Novel green PVA-fullerenol mixed matrix supported membranes for separating water-THF mixtures by pervaporation.
This study focuses first on the preparation of mixed matrix supported membranes of polyvinyl alcohol (PVA) and low-hydroxylated fullerenol C60(OH)12 used to create water selective membranes and then on their pervaporation properties for the separation of water-THF mixtures. These novel supported PVA membranes containing nano-carbon particles were prepared to reach high membrane performance for further integration in a dehydration process, such as distillation coupled to pervaporation. The separation of water-THF mixtures was performed with the supported membranes over a wide range of water concentrations in the feed mixture, i.e., from the azeotrope range up to 30 wt%, to evaluate the performance and stability of the thin active layer. SEM was used to visualize the internal morphology of the membrane. The influence of temperature on the transport properties was also investigated. All the membranes were highly water selective and stable up to 30 wt% water in the feed. The best compromise of transport properties was obtained for the C60(OH)12(5%)-PVA supported composite membrane: a permeate enrichment of 99.3 ± 0.3 wt% water and a flux of 0.25 ± 0.02 kg/(m2 h) for the separation of a mixture containing 5.7 wt% water and 94.3 wt% tetrahydrofuran (THF) at 30 °C. Considering its water stability, this supported membrane with a dense layer thinner than 2 μm appears promising for use in hybrid industrial processes to upgrade solvents with a smaller environmental footprint than conventional methods.


The effect of optimization on surface dose in intensity modulated radiotherapy (IMRT).
Although IMRT has been shown clinically to increase skin doses for some patients, it has also been shown that intensity modulated delivery does not, of itself, increase skin doses. The reason for this apparent difference is that inverse planning can result in solutions that give high fluence to tangential beam segments near the skin surface, in an attempt to counter the build-up region. In cases where the clinical target volume (CTV) stops short of the skin surface, but the planning target volume (PTV) does not, there is no clinical reason to treat the skin. The CTV-PTV margin exists purely to ensure that fields are large enough to allow for geometrical uncertainties. With an objective function based on the doses to the PTV, it is possible for a plan that gives excess fluence to the skin to have a lower objective function, and hence to be preferred in an optimization. We describe a technique of plan evaluation, based on analysis of a plan by recalculating several plans in which the isocentre has been offset by a distance equal to the CTV-PTV margin. We demonstrate that changes to a plan that reduce a PTV-based objective can give a worse dose distribution to the CTV when systematic and random set-up errors are accounted for, and increase skin dose. Several possible strategies for avoiding this problem are discussed, including the use of the skin as an organ at risk, modification of the PTV to avoid the skin, and the use of 'pretend bolus' applied in planning but not in treatment. The latter gave the best results. The possibility of using the evaluation method itself, as the basis of an objective function for optimization, is discussed.


Lower limits of detection using magnetic resonance imaging for solid components in cystic renal neoplasms.
We determined the positive predictive value (PPV) for malignancy in complex renal cysts with focal nodular enhancement seen on magnetic resonance imaging (MRI). A surgical database was reviewed to identify all patients having both a preoperative 3 dimensional (3D) renal MRI and a radical or partial nephrectomy from January 2000 through April 2004 at our hospital. A group of 21 patients were identified with focal nodular enhancement within cystic renal masses. Pathologic correlation was made in each case. We performed 286 nephrectomies during the study period. Of these patients, 159 (56%) had a preoperative MRI studies. There were 21 of 159 (13%) patients with complex cystic lesions that displayed focal nodular enhancement, 14 of which (67%) measured 10 mm or larger in size. Twenty (95%) of the 21 lesions were renal cell carcinoma. The single, benign lesion was a cystic nephroma. Fuhrman grade 1 or grade 2 cancers were found in the majority of patients (80%), and there were no grade 4 cancers. Fifteen patients had a preoperative computerized tomography (CT) scan as well and nodular enhancement was suspected in only 4 patients (27%). MRI findings upgraded these lesions in 11 patients (73%). The demonstration of solid enhancing nodular components with high-resolution 3D MRI provides excellent positive predictive value for diagnosing neoplastic cystic renal lesions, including a large percentage 10 mm or larger in size. Our experience suggests a 95% likelihood that cystic renal lesions with focal nodular enhancement are malignant. We recommend that such lesions be considered malignant.


Hypoxia-inducible factor-1alpha and hypoxia-inducible factor-2alpha are expressed in kaposi sarcoma and modulated by insulin-like growth factor-I.
Neoangiogenesis is essential for tumor development. Hypoxia-inducible factor (HIF), a transcriptional factor composed of two subunits (alpha and beta), plays a key role in this process, activating proangiogenic factors such as vascular endothelial growth factor (VEGF). The HIF alpha subunits are critically regulated by oxygen and are also modulated by growth factors. Kaposi sarcoma (KS) is a highly vascular tumor that releases large amounts of VEGF and for which we have recently described an essential role for the insulin-like growth factor (IGF) system. We therefore investigated the expression of HIF alpha subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line. Both HIF-1alpha and HIF-2alpha were expressed in KS biopsies in all tumoral stages. HIF-1alpha immunopositivity increased through the tumor development with highest expression in the late nodular stages. In KSIMM cells, IGF-I induced accumulation of both HIF alpha subunits. The induction suggests a translation mechanism as documented by cycloheximide chase experiment coupled with constant RNA levels as evaluated by quantitative real-time PCR. IGF-I-induced HIF alpha accumulation was followed by an increase in HIF function as assessed both by reporter gene assay and by induction of endogenous target gene expression (VEGF-A). Specific blockade of IGF-I receptor with alphaIR3 antibody or with picropodophyllin, a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF alpha congeners. These novel findings show the coupling between the IGF and HIF signaling in KS and suggest a coordinated contribution by these pathways to the characteristic vascular phenotype of this tumor.


Human kidney cathepsins B and L. Characterization and potential role in degradation of glomerular basement membrane.
Cathepsins B and L were purified from human kidney. SDS/polyacrylamide-gel electrophoresis demonstrated that cathepsins B and L, Mr 27000-30000, consist of disulphide-linked dimers, subunit Mr values 22000-25000 and 5000-7000. The pH optimum for the hydrolysis of methylcoumarylamide (-NHMec) substrates (see below) is approx. 6.0 for each enzyme. Km and kcat. are 252 microM and 364s-1 and 2.2 microM and 25.8 s-1 for the hydrolysis of Z-Phe-Arg-NHMec (where Z- represents benzyloxycarbonyl-) by cathepsins B and L respectively, and 184 microM and 158 s-1 for the hydrolysis of Z-Arg-Arg-NHMec by cathepsin B. A 10 min preincubation of cathepsin B (40 degrees C) or cathepsin L (30 degrees C) with E-64 (2.5 microM) results in complete inhibition. Under identical conditions Z-Phe-Phe-CHN2 (0.56 microM) completely inhibits cathepsin L but has little effect on cathepsin B. Incubation of glomerular basement membrane (GBM) with purified human kidney cathepsin L resulted in dose-dependent (10-40 nM) GBM degradation. In contrast, little degradation of GBM (less than 4.0%) was observed with cathepsin B. The pH optimum for GBM degradation by cathepsin L was 3.5. Cathepsin L was significantly more active in degrading GBM than was pancreatic elastase, trypsin or bacterial collagenase. These data suggest that cathepsin L may participate in the lysosomal degradation of GBM associated with normal GBM turnover in vivo.


Large-scale allelotype of pancreaticobiliary carcinoma provides quantitative estimates of genome-wide allelic loss.
Studies of the allelotype of human cancers have provided valuable insights into those chromosomes targeted for genetic inactivation during tumorigenesis. We present the comprehensive allelotype of 82 xenografted pancreatic or biliary cancers using 386 microsatellite markers and spanning the entire genome at an average coverage of 10 cM. Allelic losses were nonrandomly distributed across the genome and most prevalent for chromosome arms 9p, 17p, and 18q (>60%), sites of the known tumor suppressor genes CDKN2A, TP53, and MADH4. Moderate rates of loss (at any one locus) were noted for chromosome arms 3p, 6q, 8p, 17q, 18p, 21q, and 22q (40-60%). A mapping of individual loci of allelic loss revealed 11 "hot spots" of loss of heterozygosity (>30%) in addition to loci near known tumor suppressor genes, corresponding to 3p, 4q, 5q, 6q, 8p, 12q, 14q, 21q, 22q, and the X chromosome. The average genomic fractional allelic loss was 15.3% of all tested markers for the 82 xenografted cancers, with allelic loss affecting as little as 1.5% to as much as 32.1% of tested loci, a remarkable 20-fold range. We determined the chromosome location (in cM) of each of the 386 markers used based on mapping data available from the National Center for Biotechnology Information, and we provide the first distance-based estimates of chromosome material lost in a human epithelial cancer. Specifically, we found that the cumulative size of allelic losses ranged from 58 to 1160 cM, with an average loss of 561.32 cM/tumor. We compared the genomic fractional allelic loss of each xenografted cancer with known clinicopathological features for each patient and found a significant correlation with smoking status (P < 0.01). These findings offer new loci for investigation of the genetic alterations common to pancreaticobiliary cancers and aid the understanding of mechanisms of allelic loss in human carcinogenesis.


Rapid Phenotypic Convergence towards Collateral Sensitivity in Clinical Isolates of Pseudomonas aeruginosa Presenting Different Genomic Backgrounds.
Collateral sensitivity (CS) is an evolutionary trade-off by which acquisition of resistance to an antibiotic leads to increased susceptibility to another. This Achilles' heel of antibiotic resistance could be exploited to design evolution-based strategies for treating bacterial infections. To date, most studies in the field have focused on the identification of CS patterns in model strains. However, one of the main requirements for the clinical application of this trade-off is that it must be robust and has to emerge in different genomic backgrounds, including preexisting drug-resistant isolates, since infections are frequently caused by pathogens already resistant to antibiotics. Here, we report the first analysis of CS robustness in clinical strains of Pseudomonas aeruginosa presenting different ab initio mutational resistomes. We identified a robust CS pattern associated with short-term evolution in the presence of ciprofloxacin of clinical P. aeruginosa isolates, including representatives of high-risk epidemic clones belonging to sequence type (ST) 111, ST175, and ST244. We observed the acquisition of different ciprofloxacin resistance mutations in strains presenting varied STs and different preexisting mutational resistomes. Importantly, despite these genetic differences, the use of ciprofloxacin led to a robust CS to aztreonam and tobramycin. In addition, we describe the possible application of this evolutionary trade-off to drive P. aeruginosa infections to extinction by using the combination of ciprofloxacin-tobramycin or ciprofloxacin-aztreonam. Our results support the notion that the identification of robust patterns of CS may establish the basis for developing evolution-informed treatment strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens. IMPORTANCE Collateral sensitivity (CS) is a trade-off of antibiotic resistance evolution that could be exploited to design strategies for treating bacterial infections. Clinical application of CS requires it to robustly emerge in different genomic backgrounds. In this study, we performed an analysis to identify robust patterns of CS associated with the use of ciprofloxacin in clinical isolates of P. aeruginosa presenting different mutational resistomes and including high-risk epidemic clones (ST111, ST175, and ST244). We demonstrate the robustness of CS to tobramycin and aztreonam and the potential application of this evolutionary observation to drive P. aeruginosa infections to extinction. Our results support the notion that the identification of robust CS patterns may establish the basis for developing evolutionary strategies to tackle bacterial infections, including those due to antibiotic-resistant pathogens.


Disruption of rimP-SC, encoding a ribosome assembly cofactor, markedly enhances the production of several antibiotics in Streptomyces coelicolor.
Ribosome assembly cofactor RimP is one of the auxiliary proteins required for maturation of the 30S subunit in Escherichia coli. Although RimP in protein synthesis is important, its role in secondary metabolites biosynthesis has not been reported so far. Considering the close relationship between protein synthesis and the production of secondary metabolites, the function of ribosome assembly cofactor RimP on antibiotics production was studied in Streptomyces coelicolor and Streptomyces venezuelae. In this study, the rimP homologue rimP-SC was identified and cloned from Streptomyces coelicolor. Disruption of rimP-SC led to enhanced production of actinorhodin and calcium-dependent antibiotics by promoting the transcription of actII-ORF4 and cdaR. Further experiments demonstrated that MetK was one of the reasons for the increment of antibiotics production. In addition, rimP-SC disruption mutant could be used as a host to produce more peptidyl nucleoside antibiotics (polyoxin or nikkomycin) than the wild-type strain. Likewise, disruption of rimP-SV of Streptomyces venezuelae also significantly stimulated jadomycin production, suggesting that enhanced antibiotics production might be widespread in many other Streptomyces species. These results established an important relationship between ribosome assembly cofactor and secondary metabolites biosynthesis and provided an approach for yield improvement of secondary metabolites in Streptomyces.


Monitoring trehalose uptake and conversion by single bacteria using laser tweezers Raman spectroscopy.
Having the ability to monitor metabolic activity at the scale of single bacterial cells noninvasively would enable us to follow changes in the distribution of activity in bacterial systems which is of major importance for topics such as integration of metabolism and development, metabolic engineering, microbial activity and drug resistance, cell-cell interactions, and quorum sensing. Here, we used laser tweezers Raman spectroscopy to monitor the in vivo real-time uptake and conversion of trehalose by single bacterial cells. This approach can be used for the quantitative determination of sugar uptake by a single bacterium and its metabolic response to the sugar application with time. We show that uptake of trehalose can be quantified in single living bacterial cells held in place by an optical trap while simultaneously collecting Raman spectra upon application of sugar to the medium. This technique yields real-time chemical information in a label-free manner, thus eliminating the limitations of toxicity of the isotopic probes common in studying transport processes. It can substitute the laborious and time-consuming analytical evaluation. Although the single-cell Raman spectroscopy method demonstrated here is focused on the study of trehalose uptake by Sinorhizobium meliloti, the demonstrated approach is applicable to many different organisms and carbohydrates in general.


Mortality trends and the effects of débridement timing in the management of mediastinitis in the United States, 1998 to 2010.
The authors examined the relationship between débridement delay and mortality for mediastinitis patients. The authors also assessed mortality trends for mediastinitis patients between 1998 and 2010. The authors conducted a retrospective cross-sectional study with data from the Nationwide Inpatient Sample, 1998 to 2010. They studied adult patients, 18 years of age or older, who were surgically treated for mediastinitis. They used a logistic regression model adjusted for patient demographic and clinical characteristics to evaluate the association between timing of first operative débridement and in-hospital mortality. Using their logistic model, they calculated the adjusted probability of in-hospital mortality for each year of the study. Results showed that initial débridement after the fourth day of admission increased the odds of in-hospital mortality by 50 percent (odds ratio, 1.5; 95 percent confidence interval, 1.0 to 2.1). In addition, the adjusted probability of in-hospital mortality for an average patient treated for mediastinitis decreased from 10.6 percent in 1998 to 3.1 percent in 2010. There is a survival advantage from timely initial débridement in mediastinitis patients. Risk, II.


The assisted reproductive technology laboratory: toward evidence-based practice?
In the past decades, the efficiency of human assisted reproductive technologies (ART) has improved. We have witnessed important new developments such as intracytoplasmic sperm injection, blastocyst culture, vitrification, and methods for genetic analysis of human embryos. Despite these improvements, current ART laboratories are to a large extent composed of general laboratory equipment that is not designed and manufactured especially for human ART. Human reproductive cells have different physiochemical requirements than somatic cells. We encourage the development of laboratory equipment, utensils, and consumables that are designed specifically for human ART. In addition, the quality and consistency of commercially available culture media have improved, but the composition of commercially available ART culture media varies considerably. It is difficult to see the scientific rationale for this variation. Currently it is not known which of these formulations gives the best clinical results. Finally, selection of embryos in routine ART should be done with the use of variables that have been shown to have statistically independent selection power. With the advent of automatic and objective methods for recording morphology and growth kinetics of human embryos, there is a possibility to pool data sets from many different clinics. This may enable the construction of selection algorithms based on objectively recorded embryo parameters. New methods for the genetic analysis of chromosomal status of embryos may prove to be useful, but they should be tested in controlled randomized trials before being introduced for routine use in ART.


Cost and quality of life analysis of HIV self-testing and facility-based HIV testing and counselling in Blantyre, Malawi.
HIV self-testing (HIVST) has been found to be highly effective, but no cost analysis has been undertaken to guide the design of affordable and scalable implementation strategies. Consecutive HIV self-testers and facility-based testers were recruited from participants in a community cluster-randomised trial ( ISRCTN02004005 ) investigating the impact of offering HIVST in addition to facility-based HIV testing and counselling (HTC). Primary costing studies were undertaken of the HIVST service and of health facilities providing HTC to the trial population. Costs were adjusted to 2014 US$ and INT$. Recruited participants were asked about direct non-medical and indirect costs associated with accessing either modality of HIV testing, and additionally their health-related quality of life was measured using the EuroQol EQ-5D. A total of 1,241 participants underwent either HIVST (n = 775) or facility-based HTC (n = 446). The mean societal cost per participant tested through HIVST (US$9.23; 95 % CI: US$9.14-US$9.32) was lower than through facility-based HTC (US$11.84; 95 % CI: US$10.81-12.86). Although the mean health provider cost per participant tested through HIVST (US$8.78) was comparable to facility-based HTC (range: US$7.53-US$10.57), the associated mean direct non-medical and indirect cost was lower (US$2.93; 95 % CI: US$1.90-US$3.96). The mean health provider cost per HIV positive participant identified through HIVST was higher (US$97.50) than for health facilities (range: US$25.18-US$76.14), as was the mean cost per HIV positive individual assessed for anti-retroviral treatment (ART) eligibility and the mean cost per HIV positive individual initiated onto ART. In comparison to the facility-testing group, the adjusted mean EQ-5D utility score was 0.046 (95 % CI: 0.022-0.070) higher in the HIVST group. HIVST reduces the economic burden on clients, but is a costlier strategy for the health provider aiming to identify HIV positive individuals for treatment. The provider cost of HIVST could be substantially lower under less restrictive distribution models, or if costs of oral fluid HIV test kits become comparable to finger-prick kits used in health facilities.


Neurochemical evaluation of brain function with 1H magnetic resonance spectroscopy in patients with fragile X syndrome.
Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and (1)H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls (P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS.


Bronchial hyperreactivity in potroom workers and prognosis after stopping exposure.
A group of 30 potroom workers who developed an asthma-like syndrome during their work in the electrolytic extraction of aluminium (Alu-Swiss process with prebacked anodes) was followed up after stopping exposure. Subjective respiratory complaints were registered and a non-specific bronchial reactivity test using methacholine was performed once or twice during the follow up period (1984-9). After transfer to other work most workers either had an improvement in respiratory symptoms (60%) or even normalisation (27%); only 13% did not show changes. Bronchial hyperreactivity remained unchanged in 67% of workers, was less pronounced in 13%, normalised in 13%, and deteriorated in 7%. Smoking habits, atopy, and duration of exposure did not seem to have influenced the results obtained. No significant correlation was found between duration of exposure and the speed of onset of respiratory symptoms and the later prognosis of the syndrome. Based on the information collected during the period of observation it appears that reactive airway dysfunction syndrome, once induced, has a tendency to persist. An improvement in subjective complaints may be expected, however, after stopping exposure.


African Trypanosomiasis: Extracellular Vesicles Shed by Trypanosoma brucei brucei Manipulate Host Mononuclear Cells.
African trypanosomiasis or sleeping sickness is a zoonotic disease caused by Trypanosoma brucei, a protozoan parasite transmitted by Glossina spp. (tsetse fly). Parasite introduction into mammal hosts triggers a succession of events, involving both innate and adaptive immunity. Macrophages (MΦ) have a key role in innate defence since they are antigen-presenting cells and have a microbicidal function essential for trypanosome clearance. Adaptive immune defence is carried out by lymphocytes, especially by T cells that promote an integrated immune response. Like mammal cells, T. b. brucei parasites release extracellular vesicles (TbEVs), which carry macromolecules that can be transferred to host cells, transmitting biological information able to manipulate cell immune response. However, the exact role of TbEVs in host immune response remains poorly understood. Thus, the current study examined the effect elicited by TbEVs on MΦ and T lymphocytes. A combined approach of microscopy, nanoparticle tracking analysis, multiparametric flow cytometry, colourimetric assays and detailed statistical analyses were used to evaluate the influence of TbEVs in mouse mononuclear cells. It was shown that TbEVs can establish direct communication with cells of innate and adaptative immunity. TbEVs induce the differentiation of both M1- and M2-MΦ and elicit the expansion of MHCI+, MHCII+ and MHCI+MHCII+ MΦ subpopulations. In T lymphocytes, TbEVs drive the overexpression of cell-surface CD3 and the nuclear factor FoxP3, which lead to the differentiation of regulatory CD4+ and CD8+ T cells. Moreover, this study indicates that T. b. brucei and TbEVs seem to display opposite but complementary effects in the host, establishing a balance between parasite growth and controlled immune response, at least during the early phase of infection.


Recovery of ventricular function in reperfused ischemic rat hearts exposed to fatty acids.
The relationship between tissue levels of fatty acid metabolites in ischemic and reperfused hearts and recovery of mechanical function of these hearts on reperfusion was studied. Isolated rat hearts were exposed to global ischemia for periods up to 60 min under various conditions of coronary flow, O2 supply, and fatty acid concentrations and were then reperfused for either 15 or 30 min under aerobic conditions both with and without fatty acids present. Tissue levels of ATP, creatine phosphate, long-chain acyl CoA, and long-chain acyl carnitine were determined at the end of the ischemic and reperfusion periods. In some experiments K+ arrest during ischemia was used to prevent adenine nucleotide depletion both in the absence and presence of high fatty acids. Although the ability of these hearts to recover their preischemic mechanical function varied from 8 to 90% and tissue levels of acyl CoA and acyl carnitine during ischemia varied from 3- to 10-fold depending on the condition, no correlation was found between the recovery of function during reperfusion and either the presence of fatty acid or high levels of tissue long-chain acyl CoA and carnitine esters during ischemia.


Higher levels of self-reported sitting time is associated with higher risk of type 2 diabetes independent of physical activity in Chile.
Sitting behaviours have increased markedly during the last two decades in Chile. However, their associations with health outcomes such as diabetes have not been reported. Therefore, the aim of this study was to investigate the independent association of self-reported sitting time with diabetes-related markers and diabetes prevalence in Chile. This cross-sectional study included participants (aged ≥18 years) from the Chilean National Health Survey 2009-10 (n = 4457). Fasting glucose and haemoglobin A1c (HbA1c) were measured by standardized protocols. The prevalence of type 2 diabetes (T2D) was determined using WHO criteria. Physical activity (PA) and time spent sitting were determined using the Global Physical Activity Questionnaire (GPAQ). The odds ratio for T2D was 1.10 [95% CI: 1.04-1.16, P = 0.002] and 1.08 [1.02-1.14, P = 0.002] per 1 h increase in sitting time in men and women, respectively, independent of age, education, smoking, BMI and total PA. Overall, prevalence of T2D was 10.2 and 17.2% in individuals classified in the lowest and highest categories of sitting time, respectively. No significant associations were found between sitting time and glucose or HbA1c. Sitting time is positively associated with diabetes risk, independent of socio-demographic, obesity and PA levels, in the Chilean population.


Comparison of the sequences and functions of Streptococcus equi M-like proteins SeM and SzPSe.
Streptococcus equi (Streptococcus equi subsp. equi), a Lancefield group C streptococcus, causes strangles, a highly contagious purulent lymphadenitis and pharyngitis of members of the family Equidae. The antiphagocytic 58-kDa M-like protein SeM is a major virulence factor and protective antigen. The amino acid sequence and structure of SeM has been determined and compared to that of a second, 40-kDa M-like protein (SzPSe) of S. equi and to those of other streptococcal proteins. Both SeM and SzPSe are mainly alpha-helical fibrillar molecules with no homology other than that between their signal and membrane anchor sequences and are only distantly related to other streptococcal M and M-like proteins. The sequence of SzPSe indicates that it is an allele of SzP that encodes the variable protective M-like and typing antigens of S. zooepidemicus (S. equi subsp. zooepidemicus). SeM is opsonogenic for S. equi but not for the closely related S. zooepidemicus, whereas SzPSe is strongly opsonogenic for S. zooepidemicus but not for S. equi. Both proteins bind equine fibrinogen. SeM and SzPSe proteins from temporally and geographically separated isolates of S. equi are identical in size. The results taken together support previous evidence that S. equi is a clonal pathogen originating from an ancestral strain of S. zooepidemicus. We postulate that acquisition of SeM synthesis was a key element in the success of the clone because of its effect in enhancing resistance to phagocytosis and because protective immunity entails a requirement for SeM-specific antibody.


CT colonography: Friend or foe of practicing endoscopists.
To investigate the perceived impact of computed tomographic colonography (CTC) on endoscopists' current and future practice. A 21-question survey was mailed to 1570 randomly chosen American Society for Gastrointestinal Endoscopy (ASGE) members. Participants reported socio-demographics, colonoscopy volume, percentage of colonoscopies performed for screening, and likelihood of integration of CTC into their practice. A total of 367 ASGE members (23%) returned the questionnaire. Respondents were predominantly male (> 90%) and white (83%) with an average age of 49 years. Most respondents (58%) had no plans to incorporate CTC into daily practice and only 7% had already incorporated CTC into daily practice. Private practice respondents were the least likely to incorporate this modality into their daily practice (P = 0.047). Forty-three percent of participants were willing to take courses on CTC reading, particularly those with the highest volume of colonoscopy (P = 0.049). Forty percent of participants were unsure of CTC's impact on future colonoscopy volume while 21% and 18% projected a decreased and increased volume, respectively. The estimated impact of CTC volume varied significantly by age (P = 0.002). Respondents > 60 years felt that CTC would increase colonoscopy, whereas those < 40 years thought CTC would ultimately decrease colonoscopy. Practicing endoscopists are not enthusiastic about the incorporation of CTC into their daily practice and are unsure of its future impact on their practice.


Age-associated differences in triceps surae muscle composition and strength - an MRI-based cross-sectional comparison of contractile, adipose and connective tissue.
In human skeletal muscles, the aging process causes a decrease of contractile and a concomitant increase of intramuscular adipose (IMAT) and connective (IMCT) tissues. The accumulation of non-contractile tissues may contribute to the significant loss of intrinsic muscle strength typically observed at older age but their in vivo quantification is challenging. The purpose of this study was to establish MR imaging-based methods to quantify the relative amounts of IMCT, IMAT and contractile tissues in young and older human cohorts, and investigate their roles in determining age-associated changes in skeletal muscle strength. Five young (31.6 ± 7.0 yrs) and five older (83.4 ± 3.2 yrs) Japanese women were subject to a detailed MR imaging protocol, including Fast Gradient Echo, Quantitative Fat/Water (IDEAL) and Ultra-short Echo Time (UTE) sequences, to determine contractile muscle tissue and IMAT within the entire Triceps Surae complex, and IMCT within both heads of the Gastrocnemius muscle. Specific force was calculated as the ratio of isometric plantarflexor force and the physiological cross-sectional area of the Triceps Surae complex. In the older cohort, total Triceps Surae volume was smaller by 17.5%, while the relative amounts of Triceps Surae IMAT and Gastrocnemius IMCT were larger by 55.1% and 48.9%, respectively. Differences of 38.6% and 42.1% in plantarflexor force and specific force were observed. After subtraction of IMAT and IMCT from total muscle volume, differences in intrinsic strength decreased to 29.6%. Our data establishes that aging causes significant changes in skeletal muscle composition, with marked increases in non-contractile tissues. Such quantification of the remodeling process is likely to be of functional and clinical importance in elucidating the causes of the disproportionate age-associated decrease of force compared to that of muscle volume.


Distinct subtype distribution and somatic mutation spectrum of lymphomas in East Asia.
Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.


Anti-obesity effects of conjugated linoleic acid, docosahexaenoic acid, and eicosapentaenoic acid.
Obesity has become a prevailing epidemic throughout the globe. Effective therapies for obesity become attracting. Food components with beneficial effects on "weight loss" have caught increasing attentions. Conjugated linoleic acid (CLA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) belong to different families of polyunsaturated fatty acids (PUFA). However, they have similar effects on alleviating obesity and/or preventing from obesity. They influence the balance between energy intake and expenditure; and reduce body weight and/or fat deposition in animal models, but show little effect in healthy human subjects. They inhibit key enzymes responsible for lipid synthesis, such as fatty acid synthase and stearoyl-CoA desaturase-1, enhance lipid oxidation and thermogenesis, and prevent free fatty acids from entering adipocytes for lipogenesis. PUFA also exert suppressive effects on several key factors involved in adipocyte differentiation and fat storage. Despite their similar effects and shared mechanisms, they display differences in the regulation of lipid metabolism. Moreover, DHA and EPA exhibit "anti-obesity" effect as well as improving insulin sensitivity, while CLA induces insulin resistance and fatty liver in most cases. A deeper and more detailed investigation into the complex network of anti-obesity regulatory pathways by different PUFA will improve our understanding of the mechanisms of body weight control and reduce the prevalence of obesity.


Shared obsessive-compulsive disorder: broadening the concept of shared psychotic disorder.
Folie a deux (shared psychotic disorder) is often described in the context of schizophrenia. In this article we present this syndrome in a non psychotic context. We report a case of induced obsessive-compulsive disorder (OCD) in a married couple. Six months after the deterioration in the patient's OCD, his wife developed the same symptoms with no preceding history of an Axis I disorder. Neither spouse demonstrated psychotic symptomatology. The husband was successfully treated on an outpatient basis with Citalopram and Clonazepam. His wife's OCD spontaneously resolved without medication in parallel with the resolution of her husband's OCD. We highlight the uncommon phenomenon of shared psychiatric disorder occurring in the context of OCD. In the current psychiatric diagnostic nomenclature, (DSM IV and ICD10), there is no category for a non-psychotic shared psychiatric disorder. We raise the question of broadening the concept of shared disorder so as to include shared OCD and perhaps other shared psychiatric syndromes. More controlled studies are required in order to better understand the psychopathology and mechanisms of psychotic and non-psychotic shared disorders in psychiatry. We believe there are important treatment implications of such an understanding.


The association between cognitive functioning and occupational status in persons with a recent onset of psychosis.
The ability to engage in occupational activity is an important aspect of functioning in individuals with recent onset psychosis. We measured the determinants of occupational status in a sample of n = 86 adults with a recent onset of affective or nonaffective psychosis. Participants were evaluated with the Repeatable Battery of Neuropsychological Status, the Wisconsin Card Sorting Test, symptom rating scales, and other clinical and demographic measures. Results of a discriminant function analysis indicated that the most significant differences between those who worked or attended school and those who did not could be attributed to better immediate verbal memory (F = 13.16, p < .0005) and the absence of substance abuse (F = 5.17, p = .026). Occupational activity was not significantly associated with age, gender, race, or symptom severity in this population. Cognitive assessments may prove useful to identify recent onset patients who are most at risk for occupational impairment and who could most benefit from therapeutic interventions.


The enigma of Oligocene climate and global surface temperature evolution.
Falling atmospheric CO2 levels led to cooling through the Eocene and the expansion of Antarctic ice sheets close to their modern size near the beginning of the Oligocene, a period of poorly documented climate. Here, we present a record of climate evolution across the entire Oligocene (33.9 to 23.0 Ma) based on TEX86 sea surface temperature (SST) estimates from southwestern Atlantic Deep Sea Drilling Project Site 516 (paleolatitude ∼36°S) and western equatorial Atlantic Ocean Drilling Project Site 929 (paleolatitude ∼0°), combined with a compilation of existing SST records and climate modeling. In this relatively low CO2 Oligocene world (∼300 to 700 ppm), warm climates similar to those of the late Eocene continued with only brief interruptions, while the Antarctic ice sheet waxed and waned. SSTs are spatially heterogenous, but generally support late Oligocene warming coincident with declining atmospheric CO2 This Oligocene warmth, especially at high latitudes, belies a simple relationship between climate and atmospheric CO2 and/or ocean gateways, and is only partially explained by current climate models. Although the dominant climate drivers of this enigmatic Oligocene world remain unclear, our results help fill a gap in understanding past Cenozoic climates and the way long-term climate sensitivity responded to varying background climate states.


Cyclic Nucleotide Monophosphates in Plants and Plant Signaling.
Cyclic nucleotide monophosphates (cNMPs) and the enzymes that can generate them are of increasing interest in the plant sciences. Arguably, the major recent advance came with the release of the complete Arabidopsis thaliana genome that has enabled the systematic search for adenylate (ACs) or guanylate cyclases (GCs) and did eventually lead to the discovery of a number of GCs in higher plants. Many of these proteins have complex domain architectures with AC or GC centers moonlighting within cytosolic kinase domains. Recent reports indicated the presence of not just the canonical cNMPs (i.e., cAMP and cGMP), but also the noncanonical cCMP, cUMP, cIMP, and cdTMP in plant tissues, and this raises several questions. Firstly, what are the functions of these cNMPs, and, secondly, which enzymes can convert the substrate triphosphates into the respective noncanonical cNMPs? The first question is addressed here by comparing the reactive oxygen species (ROS) response of cAMP and cGMP to that elicited by the noncanonical cCMP or cIMP. The results show that particularly cIMP can induce significant ROS production. To answer, at least in part, the second question, we have evaluated homology models of experimentally confirmed plant GCs probing the substrate specificity by molecular docking simulations to determine if they can conceivably catalytically convert substrates other than ATP or GTP. In summary, molecular modeling and substrate docking simulations can contribute to the evaluation of cyclases for noncanonical cyclic mononucleotides and thereby further our understanding of the molecular mechanism that underlie cNMP-dependent signaling in planta.


Multiple primary malignancies in patients with non-small cell lung cancer.
Information regarding multiple primary malignancies is important, as it has the potential to clarify etiological factors and may indicate the need to refine patient follow-up to include screening for associated malignancies. Upper aerodigestive tract cancer often develops in patients with smoking-related lung cancer; however, little is known about the frequencies or types of other primary malignancies in patients with non-small cell lung cancer (NSCLC) without a history of smoking. We retrospectively evaluated the records of patients examined and/or treated for NSCLC at the Institute of Biomedical Research and Innovation between January 2007 and June 2012. Patients In total, 938 patients, including 599 men (never-smoker/ever-smoker: 35/564) and 339 women (never-smoker/ever-smoker: 236/103), were analyzed. Among the 209 patients (22.3%) with multiple primary malignancies, 151 had a history of smoking and 58 were never-smokers. The most common cancers were gastric (43 cases), colorectal (33 cases), and prostate (29 cases) cancer. Smoking-related cancer was more common in current smokers and ex-smokers for both men and women. Among women with NSCLC, never-smokers were more likely to have thyroid cancer than those with a history of smoking (5.1% vs. 0%, p=0.021). In this study, several differences in malignancies were observed between never-smokers and patients with a history of smoking. Thyroid cancer and NSCLC co-existed in some women without a history of smoking, implicating predisposing factors other than tobacco smoke in the onset of these cancers.


Social Transmission of Experience of Agency: An Experimental Study.
The sense of controlling one's own actions is fundamental to normal human mental function, and also underlies concepts of social responsibility for action. However, it remains unclear how the wider social context of human action influences sense of agency. Using a simple experimental design, we investigated, for the first time, how observing the action of another person or a robot could potentially influence one's own sense of agency. We assessed how observing another's action might change the perceived temporal relationship between one's own voluntary actions and their outcomes, which has been proposed as an implicit measure of sense of agency. Working in pairs, participants chose between two action alternatives, one rewarded more frequently than the other, while watching a rotating clock hand. They judged, in separate blocks, either the time of their own action, or the time of a tone that followed the action. These were compared to baseline judgements of actions alone, or tones alone, to calculate the perceptual shift of action toward outcome and vice versa. Our design focused on how these two dependent variables, which jointly provide an implicit measure of sense of agency, might be influenced by observing another's action. In the observational group, each participant could see the other's actions. Multivariate analysis showed that the perceived time of action and tone shifted progressively toward the actual time of outcome with repeated experience of this social situation. No such progressive change occurred in other groups for whom a barrier hid participants' actions from each other. However, a similar effect was observed in the group that viewed movements of a human-like robotic hand, rather than actions of another person. This finding suggests that observing the actions of others increases the salience of the external outcomes of action and this effect is not unique to observing human agents. Social contexts in which we see others controlling external events may play an important role in mentally representing the impact of our own actions on the external world.


Modeling effective dosages in hormetic dose-response studies.
Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0-1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0-26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy.


Extension of mixture-of-experts networks for binary classification of hierarchical data.
For many applied problems in the context of medically relevant artificial intelligence, the data collected exhibit a hierarchical or clustered structure. Ignoring the interdependence between hierarchical data can result in misleading classification. In this paper, we extend the mechanism for mixture-of-experts (ME) networks for binary classification of hierarchical data. Another extension is to quantify cluster-specific information on data hierarchy by random effects via the generalized linear mixed-effects model (GLMM). The extension of ME networks is implemented by allowing for correlation in the hierarchical data in both the gating and expert networks via the GLMM. The proposed model is illustrated using a real thyroid disease data set. In our study, we consider 7652 thyroid diagnosis records from 1984 to early 1987 with complete information on 20 attribute values. We obtain 10 independent random splits of the data into a training set and a test set in the proportions 85% and 15%. The test sets are used to assess the generalization performance of the proposed model, based on the percentage of misclassifications. For comparison, the results obtained from the ME network with independence assumption are also included. With the thyroid disease data, the misclassification rate on test sets for the extended ME network is 8.9%, compared to 13.9% for the ME network. In addition, based on model selection methods described in Section 2, a network with two experts is selected. These two expert networks can be considered as modeling two groups of patients with high and low incidence rates. Significant variation among the predicted cluster-specific random effects is detected in the patient group with low incidence rate. It is shown that the extended ME network outperforms the ME network for binary classification of hierarchical data. With the thyroid disease data, useful information on the relative log odds of patients with diagnosed conditions at different periods can be evaluated. This information can be taken into consideration for the assessment of treatment planning of the disease. The proposed extended ME network thus facilitates a more general approach to incorporate data hierarchy mechanism in network modeling.


Characteristics Associated With Physician Bias in Contraceptive Recommendations.
We aimed to examine associations between obstetrician-gynecologist (OBGYN) contraceptive recommendations and sociodemographic characteristics of patients and recommending physicians. OBGYNs affiliated with residency programs across the United States were recruited via email to participate in an online exploratory survey depicting scenarios of reproductive-age women of differing race and socioeconomic status, all other factors identical, and were asked to provide contraceptive recommendations. The χ2 test, Fisher's exact tests, and logistic regression were used to analyze recommendation differences based on physician and patient characteristics. Of 172 physician respondents, large proportions self-identified as White (74%) and attending physicians (56%) from the Mid-Atlantic (42%). In multivariate logistic regression, self-administered methods (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.2-0.8) and condoms (OR, 0.5; 95% CI, 0.3-0.9) were recommended significantly less to Black high SES patients compared with White high SES patients. Non-White physicians recommended tubal ligation (OR, 0.7; 95% confidence interval [CI], 0.5-0.9) significantly less than White physicians, and recommended long-acting reversible contraception (OR, 3.3, CI 2.2-5.2) and condoms (OR, 1.4; 95% CI, 1.1-1.9) significantly more. Trainee physicians recommended self-administered methods (OR, 0.3; 95% CI, 0.2-0.4), condoms (OR, 0.2; 95% CI, 0.2-0.3), and tubal ligation (OR, 0.4; 95% CI, 0.3-0.6) significantly less than attending physicians. OBGYN contraceptive recommendations differed based on patients' perceived race and SES. Recommendations also differed based on race, training level, and geographic location of the recommending physician. Results suggest that physician bias contributes to contraceptive recommendations. OBGYNs should receive education about contraceptive coercion and patient-centered decision-making so that they provide high-quality counseling to all patients.


A further insight into the sialome of the tropical bont tick, Amblyomma variegatum.
Ticks--vectors of medical and veterinary importance--are themselves also significant pests. Tick salivary proteins are the result of adaptation to blood feeding and contain inhibitors of blood clotting, platelet aggregation, and angiogenesis, as well as vasodilators and immunomodulators. A previous analysis of the sialotranscriptome (from the Greek sialo, saliva) of Amblyomma variegatum is revisited in light of recent advances in tick sialomes and provides a database to perform a proteomic study. The clusterized data set has been expertly curated in light of recent reviews on tick salivary proteins, identifying many new families of tick-exclusive proteins. A proteome study using salivary gland homogenates identified 19 putative secreted proteins within a total of 211 matches. The annotated sialome of A. variegatum allows its comparison to other tick sialomes, helping to consolidate an emerging pattern in the salivary composition of metastriate ticks; novel protein families were also identified. Because most of these proteins have no known function, the task of functional analysis of these proteins and the discovery of novel pharmacologically active compounds becomes possible.


Hyperdynamic Valve: A Rare Case of Ehlers-Danlos Syndrome.
Ehlers-Danlos syndrome is a group of rare genetic disorders of collagen characterized by skin hyperextensibility, joint hypermobility and tissue fragility. The authors describe a rare case of a 52-year-old woman that presented to the clinic with chronic joint pain and talipes equinovarum since childhood. Large eyes, sunken cheeks, thin nose and lobeless ears were noticed on clinical examination. Beighton joint hypermotility criteria were met with a positive Walker and Steinberg sign, elbow extension superior to 10° and knee extension in genu recurvatum more than 10°. An aortic diastolic grade III/VI heart murmur was heard. The complementary study was unremarkable. Moderate aortic insufficiency was found on transthoracic echocardiogram. Genetic testing confirmed positivity for COL1A2, a gene that encodes pro-alpha2 chain type of collagen, which causes cardiac-valvular Ehlers-Danlos syndrome. Authors intend to warn to collagen-related syndromes, since severe complications are associated with a reduced life expectancy for individuals with this condition.


Quantitative mouse brain phenotyping based on single and multispectral MR protocols.
Sophisticated image analysis methods have been developed for the human brain, but such tools still need to be adapted and optimized for quantitative small animal imaging. We propose a framework for quantitative anatomical phenotyping in mouse models of neurological and psychiatric conditions. The framework encompasses an atlas space, image acquisition protocols, and software tools to register images into this space. We show that a suite of segmentation tools (Avants, Epstein et al., 2008) designed for human neuroimaging can be incorporated into a pipeline for segmenting mouse brain images acquired with multispectral magnetic resonance imaging (MR) protocols. We present a flexible approach for segmenting such hyperimages, optimizing registration, and identifying optimal combinations of image channels for particular structures. Brain imaging with T1, T2* and T2 contrasts yielded accuracy in the range of 83% for hippocampus and caudate putamen (Hc and CPu), but only 54% in white matter tracts, and 44% for the ventricles. The addition of diffusion tensor parameter images improved accuracy for large gray matter structures (by >5%), white matter (10%), and ventricles (15%). The use of Markov random field segmentation further improved overall accuracy in the C57BL/6 strain by 6%; so Dice coefficients for Hc and CPu reached 93%, for white matter 79%, for ventricles 68%, and for substantia nigra 80%. We demonstrate the segmentation pipeline for the widely used C57BL/6 strain, and two test strains (BXD29, APP/TTA). This approach appears promising for characterizing temporal changes in mouse models of human neurological and psychiatric conditions, and may provide anatomical constraints for other preclinical imaging, e.g. fMRI and molecular imaging. This is the first demonstration that multiple MR imaging modalities combined with multivariate segmentation methods lead to significant improvements in anatomical segmentation in the mouse brain.


Preferences regarding disclosure of a diagnosis of dementia: a systematic review.
Studies in memory clinics suggest that the majority of patients would like to know of a diagnosis of dementia. It is less clear what preferences are in the community. Our objective was to review the literature on preferences regarding disclosure of a diagnosis of dementia and to assess key arguments in favor of and against disclosure. Systematic search of empirical studies was performed in Pubmed, Embase, and Psycinfo. We extracted preferences of individuals without cognitive impairment (general population; relatives of dementia patients; and physicians) and preferences of individuals referred to a memory clinic or already diagnosed with dementia. A meta-analysis was done using a random effects model. Our main conclusions are based on studies with a response rate ≥75%. We included 23 articles (9.065 respondents). In studies with individuals without cognitive impairment, the pooled percentage in favor of disclosure was 90.7% (95%CI: 83.8%-97.5%). In studies with patients who were referred to a memory clinic or already diagnosed with dementia, the pooled percentage that considered disclosure favorable was 84.8% (95%CI: 75.6%-94.0%). The central arguments in favor of disclosure pertained to autonomy and the possibility to plan one's future. Arguments against disclosure were fear of getting upset and that knowing has no use. The vast majority of individuals without and with cognitive impairment prefers to be informed about a diagnosis of dementia for reasons pertaining to autonomy.


Pretreatment quality of life of inoperable non-small cell lung cancer patients referred for primary radiotherapy.
This study examined the association between the most important prognostic factors in non-small cell lung carcinoma (NSCLC) and self-reported pretreatment quality of life (QoL) and the impact of the presence, severity and changes in respiratory symptoms on general symptoms and QoL. The study included 262 patients. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EORTC QLQ-LC13 were used to assess symptoms and QoL before radiotherapy. Patients with inoperable NSCLC showed major differences in self-reported QoL as a function of clinical prognostic factors. A significant association was found between World Health Organization (WHO) performance status and QoL but not other prognostic factors. Dyspnoea was the only respiratory symptom associated significantly with general symptoms, physical and psychosocial functioning and QoL. Furthermore, changes in dyspnoea were associated significantly with changes in physical and role functioning, global QoL and fatigue as assessed 6 weeks after radiotherapy. These results indicate that palliation of dyspnoea may have a significant beneficial effect on QoL and that palliation of other respiratory symptoms is not necessarily associated with improvement of general symptoms, physical and psychological functioning or global QoL.


Current status of methods to assess cancer drug resistance.
Drug resistance is the main cause of the failure of chemotherapy of malignant tumors, resistance being either preexisting (intrinsic resistance) or induced by the drugs (acquired resistance). At present, resistance is usually diagnosed during treatment after a long period of drug administration.In the present paper, methods for a rapid assessment of drug resistance are described. Three main classes of test procedures can be found in the literature, i.e. fresh tumor cell culture tests, cancer biomarker tests and positron emission tomography (PET) tests. The methods are based on the evaluation of molecular processes, i.e. metabolic activities of cancer cells. Drug resistance can be diagnosed before treatment in-vitro with fresh tumor cell culture tests, and after a short time of treatment in-vivo with PET tests. Cancer biomarker tests, for which great potential has been predicted, are largely still in the development stage. Individual resistance surveillance with tests delivering rapid results signifies progress in cancer therapy management, by providing the possibility to avoid drug therapies that are ineffective and only harmful.


PubTerm: a web tool for organizing, annotating and curating genes, diseases, molecules and other concepts from PubMed records.
Analysis, annotation and curation of biomedical scientific literature is a recurrent task in biomedical research, database curation and clinics. Commonly, the reading is centered on concepts such as genes, diseases or molecules. Database curators may also need to annotate published abstracts related to a specific topic. However, few free and intuitive tools exist to assist users in this context. Therefore, we developed PubTerm, a web tool to organize, categorize, curate and annotate a large number of PubMed abstracts related to biological entities such as genes, diseases, chemicals, species, sequence variants and other related information. A variety of interfaces were implemented to facilitate curation and annotation, including the organization of abstracts by terms, by the co-occurrence of terms or by specific phrases. Information includes statistics on the occurrence of terms. The abstracts, terms and other related information can be annotated and categorized using user-defined categories. The session information can be saved and restored, and the data can be exported to other formats. The pipeline in PubTerm starts by specifying a PubMed query or list of PubMed identifiers. Then, the user can specify three lists of categories and specify what information will be highlighted in which colors. The user then utilizes the `term view' to organize the abstracts by gene, disease, species or other information to facilitate the annotation and categorization of terms or abstracts. Other views also facilitate the exploration of abstracts and connections between terms. We have used PubTerm to quickly and efficiently curate collections of more than 400 abstracts that mention more than 350 genes to generate revised lists of susceptibility genes for diseases. An example is provided for pulmonary arterial hypertension. PubTerm saves time for literature revision by assisting with annotation organization and knowledge acquisition.


Awakening the oocyte: controlling primordial follicle development.
Oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary, often for decades, until recruited into the growing pool throughout the reproductive years. Therefore, activation of follicle growth is a major biological checkpoint that controls female reproductive potential. However, we are only just beginning to elucidate the cellular mechanisms required for either maintenance of the quiescent primordial follicle pool or initiation of follicle growth. Understanding the intracellular signalling systems that control oocyte maintenance and activation has significant implications for improving female reproductive productivity and longevity in mammals, and has application in domestic animal husbandry, feral animal population control and infertility in women.


Improved method for purification of enterotoxin from Clostridium perfringens type A.
The purification procedure of Clostridium perfringens type A enterotoxin has been improved. The cell sonic extract was precipitated twice with ammonium sulfate, first 40% saturated to concentrate the enterotoxin and then 15% saturated. The two precipitations were followed by gel filtration on Sephadex G-100. The enterotoxin appeared to be homogeneous on 7% polyacrylamide gel electrophoresis after this three-step purification procedure, with a recovery of 56% and a 12.3-fold purification. The solubility properties at different pH values, temperatures, and ammonium sulfate concentrations are also given as basis for the purification procedure.


3D simulation of internal tablet strength during tableting.
This study presents a new approach to model powder compression during tableting. The purpose of this study is to introduce a new discrete element simulation model for particle-particle bond formation during tablet compression. This model served as the basis for calculating tablet strength distribution during a compression cycle. Simulated results were compared with real tablets compressed from microcrystalline cellulose/theophylline pellets with various compression forces. Simulated and experimental compression forces increased similarly. Tablet-breaking forces increased with the calculated strengths obtained from the simulations. The calculated bond strength distribution inside the tablets showed features similar to those of the density and pressure distributions in the literature. However, the bond strength distributions at the center of the tablets varied considerably between individual tablets.


Sexual and reproductive health problems among women with mental illness attending tertiary care psychiatric outpatient clinic in India: A cross-sectional study.
Sexual and reproductive health (SRH) is a vital concern among women with mental illness (WMI) due to the increased risk for unplanned pregnancy, sexually transmitted infections (STIs), and poor obstetric outcomes. Objective of the study was to explore the current use of family planning (FP) methods, symptoms of STIs and sexual dysfunction among WMI. This descriptive study involved 404 WMI of reproductive age (18-49 years) attending tertiary care psychiatric outpatient clinics in India. During face-to-face interviews, centers for disease control and prevention (CDC)-reproductive health assessment toolkit-FP questionnaire, STI questionnaire and Female sexual function index (FSFI) were used to collect the data. Of 404 WMI, 261(64.6%) were users, and 137 (33.9%) were non-users of FP methods. About 6(1.5%) WMI did not respond FP methods question. Female sterilization was the highest among the users, 244(93%). Among non-users, 100 (73%) were unaware of choosing the effective method of FP. Most of the WMI, 377(93.3%), were unaware of STIs. The symptoms of STI reported include unusual genital discharge 62(15.3%) and genital ulcers/ sores 58(14.4 %). Most of them, 76(63.3%), were not on any treatment. The most common reason for not taking treatment was feeling ashamed 70(92.1%). Female sexual dysfunction was reported in 176(43.6%). Most of the WMI had difficulties in the arousal domain 288(71.3%), followed by low desire 233(57.7%) and dissatisfaction 186(46%). Most WMI underwent sterilization. Non-users of FP methods were not aware of choosing the effective method. Awareness about STIs was poor, and feeling ashamed was the primary reason for not availing of medical help. Nearly half of the WMI reported sexual dysfunction, among which arousal difficulties, low desire and dissatisfaction were common. Health professionals need to increase awareness about FP methods and symptoms of STIs among WMIs. Women require appropriate counselling regarding SRH and treatment for sexual dysfunction.


The impact of chemotherapy dose density and dose intensity on breast cancer outcome: what have we learned?
Optimising chemotherapy dose density and dose intensity are strategies aimed at improving outcomes in adjuvant therapy for patients with breast cancer. There are, in theory, at least five models allowing the delivery of a higher overall drug dose intensity. These are reviewed in this article and vary according to three main variables: the dose per course, the interval between doses and the total cumulative dose. Cyclophosphamide, anthracyclines and taxanes are among the most active agents for the treatment of breast cancer and, as such, they have been or are currently the focus of prospective, randomised clinical trials testing some of these dose-intensity models in the adjuvant setting. The results of recent trials suggest that anthracyclines, but not cyclophosphamide, are associated with better outcomes if used at higher doses per course and at higher cumulative doses. However, care has to be taken with premenopausal women where an increased dose of anthracycline per course but a reduced cumulative dose appears to produce a worse outcome. Moreover, decreasing the interval between doses, for anthracyclines and cyclophosphamide, does not seem to provide, so far, additional benefits for women with locally advanced breast cancer. This approach is not feasible with docetaxel, since an increase in dose density induces unwanted side-effects. These results represent our current state of knowledge, but clinical trials are being performed to evaluate further the effect of dose intensity, dose density and cumulative dose of key therapeutic agents on patient outcomes.


Selective growth of Ti3+/TiO2/CNT and Ti3+/TiO2/C nanocomposite for enhanced visible-light utilization to degrade organic pollutants by lowering TiO2-bandgap.
A convenient route was developed for the selective preparation of two stable nanocomposites, Ti3+/TiO2/CNT (labeled as TTOC-1 and TTOC-3) and Ti3+/TiO2/carbon layer (labeled as TTOC-2), from the same precursor by varying the amount of single-walled carbon nanotubes used in the synthesis. TiO2 is an effective photocatalyst; however, its wide bandgap limits its usefulness to the UV region. As a solution to this problem, our prepared nanocomposites exhibit a small bandgap and wide visible-light (VL) absorption because of the introduction of carbonaceous species and Ti3+ vacancies. The photocatalytic efficiency of the nanocomposites was examined via the degradation of methylene blue dye under VL. Excellent photocatalytic activity of 83%, 98%, and 93% was observed for TTOC-1, TTOC-2, and TTOC-3 nanocomposites within 25 min. In addition, the photocatalytic degradation efficiency of TTOC-2 toward methyl orange, phenol, rhodamine B, and congo red was 28%, 69%, 71%, and 91%, respectively, under similar experimental conditions after 25 min. Higher reusability and structural integrity of the as-synthesized photocatalyst were confirmed within five consecutive runs by photocatalytic test and X-ray diffraction analysis, respectively. The resulting nanocomposites provide new insights into the development of VL-active and stable photocatalysts with high efficiencies.


Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke.
Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population. To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA. Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1). Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort). The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017. Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend). In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.


Regulation of C-C chemokine production by murine T cells by CD28/B7 costimulation.
C-C chemokines play an important role in recruitment of T lymphocytes to inflammatory sites. T lymphocytes secrete chemokines, but the activation requirements for chemokine production by T cells are uncertain. We studied the regulation of C-C chemokine production by CD28 costimulatory signals by murine T lymphocytes. Splenocytes from BALB/c mice cultured with anti-CD3 mAb expressed macrophage-inflammatory protein (MIP)-1alpha mRNA and secreted MIP-1alpha, which was inhibited by anti-B7-1 plus anti-B7-2 mAbs. MIP-1alpha production by Ag-stimulated T cells from DO.11.10 TCR transgenic mice was augmented by anti-CD28 mAb and increased compared with DO.11.10/CD28(-/-) cells. When T cell costimulation was provided by IL-2, MIP-1alpha was not enhanced. Studies with IL-2, IL-4, STAT4, and STAT6 knock-out mice suggested that chemokine production is controlled by pathways different from those regulating T cell differentiation. Thus, CD28 costimulation may amplify an immune response by stimulating T cell survival, proliferation, and production of chemokines that recruit T cells to inflammatory sites.


Polyuric-polydipsic syndrome in a pediatric case of non-glucocorticoid remediable familial hyperaldosteronism.
Familial hyperaldosteronism (FH) encompasses 3 types of autosomal dominant hyperaldosteronisms leading to inheritable hypertension. FH type II (FH-II), undistinguishable from sporadic hyperaldosteronism, represents the most frequent cause of inheritable hypertension and is believed to only manifest in adults. FH-III is a severe variety of PA resistant to pharmacotherapy and recently demonstrated to be caused by mutations in the gene encoding the potassium channel KCNJ5. In this report, we describe a FH pediatric patient, remarkable both for age at onset and unusual presentation: a two-years old girl with polyuric-polydipsic syndrome and severe hypertension, successfully treated with canrenone and amiloride. The girl had severe hypertension, hypokalemia, hypercalciuria, suppressed renin activity, high aldosterone, and unremarkable adrenal imaging. FH type I was ruled out by glucocorticoid suppression test, PCR test for CYP11B1/CYP11B2 gene, and urinary 18-oxo-cortisol and 18-hydroxy-cortisol excretion, which was in FH-II range. In spite of a clear-cut FH-II phenotype, the girl and her mother were found to harbor a FH-III genotype with KCNJ5 mutation (c.452G>A). Treatment with canrenone was started, resulting in prompt normalization of electrolytes and remission of polyuric-polydypsic syndrome. The addition of amiloride led to a complete normalization of blood pressure. This report expands the phenotypic spectrum of FH-III to a milder end, mimiking FH-II phenotype demonstrating that pharmacotherapy may be effective. This also implies that FH-II/III should be considered in the differential diagnosis of hypertensive children and, perhaps, that the offspring of patients with hyperaldosteronism should be screened for hypertension.


Podocyte-specific deletion of dicer alters cytoskeletal dynamics and causes glomerular disease.
MicroRNAs (miRNAs) regulate gene expression by binding the 3' untranslated region of mRNAs. To define their role in glomerular function, miRNA biogenesis was disrupted in mouse podocytes using a conditional Dicer allele. Mutant mice developed proteinuria by 3 wk after birth and progressed rapidly to end-stage kidney disease. Podocyte pathology included effacement, vacuolization, and hypertrophy with crescent formation. Despite normal expression of WT1, podocytes underwent dedifferentiation, exemplified by cytoskeletal disruption with early transcriptional downregulation of synaptopodin. These abnormalities differed from Cd2ap(-/-) mice, indicating they were not a general consequence of glomerular disease. Glomerular labeling of ezrin, moesin, and gelsolin was altered at 3 wk, but expression of nestin and alpha-actinin was unchanged. Abnormal cell proliferation or apoptosis was not responsible for the glomerular injury. Mutant podocytes were incapable of synthesizing mature miRNA, as revealed by their loss of miR-30a. In contrast, expression of glomerular endothelial and mesangial cell miRNAs (miR-126 and miR-145, respectively) was unchanged. These findings demonstrate a critical role for miRNA in glomerular function and suggest a pathway that may participate in the pathogenesis of kidney diseases of podocyte origin. The unique architecture of podocytes may make them especially susceptible to cytoskeletal alterations initiated by aberrant miRNA dynamics.


Using HIV resistance tests in clinical practice.
Genotypic resistance testing is now a standard of care in HIV management. Although there are clear, published guidelines to recommend the appropriate use of these tests, clinicians and scientists still struggle to determine the optimal use of resistance tests given the finite budgets and time constraints under which they work. In this article we discuss some 'real-life' clinical situations and aim to provide a useful insight into when and where genotypic resistance testing can be optimally applied in the management of HIV-positive adults.


Exploring the barriers and enablers to attendance at rural cardiac rehabilitation programs.
The objectives of this study were to: (i) identify local barriers and enablers to the uptake of hospital-based cardiac rehabilitation (CR) programs, and (ii) identify preferred alternatives for the delivery of CR. A questionnaire administered by local CR coordinators and focus groups facilitated by the research team. Six regional hospitals in south-west Victoria offering hospital-based CR programs. Patients and their carers referred to and eligible for local CR programs; health professionals working within local CR programs. CR attendees and decliners demographics, patient and health professional perceived factors which contribute to enabling hospital-based CR attendance, patient and health professional perceived barriers to CR attendance, and receptiveness and preferences for alternative modes of CR delivery. This study identified distance to travel to hospital-based CR programs the only statistically significant factor in determining uptake of CR. Easy access to transport (63%) and to a lesser extent family support (49%) and work flexibility (43%) were the primary enablers to attendance. Of the 97 study participants, 38% were receptive to alternative CR methods such as programs in outlying communities, evening facility-based programs, home and GP based programs, telephone support and a patient manual/workbook. The results of this study provide valuable information for designing strategies to increase utilisation and improve patient acceptability of existing hospital-based CR programs. It provides a basis for pilot testing alternative modes of CR program delivery for cardiac patients in rural areas unable to access hospital-based CR.


Comparative Analysis of miRNA Expression Profiles Between Heat-Tolerant and Heat-Sensitive Genotypes of Flowering Chinese Cabbage Under Heat Stress Using High-Throughput Sequencing.
Heat stress disturbs cellular homeostasis, thus usually impairs yield of flowering Chinese cabbage (Brassica campestris L. ssp. chinensis var. utilis Tsen et Lee). MicroRNAs (miRNAs) play a significant role in plant responses to different stresses by modulating gene expression at the post-transcriptional level. However, the roles that miRNAs and their target genes may play in heat tolerance of flowering Chinese cabbage remain poorly characterized. The current study sequenced six small RNA libraries generated from leaf tissues of flowering Chinese cabbage collected at 0, 6, and 12 h after 38 °C heat treatment, and identified 49 putative novel miRNAs and 43 known miRNAs that differentially expressed between heat-tolerant and heat-sensitive flowering Chinese cabbage. Among them, 14 novel and nine known miRNAs differentially expressed only in the heat-tolerant genotype under heat-stress, therefore, their target genes including disease resistance protein TAO1-like, RPS6, reticuline oxidase-like protein, etc. might play important roles in enhancing heat-tolerance. Gene Ontology (GO) analysis revealed that targets of these differentially expressed miRNAs may play key roles in responses to temperature stimulus, cell part, cellular process, cell, membrane, biological regulation, binding, and catalytic activities. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified their important functions in signal transduction, environmental adaptation, global and overview maps, as well as in stress adaptation and in MAPK signaling pathways such as cell death. These findings provide insight into the functions of the miRNAs in heat stress tolerance of flowering Chinese cabbage.


Results of the Intergroup Rhabdomyosarcoma Study Group D9602 protocol, using vincristine and dactinomycin with or without cyclophosphamide and radiation therapy, for newly diagnosed patients with low-risk embryonal rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.
Patients with localized, grossly resected, or gross residual (orbital only) embryonal rhabdomyosarcoma (ERMS) had 5-year failure-free survival (FFS) rates of 83% and overall survival rates of 95% on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III/IV. IRSG D9602 protocol (1997 to 2004) objectives were to decrease toxicity in similar patients by reducing radiotherapy (RT) doses and eliminating cyclophosphamide for the lowest-risk patients. Subgroup A patients (lowest risk, with ERMS, stage 1 group I/IIA, stage 1 group III orbit, stage 2 group I) received vincristine plus dactinomycin (VA). Subgroup B patients (ERMS, stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide. Patients in group II/III received RT. Compared with IRS-IV, doses were reduced from 41.4 to 36 Gy for stage 1 group IIA patients and from 50 or 59 to 45 Gy for group III orbit patients. Estimated 5-year FFS rates were 89% (95% CI, 84% to 92%) for subgroup A patients (n = 264) and 85% (95% CI, 74%, 91%) for subgroup B patients (n = 78); median follow-up: 5.1 years. Estimated 5-year FFS rates were 81% (95% CI, 68% to 90%) for patients with stage 1 group IIA tumors (n = 62) and 86% (95% CI, 76% to 92%) for patients with group III orbit tumors (n = 77). Five-year FFS and OS rates were similar to those observed in comparable IRS-III patients, including patients receiving reduced RT doses, but were lower than in comparable IRS-IV patients receiving VA plus cyclophosphamide. Five-year FFS rates were similar among subgroups A and B patients.


Penicillin's catalytic mechanism revealed by inelastic neutrons and quantum chemical theory.
Penicillin, travels through bodily fluids, targeting and acylatively inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria. Somehow, it avoids metabolic degradation remaining inactive en route. To resolve this ability to switch from a non-active, to a highly reactive form, we investigated the dynamic structure-activity relationship of penicillin by inelastic neutron spectroscopy, reaction kinetics, NMR and multi-scale theoretical modelling (QM/MM and post-HF ab initio). Results show that by a self-activating physiological pH-dependent two-step proton-mediated process, penicillin changes geometry to activate its irreversibly reactive acylation, facilitated by systemic intramolecular energy management and cooperative vibrations. This dynamic mechanism is confirmed by the first ever reported characterisation of an antibiotic by neutrons, achieved on the TOSCA instrument (ISIS facility, RAL, UK).


Attitudes towards and knowledge about homosexuality among medical students in Zagreb.
The aim of the study was to investigate whether students in their fifth and sixth years of medical school in Zagreb have homophobic attitudes and assess their knowledge about homosexuality. A survey was conducted among fifth and sixth year medical students during the 2009/2010 academic year. The survey consisted of general demographic data, two validated questionnaires--"Knowledge about Homosexuality Questionnaire" and "Heterosexual Attitudes towards Homosexuality Scale"--and questions about personal experiences created for this study. The mean knowledge scores were X = 14.8 out of 20. Furthermore, gender differences in attitudes were observed, indicating less negative attitudes among the female participants. The regression model was significant (ANOVA: Sum of Squares = 38.065; df = 17, Mean Square= 2239, F = 10.6; p < 0.001) with 38% of explained variance. The significant predictor variables that indicate lower attitudes about homosexuality score were female gender (beta= -0.14, p = 0.015), sixth year of study (beta = -0.16, p = 0.009) and more knowledge about homosexuality (beta = -0.48, p < 0.001). Negative attitudes are present among the students; therefore, educational efforts should be included in the curricula of medical schools to diminish the negative perceptions of the lesbian, gay, bisexual and transgender community.


Effect of red propolis on hamster cheek pouch angiogenesis in a new sponge implant model.
To evaluate the effects of red propolis on cheek pouch angiogenesis in a hamster new model sponge implant. Forty eight animals divided into eight groups. (Groups I-IV), the animals were treated for 15 days before and 10 days after sponge implantation. (Groups V-VIII), the animals were treated for 10 days after sponge implantation (GI and GV: red propolis 100 mg/kg, GII and GVI: celecoxib 20 mg/kg, GIII and GVII: 1% gum arabic 5 mL/kg, GIV and GVIII: distilled water 5 mL/kg). On the 11th day of implantation, the animals were anesthetized for stereoscopic microscopic imaging and morphometric quantification of angiogenesis (SQAN), followed by histopathological evaluation (H&E). In the SQAN analysis, no significant difference was found between the groups. However, on histology, propolis was found reduce the population of mastocytes in the qualitative analyses (p = 0,013) in the quantitative analyses to reduce the number of blood vessels (p = 0,007), and increase the macrophage count (p = 0,001). Red propolis inhibited inflammatory angiogenesis when administered before andcontinuously after sponge implant, and was shown to have immunomodulating effects on inflammatory cells (mastocytes and macrophages) in a new sponge implant hamster model.


One-step typing of Epstein-Barr virus by polymerase chain reaction: predominance of type 1 virus in Japan.
The prevalence of two types of Epstein-Barr virus (EBV) in Japan was studied by using the polymerase chain reaction (PCR). The U2 region encoding EBV nuclear antigen 2 (EBNA-2) was chosen as the target of amplification. Consensus primers were synthesized from sequences common to the two types but encompassing a large stretch of deletion in the sequence of type 1 EBV. The primers were capable of amplifying both types at the same time but allowed differentiation of each type by the size of the amplification products. Thus we could carry out detection and typing of EBV in a one-step PCR. EBV was detected in mouth washings of 21 (23%) of 91 seropositive healthy adults. Twenty samples (22%) contained type 1 and only one (1%) type 2. Seventy-nine patients suffering from various types of tonsillitis were also studied. EBV was detected in mouth washings of 37 patients (47%). Thirty-four (43%) contained type 1 and three (4%) type 2. Double infection was not seen in either healthy donors or patients. These results indicate that type 1 EBV is highly dominant and the type 2 variant is quite rare in Japan.


The flexor indicis profundus - its morphology and clinical significance.
The knowledge on the anatomical variations of the deep flexor muscles is important due to its evolutionary significance. The flexor digitorum profundus is the deep flexor muscle of the forearm. It is a composite muscle with a dual nerve supply. The medial half of muscle is supplied by the ulnar nerve, and lateral half of the muscle is supplied by the anterior interosseous nerve, a branch of the median nerve. It flexes the distal phalanges of the medial four digits. In the present case, we observed the presence of extensive cleavage of belly and tendon of flexor digitorum profundus to form flexor indicis profundus on the right side in an adult male cadaver. Flexor indicis profundus muscle is an example of progressive type of variation and it is usually asymptomatic, but it may cause compression of the anterior interosseous nerve, which can lead to compression neuropathy. If it is enlarged, it may simulate a ganglion.


Patterns of comorbidity and psychopharmacology in adults with intellectual disability and attention deficit hyperactivity disorder: an UK national cross-sectional audit.
Background: Attention-deficit hyperactivity disorder (ADHD) is higher in people with intellectual disability (ID) compared to the general population. Available limited evidence suggests this population has increased psychological problems, diagnostic overshadowing and psychotropic prescribing. This audit Identifies and analyzes real-world characteristics, diagnostic practices, treatment, and management of ADHD in adults with ID.Research Design and Methods: Pooled retrospective case note data for people with ID and ADHD, collected from 30 organizations across the UK, were analyzed. Patients were classified into mild and moderate-profound ID groups. Associated mental health and neurodevelopmental co-morbidity, Demographics, concomitant psychotropics, and mental and behavioral concerns were collected. Group differences were reported using logistic regression models.Results: Of 445 participants, 73% had co-occurring autism spectrum disorder (ASD) and 65% were prescribed ADHD medications. Those on ADHD medication were less likely to be prescribed antipsychotics (p < 0.001) and antidepressants (p < 0.001). Multiple significant differences were found in ADHD medication response between ID groups and those with/without co-morbid ASD but not associated with challenging behavior reduction.Conclusions: High levels of neurodevelopmental and psychiatric comorbidity were found. ID severity and the presence of ASD appear to influence the use of certain psychotropic medications. Appropriate use of ADHD medication appears to reduce psychotropic polypharmacy.


Excitatory-inhibitory tone shapes decision strategies in a hierarchical neural network model of multi-attribute choice.
We are constantly faced with decisions between alternatives defined by multiple attributes, necessitating an evaluation and integration of different information sources. Time-varying signals in multiple brain areas are implicated in decision-making; but we lack a rigorous biophysical description of how basic circuit properties, such as excitatory-inhibitory (E/I) tone and cascading nonlinearities, shape attribute processing and choice behavior. Furthermore, how such properties govern choice performance under varying levels of environmental uncertainty is unknown. We investigated two-attribute, two-alternative decision-making in a dynamical, cascading nonlinear neural network with three layers: an input layer encoding choice alternative attribute values; an intermediate layer of modules processing separate attributes; and a final layer producing the decision. Depending on intermediate layer E/I tone, the network displays distinct regimes characterized by linear (I), convex (II) or concave (III) choice indifference curves. In regimes I and II, each option's attribute information is additively integrated. In regime III, time-varying nonlinear operations amplify the separation between offer distributions by selectively attending to the attribute with the larger differences in input values. At low environmental uncertainty, a linear combination most consistently selects higher valued alternatives. However, at high environmental uncertainty, regime III is more likely than a linear operation to select alternatives with higher value. Furthermore, there are conditions where readout from the intermediate layer could be experimentally indistinguishable from the final layer. Finally, these principles are used to examine multi-attribute decisions in systems with reduced inhibitory tone, leading to predictions of different choice patterns and overall performance between those with restrictions on inhibitory tone and neurotypicals.


[Immunotherapy in non-small cell lung cancer: evolution of knowledge and clinical advances].
Lung cancer represent the leading cause of cancer related-death worldwide. Although cytotoxic chemotherapy and targeted agents improved survival, the median overall survival for patients with metastatic disease remains poor. Docetaxel is still the corner stone of the second-line treatment, although associated with an unfavourable safety profile. Recent advances in the understanding of cancer immune escape system lead to the development of novel immunotherapies agent that can restore patient's immune response to cancer cells. Unlike vaccines, immune checkpoints inhibitors have shown promising results in non-small cell lung cancer patients. Especially, nivolumab and pembrolizumab, monoclonal antibodies against PD-1, provides as single agent therapy in chemotherapy refractory patients objective response rates ranging from 15%-25%, the majority of which arose quickly and were ongoing 1 year after starting treatment. Furthermore, the toxicity profile differs from that of cytotoxic chemotherapy and is much better tolerated. PD-L1 expression is a promising biomarker for selection and stratification of patients, although its prognostic and predictive role remains to be defined. Several trials are currently ongoing to define the role of immune checkpoint inhibitors in the treatment of patients with non-small cell lung cancer, their combination with cytotoxic chemotherapy or targeted agents and the efficacy and safety of double blockage of PD-1/PD-L1 and CTLA4. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating immune checkpoint inhibitors and NSCLC, considering the measured outcomes as progression free survival (PFS), overall survival (OS), and the overall response rate (ORR).