The enterocyte-associated intestinal microbiota of breast-fed infants and adults responds differently to a TNF-α-mediated pro-inflammatory stimulus.
Co-evolved as an integral component of our immune system, the gut microbiota provides specific immunological services at different ages, supporting the immune education during our infancy and sustaining a well-balanced immunological homeostasis during the course of our life. In order to figure out whether this involves differences in the microbial groups primarily interacting with the host immune system, we developed a non-invasive HT29 cell-based minimal model to fingerprint the enterocyte-associated microbiota fraction in infants and adults. After depicting the fecal microbial community of 12 breast-fed infants and 6 adults by 16S rDNA amplicon pools 454 pyrosequencing, their respective HT29 cell-associated gut microbiota fractions were characterized by the universal phylogenetic array platform HTF-Microbi.Array, both in the presence and absence of a tumor necrosis factor-alpha (TNF-α)-mediated pro-inflammatory stimulus. Our data revealed remarkable differences between the enterocyte-associated microbiota fractions in breast-fed infants and adults, being dominated by Bifidobacterium and Enterobacteriaceae the first and Bacteroides-Prevotella and Clostridium clusters IV and XIVa the second. While in adults TNF-α resulted in a profound impairment of the structure of the enterocyte-associated microbiota fraction, in infants it remained unaffected. Differently from the adult-type gut microbial community, the infant-type microbiota is structured to cope with inflammation, being co-evolved to prime the early immune response by means of transient inflammatory signals from gut microorganisms.


Laccase and its role in production of extracellular reactive oxygen species during wood decay by the brown rot basidiomycete Postia placenta.
Brown rot basidiomycetes initiate wood decay by producing extracellular reactive oxygen species that depolymerize the structural polysaccharides of lignocellulose. Secreted fungal hydroquinones are considered one contributor because they have been shown to reduce Fe(3+), thus generating perhydroxyl radicals and Fe(2+), which subsequently react further to produce biodegradative hydroxyl radicals. However, many brown rot fungi also secrete high levels of oxalate, which chelates Fe(3+) tightly, making it unreactive with hydroquinones. For hydroquinone-driven hydroxyl radical production to contribute in this environment, an alternative mechanism to oxidize hydroquinones is required. We show here that aspen wood undergoing decay by the oxalate producer Postia placenta contained both 2,5-dimethoxyhydroquinone and laccase activity. Mass spectrometric analysis of proteins extracted from the wood identified a putative laccase (Joint Genome Institute P. placenta protein identification number 111314), and heterologous expression of the corresponding gene confirmed this assignment. Ultrafiltration experiments with liquid pressed from the biodegrading wood showed that a high-molecular-weight component was required for it to oxidize 2,5-dimethoxyhydroquinone rapidly and that this component was replaceable by P. placenta laccase. The purified laccase oxidized 2,5-dimethoxyhydroquinone with a second-order rate constant near 10(4) M(-1) s(-1), and measurements of the H(2)O(2) produced indicated that approximately one perhydroxyl radical was generated per hydroquinone supplied. Using these values and a previously developed computer model, we estimate that the quantity of reactive oxygen species produced by P. placenta laccase in wood is large enough that it likely contributes to incipient decay.


Cognitive synergy in groups and group-to-individual transfer of decision-making competencies.
In a field study (148 participants organized in 38 groups) we tested the effect of group synergy and one's position in relation to the collaborative zone of proximal development (CZPD) on the change of individual decision-making competencies. We used two parallel sets of decision tasks reported in previous research to test rationality and we evaluated individual decision-making competencies in the pre-group and post-group conditions as well as group rationality (as an emergent group level phenomenon). We used multilevel modeling to analyze the data and the results showed that members of synergetic groups had a higher cognitive gain as compared to members of non-synergetic groups, while highly rational members (members above the CZPD) had lower cognitive gains compared to less rational group members (members situated below the CZPD). These insights extend the literature on group-to-individual transfer of learning and have important practical implications as they show that group dynamics influence the development of individual decision-making competencies.


Neuroeconomics.
Neuroeconomics has further bridged the once disparate fields of economics and psychology. Such convergence is almost exclusively attributable to changes within economics. Neuroeconomics has inspired more change within economics than within psychology because the most important findings in neuroeconomics have posed more of a challenge to the standard economic perspective. Neuroeconomics has primarily challenged the standard economic assumption that decision making is a unitary process--a simple matter of integrated and coherent utility maximization--suggesting instead that it is driven by the interaction between automatic and controlled processes. This article reviews neuroeconomic research in three domains of interest to both economists and psychologists: decision making under risk and uncertainty, intertemporal choice, and social decision making. In addition to reviewing new economic models inspired by this research, we also discuss how neuroeconomics may influence future work in psychology.


A critical interpretive synthesis of the intersection of domestic violence with parental issues of mental health and substance misuse.
A critical interpretive synthesis (CIS) methodology was used with the aim of informing practice with children and families when domestic and family violence (DFV) and parental issues relating to alcohol and other drugs (AOD) and mental health (MH) are also present. A CIS is grounded in the literature, but includes questioning of the literature in order to problematise gaps, contradictions and constructions of issues. A review of the literature from 2010 to 2018 was conducted with the structured search strategy identifying 40 relevant research articles. Synthesis and critique of these articles revealed three mutually informative themes through which to understand the literature and how it can inform practice. They were as follows: differences in theoretical approaches and client focus; complexity of system's collaboration; and practices converging on mothers. Taken together, these themes facilitated the development of the synthesising construct: strengthening intersection between DFV, AOD and MH sectors. Attention to practice at multiple levels that responds to the dynamics of gender and the differing impacts of violence was often lacking, particularly in the context of heightened child protection concerns where collaboration between sectors is needed. Both promising and problematic practices relating to gender dynamics and accountability converged on mothers. While there were exceptions, generally, there was an absence of engagement with, and recognition of, the impacts of fathers' patterns of using violence and control on adult and child survivors. Promising practice related to the strengthening of the mother-child relationship and attention to MH and its intersection with domestic violence. Strengthening the intersections between DFV, AOD and MH practices with attention to keeping the perpetrator of violence in view is critical to overcoming the poor practice that can occur when sectors are siloed from each other.


Assessment of cognitive impairments and seizure characteristics in electroconvulsive therapy with and without sodium valproate in manic patients.
The aim of the present study was two-fold: (1) to compare, in a controlled double-blind quasi-randomized clinical trial, treatment improvements, treatment outcome, and cognitive impairments in patients suffering from current manic episodes, while treated with electroconvulsive therapy (ECT) with and without concurrent sodium valproate therapy, and (2) to compare ECT seizure characteristics in patients with and without concurrent sodium valproate therapy. A total of 40 inpatients (mean age = 31.80 years, SD = 8.06; 75% males) suffering from bipolar disorders and currently in a manic state took part in the study. They were quasi-randomly assigned either to the target (continuation of sodium valproate administration) or to the control group (discontinuation of sodium valproate administration). All patients underwent bifrontal ECT for at least 6 sessions. Improvements and cognitive impairments were assessed, and seizure characteristics (duration, threshold) were also recorded. Manic episodes improved significantly over time, and irrespective of the group (target vs. control group). Cognitive impairments did not alter over time or between groups. Seizure duration did not change over time or between groups. Seizure threshold did not change over time, but was lower in the target than in the control group. Continuing the administration of sodium valproate neither adversely affects, nor enhances cognitive impairments or seizure duration, but reduces seizure threshold during ECT in patients suffering from manic episodes. Moreover, gender appeared to be more strongly associated with cognitive impairment and seizure activity than treatment approaches in these psychiatric conditions.


Survival and recovery of enterovirus from foods.
Type 1 poliovirus and type B1 and B6 coxsackieviruses added to eight commercial frozen or convenience foods before storage at room temperature, 10 C, and -20 C were still viable after various intervals of time up to 1 week, 1 month, and 5 months, respectively. Infectivity titers were determined in monkey kidney tissue culture. Decomposition which took place in food stored at room temperature did not affect the survival of virus, and antibiotics controlled bacterial growth during assay. A rapid, significant reduction in type B6 coxsackievirus was observed in cole slaw. Preliminary data indicate that sodium bisulfite could be the responsible ingredient. A less rapid reduction of type 1 poliovirus and type B6 coxsackievirus was found in hashed brown potatoes when stored at 10 C.


Robotics and Navigation as Learning Tools for Fellows Training in Hip Arthroplasty.
The association between implant malpositioning and complications has been repeatedly demonstrated. Recently, technological advancements have allowed for more consistent implant placement. Beyond this obvious application, these technologies may also serve as a learning tool. Thus, the aim of this study was to evaluate the accuracy of fellows' estimation of implant positioning using a robotic system. Data were prospectively collected for all patients undergoing total hip arthroplasty between September 2019 and December 2019. The fellow was blinded to the robotic system. Before reaming and broaching by the senior surgeon, the fellow was asked to place the reamer at 40° of cup inclination and 20° of version. The resulting values were recorded before the true measurements were revealed. A similar process was followed for femoral broaching. The mean difference between the estimated and actual cup inclination and version was 7.24° (P = 0.060) and 4.81° (P = 0.031), respectively. The mean difference in broach version was 7.00° (P = 0.159). Without the robotic system, 43.47% and 69.57% of patients would have had the cup placed outside of the safe zones described by Lewinnek and Callanan, respectively. The estimated anteversion of the acetabular implant was found to be markedly different from its actual anteversion. A considerable portion of the cups would have been positioned outside of the Lewinnek and Callanan "safe zones" provided that the implants would have been manually positioned. The use of robotic or navigation systems may provide useful learning tools for fellows in training to understand their own inaccuracies in estimated implant position and hence refine their abilities.


Random-subset fitting of digital holograms for fast three-dimensional particle tracking [invited].
Fitting scattering solutions to time series of digital holograms is a precise way to measure three-dimensional dynamics of microscale objects such as colloidal particles. However, this inverse-problem approach is computationally expensive. We show that the computational time can be reduced by an order of magnitude or more by fitting to a random subset of the pixels in a hologram. We demonstrate our algorithm on experimentally measured holograms of micrometer-scale colloidal particles, and we show that 20-fold increases in speed, relative to fitting full frames, can be attained while introducing errors in the particle positions of 10 nm or less. The method is straightforward to implement and works for any scattering model. It also enables a parallelization strategy wherein random-subset fitting is used to quickly determine initial guesses that are subsequently used to fit full frames in parallel. This approach may prove particularly useful for studying rare events, such as nucleation, that can only be captured with high frame rates over long times.


Recent developments of thiacalixarene based molecular motifs.
Thiacalixarenes, a subclass of "third generation" calixarenes, exhibit many interesting features such as enlarged ring size, facile chemical modification, and metal complexation due to the presence of bridging sulfur atoms. The thiacalixarene scaffold is a unique host with vast possibilities for functionalization not only at the upper and lower rim but also at the bridging sulfide groups. Modified thiacalixarenes have been used for many applications such as the detection and separation of biologically important cations, anions, and bio-analytes, mimicking molecular logic gates and devices, and synthesis of self-assembled coordination cages, multinuclear complexes, magnetic materials and luminescent materials. This review article summarizes recent developments in the derivatization methods of thiacalixarenes and their utilization in various applications.


Improving fast aspheric convex surface tests with dynamic null screens using LCDs.
A method for testing fast aspheric convex surfaces with dynamic null screens using LCDs is shown. A flat null screen is designed and displayed on an LCD monitor with drop-shaped spots in such a way that the image, which is formed by reflection on the test surface, becomes an exactly square array of circular spots if the surface is perfect. Any departure from this geometry is indicative of defects on the surface. Here the whole surface is tested at once. The position of the spots on the LCD can be changed in a dynamic way, to perform point-shifting of the image spots. The proposed procedure improves the dynamic point-shifting method. As has been shown previously, this process reduces the numerical error during the integration procedure, thereby improving the sensitivity of the test. The positioning accuracy for the screen spots is related to the LCD's spatial resolution. Results of the evaluation of a parabolic convex surface with f/#=0.22 are shown.


Impaired performance of fornix-transected rats on a distal, but not on a proximal, version of the radial-arm maze cue task.
Fornix-transected and sham-operated rats were trained on radial maze cue tasks in which the relative positions of the cues were either fixed (F condition) or varied (V condition) across trials. Proximal and distal visual stimuli were used in 2 different experiments. With proximal stimuli, fornix-transected rats were transiently impaired in the V condition and performed as well as controls in the F condition. However, using extramaze stimuli, fornix-transected rats were severely impaired in the V condition but performed normally in the F condition. According to histological analyses, performance on these cue tasks varied along with the extent of cholinergic depletion in the hippocampus. At the behavioral level, the location and stability of stimuli's relative positions seemed to have influenced rats' performance.


The gene for C10, a member of the beta-chemokine family, is located on mouse chromosome 11 and contains a novel second exon not found in other chemokines.
C10 is a recently described member of the beta-chemokine subfamily of the chemokine superfamily of cytokine proteins. Genomic clones encoding murine C10 were isolated and sequenced. The other members of the beta-chemokine family have a three-exon genomic structure containing, among other sequence similarities, four cysteines spaced in a highly conserved manner. In each of these genes, the second exon contains the first three of the four conserved cysteines, and the third exon contains the last. In contrast to this genomic structure, the C10 gene has four exons, with a novel second exon of 48 nucleotides. Exons 3 and 4 of C10 contain four cysteines distributed in the same manner as in exons 2 and 3 of other beta-chemokine family members. The novel second exon codes for a large number of charged amino acids, and this exon shows no homology to any previously described sequences in computer databases. Linkage studies showed that the C10 gene (Scya6) is closely linked to the Scya2 locus on mouse chromosome 11, indicating that the C10 gene is located in the same region of mouse chromosome 11 as other members of the beta-chemokine family. Thus, although the C10 gene contains a novel exon not found in any other members of the chemokine superfamily, its chromosomal location and conservation of cysteine residues and other structural features suggest that it evolved from the same ancestral gene as other members of the beta-chemokine family.


Safety and effectiveness of minimally invasive sacroiliac joint fusion in women with persistent post-partum posterior pelvic girdle pain: 12-month outcomes from a prospective, multi-center trial.
Postpartum posterior pelvic girdle pain (PPGP) affects nearly 20 % of women who experience back pain in the peripartum period. The sacroiliac joint is a source of this pain in 75 % of women with persistent PPGP. A subset of women will fail to obtain acceptable pain relief from the current array of non-surgical treatment options. The purpose of this study is to assess the safety and effectiveness of minimally invasive sacroiliac (SI) joint fusion in women with chronic SI joint dysfunction whose pain began in the peri-partum period whose symptoms were recalcitrant to non-surgical management. A sub-group analysis of subjects with sacroiliac joint disruption and/or degenerative sacroiliitis enrolled in a prospective, multi-center trial of SI joint fusion was performed. Subjects with PPGP were identified and compared with women without PPGP and with men. Of 172 enrolled subjects, 52 were male, 100 were females without PPGP and 20 females had PPGP. PPGP subjects were significantly younger (43.3 years, vs. 52.8 for females without PPGP and 50.5 for men, p = 0.002). There were no differences in any other demographic or baseline clinical measure. Women with PPGP experienced a significant improvement in pain (-51 mm on VAS), function (-20.6 pts on ODI) and quality of life (SF-36 PCS +10.4, MCS +7.2, EQ-5D +0.31) at 12 months after surgery. These improvements were characteristic of the overall study results; no difference was detected between sub-groups. The sacroiliac joint can be a source of pain in women with persistent PPGP and should be investigated as a pain generator. In this study, women with carefully diagnosed chronic SI joint pain from PPGP recalcitrant to conservative therapies experienced clinically beneficially improvements in pain, disability and quality of life after minimally invasive SI joint fusion using a series of triangular porous plasma spray coated implants.


Laparoscopic and open partial nephrectomy: frequency and long-term follow-up of postoperative collections.
To compare imaging findings between laproscopic and open partial nephrectomy at 6 months after surgery and to follow the evolution of the findings over time. This HIPAA-compliant retrospective study had institutional review board approval and consent was waived. A surgical database was cross-referenced with an imaging database to identify patients who underwent partial nephrectomy and computed tomographic and/or magnetic resonance imaging within 6 months of surgery. Fifty-eight patients (mean age, 61 years; range, 34-78 years; 21 women, 37 men) underwent 62 partial nephrectomies (laparoscopic, 31; open, 31) to remove 68 masses. Two radiologists in consensus reviewed images obtained between 10 days and 72 months (mean, 28 months) after surgery. Preoperative mass size and location and postoperative kidney orientation, fat stranding, parenchymal defect, collection (including size, location, and appearance), and other complications were recorded. Relative incidence of postoperative imaging findings, demographics, and initial imaging findings of both groups were statistically assessed by using Student t and chi(2) tests corrected for multiple comparisons. Common imaging findings following surgery included kidney displacement (48% [30 of 62]), perinephric fat stranding (93% [63 of 68]), parenchymal defect (74% [50 of 68]), and a non-fat-containing postoperative collection 75%, with significantly more posterior renal displacement (P < .01) and a trend toward more persistent fat stranding in the open surgery group. Fifty-one collections were identified in 74% (43 of 58) of patients, with significantly more collections in the laparoscopic (90% [27 of 30] vs 55% [16 of 29]; P < .05). The proportion of resolved collections increased over time, with significantly more resolving in the open group within 24 months of surgery (P < .05). Development or resolution of a collection was not dependent on age, sex, preoperative lesion size, or location (P > .05). Prevalence of findings 2-3 years after partial nephrectomy depends on the surgical approach. After laparoscopic partial nephrectomy, collections are more frequently detected on images and may take longer to resolve than following an open approach.


Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure.
Aberrant activation of the translation initiation machinery is a common property of malignant cells, and is essential for breast carcinoma cells to manifest a malignant phenotype. How does sustained activation of the rate limiting step in protein synthesis so fundamentally alter a cell? In this report, we test the post transcriptional operon theory as a possible mechanism, employing a model system in which apoptosis resistance is conferred on NIH 3T3 cells by ectopic expression of eIF4E. We show (i) there is a set of 255 transcripts that manifest an increase in translational efficiency during eIF4E-mediated escape from apoptosis; (ii) there is a novel prototype 55 nt RNA consensus hairpin structure that is overrepresented in the 5'-untranslated region of translationally activated transcripts; (iii) the identified consensus hairpin structure is sufficient to target a reporter mRNA for translational activation under pro-apoptotic stress, but only when eIF4E is deregulated; and (iv) that osteopontin, one of the translationally activated transcripts harboring the identified consensus hairpin structure functions as one mediator of the apoptosis resistance seen in our model. Our findings offer genome-wide insights into the mechanism of eIF4E-mediated apoptosis resistance and provide a paradigm for the systematic study of posttranscriptional control in normal biology and disease.


Doxorubicin-Induced Cardiomyopathy in Children.
Doxorubicin-induced cardiotoxicity in childhood cancer survivors is a growing problem. The population of patients at risk for cardiovascular disease is steadily increasing, as five-year survival rates for all types of childhood cancers continue to improve. Doxorubicin affects the developing heart differently from the adult heart and in a subset of exposed patients, childhood exposure leads to late, irreversible cardiomyopathy. Notably, the prevalence of late-onset toxicity is increasing in parallel with improved survival. By the year 2020, it is estimated that there will be 500,000 childhood cancer survivors and over 50,000 of them will suffer from doxorubicin-induced cardiotoxicity. The majority of the research to-date, concentrated on childhood cancer survivors, has focused mostly on clinical outcomes through well-designed epidemiological and retrospective cohort studies. Preclinical studies have elucidated many of the cellular mechanisms that elicit acute toxicity in cardiomyocytes. However, more research is needed in the areas of early- and late-onset cardiotoxicity and more importantly improving the scientific understanding of how other cells present in the cardiac milieu are impacted by doxorubicin exposure. The overall goal of this review is to succinctly summarize the major clinical and preclinical studies focused on doxorubicin-induced cardiotoxicity. As the prevalence of patients affected by doxorubicin exposure continues to increase, it is imperative that the major gaps in existing research are identified and subsequently utilized to develop appropriate research priorities for the coming years. Well-designed preclinical research models will enhance our understanding of the pathophysiology of doxorubicin-induced cardiotoxicity and directly lead to better diagnosis, treatment, and prevention. © 2019 American Physiological Society. Compr Physiol 9:905-931, 2019.


Estimating fish consumption rates for Ontario Amerindians.
The routine assessment of human exposure to contaminants requires that exposure via consumption of freshwater fish be considered because many chemicals persist and/or bioaccumulate in fish. Estimates of fish consumption rate were determined for Ontario Amerindians from data on the concentration of mercury in the hair of 4,327 Amerindians residing in 58 reserves across the province, combined with data on mercury concentrations in three commonly consumed species of fish collected from lakes surrounding these reserves. Estimated rates of fish consumption were found to differ between sexes, with males consuming a geometric mean of 19 g of fish per day, while females were estimated to consume a geometric mean of 14 g/day. Fish consumption rate was found to increase with increasing latitude, a surrogate measure of community isolation, and to increase with age. Seasonal variation was also noted, with fish consumption rates being highest during summer months and lowest in winter. These data may provide regulatory agencies with a more statistically representative basis upon which to establish assumptions concerning fish consumption rates for risk assessment purposes. Factors such as the location of the exposed population, age and sex of exposed individuals, and time of year in which an assessment is being conducted, should also be considered as specific situations require.


Autonomic responses during inhalation of natural fragrance of Cedrol in humans.
It is well known that odors affect behaviors and autonomic functions. Previous studies reported that some compounds in cedar wood essence induced behavioral changes including sedative effects. In the present study, we analyzed cardiovascular and respiratory functions while subjects were inhaling fumes of pure compound (Cedrol) which was extracted from cedar wood oil. Vaporized Cedrol (14.2+/-1.7 microg/l, 5 l/min) and blank air (5 l/min) were presented to healthy human subjects (n=26) via a face mask, while ECGs, heart rate (HR), systolic blood pressure (SBP), diastolic BP (DBP), and respiratory rates (RR) were monitored. Statistical analyses indicated that exposure to Cedrol significantly decreased HR, SBP, and DBP compared to blank air while it increased baroreceptor sensitivity. Furthermore, respiratory rate was reduced during exposure to Cedrol. These results, along with the previous studies reporting close relationship between respiratory and cardiovascular functions, suggest that these changes in respiratory functions were consistent with above cardiovascular alterations. Spectral analysis of HR variability indicated an increase in high frequency (HF) component (index of parasympathetic activity), and a decrease in ratio of low frequency to high frequency components (LF/HF) (index of sympathovagal balance) during Cedrol inhalation. Furthermore, Cedrol inhalation significantly decreased LF components of both SBP and DBP variability, which reflected vasomotor sympathetic activity. Taken together, these patterns of changes in the autonomic parameters indicated that Cedrol inhalation induced an increase in parasympathetic activity and a reduction in sympathetic activity, consistent with the idea of a relaxant effect of Cedrol.


Meat consumption and risk of lung cancer among never-smoking women.
The relationship between diet and lung cancer, apart from the protective effect of fruit and vegetables, is poorly understood. Reports on the role of dietary components such as meat are inconsistent, and few studies include sufficient numbers of nonsmokers. We examined the relationship between meat consumption and never-smoking lung cancer in a hospital-based case-control study of Singapore Chinese women, a population with low smoking prevalence. Three hundred and ninety-nine cases and 815 controls were recruited, of whom 258 cases and 712 controls were never smokers. A standardized questionnaire (which included a food frequency questionnaire module) was administered by trained interviewers. Among these never smokers, fruit and vegetable intake were inversely associated with lung cancer risk. Seventy-two percent of meat consumed was white meat (chicken or fish). Meat consumption overall was inversely associated with lung cancer [adjusted odds ratio (OR), 0.88, 0.59 for second, third tertiles, P (trend) = .012]. An inverse relationship between fish consumption and lung cancer (adjusted OR, 0.81, 0.47 for 2nd, 3rd tertiles, P (trend) < .001) was observed. No association was seen between consumption of processed meats and lung cancer, nor between dietary heterocyclic amines and lung cancer. Our data suggest that fish consumption may be protective against lung cancer in never smokers.


Sequence-Independent Self-Assembly of Germ Granule mRNAs into Homotypic Clusters.
mRNAs enriched in membraneless condensates provide functional compartmentalization within cells. The mechanisms that recruit transcripts to condensates are under intense study; however, how mRNAs organize once they reach a granule remains poorly understood. Here, we report on a self-sorting mechanism by which multiple mRNAs derived from the same gene assemble into discrete homotypic clusters. We demonstrate that in vivo mRNA localization to granules and self-assembly within granules are governed by different mRNA features: localization is encoded by specific RNA regions, whereas self-assembly involves the entire mRNA, does not involve sequence-specific, ordered intermolecular RNA:RNA interactions, and is thus RNA sequence independent. We propose that the ability of mRNAs to self-sort into homotypic assemblies is an inherent property of an messenger ribonucleoprotein (mRNP) that is augmented under conditions that increase RNA concentration, such as upon enrichment in RNA-protein granules, a process that appears conserved in diverse cellular contexts and organisms.


Qishenyiqi protects ligation-induced left ventricular remodeling by attenuating inflammation and fibrosis via STAT3 and NF-κB signaling pathway.
Qi-shen-yi-qi (QSYQ), a formula used for the routine treatment of heart failure (HF) in China, has been demonstrated to improve cardiac function through down-regulating the activation of the Renin-Angiotensin-Aldosterone System (RAAS). However, the mechanisms governing its therapeutic effects are largely unknown. The present study aims to demonstrate that QSYQ treatment can prevent left ventricular remodeling in heart failure by attenuating oxidative stress and inhabiting inflammation. Sprague-Dawley (SD) rats were randomly divided into 6 groups: sham group, model group (LAD coronary artery ligation), QSYQ group with high dosage, middle dosage and low dosage (LAD ligation and treated with QSYQ), and captopril group (LAD ligation and treated with captopril as the positive drug). Indicators of fibrosis (Masson, MMPs, and collagens) and inflammation factors were detected 28 days after surgery. Results of hemodynamic alterations (dp/dt value) in the model group as well as other ventricular remodeling (VR) markers, such as MMP-2, MMP-9, collagen I and III elevated compared with sham group. VR was accompanied by activation of RAAS (angiotensin II and NADPHoxidase). Levels of pro-inflammatory cytokines (TNF-α, IL-6) in myocardial tissue were also up-regulated. Treatment of QSYQ improved cardiac remodeling through counter-acting the aforementioned events. The improvement of QSYQ was accompanied with a restoration of angiotensin II-NADPHoxidase-ROS-MMPs pathways. In addition, "therapeutic" QSYQ administration can reduce both TNF-α-NF-B and IL-6-STAT3 pathways, respectively, which further proves the beneficial effects of QSYQ. Our study demonstrated that QSYQ protected LAD ligation-induced left VR via attenuating AngII -NADPH oxidase pathway and inhabiting inflammation. These findings provide evidence as to the cardiac protective efficacy of QSYQ to HF and explain the beneficial effects of QSYQ in the clinical application for HF.


Evaluating a brief alcohol intervention with fraternities.
The current study tested the efficacy of a brief intervention designed to reduce drinking and drinking-related consequences among first-year fraternity members. Twelve fraternities were randomly assigned to receive either a motivational enhancement intervention with individual and housewide feedback components (n = 6 houses) or a treatment-as-usual control condition (n = 6 houses). Individual feedback was delivered either by peer interviewers or professional research staff. Participants were assessed during their pledge (first) year of house membership and during a follow-up period 1 year later. Of the participants who completed follow-up (N = 120), fraternity members who received the brief intervention reported significant reductions in alcohol use (total average consumption) and typical peak blood alcohol concentrations when compared with fraternity members in the control condition. No differences in drinking-related consequences were observed. Fraternity members who received their individualized feedback from peer interviewers and professional members of the research staff reported similar outcomes. Results provide support for the efficacy of a brief motivational enhancement intervention in reducing drinking within this high-risk population. The cost-effective use of peer interviewers appears to be a promising strategy for delivering individualized prevention programming in college populations.


Successful triple immunoenzymatic method employing primary antibodies from same species and same immunoglobulin subclass.
Protocols for immunohistochemical (IHC) detection of multiple antigens in the same tissue sections have been developed using primary antibodies directly conjugated to different enzymes or fluorochromes, or ones that have been raised in different species, or from different immunoglobulin (Ig) classes or subclasses. For antibodies lacking such dissimilarities, very few proposals have been published with varying degrees of generalizability. In this report we present a successful triple IHC protocol engaging three unconjugated monoclonal primary antibodies raised in the same species and of the same Ig subclass. Compared to other methods, our results showed that denaturation of the preceding reaction complex by microwave heating, combined with additional suppression of enzyme activity, enabled the detection of all three reactions by using the same detection system, with no cross reaction observed. Moreover, expression patterns of each of the three antigens in the triple stained sections, was found to be similar to the pattern observed when single staining was performed. Unlike previous reports, no damage of targeted antigens or tissues did occur following this protocol. Furthermore, the contrast of the colors employed was investigated by computerized color deconvolution, and the three reactions products were successfully separated into three individual images that could be used for further objective quantification.


Long-term treatment with a specific Rho-kinase inhibitor suppresses cardiac allograft vasculopathy in mice.
Cardiac allograft vasculopathy (CAV) continues to be a major cause of late graft failure after cardiac transplantation. We have demonstrated that Rho-kinase, an effector of the small GTPase Rho, plays an important role in the pathogenesis of arteriosclerosis. In this study, we examined whether the Rho-kinase-mediated pathway is also involved in the pathogenesis of CAV using a specific Rho-kinase inhibitor and a dominant-negative Rho-kinase. Hearts from AKR mice were heterotopically transplanted to C3H/He (allograft) or AKR mice (isograft), and the effects of long-term oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil, on CAV were examined at 2 and 4 weeks after the transplantation. Coronary remodeling in the allografts characterized by intimal thickening and perivascular fibrosis was dose-dependently suppressed in the fasudil group compared with the control group (P<0.01, n=9 to 10). The inhibitory effects of hydroxyfasudil were mimicked by in vivo gene transfer of dominant-negative Rho-kinase (P<0.05, n=4). Among the proinflammatory cytokines examined, those of macrophage migration inhibitory factor, interferon-gamma, and transforming growth factor-beta1 were upregulated in the control group and were dose-dependently inhibited in the fasudil group (P<0.01, n=5). Vascular inflammation in the allografts, as evidenced by accumulation of inflammatory cells (macrophages and T cells), was also significantly inhibited in the fasudil group (P<0.05, n=5 to 10). These results indicate that long-term treatment with fasudil suppresses CAV in mice, suggesting that Rho-kinase is an important therapeutic target for the prevention of CAV.


Efficacy and cultural appropriateness of psychosocial interventions for paediatric burn patients and caregivers: a systematic review.
Paediatric burns are highly painful and traumatising injuries that are overrepresented among Aboriginal and Torres Strait Islander people. Paediatric burn patients' pain remains poorly managed by pharmacological interventions, leading to increased anxiety, distress, and trauma in patients and their caregivers. Non-pharmacological psychosocial interventions have been suggested as effective in reducing pain and psychological morbidities among paediatric burn patients and their caregivers; however, their degree of effectiveness and appropriateness for Aboriginal and Torres Strait Islander people is unclear. A non-date restricted systematic review was conducted through four databases. Studies published in English assessing psychosocial interventions on paediatric burn patients' physical pain along with theirs and/or their caregiver's anxiety, distress, or trauma symptoms were identified and included in this review. Included studies were assessed for their ability to reduce one of the outcomes of interests and for their reflection of Aboriginal and Torres Strait Islander peoples' perspectives of health. Of the 3178 identified references, 17 were eligible. These include distraction based techniques (n = 8), hypnosis/familiar imagery (n = 2), therapeutic approaches (n = 4), and patient preparation/procedural control (n = 3). Distraction techniques incorporating procedural preparation reduced pain, while discharge preparation and increased 'patient control' reduced patient and caregiver anxiety; and internet based Cognitive Behaviour Therapy reduced short-term but not long-term post-traumatic stress symptoms. No interventions reflected Aboriginal and Torres Strait Islander peoples' perspectives of health; and few targeted caregivers or focused on reducing their symptoms. The development and assessment of psychosocial interventions to appropriately meet the needs of Aboriginal and Torres Strait Islander paediatric burn patients is required.


Mortality trends in a cohort of opiate addicts, Catalonia, Spain.
Opiate addiction affects young adults whose life expectancy is reduced as a consequence of their habit. In the midst of the AIDS epidemic, the present study objective was to analyse recent overall and cause-specific mortality trends among opiate addicts in Catalonia (Spain). Mortality was assessed retrospectively in an opiate addict cohort assembled from admissions to hospital emergency wards and drug treatment centres during the period 1985-1991. The cohort included 12 711 opiate addicts (12 045 men and 3666 women) aged 15-44 years. Overall and cause-specific mortality trends were analysed using age as the time scale and Cox regression with staggered entry determined by the age at entry in the study. Annual trends were adjusted by sex and source of entry, and were stratified by length of opiate use. Mortality rates increased throughout the entire period from 13.8 to 34.8 deaths per 1000 person-years, with a statistically significant increase in 1987-1988 and 1988-1989. In a model including age, gender, source of entry and length of drug use, risk increased significantly in men and for longer length of use, but not with age and for source of entry into the study cohort. The causes of death associated with high mortality rates were AIDS and the causes directly related to addiction. A threefold increase in mortality rates was observed during the period, mainly accounted for by AIDS and direct addiction-related causes. Length of opiate use was an important determinant of mortality.


Prevalence of loss of all teeth (edentulism) and associated factors in older adults in China, Ghana, India, Mexico, Russia and South Africa.
Little information exists about the loss of all one's teeth (edentulism) among older adults in low- and middle-income countries. This study examines the prevalence of edentulism and associated factors among older adults in a cross-sectional study across six such countries. Data from the World Health Organization (WHO's) Study on global AGEing and adult health (SAGE) Wave 1 was used for this study with adults aged 50-plus from China (N = 13,367), Ghana (N = 4724), India (N = 7150), Mexico (N = 2315), Russian Federation (N = 3938) and South Africa (N = 3840). Multivariate regression was used to assess predictors of edentulism. The overall prevalence of edentulism was 11.7% in the six countries, with India, Mexico, and Russia has higher prevalence rates (16.3%-21.7%) than China, Ghana, and South Africa (3.0%-9.0%). In multivariate logistic analysis sociodemographic factors (older age, lower education), chronic conditions (arthritis, asthma), health risk behaviour (former daily tobacco use, inadequate fruits and vegetable consumption) and other health related variables (functional disability and low social cohesion) were associated with edentulism. The national estimates and identified factors associated with edentulism among older adults across the six countries helps to identify areas for further exploration and targets for intervention.


The autoimmune bases of infertility and pregnancy loss.
Several lines of evidence suggest that autoimmune mechanisms may influence the reproductive life and fertility of both sexes, commonly manifesting as infertility or pregnancy loss. Part of the controversy that characterizes this assumption derives from the overlooked suspect of autoimmune conditions in the absence of symptoms or the limited physician awareness in a gynecological setting. Numerous autoimmune diseases, including but not limited to systemic lupus erythematosus and anti-phospholipid syndrome, may be associated with infertility and pregnancy loss through different putative mechanisms. First, serum autoantibodies such as anti-phospholipid, anti-thyroid, or antinuclear antibodies may be directly associated with infertility, regardless of the presence of a clinically overt autoimmune disease. Second, autoimmunity may affect all stages of fertility, via ovarian failure, testicular failure, implantation failure, and pregnancy loss. Third, infertility may also be secondary to vasculitis associated with other conditions such as systemic lupus erythematosus and diabetes mellitus. This review article will illustrate and critically discuss the available data on the link between the breakdown of tolerance that characterizes autoimmune diseases and the changes in reproductive life that affect patients in real clinical setting and that often constitute the iatrotropic stimulus.


Pain in Guillain-Barre syndrome: a long-term follow-up study.
Pain in Guillain-Barré syndrome (GBS) may be pronounced and is often overlooked. To obtain detailed information about pain in GBS and its clinical variants. This was a prospective cohort study in 156 patients with GBS (including 18 patients with Miller Fisher syndrome [MFS]). We assessed the location, type, and intensity of pain using questionnaires at standard time points during a 1-year follow-up. Pain data were compared to other clinical features and serology. Pain was reported in the 2 weeks preceding weakness in 36% of patients, 66% reported pain in the acute phase (first 3 weeks after inclusion), and 38% reported pain after 1 year. In the majority of patients, the intensity of pain was moderate to severe. Longitudinal analysis showed high mean pain intensity scores during the entire follow-up. Pain occurred in the whole spectrum of GBS. The mean pain intensity was predominantly high in patients with GBS (non-MFS), patients with sensory disturbances, and severely affected patients. Only during later stages of disease, severity of weakness and disability were significantly correlated with intensity of pain. Pain is a common and often severe symptom in the whole spectrum of GBS (including MFS, mildly affected, and pure motor patients). As it frequently occurs as the first symptom, but may even last for at least 1 year, pain in GBS requires full attention. It is likely that sensory nerve fiber involvement results in more severe pain.


[The newest therapeutic directions in the rehabilitation of patients with mental disorders].
In this paper, the authors attempted to present the comprehensive literature review on the newest therapeutic interventions such as cognitive remediation therapy (CRT), mindfulness-based cognitive therapy (MBCT), social cognition and interaction training (SCIT), and acceptance and commitment therapy (ACT) which appeared promising whilst their implementing among schizophrenic patients, patients with anxiety disorders, eating disorders, and affective disorders. In the presented work particular attention was focused on two kinds of psychotherapeutic interventions: social cognitive trainings and cognitive remediation therapy (CRT) and their effectiveness in the rehabilitation process of schizophrenic patients. The growing body of research based on application of the above mentioned techniques in psychiatric population gives remarkable hope to improve quality of cognitive and psychosocial therapeutic interventions and to set up both complex and comprehensive therapeutic programme for patients with mental disorders.


Canadian Physical Activity Guidelines for the Early Years (aged 0-4 years).
The Canadian Society for Exercise Physiology (CSEP), with assistance from multiple partners, stakeholders, and researchers, developed the first Canadian Physical Activity Guidelines for the Early Years (aged 0-4 years). These national guidelines were created in response to an urgent call from public health, health care, child care, and fitness practitioners for healthy active living guidance for the early years. The guideline development process was informed by the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument and the evidence assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The recommendations are informed by evidence from a systematic review that examined the relationships between physical activity and health indicators (healthy body weight, bone and skeletal health, motor skill development, psychosocial health, cognitive development, and cardio-metabolic disease risk factors) for three age groups (infants aged <1 year; toddlers aged 1-2 years; preschoolers aged 3-4 years). The new guidelines include a preamble to provide context, followed by the specific recommendations. The final guidelines benefitted from an extensive on-line consultation process with input from over 900 domestic and international stakeholders, end-users, and key informants. The final guideline recommendations state that for healthy growth and development, infants (aged <1 year) should be physically active several times daily - particularly through interactive floor-based play. Toddlers (aged 1-2 years) and preschoolers (aged 3-4 years) should accumulate at least 180 min of physical activity at any intensity spread throughout the day, including a variety of activities in different environments, activities that develop movement skills, and progression toward at least 60 min of energetic play by 5 years of age. More daily physical activity provides greater benefits.


EIT Imaging of admittivities with a D-bar method and spatial prior: experimental results for absolute and difference imaging.
Electrical impedance tomography (EIT) is an emerging imaging modality that uses harmless electrical measurements taken on electrodes at a body's surface to recover information about the internal electrical conductivity and or permittivity. The image reconstruction task of EIT is a highly nonlinear inverse problem that is sensitive to noise and modeling errors making the image reconstruction task challenging. D-bar methods solve the nonlinear problem directly, bypassing the need for detailed and time-intensive forward models, to provide absolute (static) as well as time-difference EIT images. Coupling the D-bar methodology with the inclusion of high confidence a priori data results in a noise-robust regularized image reconstruction method. In this work, the a priori D-bar method for complex admittivities is demonstrated effective on experimental tank data for absolute imaging for the first time. Additionally, the method is adjusted for, and tested on, time-difference imaging scenarios. The ability of the method to be used for conductivity, permittivity, absolute as well as time-difference imaging provides the user with great flexibility without a high computational cost.


Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association.
Epidemiology and experimental studies provide an overwhelming support of the notion that diets high in red or processed meat accompany an elevated risk of developing pre-neoplastic colorectal adenoma and frank colorectal carcinoma (CRC). The underlying mechanisms are disputed; thus several hypotheses have been proposed. A large body of reports converges, however, on haem and nitrosyl haem as major contributors to the CRC development, presumably acting through various mechanisms. Apart from a potentially higher intestinal mutagenic load among consumers on a diet rich in red/processed meat, other mechanisms involving subtle interference with colorectal stem/progenitor cell survival or maturation are likewise at play. From an overarching perspective, suggested candidate mechanisms for red/processed meat-induced CRC appear as three partly overlapping tenets: (i) increased N-nitrosation/oxidative load leading to DNA adducts and lipid peroxidation in the intestinal epithelium, (ii) proliferative stimulation of the epithelium through haem or food-derived metabolites that either act directly or subsequent to conversion, and (iii) higher inflammatory response, which may trigger a wide cascade of pro-malignant processes. In this review, we summarize and discuss major findings of the area in the context of potentially pertinent mechanisms underlying the above-mentioned association between consumption of red/processed meat and increased risk of developing CRC.


Assessment of microRNA differential expression and detection in multiplexed small RNA sequencing data.
Small RNA sequencing can be used to gain an unprecedented amount of detail into the microRNA transcriptome. The relatively high cost and low throughput of sequencing bases technologies can potentially be offset by the use of multiplexing. However, multiplexing involves a trade-off between increased number of sequenced samples and reduced number of reads per sample (i.e., lower depth of coverage). To assess the effect of different sequencing depths owing to multiplexing on microRNA differential expression and detection, we sequenced the small RNA of lung tissue samples collected in a clinical setting by multiplexing one, three, six, nine, or 12 samples per lane using the Illumina HiSeq 2000. As expected, the numbers of reads obtained per sample decreased as the number of samples in a multiplex increased. Furthermore, after normalization, replicate samples included in distinct multiplexes were highly correlated (R > 0.97). When detecting differential microRNA expression between groups of samples, microRNAs with average expression >1 reads per million (RPM) had reproducible fold change estimates (signal to noise) independent of the degree of multiplexing. The number of microRNAs detected was strongly correlated with the log2 number of reads aligning to microRNA loci (R = 0.96). However, most additional microRNAs detected in samples with greater sequencing depth were in the range of expression which had lower fold change reproducibility. These findings elucidate the trade-off between increasing the number of samples in a multiplex with decreasing sequencing depth and will aid in the design of large-scale clinical studies exploring microRNA expression and its role in disease.


The influence of brain death on liver function.
In this study, we investigated the influence of brain death on inflammatory response and the effects of brain death on liver function both directly after explantation and after reoxygenation. The influence of brain death on liver function was studied in rats using a brain death model and the liver slice model to mimic reoxygenation. Liver function was assessed by measuring the ATP content and the ATP-driven urea synthesis. The activation of non-parenchymal cells was studied by measuring mRNA levels of IL-10, cytokine production (IL-10 and IL-1 beta) and inducible nitric oxide synthases (iNOS) upregulation (mRNA) and protein level. Brain death had no direct influence on the ATP content of the liver. However, it led to induction of several cytokines because of activation of non-parenchymal cells, which led to upregulation of iNOS and to nitric oxide metabolites production. It is known that cytokine production may influence the drug metabolism capacity; however, no influence of brain death on drug metabolism was observed. An explanation may be the relatively short experimental period. Kupffer cells seem to be activated during the onset of brain death induction; however, they become quiescent when liver slices of brain dead rats were reoxygenated during incubation. Other non-parenchymal cells, possibly the endothelial cells, remain activated during incubation and reoxygenation in slices from brain death donors but not in slices from control livers. Future experiments in our rat liver transplantation model need to elucidate the implications of these findings.


beta-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity.
In several pedigrees of early onset familial Alzheimer's disease (FAD), point mutations in the beta-amyloid precursor protein (APP) gene are genetically linked to the disease. This finding implicates APP in the pathogenesis of Alzheimer's disease in these individuals. To understand the in vivo function of APP and its processing, we have generated an APP-null mutation in mice. Homozygous APP-deficient mice were viable and fertile. However, the mutant animals weighed 15%-20% less than age-matched wild-type controls. Neurological evaluation showed that the APP-deficient mice exhibited a decreased locomotor activity and forelimb grip strength, indicating a compromised neuronal or muscular function. In addition, four out of six homozygous mice showed reactive gliosis at 14 weeks of age, suggesting an impaired neuronal function as a result of the APP-null mutation.


Factors affecting the duration of nestling period and fledging order in Tengmalm's owl (Aegolius funereus): effect of wing length and hatching sequence.
In altricial birds, the nestling period is an important part of the breeding phase because the juveniles may spend quite a long time in the nest, with associated high energy costs for the parents. The length of the nestling period can be variable and its duration may be influenced by both biotic and abiotic factors; however, studies of this have mostly been undertaken on passerine birds. We studied individual duration of nestling period of 98 Tengmalm's owl chicks (Aegolius funereus) at 27 nests during five breeding seasons using a camera and chip system and radio-telemetry. We found the nestlings stayed in the nest box for 27 - 38 days from hatching (mean ± SD, 32.4 ± 2.2 days). The individual duration of nestling period was negatively related to wing length, but no formally significant effect was found for body weight, sex, prey availability and/or weather conditions. The fledging sequence of individual nestlings was primarily related to hatching order; no relationship with wing length and/or other factors was found in this case. We suggest the length of wing is the most important measure of body condition and individual quality in Tengmalm's owl young determining the duration of the nestling period. Other differences from passerines (e.g., the lack of effect of weather or prey availability on nestling period) are considered likely to be due to different life-history traits, in particular different food habits and nesting sites and greater risk of nest predation among passerines.


Optimal hemoglobin concentration in patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury.
The review outlines recent clinical and experimental studies regarding the effects of red blood-cell transfusion on clinical outcome in neurocritical patients, including patients with subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Optimal hemoglobin transfusion trigger and the role of other transfusion indicators for neurocritical patients are discussed. Acute anemia (hemoglobin levels near 7 g/dl) is well tolerated by healthy subjects, but extreme anemia might negatively affect clinical outcome of neurocritical patients. Conversely, high hemoglobin levels, attained by means other than red blood-cell transfusion, improve clinical outcome, whereas red blood-cell transfusion is associated with poorer clinical outcome (mortality, length of stay and disability) in patients presenting subarachnoid hemorrhage, acute ischemic stroke and traumatic brain injury. Studies defining the optimal hemoglobin concentration in neurocritical patients are lacking, but a restrictive transfusion policy seems to be safe and is often recommended. In the near future, signals coming from the brain, such as brain tissue oxygen tension and regional cerebral oxygen saturation, might potentially be developed into transfusion triggers. Both severe anemia and red blood-cell transfusion may negatively influence clinical outcome in neurocritical patients. Acceptance of low hemoglobin concentrations may be justified by avoiding negative transfusion effects. No evidence-based transfusion trigger in neurocritical patients can be recommended.


Recognizing a Heart Attack: Patients' Knowledge of Cardiovascular Risk Factors and Its Relation to Prehospital Decision Delay in Acute Coronary Syndrome.
In acute coronary syndromes (ACSs), longer decision delay - the time patients wait before seeking medical attention after symptoms have started - increases the risk of complications and death. However, many patients wait much longer than recommended and research is needed investigating how patient decision delay can be reduced. In a cross-sectional study of 120 ACS survivors, we investigated the relationship between knowledge of cardiovascular risk factors and decision delay. Several days after the onset of a cardiac event, patients completed a questionnaire measuring demographics, decision delay, objective knowledge of cardiovascular risks factors and of ACS symptoms, and subjective perceptions of symptoms during the cardiac episode. Relevant clinical data were extracted from patients' medical records. In a multiple linear regression analysis, controlling for demographic and clinical factors, objective knowledge of cardiovascular risk factors and ACS symptoms, and subjective attributions of symptoms to a cardiac cause were related to shorter decision delays. Among patients with relatively high knowledge of risk factors, only 5% waited more than 1 h to seek help, compared to 22% among patients with relatively low knowledge. These results suggest that knowledge of the factors that increase the risk of developing cardiovascular disease could play a role in patient decision making during an acute cardiac event. We discuss methodological issues and potential underlying mechanisms related to decision heuristics and biases, which can inform future research.


Selective absorption of visible light in film-coupled nanoparticles by exciting magnetic resonance.
We numerically demonstrate selective absorption of visible light in film-coupled nanoparticle metamaterials by excitation of magnetic resonance. The physical mechanism of magnetic resonance is elucidated with the help of electromagnetic field distribution. Resonance wavelengths are shown to be strongly dependent on geometric parameters. Representative inductor-capacitor models are employed to further confirm the underlying mechanism and explain the unique behaviors of magnetic resonance in film-coupled nanoparticle metamaterials.


Favourable medium term outcome following hepatic vein recanalisation and/or transjugular intrahepatic portosystemic shunt for Budd Chiari syndrome.
We report our experience with management of patients with Budd Chiari syndrome over the past two decades. In 1996 we described a novel approach involving recanalisation of hepatic veins by combined percutaneous and transvenous approaches. This was incorporated into an algorithm published in 1999 in which our preferred treatment for all cases of Budd Chiari syndrome with short segment occlusion or stenosis of the hepatic veins involves recanalisation of the hepatic veins by transvenous or combined percutaneous-transvenous approaches. In symptomatic Budd Chiari syndrome where recanalisation is not possible, we perform transjugular intrahepatic portosystemic shunts (TIPS) because TIPS decompresses the portal circulation directly in an adjustable way. In this series of patients with Budd Chiari syndrome treated with radiological interventions alone, we assess their medium term outcome using two independent objective prognostic indices. We retrospectively studied 61 patients with non-malignant Budd Chiari syndrome treated by radiological intervention alone in our centre. Actuarial survival for the entire cohort at one year and five years was 94% and 87%, respectively. Survival of our patients with mild disease (according to the Murad classification) was 100% at one year and at five years, with intermediate disease severity 94% at one year and 86% at five years, and with severe disease 85% at one year and 77% at five years. Management of Budd Chiari syndrome by interventional radiology resulted in excellent medium term survival for patients in all categories of disease severity.


Antigenic diversity of meningococcal outer membrane protein PorA has implications for epidemiological analysis and vaccine design.
The currently used serological subtyping scheme for the pathogen Neisseria meningitidis is not comprehensive, a proportion of isolates are reported as not subtypeable (NST), and few isolates are fully characterized with two subtypes for each strain. To establish the reasons for this and to assess the effectiveness of DNA-based subtyping schemes, dot blot hybridization and nucleotide sequence analyses were used to characterize the genes encoding antigenic variants of the meningococcal subtyping antigen, the PorA protein. A total of 233 strains, including 174 serologically NST and 59 partially or completely subtyped meningococcal strains, were surveyed. The NST isolates were chosen to be temporally and geographically representative of NST strains, isolated in England and Wales, and submitted to the Meningococcal Reference Unit in the period 1989 to 1991. The DNA-based analyses demonstrated that all of the strains examined possessed a porA gene. Some of these strains were serologically NST because of a lack of monoclonal antibodies against certain PorA epitopes; in other cases, strains expressed minor variants of known PorA epitopes that did not react with monoclonal antibodies in serological assays. Lack of expression remained a possible explanation for serological typing failure in some cases. These findings have important implications for epidemiological analysis and vaccine design and demonstrate the need for genetic characterization, rather than phenotypic characterization using monoclonal antibodies, for the identification of meningococcal strains.


California Public Hospitals Improved Quality of Care Under Medicaid Waiver Program.
California has 12 county-owned and operated hospital systems and 5 University of California hospitals designated as public hospitals. These organizations deliver the majority of inpatient care and a significant amount of outpatient care to Medicaid patients in the state. In 2010, California was the first state in the nation to implement a five-year Delivery System Reform Incentive Payment (DSRIP) program under the Section §1115 Medicaid "Bridge to Reform" waiver to improve the capacity of these hospitals to deliver high quality and more efficient care. The California DSRIP was the first program in a continuing national initiative to reform the Medicaid delivery system while remaining budget neutral. An extensive evaluation revealed major advances in infrastructure development, delivery of health care, and patient outcomes during the program. The results highlight the importance of joint federal and state investments in bolstering the capacity of safety net providers to deliver high-quality care, and they emphasize the need for continued investment in the safety net. The California DSRIP was followed by a program called Public Hospital Redesign and Incentives in Medi-Cal (PRIME), which incentivizes improvements in expanded and new areas of care not addressed by DSRIP


Hemodynamic consequences of ventricular interaction as assessed by model analysis.
Because of close anatomic association, the pressure and volume in one ventricle can directly influence the pressure and volume in the opposite ventricle. To examine the importance of ventricular interdependence in controlling the circulation, we developed a computer model in which ventricular interdependence could be turned on and off. Left ventricular chamber contractility, as judged by maximal elastance (Emax), was enhanced on the order of 10% as a result of ventricular interaction, whereas right ventricular Emax was affected by as much as 60% under physiological conditions. With increases in systemic vascular resistance, ventricular interaction caused a smaller stroke volume (SV) decrease than with no interaction. For canine data (SV = 21.4 ml), doubling systemic vascular resistance decreased SV by 3.7 without ventricular interdependence, 3.5 with diastolic ventricular interdependence, and 3.3 ml with diastolic and systolic ventricular interdependence. In contrast, with increases in pulmonary vascular resistance, ventricular interaction caused a greater decrease in SV than with no interaction present. Decreasing left ventricular free wall elastance or right ventricular free wall elastance decreased SV. Diastolic ventricular interdependence reduced the SV changes, whereas systolic ventricular interdependence accentuated the SV changes with alterations in right and left ventricular free-wall elastance. The results of the present simulation demonstrate the importance of ventricular interdependence in the observed responses of the right ventricle to volume overload, pressure overload, and ischemia.


Desulforegula conservatrix gen. nov., sp. nov., a long-chain fatty acid-oxidizing, sulfate-reducing bacterium isolated from sediments of a freshwater lake.
A novel sulfate-reducing bacterium, strain Mb1PaT, was isolated from the sediments of a freshwater floodplain lake. Cells of strain Mb1PaT were rod-shaped, 1-1.3 microm wide and 2.6-3 microm long, motile and Gram-negative. The bacterium grew on straight-chain carboxylic acids with 4-17 carbon atoms. Electron donors with an even number of carbon atoms were oxidized to acetate and electron donors with an odd number of carbon atoms were oxidized to acetate and propionate. No other compounds were found to be used as electron donors. No growth occurred in the absence of sulfate. The optimum temperature for growth was between 25 and 30 degrees C and the maximum temperature for growth was 32 degrees C. Strain Mb1PaT grew very slowly in medium with 5 g NaCl l(-1) with optimum growth occurring with up to 1.0 g NaCl l(-1). Analysis of the 16S rRNA gene showed that strain Mb1PaT belonged to the delta-subclass of the Proteobacteria, was a member of the family Desulfobacteraceae, but lacked similarity with any currently described representatives. The combined phylogenetic analysis and physiological data indicate that strain Mb1PaT represents a new genus and the name Desulforegula conservatrix is proposed. The type strain is Mb1PaT (= DSM 13527T = ATCC BAA-134T).


Ketorolac attenuates cardiopulmonary derangements in sheep with combined burn and smoke inhalation injury.
Massive cutaneous burn combined with smoke inhalation causes high mortality in fire victims. Cyclo-oxygenase (COX) and inducible nitric oxide (NO) synthase (iNOS) have been shown to be up-regulated in burn injury. Ketorolac, a non-steroidal, anti-inflammatory agent (NSAID), inhibits prostaglandin and thromboxane synthesis through inhibition of COX. NSAIDs have been shown to down-regulate iNOS. Thus we hypothesized that treatment with ketorolac would attenuate burn/smoke-related cardiopulmonary derangements. We conducted a fully controlled long-term laboratory investigation in an Intensive Care Unit setting. Eighteen female sheep were surgically prepared for chronic study. After a recovery period of 5 days, a tracheotomy was performed under ketamine/halothane anaesthesia. Sheep were given a 40% total body surface third-degree burn and insufflated with cotton smoke (48 breaths, <40 degrees C). Sheep were divided into three groups: sham (not injured and not treated; n =6), control (injured, but not treated; n =6) and treated (injured and administered ketorolac 60 mg/day; n =6). The sham group had stable cardiopulmonary and systemic haemodynamics. Control animals showed depressed cardiopulmonary function, decreased pulmonary gas exchange, increased pulmonary microvascular leakage and decreased left ventricle stroke work index with elevated left atrial pressure. Systemic vascular leak in control animals was evidenced by robust haemoconcentration (haematocrit and fluid net balance). Treatment with ketorolac prevented all of these morbidities. Post-treatment with ketorolac also resulted in significant inhibition of elevated plasma nitrite/nitrate levels in control animals. These results suggest that ketorolac may ameliorate cardiopulmonary morbidity, at least in part, by inhibiting excessive NO.


Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment.
The wide spectrum of clinical outcomes following infection with Mycobacterium tuberculosis is largely determined by the host immune response; therefore, we studied several clinically defined groups of individuals (n = 120) that differ in their ability to contain the bacillus. To quantitate M. tuberculosis-specific T cells directly ex vivo, we enumerated IFN-gamma-secreting CD4 T cells specific for ESAT-6, a secreted Ag that is highly specific for M. tuberculosis, and a target of protective immune responses in animal models. We found that frequencies of circulating ESAT-6 peptide-specific IFN-gamma-secreting CD4 T cells were higher in latently infected healthy contacts and subjects with minimal disease and low bacterial burdens than in patients with culture-positive active pulmonary tuberculosis (p = 0.009 and p = 0.002, respectively). Importantly, the frequency of these Ag-specific CD4 T cells fell progressively in all groups with treatment (p = 0.005), suggesting that the lower responses in patients with more extensive disease were not due to tuberculosis-induced immune suppression. This population of M. tuberculosis Ag-specific Th1-type CD4 T cells appears to correlate with clinical phenotype and declines during successful therapy; these features are consistent with a role for these T cells in the containment of M. tuberculosis in vivo. Such findings may assist in the design and evaluation of novel tuberculosis vaccine candidates.


Involvement of p300/CBP and epigenetic histone acetylation in TGF-β1-mediated gene transcription in mesangial cells.
Transforming growth factor-β1 (TGF-β1)-induced expression of plasminogen activator inhibitor-1 (PAI-1) and p21 in renal mesangial cells (MCs) plays a major role in glomerulosclerosis and hypertrophy, key events in the pathogenesis of diabetic nephropathy. However, the involvement of histone acetyl transferases (HATs) and histone deacetylases (HDACs) that regulate epigenetic histone lysine acetylation, and their interaction with TGF-β1-responsive transcription factors, are not clear. We evaluated the roles of histone acetylation, specific HATs, and HDACs in TGF-β1-induced gene expression in rat mesangial cells (RMCs) and in glomeruli from diabetic mice. Overexpression of HATs CREB binding protein (CBP) or p300, but not p300/CBP-activating factor, significantly enhanced TGF-β1-induced PAI-1 and p21 mRNA levels as well as transactivation of their promoters in RMCs. Conversely, they were significantly attenuated by HAT domain mutants of CBP and p300 or overexpression of HDAC-1 and HDAC-5. Chromatin immunoprecipitation assays showed that TGF-β1 treatment led to a time-dependent enrichment of histone H3-lysine9/14-acetylation (H3K9/14Ac) and p300/CBP occupancies around Smad and Sp1 binding sites at the PAI-1 and p21 promoters. TGF-β1 also enhanced the interaction of p300 with Smad2/3 and Sp1 and increased Smad2/3 acetylation. High glucose-treated RMCs exhibited increased PAI-1 and p21 levels, and promoter H3K9/14Ac, which were blocked by TGF-β1 antibodies. Furthermore, increased PAI-1 and p21 expression was associated with elevated promoter H3K9/14Ac levels in glomeruli from diabetic mice. Thus TGF-β1-induced PAI-1 and p21 expression involves interaction of p300/CBP with Smads and Sp1, and increased promoter access via p300/CBP-induced H3K9/14Ac. This in turn can augment glomerular dysfunction linked to diabetic nephropathy.


The reliability of sampling three to six nodes for staging breast cancer.
To test the hypothesis that a correct qualitative assessment of axillary nodal status can be established by examining only a limited number of lymph nodes. Slides from 499 pN1 or pN0 axillary dissection specimens relating to symptomatic breast cancer cases operated on at our institution between 1991 and 1996 were reviewed. Nodes were ranked in descending order on the basis of their estimated size and lymphoid or metastatic tissue content. After ranking, all nodes were studied microscopically; 265 axillary clearance specimens were positive. Assessment of the 3-6 largest/firmest nodes can lead to the detection of 93-98% of node positive patients and can give a correct qualitative assessment of axillary node status in 96-99%. Sampling the 4-6 largest/firmest nodes seems to be a reliable alternative for the staging of symptomatic breast cancer. These results suggest a reconsideration of the generally held view that a minimum of 10 nodes is required for adequate identification of the pN0 category.


PSPC1 mediates TGF-β1 autocrine signalling and Smad2/3 target switching to promote EMT, stemness and metastasis.
Activation of metastatic reprogramming is critical for tumour metastasis. However, more detailed knowledge of the underlying mechanism is needed to enable targeted intervention. Here, we show that paraspeckle component 1 (PSPC1), identified in an aberrant 13q12.11 locus, is upregulated and associated with poor survival in patients with cancer. PSPC1 promotes tumorigenesis, epithelial-to-mesenchymal transition (EMT), stemness and metastasis in multiple cell types and in spontaneous mouse cancer models. PSPC1 is the master activator for transcription factors of EMT and stemness and accompanies c-Myc activation to facilitate tumour growth. PSPC1 increases transforming growth factor-β1 (TGF-β1) secretion through an interaction with phosphorylated and nuclear Smad2/3 to potentiate TGF-β1 autocrine signalling. Moreover, PSPC1 acts as a contextual determinant of the TGF-β1 pro-metastatic switch to alter Smad2/3 binding preference from tumour-suppressor to pro-metastatic genes. Having validated the PSPC1-Smads-TGF-β1 axis in various cancers, we conclude that PSPC1 is a master activator of pro-metastatic switches and a potential target for anti-metastasis drugs.


Medication as a risk factor for falls in older women in Brazil.
To assess the prevalence of falls and their association with the use of medications among elderly women in the city of Rio de Janeiro, Brazil. Falls among the elderly are likely to gain additional public health importance in Brazil and many other developing countries given the rapid growth of the elderly populations in those nations. A cross-sectional study was carried out with women who were participating in the educational, cultural, and medical care activities of the Open University of the Third Age (OUTA), a group that works to promote the welfare of elderly people in the city of Rio de Janeiro. The women in the study were all 60 years old or older, were able to walk, had no cognitive impairment, and were living in the community (rather than living in a facility exclusively for older persons). A questionnaire was used that asked about falls within the 12 months prior to the interview, medications used in the previous 15 days, current and past health problems, and demographic characteristics. Women who were interviewed face-to-face also had their blood pressure checked. Two outcome variables were defined: (1) "fallers," who had suffered one or more falls (contrasted with "nonfallers") and (2) "recurrent fallers," who had had two or more falls (contrasted with those who had had one or no falls, called "nonrecurrent fallers"). A total of 634 women were interviewed face-to-face at the OUTA facilities. Among these in-person interviewees, 23.3% reported one fall in the previous year, and 14.0% reported two or more falls in that period. Considering both prescribed drugs and over-the-counter drugs, only 9.1% of these women were not using any medications, 52.7% were using 1 to 4 medications, 34.4% were using 5 to 10, and 3.8% were using 11 to 17 medications. In comparison to nonusers, users of diuretics who also suffered from musculoskeletal disease were 1.6 times as likely to report having suffered a single fall in the preceding year, after adjusting for cardiovascular disease. Recurrent falls were reported 2.0 times as often among beta-blocker users as among nonusers, after adjusting for cardiovascular disease. The risk of recurrent falls among users of anxiolytics/sedatives who had postural hypotension was 4.9 times as high as among nonusers. Our data indicate an association between single falls and recurrent falls and several groups of medications. Some falls could be avoided through the more rational use of drugs, and measures should be developed and implemented to encourage this.


Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
We report our results of 1000 diagnostic WES cases based on 2819 sequenced samples from 54 countries with a wide phenotypic spectrum. Clinical information given by the requesting physicians was translated to HPO terms. WES processes were performed according to standardized settings. We identified the underlying pathogenic or likely pathogenic variants in 307 families (30.7%). In further 253 families (25.3%) a variant of unknown significance, possibly explaining the clinical symptoms of the index patient was identified. WES enabled timely diagnosing of genetic diseases, validation of causality of specific genetic disorders of PTPN23, KCTD3, SCN3A, PPOX, FRMPD4, and SCN1B, and setting dual diagnoses by detecting two causative variants in distinct genes in the same patient. We observed a better diagnostic yield in consanguineous families, in severe and in syndromic phenotypes. Our results suggest that WES has a better yield in patients that present with several symptoms, rather than an isolated abnormality. We also validate the clinical benefit of WES as an effective diagnostic tool, particularly in nonspecific or heterogeneous phenotypes. We recommend WES as a first-line diagnostic in all cases without a clear differential diagnosis, to facilitate personal medical care.


Role of Surface Precipitation in Copper Sorption by the Hydrous Oxides of Iron and Aluminum.
Isotherms were developed at pH 6.9 for adsorption (ADS) and coprecipitation (CPT) of Cu by hydrous oxides of Fe (HFO) and Al (HAO) to study the role of sorbate/sorbent ratio in metal cation removal. For low sorbate/sorbent conditions, HFO had a higher Cu retention capacity than HAO regardless of contact methodology. For either oxide, CPT was consistently more effective than ADS in removing Cu from solution. At high sorbate/sorbent ratios, surface precipitation dominates and the oxide's net cation retention capacity depends on the nature and solubility of the precipitate formed at the oxide-water interface. X-ray diffraction patterns and isotherms of HAO for both ADS and CPT suggest formation of a solid solution [e.g., CuAl2O4(s)] with dramatically lower solubility than Cu(OH)2(s) precipitated in bulk solution. In contrast, Cu precipitated on the HFO surface exhibited a solubility comparable to the bulk precipitated Cu(OH)2(s). Therefore, at high sorbate/sorbent ratios, HAO has a higher Cu "apparent" sorption capacity than HFO. The relative utility of these oxides as metal scavengers thus depends markedly on sorbate/sorbent conditions. Copyright 1999 Academic Press.


Protective and antidiabetic effects of extract from Nigella sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: an experimental study with histopathological evaluation.
Diabetes in humans induces chronic complications such as cardiovascular damage, cataracts and retinopathy, nephropathy and polyneuropathy. The most common animal model of human diabetes is streptozotocin (STZ)-induced diabetes in the rat. The present study investigated the effects of Nigella sativa hydroalcholic extract on glucose concentrations in streptozotocin (STZ) diabetic rats. In this study Twenty-five Wister-Albino rats (aged 8-9 weeks and weighing 200-250 g) were tested. Rats were divided into five experimental groups (control, untreated STZ-diabetic (60 mg/kg B.W., IP), treated STZ-diabetic with hydroalcholic extract of Nigella Sativa (NS) (5 mg/kg B.W, IP), treated STZ-diabetic with hydroalcholic extract of NS (10 mg/kg B.W., IP) and treated STZ-diabetic with hydroalcholic extract of NS (20 mg/kg B.W., IP and 32 days were evaluated to assess its effect on fasting blood glucose (FBG), and in different groups fasting blood glucose (FBG) and body weight (BW) were measured in the particular days (1, 16 and 32). At the end of the study, the animals were fasted overnight, anaesthetized with an intraperitoneal injection of sodium pentobarbital (60 mg/kg), and sacrificed for obtaining tissues samples (liver, pancreases). The number of islets and cells were counted and the islet diameters were determined by calibrated micrometer. The glycogen content in the liver was examined by Periodic Acid-Schiff (PAS) staining. Treatment with NS (5 mg/kg b.w.) markedly increased BW gain and the FBG level was significantly (p<0.001) reduced when compared to the control. Histopathological examination showed that the NS (5 mg/kg b.w.) partially recovered hepatic glycogen content and protected the great deal of the pancreatic islet cells. The number of islets, cells and islets diameter were found statistically significant when compared to the control (p<0.01, p<0.05). Higher doses of NS did not exhibit any therapeutic effect. These results showed that hydroalcholic extract of NS at low doses has hypoglycemic effect and ameliorative effect on regeneration of pancreatic islets and may be used as a therapeutic agent in the management of diabetes mellitus. The hypoglycemic effect observed could be due to amelioration of β-cell, thus leading to increased insulin levels. Consequently, N. sativa may prove clinically useful in the treatment of diabetics and in the protection of β-cells against streptozotocin. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1845133011104231.


iTRAQ-based proteomic profiling of the barnacle Balanus amphitrite in response to the antifouling compound meleagrin.
Marine biofouling refers to the unwanted accumulation of fouling organisms, such as barnacles, on artificial surfaces, resulting in severe consequences for marine industries. Meleagrin is a potential nontoxic antifoulant that is isolated from the fungus Penicillium sp.; however, its mechanistic effect mode of action on larval settlement remains unknown. Here, we applied iTRAQ coupled with 2D LC-MS/MS proteomic analysis to investigate the effect of meleagrin on the proteomic expression profile of cyprid development and aging in the barnacle Balanus amphitrite . Fifty proteins were differentially expressed in response to treatment with meleagrin, among which 26 proteins were associated with cyprid development/aging and 24 were specifically associated with the meleagrin treatment. The 66 proteins that were associated with aging only remained unaltered during exposure to meleagrin. Using KEGG analysis, those proteins were assigned to several groups, including metabolic pathways, ECM-receptor interactions, and the regulation of the actin cytoskeleton. Among the 24 proteins that were not related to the development/aging process, expression of the cyprid major protein (CMP), a vitellogenin-like protein, increased after the meleagrin treatment, which suggested that meleagrin might affect the endocrine system and prevent the larval molting cycle. With the exception of the chitin binding protein that mediates the molting process and ATPase-mediated energy processes, the majority of proteins with significant effects in previous studies in response to cyprid treatment with butenolide and polyether B remained unchanged in the present study, suggesting that meleagrin may exhibit a different mechanism.


In vivo localization of human acetylcholinesterase-derived species in a β-sheet conformation at the core of senile plaques in Alzheimer's disease.
Many neurodegenerative diseases are characterized by amyloid deposition. In Alzheimer's disease (AD), β-amyloid (Aβ) peptides accumulate extracellularly in senile plaques. The AD amyloid cascade hypothesis proposes that Aβ production or reduced clearance leads to toxicity. In contrast, the cholinergic hypothesis argues for a specific pathology of brain cholinergic pathways. However, neither hypothesis in isolation explains the pattern of AD pathogenesis. Evidence suggests that a connection exists between these two scenarios: the synaptic form of human acetylcholinesterase (hAChE-S) associates with plaques in AD brains; among hAChE variants, only hAChE-S enhances Aβ fibrillization in vitro and Aβ deposition and toxicity in vivo Only hAChE-S contains an amphiphilic C-terminal domain (T40, AChE575-614), with AChE586-599 homologous to Aβ and forming amyloid fibrils, which implicates T40 in AD pathology. We previously showed that the amyloid scavenger, insulin-degrading enzyme (IDE), generates T40-derived amyloidogenic species that, as a peptide mixture, seed Aβ fibrillization. Here, we characterized 11 peptides from a T40-IDE digest for β-sheet conformation, surfactant activity, fibrillization, and seeding capability. We identified residues important for amyloidogenicity and raised polyclonal antibodies against the most amyloidogenic peptide. These new antisera, alongside other specific antibodies, labeled sections from control, hAChE-S, hAPPswe, and hAChE-S/hAPPswe transgenic mice. We observed that hAChE-S β-sheet species co-localized with Aβ in mature plaque cores, surrounded by hAChE-S α-helical species. This observation provides the first in vivo evidence of the conformation of hAChE-S species within plaques. Our results may explain the role of hAChE-S in Aβ deposition and aggregation, as amyloidogenic hAChE-S β-sheet species might seed Aβ aggregation.


Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.
Observational clinical data from cladribine-treated patients with relapsing forms of multiple sclerosis (MS) were recorded in the Australian MS registry powered by the MSBase registry platform (5-year follow-up) and analysed to complement information from the pivotal cladribine clinical trials in MS. A cohort of 90 cladribine-treated patients with follow-up data reported by treating physicians and recorded in the Australian MSBase registry (database lock February 2016) were examined. Clinical data included Expanded Disability Status Scale (EDSS) scores, relapses and other disease-modifying drugs (DMDs) administered before and after cladribine treatment. Mean age on starting cladribine was 47 years; mean age at MS onset was 34 years, and median baseline EDSS score was 5.25. Disability trajectories in patients with sufficient follow-up suggested an overall increasing trend prior to cladribine treatment which was reduced during the 2-year post-treatment. Approximately 80% of patients were EDSS progression-free, 65% remained relapse-free after 2 years and median time to next DMD was 1.7 years. These observational data suggest a disease-modifying effect in this cohort of relapsing MS patients characterised by older and more disabled patients. Since these data represent a single-arm cohort, clinical trials and larger comparative post-marketing studies are needed to validate and extend these findings.


Mechanics and nanovoid nucleation dynamics: effects of polar functionality in glassy polymer networks.
We use molecular simulations and experiments to rationalize the properties of a class of networks based on dicyclopentadiene (DCPD), a polymer with excellent fracture toughness and a high glass transition temperature (Tg), copolymerized with 5-norbornene-2-methanol (NBOH). DCPD is a highly non-polar hydrocarbon, while NBOH contains a hydroxy group, introducing polar functionality and hydrogen bonds (H-bonds). NBOH thus represents a possible route to improve the chemical compatibility of DCPD-based networks with less-hydrophobic materials. We systematically vary the NBOH content (polar chemistry) in DCPD networks, while keeping other network parameters nearly constant, including the molecular weight between cross-links, chain rigidity, and Tg. Using molecular dynamics (MD) simulations, we quantify the thermovolumetric and mechanical properties, including Tg, cohesive energy density, stiffness, and yield strength. We compare these results with experiments on networks of similar composition, finding good agreement. The relation between these properties and polar chemistry are studied by examining a secondary network of physical cross-links, formed by hydrogen bonds between NBOH units. Further, we examine nanovoid formation, an energy dissipation mechanism hypothesized to contribute to the toughness of pDCPD. Using metadynamics to accelerate sampling, we quantify the nanovoid nucleation rate under hydrostatic tension, similar to the stress state in the plastic zone preceding a crack tip. Small additions of NBOH have minimal effect, but the rate drops steeply with larger amounts. Several properties are mapped at nanometer scales, including stiffness and mobility, and associated with void nucleation. Estimates of the length- and time-scale of the plastic zone near a crack tip are used in discussing nanovoid formation as a plausible toughening mechanism in these materials. Overall, the results suggest that pDCPD tolerates the addition of some polar chemistry without degrading its excellent mechanical properties.


Parkinson disease patients' perspectives on palliative care needs: What are they telling us?
A growing body of literature suggests that patients with Parkinson disease (PD) have many unmet needs under current models of care that may be addressed through palliative care approaches. A first step in improving care for patients with PD through palliative care principles is to better understand patient perspectives on their perceived needs and care preferences. A total of 30 in-depth individual interviews and 4 focus groups were held to elicit the perspectives of patients with PD on unmet palliative care needs and preferences for addressing these needs. We used ATLAS.ti and inductive qualitative data analysis techniques to interpret responses. Patients articulated major challenges in living with a diverse and complex set of motor and nonmotor symptoms; feelings of loss; changes in roles, relationships, and concept of self; and expressed concerns about the future. Participants discussed gaps in their care, including support at the time of diagnosis, education about the disease, and advance care planning. There was an expressed interest in and openness of participants to interdisciplinary approaches for addressing these needs. PD has a profound effect on multiple domains of a person's life starting at diagnosis. Patients desired individualized care and identified several areas where care from their primary neurologist could be improved. Patients were receptive to outpatient team-based palliative care services to address psychosocial issues, adjustment to illness (particularly at diagnosis and with progression), nonmotor symptom control, and advance care planning as an adjunct to usual care. Future research is needed to develop and test the effectiveness of palliative approaches to improve the care of patients with PD.


Validation of Persian rapid estimate of adult literacy in dentistry.
The aim of the present study was to establish the psychometric properties of the Rapid Estimate of adult Literacy in Dentistry-99 (REALD-99) in the Persian language for use in an Iranian population (IREALD-99). A total of 421 participants with a mean age of 28 years (59% male) were included in the study. Participants included those who were 18 years or older and those residing in Quazvin (a city close to Tehran), Iran. A forward-backward translation process was used for the IREALD-99. The Test of Functional Health Literacy in Dentistry (TOFHLiD) was also administrated. The validity of the IREALD-99 was investigated by comparing the IREALD-99 across the categories of education and income levels. To further investigate, the correlation of IREALD-99 with TOFHLiD was computed. A principal component analysis (PCA) was performed on the data to assess unidimensionality and strong first factor. The Rasch mathematical model was used to evaluate the contribution of each item to the overall measure, and whether the data were invariant to differences in sex. Reliability was estimated with Cronbach's α and test-retest correlation. Cronbach's alpha for the IREALD-99 was 0.98, indicating strong internal consistency. The test-retest correlation was 0.97. IREALD-99 scores differed by education levels. IREALD-99 scores were positively related to TOFHLiD scores (rh = 0.72, P < 0.01). In addition, IREALD-99 showed positive correlation with self-rated oral health status (rh = 0.31, P < 0.01) as evidence of convergent validity. The PCA indicated a strong first component, five times the strength of the second component and nine times the third. The empirical data were a close fit with the Rasch mathematical model. There was not a significant difference in scores with respect to income level (P = 0.09), and only the very lowest income level was significantly different (P < 0.01). The IREALD-99 exhibited excellent reliability on repeated administrations, as well as internal consistency. The IREALD-99 can be used for the basic screening of oral health literacy among the Iranian population.