associated with substantial morbidity and mortality. Most patients with nosocomial pneumonia are those with extremes of age, severe underlying disease, immunosuppression, depressed sensorium, and cardiopulmonary disease, and those who have had thoracoabdominal surgery. Although patients with mechanically assisted ventilation do not comprise a major proportion of patients with nosocomial pneumonia, they have the highest risk of developing the infection. Most bacterial nosocomial pneumonias occur by aspiration of bacteria colonizing the oropharynx or upper gastrointestinal tract of the patient. Intubation and mechanical ventilation greatly increase the risk of nosocomial bacterial pneumonia because they alter first-line patient defenses. Pneumonias due to Legionella spp., Aspergillus spp., and influenza virus are often caused by inhalation of contaminated aerosols. Respiratory syncytial virus (RSV) infection usually follows viral inoculation of the conjunctivae or nasal mucosa by contaminated hands. Traditional preventive measures for nosocomial pneumonia include decreasing aspiration by the patient, preventing cross-contamination or colonization via hands of personnel, appropriate disinfection or sterilization or respiratory therapy devices, use of available vaccines to protect against particular infections, and education of hospital staff and patients. New measures under investigation involve reducing oropharyngeal and gastric colonization by pathogenic microorganisms.


The Impact of the Direct Participation of Workers on the Rates of Absenteeism in the Spanish Labor Environment.
The aim of this research was to study the relationship between the different levels of direct participation of workers (passive, consultative or active-delegated) in risk prevention management with the levels of absenteeism in Spain. To this end, a transversal study was carried out using microdata from the Second European Survey of Companies on New and Emerging Risks (ESENER-2-Spain, 2014) with a master population of 3162 work centres. A multinomial logistic regression model was carried out, with the dependent variable being the levels of absenteeism and the independent variables, the participation indicators and preventive management, calculating the adjusted odds ratio (aOR) between all the independent and control variables, with their corresponding 95% confidence intervals (95% IC). The results obtained showed how the active-delegative participation of workers in the design and adoption of psychosocial risk prevention measures reported 2.33 less probabilities of having a very high or fairly high level of absenteeism (aOR = 0.43; 95%IC:0.27-0.69). However, having documented aspects of preventive management (plan, risk assessment, planning measures) did not have any impact on absenteeism levels, which shows that we can fall into an unrealistic institutional mirage of security with active policies of co-education or co-management being necessary to reduce absenteeism.


Vitiligo road map.
Vitiligo is a depigmenting disorder stemming from melanocyte loss or dysfunction. It has a complex, multifaceted etiology. We constructed a "vitiligo road map," consisting of basic science, clinical, and treatment components, in order to better portray our current understanding of vitiligo pathogenesis and reflect upon novel biomarkers and therapeutic targets for future research. The melanocyte map elaborates on the molecular processes and intracellular signaling pathways initiated by various external autocrine/paracrine factors in representing normal melanocyte homeostatic functions modulating its viability, proliferation, differentiation, dendricity, migration, and melanogenic processes. This vitiligo map identifies known inducers/triggers of vitiligo onset and progression that cultivate a microenvironment for melanocyte disappearance, real or functional. This map describes the molecular mechanisms of currently utilized clinical and experimental treatments of vitiligo that facilitate repigmentation.


[Interaction of local anesthetics with bilayer phospholipid membranes].
Local anesthetics--cocaine, lidocaine, novocaine were tested for conductivity of bilayer lipid membranes containing anion-selective channels formed by polyene antibiotic amphotericin B. It has been shown that 5 X 10(-4) M cocaine doubles the membrane conductance. The line of efficiency of the tested anesthetics is: cocaine greater than lidocaine greater than novocaine. Possible molecular mechanism of the discovered effect is discussed.


Risk factors for venous ulceration in patients with varicose veins of lower extremities.
The aim of this case-control study was to explore the potential risk factors for venous ulceration in patients with varicose veins of lower extremities and to establish a simplified diagnostic score model. Seventy subjects with varicose veins of lower extremities and venous ulceration were compared with 1164 controls with varicose veins of lower extremities and no history of venous ulceration. Stepwise multivariate logistic regression analysis was used to identify the risk factors for venous ulceration. The steps in developing the diagnostic score model were based on the Framingham Heart study. The area under the receiver operating characteristic curve (AUC) was calculated to assess the diagnostic ability of the diagnostic score model. Multivariate analysis showed that men, overweight, obesity, longer duration varicose veins, deep venous valve insufficiency, low lymphocyte counts, and high fibrinogen concent were independently associated with an increased risk of venous ulceration. The AUC for the diagnostic score model was 0.75, which indicated good discriminatory ability. Special attention should be paid to the high-risk group of patients with lower extremity varicose veins. The diagnostic score model might be a useful screening tool for clinicians, policy makers, and patients.


Use of global sagittal flexibility to predict proximal junctional kyphosis after spinal deformity surgery.
Sagittal alignment is an important predictor of functional outcomes after surgery for adult spinal deformity (ASD). A rigid spinal column may create a large lever arm that may impact the rate of proximal junctional kyphosis (PJK) after ASD surgery. In this study, the authors sought to determine whether relatively low preoperative global spinal flexibility (i.e., rigid spine) predicts increased incidence of PJK at 1 year after ASD surgery. The authors retrospectively reviewed long-segment thoracolumbar fusions with pelvic fixation performed at a single tertiary care center between October 2015 and September 2020 in patients with a minimum of 1-year radiographic and clinical follow-up. Two cohorts were established on the basis of the optimal value for spinal flexibility, as defined by the absolute difference between the preoperative standing and supine C7 sagittal vertical axes, which the authors termed global sagittal flexibility (GSF). Demographic information, radiographs, various associated complications, and patient-reported outcome measures (PROMs) were analyzed. Eighty-five patients met the inclusion criteria. Receiver operating characteristic (ROC) analysis using GSF to predict an increase in the proximal junctional sagittal Cobb angle (PJCA) greater than or equal to 10° at 1-year follow-up provided an area under the curve of 0.64 and identified an optimal GSF threshold value of 3.7 cm. Patients with GSF > 3.7 cm were considered globally flexible (48 patients), and those with GSF ≤ 3.7 cm were classified as rigid (37 patients). Rigid patients were noted to have a significantly higher risk of ΔPJCA ≥ 10° at 1-year follow-up (51.4% vs 29.3%, p = 0.049). No changes in the reoperation rates or PROMs based on GSF were observed in the 1- or 2-year postoperative window. Based on these retrospective data, preoperative global spinal rigidity portends an independently elevated risk for the development of PJK after ASD surgery. No differences in other complication rates or PROMs data were observed between groups. Data collection was limited to a 2-year postoperative window; therefore, longer follow-up is required to further elucidate the relationship between rigidity and reoperation rates. Based on these retrospective data, flexibility may influence the outcomes of patients with ASD.


Aqueous Ginger (Zingiber officinale) Extract Ameliorates the Harmful Effects of High-Dose Lornoxicam in Albino Male Rats.
Lornoxicam is a potent oxicam-class nonsteroidal anti-inflammatory drug (NSAID) with analgesic, anti-inflammatory, and antipyretic effects. Its impacts on many biological functions are not fully understood. We measured various biomarkers in male albino rats provided an oral aqueous ginger extract before IM administration of therapeutic and 2× the therapeutic doses of lornoxicam. The aqueous ginger plant extract was characterized by mass spectroscopy, and its effects were determined by examining free radical scavenging activity, blood parameters, renal and hepatic function, semen quality, proinflammatory cytokines, antioxidant markers, and histopathology. Rats administered lornoxicam had significantly higher liver and kidney function biomarker values, TNF-α, interleukin-6, and sperm abnormalities than the control rats. The overall erythrocyte count, packed cell volume, prostaglandin, and sperm counts were all considerably lower in the experimental animals. Histological changes were found in the liver, spleen, and testes of rats administered lornoxicam alone. In rats, pretreatment with ginger extract reduced the majority of the negative effects of conventional and high dosages of lornoxicam.


The Best Approach for Laparoscopic Fluorescence Cholangiography: Overview of the Literature and Optimization of Dose and Dosing Time.
Fluorescence cholangiography using indocyanine green (ICG) can enhance orientation of bile duct anatomy during laparoscopic cholecystectomy. To ensure clear discrimination between bile ducts and liver, the fluorescence ratio between both should be sufficient. This ratio is influenced by the ICG dose and timing of fluorescence imaging. We first systematically identified all strategies for fluorescence cholangiography. Second, we aimed to optimize the dose of ICG and dosing time in a prospective clinical trial. PubMed was searched for clinical trials studying fluorescence cholangiography. Furthermore, 28 patients planned to undergo laparoscopic cholecystectomy were divided into 7 groups, receiving different intravenous doses (5 or 10 mg ICG) at different time points (0.5, 2, 4, 6, or 24 hours prior to surgery). The systematic review revealed 27 trials including 1057 patients. The majority of studies used 2.5 mg administered within 1 hour before imaging. Imaging 3 to 24 hours after ICG administration was never studied. The clinical trial demonstrated that the highest bile duct-to-liver ratio was achieved 3 to 7 hours after administration of 5 mg and 5 to 25 hours after administration of 10 mg ICG. Up to 3 hours after administration of 5 mg and up to 5 hours after administration of 10 mg ICG, the liver was equally or more fluorescent than the cystic duct, resulting in a ratio ≤1.0. This study shows for the first time that the interval between ICG administration and intraoperative fluorescence cholangiography should be extended. Administering 5 mg ICG at least 3 hours before imaging is easy to implement in everyday clinical practice and results in bile duct-to-liver ratios >1.0.


Spiking neural circuits with dendritic stimulus processors : encoding, decoding, and identification in reproducing kernel Hilbert spaces.
We present a multi-input multi-output neural circuit architecture for nonlinear processing and encoding of stimuli in the spike domain. In this architecture a bank of dendritic stimulus processors implements nonlinear transformations of multiple temporal or spatio-temporal signals such as spike trains or auditory and visual stimuli in the analog domain. Dendritic stimulus processors may act on both individual stimuli and on groups of stimuli, thereby executing complex computations that arise as a result of interactions between concurrently received signals. The results of the analog-domain computations are then encoded into a multi-dimensional spike train by a population of spiking neurons modeled as nonlinear dynamical systems. We investigate general conditions under which such circuits faithfully represent stimuli and demonstrate algorithms for (i) stimulus recovery, or decoding, and (ii) identification of dendritic stimulus processors from the observed spikes. Taken together, our results demonstrate a fundamental duality between the identification of the dendritic stimulus processor of a single neuron and the decoding of stimuli encoded by a population of neurons with a bank of dendritic stimulus processors. This duality result enabled us to derive lower bounds on the number of experiments to be performed and the total number of spikes that need to be recorded for identifying a neural circuit.


Turning on resonant SERRS using the chromophore-plasmon coupling created by host-guest complexation at a plasmonic nanoarray.
An active molecular plasmonics system is demonstrated where a supramolecular chromophore generated in a host-guest binding event couples with the localized surface plasmon resonance (LSPR) arising from gold nanodisc gratings. This coupling was achieved by wavelength-matching the chromophore and the LSPR with the laser excitation, thus giving rise to surface-enhanced resonance Raman scattering (SERRS). The chromophore is a broad charge-transfer (CT) band centered at 865 nm (epsilon = 3500 M(-1) cm(-1)) generated by the complexation of cyclobis(paraquat-p-phenylene) (CBPQT(4+)) and the guest molecule tetrathiafulvalene (TTF). The substrates consist of sub-1-microm gold nanodisc arrays which display dimension-tunable plasmon wavelengths (600-1000 nm). The vibrational spectra of the complex arising from SERRS (lambda(exc) = 785 nm) were generated by irradiating an array (lambda(LSPR) = 765 nm) through the solution to give a chromophore-specific signature with the intensities surface enhanced by approximately 10(5). Surface adsorption of the empty and complexed CBPQT(4+) is also implicated in bringing the chromophore into the electric field arising from the surface-localized plasmon. In a titration experiment, the SERRS effect was then used to verify the role of resonance in turning on the spectrum and to accurately quantify the binding between surface-adsorbed CBPQT(4+) and TTF. The use of a nonpatterned gold substrate as well as a color mismatched complex did not show the enhancement, thus validating that spectral overlap between the chromophore and plasmon resonance is key for resonance surface enhancement. Simulations of the electric fields of the arrays are consistent with interdisc plasmon coupling and the observed enhancement factors. The creation of a responsive plasmonic device upon the addition of the guest molecule and the subsequent coupling of the CT chromophore to the plasmon presents favorable opportunities for applications in molecular sensing and active molecular plasmonics.


Protection of nonhuman primates against two species of Ebola virus infection with a single complex adenovirus vector.
Ebola viruses are highly pathogenic viruses that cause outbreaks of hemorrhagic fever in humans and other primates. To meet the need for a vaccine against the several types of Ebola viruses that cause human diseases, we developed a multivalent vaccine candidate (EBO7) that expresses the glycoproteins of Zaire ebolavirus (ZEBOV) and Sudan ebolavirus (SEBOV) in a single complex adenovirus-based vector (CAdVax). We evaluated our vaccine in nonhuman primates against the parenteral and aerosol routes of lethal challenge. EBO7 vaccine provided protection against both Ebola viruses by either route of infection. Significantly, protection against SEBOV given as an aerosol challenge, which has not previously been shown, could be achieved with a boosting vaccination. These results demonstrate the feasibility of creating a robust, multivalent Ebola virus vaccine that would be effective in the event of a natural virus outbreak or biological threat.


Asthma prevalence among 16- to 18-year-old adolescents in Saudi Arabia using the ISAAC questionnaire.
Most of the studies investigating the prevalence of asthma in various countries have focused on children below the age of 15 years or adults above the age of 18 years. There is limited knowledge concerning the prevalence of asthma in 16- to 18-year-old adolescents. Our objective was to study the prevalence of asthma and associated symptoms in 16- to 18-year-old adolescents in Saudi Arabia. A cross-sectional study was conducted in secondary (high) schools in the city of Riyadh utilizing the International Study of Asthma and Allergies in Children (ISAAC) questionnaire tool. Out of 3073 students (1504 boys and 1569 girls), the prevalence of lifetime wheeze, wheeze during the past 12 months and physician-diagnosed asthma was 25.3%, 18.5% and 19.6%, respectively. The prevalence of exercise-induced wheezing and night coughing in the past 12 months was 20.2% and 25.7%, respectively. The prevalence of rhinitis symptoms in students with lifetime wheeze, physician-diagnosed asthma and exercise-induced wheeze was 61.1%, 59.9% and 57.4%, respectively. Rhinitis symptoms were significantly associated with lifetime wheeze (OR = 2.5, p value < 0.001), physician-diagnosed asthma (OR = 2.2, p < 0.001), and exercise-induced wheeze (OR = 1.9, p value < 0.001). The prevalence of asthma and associated symptoms in 16- to 18-year-old adolescents in Saudi Arabia is high, although it is within range of reported prevalence rates from various parts of the world.


TRAF6 promotes atypical ubiquitination of mutant DJ-1 and alpha-synuclein and is localized to Lewy bodies in sporadic Parkinson's disease brains.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the Substantia Nigra and the formation of ubiquitin- and alpha-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs). Although most PD cases are sporadic, families with genetic mutations have been found. Mutations in PARK7/DJ-1 have been associated with autosomal recessive early-onset PD, while missense mutations or duplications of aSYN (PARK1, PARK4) have been linked to dominant forms of the disease. In this study, we identify the E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6) as a common player in genetic and sporadic cases. TRAF6 binds misfolded mutant DJ-1 and aSYN. Both proteins are substrates of TRAF6 ligase activity in vivo. Interestingly, rather than conventional K63 assembly, TRAF6 promotes atypical ubiquitin linkage formation to both PD targets that share K6-, K27- and K29- mediated ubiquitination. Importantly, TRAF6 stimulates the accumulation of insoluble and polyubiquitinated mutant DJ-1 into cytoplasmic aggregates. In human post-mortem brains of PD patients, TRAF6 protein colocalizes with aSYN in LBs. These results reveal a novel role for TRAF6 and for atypical ubiquitination in PD pathogenesis.


[Prevention and detection of oral cancer: participatory planning as a strategy to broaden coverage in the elderly population].
With respect to addressing oral cancer as a public health problem and the need to conduct early diagnosis to ensure a favorable prognosis for patients, the city of Marilia in the state of São Paulo stages an annual campaign for prevention and early detection of oral cancer. This study sets out to evaluate the participatory planning of the teams at health facilities, seeking to list the difficulties encountered and strategies adopted over a five-year period (2006-2011) by analyzing the coverage of oral examinations for prevention and detection of disease. Strategies for tackling difficulties, issues of epidemiological coordination and surveillance raised by dentists, generated an increase in the coverage of tests performed in the population (> 60 years) from 21% in 2006 to 62% in 2011. The conclusion is that the development of strategies with the participation of health teams produces quite encouraging results, ensuring that the lesions of oral cancer are diagnosed and treated early from the perspective of a more favorable prognosis.


Vitamin D and cognitive function: A Mendelian randomisation study.
The causal nature of the association between hypovitaminosis D and poor cognitive function in mid- to later-life is uncertain. Using a Mendelian randomisation(MR) approach, we examined the causal relationship between 25(OH)D and cognitive function. Data came from 172,349 participants from 17 cohorts. DHCR7(rs12785878), CYP2R1 rs12794714) and their combined synthesis score were chosen to proxy 25(OH)D. Cognitive tests were standardised into global and memory scores. Analyses were stratified by 25(OH)D tertiles, sex and age. Random effects meta-analyses assessed associations between 25(OH)D and cognitive function. Associations of serum 25(OH)D with global and memory-related cognitive function were non-linear (lower cognitive scores for both low and high 25(OH)D, p curvature ≤ 0.006), with much of the curvature attributed to a single study. DHCR7, CYP2R1, and the synthesis score were associated with small reductions in 25(OH)D per vitamin D-decreasing allele. However, coefficients for associations with global or memory-related cognitive function were non-significant and in opposing directions for DHCR7 and CYP2R1, with no overall association observed for the synthesis score. Coefficients for the synthesis score and global and memory cognition were similar when stratified by 25(OH)D tertiles, sex and age. We found no evidence for serum 25(OH)D concentration as a causal factor for cognitive performance in mid- to later life.


Topical applications of ozone and ozonated oils as anti-infective agents: an insight into the patent claims.
Orthodox medicine has been very active in the field of topical anti-infective agents and current chemotherapy has procured valid antibiotics, antivirals, vaccines, antibodies, and antiparasitic drugs to be parenterally and/or topically used. However, these drugs may cause side effects and sometimes provide unsatisfactory results because pathogens become drug-resistant. Another drawback is represented by their cost, which compromise their use or their availability in poor Countries. Therefore, there is a critical need for new strategies to treat dermatological affections. The old intuition for using ozone in the treatment of necrotic wounds, especially if due to anaerobic bacteria, is now justified by the studies about reactive oxygen species generation by granulocytes and macrophages as the first line of defense during an infection. As a consequence, the disinfectant value of ozone has been increasingly appreciated during the last fifteen years. This review summarizes the patents filed and issued, with particular emphasis to the more recent patents, about the anti-infective topical use of ozone: i) in the gaseous form; ii) after gaseous ozone saturation of aqueous, not-oily pharmaceutical vehicles and solvents; iii) where gaseous ozone chemically reacts with unsaturated substrates leading to therapeutically active ozonated derivatives. We hope that recent advances and a better understanding of the ozone chemistry and biology will be able to create the mental attitude to prove the validity of large-scale therapeutic use of both ozone and ozone derivatives as topical anti-infective agents by performing multicenter, randomized clinical studies, as aptly requested by orthodox medicine.


Delayed fatal hemorrhage from pseudoaneurysm of the hepatic artery after percutaneous liver biopsy.
Hemorrhage is the most common serious complication of percutaneous liver biopsy. Liver biopsy is usually done in an outpatient setting because most significant hemorrhage is evident within a few hours after biopsy. Delayed hemorrhage occurs much less frequently but carries a much higher mortality. We present a 41-yr-old man with chronic hepatitis C who underwent a percutaneous liver biopsy uneventfully but was found to have a pseudoaneurysm of the hepatic artery 5 days later. Shortly after admission, the patient experienced bleeding into the liver from the pseudoaneurysm, which was controlled initially by angiographic embolization. However, recurrent bleeding could not be controlled by repeat angiography and surgical intervention, and the patient expired. The diagnosis and management of pseudoaneurysm of the hepatic artery complicating liver biopsy is reviewed.