A pragmatic algorithm to select appropriate antiseizure medications in patients with epilepsy.
Antiseizure medications (ASMs) are the first-line treatment for epilepsy. Many ASMs are available; this offers the opportunity to improve therapy by tailoring it to individual characteristics, but also increases the possibility of healthcare professionals making inappropriate treatment choices. To assist healthcare professionals, we developed a pragmatic algorithm aimed at facilitating medication selection for individuals whose epilepsy begins at age 10 years and older. Utilizing available evidence and a Delphi panel-based consensus process, a group of epilepsy experts developed an algorithm for selection of ASMs, depending on the seizure type(s) and the presence of relevant clinical variables (age, gender, comorbidities, and comedications). The algorithm was implemented into a web-based application that was tested and improved in an iterative process. The algorithm categorizes ASMs deemed to be appropriate for each seizure type or combination of seizure types into three groups, with group 1 ASMs considered preferred, group 2 considered second line, and group 3 considered third line. Depending on the presence of relevant clinical variables, the ranking of individual ASMs is adjusted in the prioritization scheme to tailor recommendations to the characteristics of the individual. The algorithm is available on a web-based application at: https://epipick.org/#/. The proposed algorithm is user-friendly, requires less than 2 minutes to complete, and provides the user with a range of appropriate treatment options from which to choose. This should facilitate its broad utilization and contribute to improve epilepsy management for healthcare providers who desire advice, particularly those who lack special expertise in the field.


Sensitive Periods for the Effect of Child Maltreatment on Psychopathology Symptoms in Adolescence.
Child maltreatment is among the strongest risk factors for mental disorders. However, little is known about whether there are ages when children may be especially vulnerable to its effects. We sought to identify potential sensitive periods when exposure to the 2 most common types of maltreatment (neglect and harsh physical discipline) had a particularly detrimental effect on youth mental health. Data came from the Future of Families and Child Wellbeing Study (FFCWS), a birth cohort oversampled from "fragile families" (n = 3,474). Maltreatment was assessed at 3, 5, and 9 years of age using an adapted version of the Parent-Child Conflict Tactics Scales (CTS-PC). Using least angle regression, we examined the relationship between repeated measures of exposure to maltreatment on psychopathology symptoms at age 15 years (Child Behavior Checklist; CBCL/6-18). For comparison, we evaluated the strength of evidence to support the existence of sensitive periods in relation to an accumulation of risk model. We identified sensitive periods for harsh physical discipline, whereby psychopathology symptom scores were highest among girls exposed at age 9 years (r2 = 0.67 internalizing symptoms; r2 = 1% externalizing symptoms) and among boys exposed at age 5 years (r2 = 0.41%). However, for neglect, the accumulation of risk model explained more variability in psychopathology symptoms for both boys and girls. Child maltreatment may have differential effects based on the child's sex, type of exposure, and the age at which it occurs. These findings provide additional evidence for clinicians assessing the benefits and drawbacks of screening efforts and point toward possible mechanisms driving increased vulnerability to psychopathology.


Homogeneity in the association of body mass index with type 2 diabetes across the UK Biobank: A Mendelian randomization study.
Lifestyle interventions to reduce body mass index (BMI) are critical public health strategies for type 2 diabetes prevention. While weight loss interventions have shown demonstrable benefit for high-risk and prediabetic individuals, we aimed to determine whether the same benefits apply to those at lower risk. We performed a multi-stratum Mendelian randomization study of the effect size of BMI on diabetes odds in 287,394 unrelated individuals of self-reported white British ancestry in the UK Biobank, who were recruited from across the United Kingdom from 2006 to 2010 when they were between the ages of 40 and 69 years. Individuals were stratified on the following diabetes risk factors: BMI, diabetes family history, and genome-wide diabetes polygenic risk score. The main outcome measure was the odds ratio of diabetes per 1-kg/m2 BMI reduction, in the full cohort and in each stratum. Diabetes prevalence increased sharply with BMI, family history of diabetes, and genetic risk. Conversely, predicted risk reduction from weight loss was strikingly similar across BMI and genetic risk categories. Weight loss was predicted to substantially reduce diabetes odds even among lower-risk individuals: for instance, a 1-kg/m2 BMI reduction was associated with a 1.37-fold reduction (95% CI 1.12-1.68) in diabetes odds among non-overweight individuals (BMI < 25 kg/m2) without a family history of diabetes, similar to that in obese individuals (BMI ≥ 30 kg/m2) with a family history (1.21-fold reduction, 95% CI 1.13-1.29). A key limitation of this analysis is that the BMI-altering DNA sequence polymorphisms it studies represent cumulative predisposition over an individual's entire lifetime, and may consequently incorrectly estimate the risk modification potential of weight loss interventions later in life. In a population-scale cohort, lower BMI was consistently associated with reduced diabetes risk across BMI, family history, and genetic risk categories, suggesting all individuals can substantially reduce their diabetes risk through weight loss. Our results support the broad deployment of weight loss interventions to individuals at all levels of diabetes risk.


Unified field analysis method for IR/MW micro-mirror array beam combiner.
The aperture field integration method (AFIM) is proposed and utilized to efficiently compute the field distributions of infrared/microwave (IR/MW) micro-mirror array beam combiners, including the MW near-field distribution and the IR far-field distribution. The MW near-field distributions of single-dielectric-layer beam combiners with 1, 11, and 101 micromirrors are analyzed by AFIM. Compared to the commonly used multilevel fast multipole method (MLFMM) in the computation of MW near-field distribution, the memory requirement and CPU time consumption are reduced drastically from 16.92 GB and 3.26 h to 0.66 MB and 0.55 s, respectively. The calculation accuracy is better than 96%, when the MW near-field distribution is computed. The IR far-field computational capability is validated by comparing the results obtained through AFIM and experiment. The MW near field and IR far field of a circular and a square shape of three-layer micro-mirror array beam combiners are also analyzed. Four indicators E pv , E rms , φ pv , and φ rms representing the amplitude and phase variations are proposed to evaluate the MW near-field uniformity. The simulation results show that the increase of beam combiner size can improve the uniformity of the MW near field, and that the square shape has less influence on the uniformity of the MW near field than the circular one. The zeroth-order diffraction primary maximum intensity of the IR far field is decreased by 1/cos 2 α 0 times compared to that of the equivalent mirror, where α 0 is the oblique angle of each micromirror. When the periodic length of the micro-mirror array is less than 0.1 mm, the position of the secondary maximum will exceed the size of the focal plane array. Simultaneously, the half-width of the zeroth-order diffraction primary maximum is less than the size of a single pixel. Thus, IR images with high quality will be obtained. The simulation results show that the AFIM as a unified method can be applied to design, analyze, evaluate, and optimize IR/MW micro-mirror array beam combiners.


Efficacy and safety of recombinant human bone morphogenetic protein-2/calcium phosphate matrix for closed tibial diaphyseal fracture: a double-blind, randomized, controlled phase-II/III trial.
Recombinant human bone morphogenetic protein-2 (rhBMP-2) applied on an absorbable collagen sponge improves open tibial fracture-healing as an adjunct to unreamed intramedullary nail fixation. We evaluated rhBMP-2 and a new, injectable calcium phosphate matrix (CPM) formulation in acute closed tibial diaphyseal fractures treated with reamed intramedullary nail fixation. Patients were randomized (1:2:2:1) to receive standard of care, which consisted of definitive fracture fixation within seventy-two hours of injury with a locked intramedullary nail after reaming; standard of care and injection with 1.0 mg/mL of rhBMP-2/CPM; standard of care and injection with 2.0 mg/mL of rhBMP-2/CPM; or standard of care and injection with buffer/CPM, to evaluate the activity of the CPM delivery matrix and provide for sponsor and investigator blinding. The co-primary end points of the study were the effects of rhBMP-2/CPM on the time to fracture union (based on blinded assessment of radiographs) and the time to return to normal function (based on blinded assessment of the time to full weight-bearing without pain at the fracture site) compared with standard of care alone. Three hundred and sixty-nine patients were randomized and included in the intent-to-treat population. This study was terminated after an interim analysis (180 patients with six months of follow-up) revealed no shortening in the time to fracture union in the active treatment arms compared with the standard of care control (the SOC group). In the final primary analysis, the median time to radiographic fracture union was not significantly different for the SOC (13.1 weeks), 1.0-mg/mL rhBMP-2/CPM (13.0 weeks), 2.0-mg/mL rhBMP-2/CPM (15.9 weeks), or buffer/CPM (15.4 weeks) treatment groups. The median time to pain-free full weight-bearing was also not significantly different among the SOC (13.4 weeks), 1.0-mg/mL rhBMP-2/CPM (13.4 weeks), 2.0-mg/mL rhBMP-2/CPM (14.3 weeks), and buffer/CPM (16.4 weeks) treatment groups. In patients with closed tibial fractures treated with reamed intramedullary nailing, the time to fracture union and pain-free full weight-bearing were not significantly reduced by rhBMP-2/CPM compared with standard of care alone. 24306696


How Participatory Music Engagement Supports Mental Well-being: A Meta-Ethnography.
Participatory music engagement has the capacity to support well-being. Yet, there is little research that has scrutinized the processes through which music has an effect. In this meta-ethnography [PROSPERO CRD42019130164], we conducted a systematic search of 19 electronic databases and a critical appraisal to identify 46 qualitative studies reporting on participants' subjective views of how participatory music engagement supports their mental well-being. Synthesis of first-order and second-order interpretations using thematic coding resulted in four third-order pathways that account for how participatory music engagement supports mental well-being: managing and expressing emotions, facilitating self-development, providing respite, and facilitating connections. Our interpretation suggests that people benefit from participatory music engagement by engaging with specific and multiple processes that meet their individual needs and circumstances. These findings inform research directions within the field of music and well-being, as well as guiding the development and delivery of future music interventions.


A functional analysis of the role of IGF2 in IDDM2-encoded susceptibility to type 1 diabetes.
Genetic studies have identified a number of loci demonstrating linkage to type 1 diabetes. One of the largest single contributors to genetic susceptibility, after the major histocompatability complex, is the IDDM2 locus, which maps to a nontranscribed variable number of tandem repeats (VNTR) minisatellite upstream of the insulin (INS) and insulin-like growth factor 2 (IGF2) genes. In a progression from population to functional studies, recent reports have shown that VNTR susceptibility alleles (class I) have different transcriptional effects on INS than protective VNTR alleles (class III) in thymus and pancreas, two tissues important in the pathogenesis of the disease. Similar VNTR transcriptional effects on IGF2 have also been proposed as a mechanism by which the IDDM2 locus confers susceptibility in addition to, or instead of, effects on INS. We evaluated this hypothesis by comparing IGF2 expression levels from chromosomes with the protective class III alleles to those with class I alleles in tissues relevant to type 1 diabetes pathogenesis. In thymus, class III alleles were associated with an IGF2 mRNA level of 4.7 +/- 0.9 (mean +/- SE, arbitrary units, n = 12) compared with 4.7 +/- 1.3 for class I alleles (n = 17). The same absence of a significant difference was found in pancreas, where class III alleles were associated with a level of 28.4 +/- 4.2 (n = 7) and class I alleles with a level of 29.5 +/- 5.2 (n = 6). There was a significant correlation between fetal age and IGF2 in both tissues, but fetal ages were not different in the genotype groups compared. We therefore did not detect any significant difference in IGF2 mRNA levels associated with the protective class of VNTR alleles as compared with the predisposing class. This is evidence against the hypotheses that have suggested IGF2 is a mediator of IDDM2-encoded susceptibility and corroborates previous studies suggesting insulin is the gene involved.


A Micelle Electrolyte Enabled by Fluorinated Ether Additives for Polysulfide Suppression and Li Metal Stabilization in Li-S Battery.
The Li-S battery is a promising next-generation technology due to its high theoretical energy density (2600 Wh kg-1) and low active material cost. However, poor cycling stability and coulombic efficiency caused by polysulfide dissolution have proven to be major obstacles for a practical Li-S battery implementation. In this work, we develop a novel strategy to suppress polysulfide dissolution using hydrofluoroethers (HFEs) with bi-functional, amphiphlic surfactant-like design: a polar lithiophilic "head" attached to a fluorinated lithiophobic "tail." A unique solvation mechanism is proposed for these solvents whereby dissociated lithium ions are readily coordinated with lithiophilic "head" to induce self-assembly into micelle-like complex structures. Complex formation is verified experimentally by changing the additive structure and concentration using small angle X-ray scattering (SAXS). These HFE-based electrolytes are found to prevent polysulfide dissolution and to have excellent chemical compatibility with lithium metal: Li||Cu stripping/plating tests reveal high coulombic efficiency (>99.5%), modest polarization, and smooth surface morphology of the uniformly deposited lithium. Li-S cells are demonstrated with 1395 mAh g-1 initial capacity and 71.9% retention over 100 cycles at >99.5% efficiency-evidence that the micelle structure of the amphiphilic additives in HFEs can prohibit polysulfide dissolution while enabling facile Li+ transport and anode passivation.


Clinical value of ELISA assays for IgM and IgG rheumatoid factors.
The clinical value of enzyme linked immunosorbent assays (ELISA) assays for IgM and IgG rheumatoid factors was assessed in a series of studies using rabbit IgG as antigen. The tests were reproducible with intra-assay coefficients of variation of 6% and could be simply and rapidly performed. Normal ranges were established using 106 sera from healthy controls. In a cross sectional study of 208 rheumatoid patients these assays were compared with the Rose-Waaler and laser nephelometric assessments of rheumatoid factor. In some patients there were discrepancies between rheumatoid factor positivity determined by one method or another. IgM ELISA and Rose-Waaler titres showed a significant correlation (r = +0.58; p less than 0.001), but there was a low correlation between IgM and IgG ELISA (r = +0.27; p less than 0.001). There was no evidence to show that the measurement of IgM or IgG rheumatoid factor gave significantly more clinical information than traditional tests such as the Rose-Waaler or latex agglutination tests.


Cognitive function and oral health among community-dwelling older adults.
Both oral health problems and cognitive impairment are relatively common among older adults. Poorer oral health appears to contribute to a decline in quality of life and to be related to various medical conditions. Little is known about the relationship of cognitive function to oral health among community-dwelling older adults. The sample included 1984 dentate community-dwelling older adults 60 years old or older from the National Health and Nutrition Examination Survey (NHANES, 1999-2002) who completed both the study cognitive measure and dental examination. Weighted descriptive and multivariate regression analyses were performed. Multivariate analyses showed that cognitive function was associated with oral health. Individuals with lower cognitive scores had a higher number of decayed and missing teeth and a higher proportion of periodontitis sites. The predicted number of decayed teeth increased by 0.01 with each 1-point decrease in the Digit Symbol Substitution Test score; the number of missing teeth increased by 0.02; and the percentage of sites with periodontal disease increased by 0.02. In addition, individuals' sociodemographic characteristics, health behavior, and regular dental checkups were significantly associated with oral health. This study suggests that community-dwelling elders with lower cognitive function scores have greater deterioration of oral health. This study provides a preliminary knowledge base for the development of early intervention strategies to address oral health problems among older adults.


Abrupt warming and salinification of intermediate waters interplays with decline of deep convection in the Northwestern Mediterranean Sea.
The Mediterranean Sea is a hotspot for climate change, and recent studies have reported its intense warming and salinification. In this study, we use an outstanding dataset relying mostly on glider endurance lines but also on other platforms to track these trends in the northwestern Mediterranean where deep convection occurs. Thanks to a high spatial coverage and a high temporal resolution over the period 2007-2017, we observed the warming (+0.06 [Formula: see text]C year[Formula: see text]) and salinification (+0.012 year[Formula: see text]) of Levantine Intermediate Water (LIW) in the Ligurian Sea. These rates are similar to those reported closer to its formation area in the Eastern Mediterranean Sea. Further downstream, in the Gulf of Lion, the intermediate heat and salt content were exported to the deep layers from 2009 to 2013 thanks to deep convection processes. In 2014, a LIW step of +0.3 [Formula: see text]C and +0.08 in salinity could be observed concomitant with a weak winter convection. Warmer and more saline LIW subsequently accumulated in the northwestern basin in the absence of intense deep convective winters until 2018. Deep stratification below the LIW thus increased, which, together with the air-sea heat fluxes intensity, constrained the depth of convection. A key prognostic indicator of the intensity of deep convective events appears to be the convection depth of the previous year.


Understanding Karma Police: The Perceived Plausibility of Noun Compounds as Predicted by Distributional Models of Semantic Representation.
Noun compounds, consisting of two nouns (the head and the modifier) that are combined into a single concept, differ in terms of their plausibility: school bus is a more plausible compound than saddle olive. The present study investigates which factors influence the plausibility of attested and novel noun compounds. Distributional Semantic Models (DSMs) are used to obtain formal (vector) representations of word meanings, and compositional methods in DSMs are employed to obtain such representations for noun compounds. From these representations, different plausibility measures are computed. Three of those measures contribute in predicting the plausibility of noun compounds: The relatedness between the meaning of the head noun and the compound (Head Proximity), the relatedness between the meaning of modifier noun and the compound (Modifier Proximity), and the similarity between the head noun and the modifier noun (Constituent Similarity). We find non-linear interactions between Head Proximity and Modifier Proximity, as well as between Modifier Proximity and Constituent Similarity. Furthermore, Constituent Similarity interacts non-linearly with the familiarity with the compound. These results suggest that a compound is perceived as more plausible if it can be categorized as an instance of the category denoted by the head noun, if the contribution of the modifier to the compound meaning is clear but not redundant, and if the constituents are sufficiently similar in cases where this contribution is not clear. Furthermore, compounds are perceived to be more plausible if they are more familiar, but mostly for cases where the relation between the constituents is less clear.


Breast-conserving treatment for stage I and II cancer. Tumour excision, axillary dissection, peri-operative interstitial irradiation, with or without peri-operative chemotherapy, followed by breast irradiation--the Tygerberg Hospital experience.
Since 1984 breast-conserving treatment has been the treatment of choice for patients at Tygerberg Hospital with early breast cancer. Peri-operative interstitial brachytherapy in breast cancer is described in detail. In the 221 patients treated (225 breasts), 197 breasts received iridium implants and 26 patients received peri-operative chemotherapy (POPFAC). There were 6 recurrences in treated breasts, 3 within the booster area and 3 outside. There were 5 salvage mastectomies, and 1 patient was treated by excision and radiotherapy. Metastases developed in 27 patients. Two patients underwent mastectomy for severe radiation changes and 7 developed postoperative wound infection after POPFAC. Five patients, who had re-excisions and prolonged seroma formation, developed delayed wound infection after POPFAC. Five patients, who had re-excisions and prolonged seroma formation, developed delayed wound infection. The importance of mammography, patient selection, tumour-free margins and radiation dosage are discussed.


Rat brain endothelial cell lines for the study of blood-brain barrier permeability and transport functions.
(1) In vitro models of the BBB have been developed from cocultures between bovine, porcine, rodent or human brain capillary endothelial cells with rodent or human astrocytes. Since most in vivo BBB studies have been performed with small laboratory animals, especially rats, it is important to establish a rat brain endothelial (RBE) cell culture system that will allow correlations between in vitro and in vivo results. The present review will constitute a brief description of the best characterized RBE cell lines (RBE4, GP8/3.9, GPNT, RBEC1, TR-BBBs and rBCEC4 cell lines) and will summarize their recent and important contribution to our current knowledge of the BBB transport functions and permeability to blood-borne solutes, drugs, and cells. (2) In most cases, primary cultures of RBE cells were transduced with an immortalizing gene (SV40 or polyoma virus large T-antigen or adenovirus E1A), either by transfection of plasmid DNA or by infection using retroviral vectors. In one case however, the conditionally immortalized TR-BBB cell line was derived from primary cultures of brain endothelial cells of SV40-T-expressing transgenic rats. (3) All cell lines appear to have an endothelial morphology. The absence of foci formation would mean that the cells are not transformed. The endothelial origin is shown by the expression of Factor VIII-related antigen. Immortalized RBE cells express all the enzymes and transporters that are considered as specific for the blood-brain barrier endothelium, with similar characteristics to those expected from in vivo analyses, but at a significantly lower level. Some RBE cell lines are responsive to astroglial factors, such as RBE4 cells, rBEC4, and TR-BBB cells. None of the immortalized RBE cell lines appear to generate the necessary restrictive paracellular barrier properties that would allow to use them in transendothelial permeability screening. (4) RBE cell lines have been used to demonstrate that transporters such as organic cation transporter/carnitine transporter, serotonin transporter, and the ATA2 system A isoform are expressed in rat brain endothelium. When the transporter is shown to be expressed with the same properties in the immortalized RBE cells as in vivo, regulation studies may be initiated even if the transporter is down-regulated. Pharmacological applications have been proposed with well-characterized transporters such as monocarboxylic acid transporter-1, large neutral amino acid tansporter-1, nucleoside carrier systems, and P-glycoprotein. RBE cell monolayers have also been used to investigate the mechanism of the transendothelial transport of large molecules, such as immunoliposomes or nanoparticles, potentially useful as drug delivery vectors to the brain. (5) RBE4 and GP8 cell lines have been extensively used to demonstrate that intercellular adhesion molecule-1 (ICAM-1) engagement in brain endothelial cells triggers multiple signal transduction pathways. Using functional assays, it was established that ICAM-1 signaling is intimately and actively involved in facilitating lymphocyte infiltration. (6) Several RBE cell lines have been described, which constitute tentative in vitro models of the rat BBB. The major limitation of these models generally appears to be due to their relatively high paracellular permeability to small molecules, thus limiting their use for permeability studies. The strategies developed for the production of these RBE cell lines will enable the characterization of still more efficient permeability models, as well as the immortalization of human brain endothelial cells.


Dynamics of the metallo-beta-lactamase from Bacteroides fragilis in the presence and absence of a tight-binding inhibitor.
A significant determinant for the broad substrate specificity of the metallo-beta-lactamases from Bacteroides fragilis and other similar organisms is the presence of a plastic substrate binding site that is nevertheless capable of tight substrate binding in the Michaelis complex. To achieve these two competing ends, the molecule apparently employs a flexible flap that closes over the active site in the presence of substrate. These characteristics imply that dynamic changes are an important component of the mechanism of action of these enzymes. The backbone and tryptophan side chain dynamics of the metallo-beta-lactamase from B. fragilis have been examined using (15)N NMR relaxation measurements. Two states of the protein were examined, in the presence and absence of a tight-binding inhibitor. Relaxation measurements were analyzed by the model-free method. Overall, the metallo-beta-lactamase molecule is rigid and shows little flexibility except in loops. The flexibility of the loop that covers the active site is not unusually great as compared to the other loops of the protein. Local motion on a picosecond time scale was found to be very similar throughout the protein in the presence and absence of the inhibitor, but a significant difference was observed in the motions on a nanosecond time scale (tau(e)). Large-amplitude motions with a time constant of about 1.3 ns were observed for the flexible flap region (residues 45-55) in the absence of the inhibitor. These motions were completely damped out in the presence of the inhibitor. In addition, the motion of a tryptophan side chain at the tip of the beta-hairpin of the flap shows a very significant difference in motion on the ps time scale. These results indicate that the motions of the polypeptide chain in the flap region can be invoked to explain both the wide substrate specificity (the free form has considerable amplitude of motion in this region) and the catalytic efficiency of the metallo-beta-lactamase (the motions are damped out when the inhibitor and by implication a substrate binds in the active site).


Bamboo Plantations for Phytoremediation of Pig Slurry: Plant Response and Nutrient Uptake.
On Réunion Island, a French overseas territory located in the western Indian Ocean, increasing pig livestock farming is generating large quantities of slurry. Most of it is spread on a little agricultural land due to the insular context. Considering the limitation of the quantities that can be spread on agricultural areas (European "Nitrate Directive" 91/676/EEC), the use of wastewater treatment systems using phytoremediation principles is an attractive option for the pig slurry treatment. A wastewater treatment system using bamboo groves was assessed for the pig slurry treatment. Three field plots were designed on an agricultural area and planted with 40 bamboo clumps on each plot. A total of 67 m3 of pig slurry was spread on two plots in two forms: raw slurry and centrifuged slurry. The latter plot was watered with tap water. The total amount of nitrogen, phosphorus and potassium was 5.3, 1.4 and 5.5 t·ha-1, respectively, for the raw slurry treatment and 4.2, 0.4 and 5.1 t·ha-1, respectively, for the centrifuged slurry treatment. The response of bamboo species to pig slurry application was determined using morphologic parameters, Chlorophyll a fluorescence measurements and biomass yield. Compared to the control, the biomass increased by 1.8 to 6 times, depending on the species and the form of slurry. Depending on the species, the average biomass ranged from 52 to 135 t.DM.ha-1 in two years of experiment.


A neurodevelopmental model of schizophrenia: neonatal disconnection of the hippocampus.
In the context of our current knowledge about schizophrenia, heuristic models of psychiatric disorders may be used to test the plausibility of theories developed on the basis of new emerging biological findings, explore mechanisms of schizophrenia-like phenomena, and develop potential new treatments. In a series of studies, we have shown that neonatal excitotoxic lesions of the rat ventral hippocampus (VH) may serve as a heuristic model. The model appears to mimic a spectrum of neurobiological and behavioral features of schizophrenia, including functional pathology in presumably critical brain regions interconnected with the hippocampal formation and targeted by antipsychotic drugs - the striatum/nucleus accumbens and the prefrontal cortex, and leads in adolescence or early adulthood to the emergence of abnormalities in a number of dopamine related behaviors. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development, that produces subtle, if any, anatomical changes in the hippocampus, may be sufficient to disrupt normal maturation of the prefrontal cortex (and perhaps, other interconnected late maturing regions) and trigger behavioral changes similar to those observed in animals with the permanent excitotoxic lesion. These results represent a potential new model of aspects of schizophrenia without a gross anatomical lesion.


New Business Structures Creating Organizational Opportunities and Challenges for Work Disability Prevention.
Purpose Flexible work arrangements are growing in order to develop resource-efficient production and because of advanced technologies, new societal values, changing demographics, and globalization. The article aims to illustrate the emerging challenges and opportunities for work disability prevention efforts among workers in alternate work arrangements. Methods The authors participated in a year-long collaboration that ultimately led to an invited 3-day conference, "Improving Research of Employer Practices to Prevent Disability," held October 14-16, 2015, in Hopkinton, Massachusetts, USA. The collaboration included a topical review of the literature, group conference calls to identify key areas and challenges, drafting of initial documents, review of industry publications, and a conference presentation that included feedback from peer researchers and a roundtable discussion with experts having direct employer experience. Results Both worker and employer perspectives were considered, and four common alternate work arrangements were identified: (a) temporary and contingent employment; (b) small workplaces; (c) virtual work/telework; and (d) lone workers. There was sparse available research of return-to-work (RTW) and workplace disability management strategies with regard to alternate work patterns. Limited research findings and a review of the grey literature suggested that regulations and guidelines concerning disabled workers are often ambiguous, leading to unsatisfactory protection. At the workplace level, there was a lack of research evidence on how flexible work arrangements could be handled or leveraged to support RTW and prevent disability. Potential negative consequences of this lack of organizational guidance and information are higher costs for employers and insurers and feelings of job insecurity, lack of social support and integration, or work intensification for disabled workers. Conclusions Future studies of RTW and workplace disability prevention strategies should be designed to reflect the multiple work patterns that currently exist across many working populations, and in particular, flexible work arrangements should be explored in more detail as a possible mechanism for preventing disability. Labor laws and policies need to be developed to fit flexible work arrangements.


USE OF MULTIPLE SINGULAR VALUE DECOMPOSITIONS TO ANALYZE COMPLEX INTRACELLULAR CALCIUM ION SIGNALS.
We compare calcium ion signaling (Ca(2+)) between two exposures; the data are present as movies, or, more prosaically, time series of images. This paper describes novel uses of singular value decompositions (SVD) and weighted versions of them (WSVD) to extract the signals from such movies, in a way that is semi-automatic and tuned closely to the actual data and their many complexities. These complexities include the following. First, the images themselves are of no interest: all interest focuses on the behavior of individual cells across time, and thus, the cells need to be segmented in an automated manner. Second, the cells themselves have 100+ pixels, so that they form 100+ curves measured over time, so that data compression is required to extract the features of these curves. Third, some of the pixels in some of the cells are subject to image saturation due to bit depth limits, and this saturation needs to be accounted for if one is to normalize the images in a reasonably un-biased manner. Finally, the Ca(2+) signals have oscillations or waves that vary with time and these signals need to be extracted. Thus, our aim is to show how to use multiple weighted and standard singular value decompositions to detect, extract and clarify the Ca(2+) signals. Our signal extraction methods then lead to simple although finely focused statistical methods to compare Ca(2+) signals across experimental conditions.


Pediatricians and health literacy: descriptive results from a national survey.
To describe pediatricians' self-reported experiences with health literacy, use of basic and enhanced communication techniques, and perceived barriers to effective communication during office visits. A national, random sample of 1605 nonretired, posttraining American Academy of Pediatrics members were surveyed in 2007 about health literacy and patient communication as part of the Periodic Survey of Fellows. The response rate was 56% (N = 900). Eight-one percent of the pediatricians were aware of a situation in the previous 12 months in which a parent had not sufficiently understood health information that had been delivered to him or her. In addition, 44% of all pediatricians were aware of a communication-related error in patient care within the previous 12 months. Using simple language (99%), repeating key information (92%), and presenting only 2 or 3 concepts at a time (76%) were the most commonly used communication strategies. Enhanced communication techniques recommended by health literacy experts such as teach-back and indicating key points on written educational materials were used less often (23% and 28%, respectively). The most common reported barriers to effective communication were limited time to discuss information (73%), volume of information (65%), and complexity of information (64%). The majority of physicians rated themselves highly in their ability to identify caregiver understanding (64%), but only 21% rated themselves as very good or excellent in identifying a parent with a literacy problem. Fifty-seven percent of the respondents were interested in training to improve communication skills, and 58% reported that they would be very likely to use easy-to-read written materials, if available from the American Academy of Pediatrics. Pediatricians are aware of health literacy-related problems and the need for good communication with families but struggle with time demands to implement these skills. Despite awareness of communication-related errors in patient care, pediatricians report underutilizing enhanced techniques known to improve communication.


Novel Chitohexaose Analog Protects Young and Aged mice from CLP Induced Polymicrobial Sepsis.
In Gram-negative bacterial sepsis, production of excess pro-inflammatory cytokines results in hyperinflammation and tissue injury. Anti-inflammatory cytokines such as IL-10 inhibit inflammation and enhance tissue healing. Here, we report a novel approach to treat septicemia associated with intra-abdominal infection in a murine model by delicately balancing pro- and anti-inflammatory cytokines. A novel oligosaccharide compound AVR-25 selectively binds to the TLR4 protein (IC50 = 0.15 µM) in human peripheral blood monocytes and stimulates IL-10 production. Following the cecal ligation and puncture (CLP) procedure, intravenous dosing of AVR-25 (10 mg/kg, 6-12 h post-CLP) alone and in combination with antibiotic imipenem protected both young adult (10-12 week old) and aged (16-18 month old) mice against polymicrobial infection, organ dysfunction, and death. Proinflammatory cytokines (TNF-α, MIP-1, i-NOS) were decreased significantly and restoration of tissue damage was observed in all organs. A decrease in serum C-reactive protein (CRP) and bacterial colony forming unit (CFU) confirmed improved bacterial clearance. Together, these findings demonstrate the therapeutic ability of AVR-25 to mitigate the storm of inflammation and minimize tissue injury with high potential for adjunctive therapy in intra-abdominal sepsis.


Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.
Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders.


Up-regulation of endoplasmic reticulum stress-related genes during the early phase of treatment of cultured cortical neurons by the proteasomal inhibitor lactacystin.
Inhibition of proteasome degradation pathway has been implicated in neuronal cell death leading to neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. We and others demonstrated that treatment of cortical neurons with the proteasomal inhibitor lactacystin leads to apoptosis. We discovered by microarray analysis that lactacystin treatment modulates the expression of both potentially neuroprotective as well as pro-apoptotic genes in neurons. However, the significance of the genes which upon transcriptional modulation contributed to proteasomal inhibition-induced apoptosis, remained unidentified. By employing microarray analysis to decipher the time-dependent changes in transcription of these genes in cultured cortical neurons, we discovered different groups of genes were transcriptionally regulated in the early and late phase of lactacystin-induced cell death. In the early phase, several neuroprotective genes such as those encoding the proteasome subunits and ubiquitin-associated enzymes, as well as the heat-shock proteins (HSP) were up-regulated. However, the pro-apoptotic endoplasmic reticulum (ER) stress-associated genes were also up-regulated at the early phase of lactacystin-induced neuronal cell death. In the late phase, genes encoding antioxidants and calcium-binding proteins were up-regulated while those associated with cholesterol biosynthesis were down-regulated. The data suggest that ER stress may participate in mediating the apoptotic responses induced by proteasomal inhibition. The up-regulation of the neuroprotective antioxidant genes and calcium-binding protein genes and down-regulation of the cholesterol biosynthesis genes in the later phase are likely consequences of stimulation of the pro-apoptotic signaling pathways in the early phase of lactacystin treatment.


Gene transfer and protein dynamics in stem cells using single cell electroporation in a microfluidic device.
There is great interest in genetic modification of bone marrow-derived mesenchymal stem cells (MSC), not only for research purposes but also for use in (autologous) patient-derived-patient-used transplantations. A major drawback of bulk methods for genetic modifications of (stem) cells, like bulk-electroporation, is its limited yield of DNA transfection (typically then 10%). This is even more limited when cells are present at very low numbers, as is the case for stem cells. Here we present an alternative technology to transfect cells with high efficiency (>75%), based on single cell electroporation in a microfluidic device. In a first experiment we show that we can successfully transport propidium iodide (PI) into single mouse myoblastic C2C12 cells. Subsequently, we show the use of this microfluidic device to perform successful electroporation of single mouse myoblastic C2C12 cells and single human MSC with vector DNA encoding a green fluorescent-erk1 fusion protein (EGFP-ERK1 (MAPK3)). Finally, we performed electroporation in combination with live imaging of protein expression and dynamics in response to extracellular stimuli, by fibroblast growth factor (FGF-2). We observed nuclear translocation of EGFP-ERK1 in both cell types within 15 min after FGF-2 stimulation. Due to the successful and promising results, we predict that microfluidic devices can be used for highly efficient small-scale 'genetic modification' of cells, and biological experimentation, offering possibilities to study cellular processes at the single cell level. Future applications might be small-scale production of cells for therapeutic application under controlled conditions.


OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for primary prevention of osteoarthritis by joint injury prevention in sport and recreation.
The risk of post-traumatic osteoarthritis (PTOA) substantially increases following joint injury. Research efforts should focus on investigating the efficacy of preventative strategies in high quality randomized controlled trials (RCT). The objective of these OARSI RCT recommendations is to inform the design, conduct and analytical approaches to RCTs evaluating the preventative effect of joint injury prevention strategies. Recommendations regarding the design, conduct, and reporting of RCTs evaluating injury prevention interventions were established based on the consensus of nine researchers internationally with expertise in epidemiology, injury prevention and/or osteoarthritis (OA). Input and resultant consensus was established through teleconference, face to face and email correspondence over a 1 year period. Recommendations for injury prevention RCTs include context specific considerations regarding the research question, research design, study participants, randomization, baseline characteristics, intervention, outcome measurement, analysis, implementation, cost evaluation, reporting and future considerations including the impact on development of PTOA. Methodological recommendations for injury prevention RCTs are critical to informing evidence-based practice and policy decisions in health care, public health and the community. Recommendations regarding the interpretation and conduct of injury prevention RCTs will inform the highest level of evidence in the field. These recommendations will facilitate between study comparisons to inform best practice in injury prevention that will have the greatest public health impact.


A high-protein breakfast induces greater insulin and glucose-dependent insulinotropic peptide responses to a subsequent lunch meal in individuals with type 2 diabetes.
The previous meal modulates the postprandial glycemic responses to a subsequent meal; this is termed the second-meal phenomenon. This study examined the effects of high-protein vs. high-carbohydrate breakfast meals on the metabolic and incretin responses after the breakfast and lunch meals. Twelve type 2 diabetic men and women [age: 21-55 y; body mass index (BMI): 30-40 kg/m(2)] completed two 7-d breakfast conditions consisting of 500-kcal breakfast meals as protein (35% protein/45% carbohydrate) or carbohydrate (15% protein/65% carbohydrate). On day 7, subjects completed an 8-h testing day. After an overnight fast, the subjects consumed their respective breakfast followed by a standard 500-kcal high-carbohydrate lunch meal 4 h later. Blood samples were taken throughout the day for assessment of 4-h postbreakfast and 4-h postlunch total area under the curve (AUC) for glucose, insulin, C-peptide, glucagon, glucose-dependent insulinotropic peptide (GIP), and glucagon-like peptide 1 (GLP-1). Postbreakfast glucose and GIP AUCs were lower after the protein (17%) vs. after the carbohydrate (23%) condition (P < 0.05), whereas postbreakfast insulin, C-peptide, glucagon, and GLP-1 AUCs were not different between conditions. A protein-rich breakfast may reduce the consequences of hyperglycemia in this population. Postlunch insulin, C-peptide, and GIP AUCs were greater after the protein condition vs. after the carbohydrate condition (second-meal phenomenon; all, P < 0.05), but postlunch AUCs were not different between conditions. The overall glucose, glucagon, and GLP-1 responses (e.g., 8 h) were greater after the protein condition vs. after the carbohydrate condition (all, P < 0.05). In type 2 diabetic individuals, compared with a high-carbohydrate breakfast, the consumption of a high-protein breakfast meal attenuates the postprandial glucose response and does not magnify the response to the second meal. Insulin, C-peptide, and GIP concentrations demonstrate the second-meal phenomenon and most likely aid in keeping the glucose concentrations controlled in response to the subsequent meal. The trial was registered at www.clinicaltrials.gov/ct2/show/NCT02180646 as NCT02180646.


A mutagenesis screen for essential plastid biogenesis genes in human malaria parasites.
Endosymbiosis has driven major molecular and cellular innovations. Plasmodium spp. parasites that cause malaria contain an essential, non-photosynthetic plastid-the apicoplast-which originated from a secondary (eukaryote-eukaryote) endosymbiosis. To discover organellar pathways with evolutionary and biomedical significance, we performed a mutagenesis screen for essential genes required for apicoplast biogenesis in Plasmodium falciparum. Apicoplast(-) mutants were isolated using a chemical rescue that permits conditional disruption of the apicoplast and a new fluorescent reporter for organelle loss. Five candidate genes were validated (out of 12 identified), including a triosephosphate isomerase (TIM)-barrel protein that likely derived from a core metabolic enzyme but evolved a new activity. Our results demonstrate, to our knowledge, the first forward genetic screen to assign essential cellular functions to unannotated P. falciparum genes. A putative TIM-barrel enzyme and other newly identified apicoplast biogenesis proteins open opportunities to discover new mechanisms of organelle biogenesis, molecular evolution underlying eukaryotic diversity, and drug targets against multiple parasitic diseases.


Compensatory growth in juvenile roach Rutilus caspicus: effect of starvation and re-feeding on growth and digestive surface area.
The aim of this study was to investigate compensatory growth in juvenile Rutilus caspicus during starvation and re-feeding periods. The results confirmed the existence of compensatory growth in R. caspicus which depended on the duration of food deprivation. Complete compensatory growth occurred in the fish that were food deprived for at least 3 weeks. Starvation and re-feeding had no significant effect on the digestive somatic index and intestinal surface areas in the fish that were food deprived for 1 week, while they showed a significant decrease and increase, during starvation and re-feeding in the fish that were food deprived for 2 and 3 weeks. This knowledge may have application in aquaculture, as appropriate exploitation of compensatory growth can give increased growth rate and feeding efficiency.


Matrix metalloproteinases and their inhibitors in aqueous humor of patients with pseudoexfoliation syndrome/glaucoma and primary open-angle glaucoma.
To determine the presence, activity, and quantitative differences of matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) in aqueous humor and serum samples of patients with pseudoexfoliation (PEX) syndrome, PEX glaucoma (PEXG), primary open-angle glaucoma (POAG), and cataract. Aqueous humor and serum samples were collected from 100 patients with PEX syndrome, PEX glaucoma (PEXG), POAG, and cataract, respectively. Levels of MMP-1, -2, -3, -7, -9, and -12 and TIMP-1 and -2 were determined by zymography, Western blot analysis, and specific immunoassays. Activity assay kits were used to quantitate levels of endogenously activated MMP-2 and -9. MMP-2, -3, -7, -9, and -12 and TIMP-1 and -2 were identified in human aqueous humor samples from all groups of patients with a six to sevenfold molar excess of TIMPs over MMPs. Whereas serum samples showed no significant differences, total MMP-2 and -3 and TIMP-1 and -2 were detected at significantly higher concentrations in aqueous samples from PEX eyes with and without glaucoma compared with cataractous eyes. MMP-2 and -3 and TIMP-1 were also detected in higher, but not significantly different, amounts in aqueous samples of POAG eyes. However, levels of endogenously activated MMP-2 were significantly decreased in both PEX and POAG samples. The ratio of MMP-2 to its principal inhibitor TIMP-2 was balanced in cataract samples, but was decreased in samples from patients with PEXG, resulting in an excess of TIMP-2 over MMP-2. The findings suggest that complex changes in the local MMP-TIMP balance and reduced MMP activity in aqueous humor may promote the abnormal matrix accumulation characteristic of PEX syndrome and may be causally involved in the pathogenesis of both PEX glaucoma and POAG.


Socioeconomic Impacts of the COVID-19 Lockdown on the Mental Health and Life Satisfaction of the Japanese Population.
COVID-19 has been a global challenge ever since its emergence, with reports suggesting negative effects on the mental health and well-being of people. We investigated the associations of the socioeconomic changes driven by the pandemic, illness, well-being, and fear of COVID-19 in Japan. Totally, 565 Japanese individuals completed an online survey, including questions on their self-restraint and changing incomes, and the Fear of COVID-19 Scale; Depression, Anxiety, Stress Scale; and present, past, and future life satisfaction scale. Analysis using structural equation models revealed that refraining from going out was a predictor of illness due to the fear of COVID-19. Decreased income predicted increased illness, but was not due to fear of COVID-19. These results suggested that the interaction between decreased time outside and increased fear of COVID-19 could affect illness. Our study suggests the role of fear of COVID-19 during pandemic and the socioeconomic impacts on mental health.


Fragment reconstitution of a small protein: disulfide mutant of a short C-terminal fragment derived from streptococcal protein G.
Hierarchical studies on the folding of protein G B1 domain have shown that the C-terminal fragment (C16) has a considerable amount of beta-hairpin structure that exchanges between the folded and unfolded states at room temperature, and that the C16 fragment binds noncovalently to an N-terminal fragment (N40) under physiological conditions. Those studies have led us to the hypothesis that the amphipathic beta-hairpin structure of C16 initiates folding of the domain. To obtain a more detailed understanding of the folding mechanism of the domain, we designed a mutant of C16 (SS16ox) with a disulfide bond between residues 41 and 56, and then examined the interaction of the mutant with N40 by surface plasmon resonance (SPR) and by thermal denaturation studies using circular dichroism. SS16ox strongly interacted with N40, with an equilibrium constant, KD, that was 7-fold higher than wild-type. The association rate constant, kon, of SS16ox was 8.7-fold higher than that of wild-type. This strong interaction can be explained by the entropic effect of the disulfide bond. The introduction of the disulfide bond into C16 stabilizes the beta-hairpin structure of C16, accelerates the association rate with N40, and then stabilizes the whole complex. These results support a hypothetical folding mechanism of protein G where the amphipathic beta-hairpin structure of C16 acts as a nucleus and accelerates folding of the whole molecule.


The association between papillary thyroid carcinoma and histologically proven Hashimoto's thyroiditis: a meta-analysis.
No consensus exists on the association between papillary thyroid carcinoma (PTC) and Hashimoto's thyroiditis (HT). To resolve this controversy, this study aimed to evaluate the relationship between the two conditions using a meta-analysis. We searched relevant published studies using citation databases including PubMed, Embase, and ISI Web of Science. The effect sizes of clinicopathologic parameters were calculated by odds ratio (OR), weighted mean difference, or hazard ratio (HR). The effect sizes were combined using a random-effects model. Thirty-eight eligible studies including 10 648 PTC cases were selected. Histologically proven HT was identified in 2471 (23.2%) PTCs. HT was more frequently observed in PTCs than in benign thyroid diseases and other carcinomas (OR=2.8 and 2.4; P<0.001). PTCs with coexisting HT were significantly related to female patients (OR=2.7; P<0.001), multifocal involvement (OR=1.5; P=0.010), no extrathyroidal extension (OR=1.3; P=0.002), and no lymph node metastasis (OR=1.3; P=0.041). Moreover, PTCs with HT were significantly associated with long recurrence-free survival (HR=0.6; P=0.001). Our meta-analysis showed that PTC is significantly associated with pathologically confirmed HT. PTC patients with HT have favorable clinicopathologic characteristics compared with PTCs without HT. However, patients with HT need to be carefully monitored for the development of PTC.


Protein/DNA arrays identify nitric oxide-regulated cis-element and trans-factor activities some of which govern neuroblastoma cell viability.
Toxic nitric oxide (NO) levels can regulate gene expression. Using a novel protein/DNA array, we show that toxic NO levels regulate the binding of trans-factors to various cis-elements in neuroblastoma cells, including CRE and those recognized by the transcription factors AP1, AP2, Brn-3a, EGR, E2F1 and SP1. Functionality of some of the cis-elements was confirmed by electro mobility shift and reporter assays. Interestingly, CREB, AP-1, Brn-3a, EGR and E2F1 can control mammalian cell viability. NO induced the anti-apoptotic Bcl-2 protein and its mRNA prior to the onset of death of 30-60% of the cells. Promoter analysis of the bcl-2 gene confirmed the involvement of a CRE in NO-dependent bcl-2 transcription. Neuroblastoma cells over-expressing bcl-2 became much more resistant to NO-induced apoptosis; conversely, Bcl-2 knockdown cells were rendered markedly more sensitive to NO. Together these results suggest that Bcl-2 counteracts NO-induced apoptosis in a fraction of the cell population. Thus, NO stimulates the binding of many trans-factors to their cognate cis-elements, some of which can regulate cell viability through transcriptional activation of target genes. Our results emphasize that a DNA/protein array approach can reveal novel, global transcription factor activities stimulated by cell death-regulating molecules.


Plasma total cholesterol level and some related factors in northern Iranian people.
In middle age people, hypercholesterolemia (HC) has been included as a risk factor for cardiovascular disease. The main objective of this study was to evaluate the prevalence of HC and some related factors in the north of Iran. This was a population-based cross-sectional study that enrolled 1995 subjects (997 males and 998 females) in 25-65 year age using stratified cluster sampling. Interviewers recorded the data using a multidimensional questionnaire including anthropometric indexes. Plasma cholesterol was measured in the morning after a 12-hour fast and determined by an auto-analyzer. HC was defined by a total plasma total cholesterol level over 200 mg/dl. The SPSS.16 software was used to analyze data. The mean age of the participant was 44.2 years and mean ± SD plasma total cholesterol level in men and women was 196.7 ± 39.11 and 209.4 ± 42.9, respectively. Generally, the prevalence of HC was 50.4% with a significant differences between men (44.7%) and women (57%) (P < 0.05). The mean plasma total cholesterol levels were significantly differenced among age groups, location area, BMI, and waist circumferences (P < 0.001). Women gender (OR = 1.64), 55-65 years old (OR = 2.79), BMI ≥40 kg/m(2) (OR = 10.0), and abdominal obesity (OR = 2.47) were associated with increased risk of HC (P = 0.001 and 95%CI for all). HC is one of the most health problems in the northern Iran and it is more common in women than in men. General and abdominal obesity are the most common risk factors for HC.


Multimodal imaging in type 2 idiopathic macular telangiectasia.
Macular telangiectasia Type 2 is a bilateral, progressive potentially blinding retinal disease characterized by both vascular and neurodegenerative signs that have been documented using different imaging techniques. The correlation between macular telangiectasia Type 2 signs from various imaging modalities is unknown. Our aim was to investigate the relationship of various macular telangiectasia Type 2 signs using fundus fluorescein angiography, optical coherence tomography and dual-wavelength autofluorescence images. Participants were selected from the macular telangiectasia Type 2 Natural History Observation Study, based on a confirmed diagnosis and the availability of images. Signs in fundus fluorescein angiography, dual-wavelength autofluorescence, and optical coherence tomography images were graded according to standardized categories, and agreement among the multimodel imaging was assessed statistically. One hundred and ninety-one eyes of 96 patients were examined. Significant correlations were found between early and late fundus fluorescein angiography (ρ = 0.82, P < 0.0001), luteal pigment loss and early/late fundus fluorescein angiography signs (ρ = 0.52, P < 0.0001 and ρ = 0.62, P < 0.0001, respectively), inner and outer segment break length and pigment loss (Class 1 vs. 2/3, P < 0.0001; Class 2 vs. 3, P = 0.04). Correlation between pigment loss and retinal spaces/atrophic retinal restructuring was fair (κ = 0.25-0.33). Bilateral symmetry was slight to substantial (κ = 0.18-0.62). Our data demonstrate the relative extent of neurodegenerative and vascular signs; it may be useful for designing systems for staging disease severity using multimodal imaging and may also provide clues to the pathogenesis of the disease.


Unexpected electron spin density on the axial methionine ligand in CuA suggests its involvement in electron pathways.
The CuA center is a paradigm for the study of long-range biological electron transfer. This metal center is an essential cofactor for terminal oxidases like cytochrome c oxidase, the enzymatic complex responsible for cellular respiration in eukaryotes and in most bacteria. CuA acts as an electron hub by transferring electrons from reduced cytochrome c to the catalytic site of the enzyme where dioxygen reduction takes place. Different electron transfer pathways have been proposed involving a weak axial methionine ligand residue, conserved in all CuA sites. This hypothesis has been challenged by theoretical calculations indicating the lack of electron spin density in this ligand. Here we report an NMR study with selectively labeled methionine in a native CuA. NMR spectroscopy discloses the presence of net electron spin density in the methionine axial ligand in the two alternative ground states of this metal center. Similar spin delocalization observed on two second sphere mutants further supports this evidence. These data provide a novel view of the electronic structure of CuA centers and support previously neglected electron transfer pathways.


BrachyView: development of an algorithm for real-time automatic LDR brachytherapy seed detection.
BrachyView is a novel in-body imaging system developed to provide real-time intraoperative dosimetry for low dose rate prostate brachytherapy treatments. Seed positions can be reconstructed after in-vivo implantation using a high-resolution pinhole gamma camera inserted into the patient rectum. The obtained data is a set of 2D projections of the seeds on the image plane. The 3D reconstruction algorithm requires the identification of the seed's centre of mass. This work presents the development and techniques adopted to build an algorithm that provides the means for fully automatic seed centre of mass identification and 3D position reconstruction for real-time applications. The algorithm presented uses a local feature detector, speeded up robust features, to perform detection of brachytherapy seed 2D projections from images, allowing for robust seed identification. Initial results have been obtained with datasets of 30, 96 and 98 I-125 brachytherapy seeds implanted into a prostate gel phantom. It can detect 97% of seeds and correctly match 97% of seeds. The average overall computation time of 2.75 s per image and improved reconstruction accuracy of 22.87% for the 98 seed dataset was noted. Elimination processes for initial false positive detection removal have shown to be extremely effective, resulting in a 99.9% reduction of false positives, and when paired with automatic frame alignment and subtraction procedures allows for the effective removal of excess counts generated by previously implanted needles. The proposed algorithm will allow the BrachyView system to be used as a real-time intraoperative dosimetry tool for low dose rate prostate brachytherapy treatments.


The kidney in normal pregnancy and preeclampsia.
Complicating up to 8% of pregnancies, preeclampsia is, in fact, the most common glomerular disease worldwide. In this article, we review the effect of normal pregnancy on the kidney as well as the role of the kidney in preeclampsia. We discuss blood pressure in pregnancy and preeclampsia, followed by the physiology of hyperfiltration in normal pregnancy as well as the pathophysiology of hypofiltration and proteinuria in preeclampsia. Recent studies have suggested that the clinical syndrome of preeclampsia, which recovers rapidly after delivery of the placenta, is caused by impaired vascular endothelial growth factor signaling that disturbs the status of vascular dilatation as well as the symbiosis between the glomerular endothelium and the podocytes. Finally, we discuss the intriguing association between chronic kidney disease (CKD) and preeclampsia. We hypothesize that the imbalance between angiogenic and anti-angiogenic factors, which may be common to both preeclampsia and CKD, might explain why CKD predisposes pregnant women to develop preeclampsia.


Thermo- and photoinduced spin state switching in an iron(II) 2D coordination network associated with large light-induced thermal hysteresis and tuning of dimensionality via ligand modulation.
Three iron(ii) complexes, [Fe(L1)2(NCS)2(MeOH)2] (1), [Fe(L1)2(NCSe)2(MeOH)2] (2), and [Fe(L2)2(NCS)2]n (3) (L1 = 2,5-dipyridyl-3,4-ethylenedioxythiophene and L2 = 2,5-diethynylpyridinyl-3,4-ethylenedioxythiophene), have been synthesized using redox-active luminescent ethylenedioxythiophene (EDOT)-based ligands, and characterized by variable temperature single-crystal X-ray diffraction, (photo)magnetic, optical reflectivity, and spectroscopy studies. Magneto-structural investigations revealed that 1 and 2 are mononuclear with a FeN4O2 octahedral coordination geometry and remain in a high-spin (HS) (S = 2) state in a temperature range of 2-280 K. Interestingly, a 2D coordination network structure with FeN6 surrounding each iron center was observed for 3, which exhibits reversible thermo-induced spin-state switching between the paramagnetic high-spin (HS) (S = 2) and diamagnetic low-spin (LS) (S = 0) states at around 105 K (T1/2). Furthermore, optical reflectivity and photomagnetic measurements at low temperature confirmed that 3 shows reversible ON/OFF switching between the photoinduced excited paramagnetic HS metastable state and diamagnetic LS state under light irradiation (ON mode using red light and OFF mode using green light). Finally, the photoinduced excited HS state can be reversibly relaxed back to the diamagnetic ground LS state by heating the system at ca. 88 K (TLIESST = 88 K) (light-induced excited spin state trapping (LIESST) effect). Furthermore, 3 also showed an exciting and unique 18 K wide light-induced thermal hysteresis (LITH) effect above liquid nitrogen temperature (100 K). DFT and CASSCF level theoretical calculations were utilized to better understand the magneto-structural correlations of these complexes.


Preventive care checklist form. Evidence-based tool to improve preventive health care during complete health assessment of adults.
Preventive care is a cornerstone in the practice of family medicine, but is often difficult to provide because of a lack of time and logistic difficulties. To develop an evidence-based practice-relevant preventive care checklist form to be used by family physicians during complete health assessment of adults. Guidelines for preventive health care of adults at average risk from the Canadian Task Force on Preventive Health Care and from other Canadian sources where the Task Force guidelines were not up-to-date were reviewed. Checklist forms covering recommended preventive health care maneuvers were created. The forms incorporate evidence-based preventive care guidelines as well as non-evidence-based components that are a part of routine practice. The forms require few resources to implement, are cost-effective, and are easy to use. The forms list items needed to meet provincial billing requirements for complete health assessments and have space for physicians to make notes. The forms can be used electronically or printed off and photocopied for use in paper-based charts. The Preventive Care Checklist Form is a low-cost, easy-to-use tool that merges practice maneuvers with evidence-based recommendations. It could help improve preventive care practices in Canada.


Over-expression of phosphorylated mammalian target of rapamycin is associated with poor survival in oesophageal adenocarcinoma: a tissue microarray study.
Protein kinase mammalian target of rapamycin (mTOR) is an important downstream effector of the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway. In several tumour types, phosphorylated mTOR (p-mTOR) over-expression is an independent prognostic marker for poor survival. However, p-mTOR expression has not been assessed in oesophageal adenocarcinoma (OAC). Tumour cores of 154 patients with OAC were included in a tissue microarray (TMA). Scoring criteria were based on p-mTOR staining intensity. 147 (95.5%) patients were available for immunohistochemical evaluation. Over-expression of p-mTOR was detected in 29 (19.7%) tumours, whereas 118 (80.3%) patients showed negative expression. Over-expression was significantly associated with poor overall survival in univariate analysis (HR 1.648; 95% CI 1.019 to 2.664; p=0.042). Median survival was 21.2 months in patients with p-mTOR over-expression and 29.0 in the negative p-mTOR group (p=0.040). In addition, a trend towards p-mTOR over-expression and vasoinvasive growth was seen (p=0.057). In multivariate analysis, including clinical and pathological variables (p<0.10), only T-stage (HR 2.795; 95% CI 1.343 to 5.813; p=0.006) and differentiation grade (HR 2.198; 95% CI 1.353 to 3.570; p=0.001) were independent prognostic markers of poor survival. p-mTOR over-expression was detected in 19.7% of patients with OAC and was associated with poor overall survival.


Structure and evolutionary conservation of the plant N-end rule pathway.
The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal amino acid residue. While some N-terminal residues result in metabolically stable proteins, other, so-called destabilizing residues, lead to rapid protein turnover. The N-end rule pathway, which mediates the recognition and degradation of proteins with N-terminal destabilizing residues, is present in all organisms examined, including prokaryotes. This protein degradation pathway has a hierarchical organization in which some N-terminal residues, called primary destabilizing residues, are directly recognized by specific ubiquitin ligases. Other destabilizing residues, termed secondary and tertiary destabilizing residues, require modifications before the corresponding proteins can be targeted for degradation by ubiquitin ligases. In eukaryotes, the N-end rule pathway is a part of the ubiquitin/proteasome system and is known to play essential roles in a broad range of biological processes in fungi, animals and plants. While the structure of the N-end rule pathway has been extensively studied in yeast and mammals, knowledge of its organization in plants is limited. Using both tobacco and Arabidopsis, we identified the complete sets destabilizing and stabilizing N-terminal residues. We also characterized the hierarchical organization of the plant N-end rule by identifying and determining the specificity of two distinct N-terminal amidohydrolases (Nt-amidases) of Arabidopsis that are essential for the destabilizing activity of the tertiary destabilizing residues Asn and Gln. Our results indicate that both the N-end rule itself and mechanistic aspects of the N-end rule pathway in angiosperms are very similar to those of mammals.


[Study on genetic-chemical relation of Pterocephali Herba based on DNA barcode and UFLC].
DNA barcoding technique in combination with UFLC analysis technology was used to evaluate the quality of Tibetan medicine Pterocephalus hookeri from species identification and chemical qualitative and other aspects. Hybrid identification was established by DNA barcoding; UFLC-PDA was adopted to analyse fingerprint of different parts of Pterocephali Herba, and SPSS and Grey relation software were used for data analysis. The result showed that DNA barcoding is an accurate and reliable method in origin identification of Pterocephalus hookeri. The compounds in overground is more than underground by analysis of the different part fingerprint by UFLC. The genetic gene may be involved in the secondary metabolites of iridoid glycosides. Pertinence between gene and chemical component, as a new model established, could be suited for quality evaluation and resources protection.


Kinesin-5-independent mitotic spindle assembly requires the antiparallel microtubule crosslinker Ase1 in fission yeast.
Bipolar spindle assembly requires a balance of forces where kinesin-5 produces outward pushing forces to antagonize the inward pulling forces from kinesin-14 or dynein. Accordingly, Kinesin-5 inactivation results in force imbalance leading to monopolar spindle and chromosome segregation failure. In fission yeast, force balance is restored when both kinesin-5 Cut7 and kinesin-14 Pkl1 are deleted, restoring spindle bipolarity. Here we show that the cut7Δpkl1Δ spindle is fully competent for chromosome segregation independently of motor activity, except for kinesin-6 Klp9, which is required for anaphase spindle elongation. We demonstrate that cut7Δpkl1Δ spindle bipolarity requires the microtubule antiparallel bundler PRC1/Ase1 to recruit CLASP/Cls1 to stabilize microtubules. Brownian dynamics-kinetic Monte Carlo simulations show that Ase1 and Cls1 activity are sufficient for initial bipolar spindle formation. We conclude that pushing forces generated by microtubule polymerization are sufficient to promote spindle pole separation and the assembly of bipolar spindle in the absence of molecular motors.


The complete plastome sequences of Mangifera indica L. (Anacardiaceae).
In this study, we determined the complete plastome sequence of Mangifera indica L. (Anacardiaceae) (NCBI acc. no. KX871231). The complete plastome is 157,780 bp in length, and consists of a large single copy of 86,673 bp and a small single copy of 18,349 bp, separated by two inverted repeats of 25,792 bp. The plastome contains 112 genes, of which 78 are protein-coding genes, 30 are tRNA genes, and four are rRNA genes. Sixteen genes contain one intron and two genes have two introns. The average A-T content of the plastome is 62.1%. The M. indica plastome has approximately 15 kb inversion between trnT-UGU and trnT-GGU. We identify a palindromic repeat of 18 bp (ATTCTTTTTTTTTTTTTT/AAAAAAAAAAAAAAGAAT) near the inversion breakpoints of M. indica plastome. Phylogenetic analysis revealed that M. indica is a sister group of Rhus chinensis with 100% bootstrap support. Anacardiaceae clade is a sister group of Boswellia sacra (Burseraceae) with 100% bootstrap support.


Exercise Intensity Influences Prefrontal Cortex Oxygenation during Cognitive Testing.
Activation changes in the prefrontal cortex (PFC) regions have been linked to acute exercise-induced improvements in cognitive performance. The type of exercise performed may influence PFC activation, and further impact cognitive function. The present study aimed to compare PFC activation during cognitive testing after moderate-intensity, high intensity, and yoga exercises, and to determine if PFC activation is linked to cognitive performance. Eight subjects (four male and four female), aged 35 ± 5 completed a control, high intensity, moderate intensity, and yoga exercises followed by administration of a cognitive task (NIH Toolbox Fluid Cognition). Left and right PFC activation (LPFC and RPFC, respectively) were evaluated by measuring hemoglobin difference (Hbdiff) changes during post-exercise cognitive assessment using functional near infrared spectroscopy (fNIRS). Activation during the cognitive test was higher in the LPFC after moderate intensity exercise compared to control, high intensity, and yoga (5.30 ± 6.65 vs. 2.26 ± 2.40, 2.50 ± 1.48, 2.41 ± 2.36 μM, p < 0.05, respectively). A negative relationship was detected between LPFC and processing speed after exercise. PFC activation did not align with cognitive performance. However, acute exercise, regardless of type, appeared to alter neural processing. Specifically, less PFC activation was required for a given neural output after exercise.


Biopesticide Activity from Drimanic Compounds to Control Tomato Pathogens.
Tomato crops can be affected by several infectious diseases produced by bacteria, fungi, and oomycetes. Four phytopathogens are of special concern because of the major economic losses they generate worldwide in tomato production; Clavibacter michiganensis subsp. michiganensis and Pseudomonas syringae pv. tomato, causative agents behind two highly destructive diseases, bacterial canker and bacterial speck, respectively; fungus Fusarium oxysporum f. sp. lycopersici that causes Fusarium Wilt, which strongly affects tomato crops; and finally, Phytophthora spp., which affect both potato and tomato crops. Polygodial (1), drimenol (2), isonordrimenone (3), and nordrimenone (4) were studied against these four phytopathogenic microorganisms. Among them, compound 1, obtained from Drimys winteri Forst, and synthetic compound 4 are shown here to have potent activity. Most promisingly, the results showed that compounds 1 and 4 affect Clavibacter michiganensis growth at minimal inhibitory concentrations (MIC) values of 16 and 32 µg/mL, respectively, and high antimycotic activity against Fusarium oxysporum and Phytophthora spp. with MIC of 64 µg/mL. The results of the present study suggest novel treatment alternatives with drimane compounds against bacterial and fungal plant pathogens.


Safety and efficacy of iron(III)-hydroxide polymaltose complex / a review of over 25 years experience.
The following review of iron(III)-hydroxide polymaltose complex (IPC, Maltofer) shows that iron is significantly bioavailable after oral administration, especially in iron-deficient subjects. Numerous clinical trials in men, women, children and infants have shown that IPC is effective in treating iron deficiency anaemia (IDA). Due to its kinetic properties, IPC is best given with meals, and probably in an iron dose slightly higher than that of the classical iron salts. In terms of acceptance and patient compliance, IPC presents a clear advantage over ferrous salts. Many studies have shown a lower rate of treatment interruption with IPC than with ferrous salts. This is usually associated with a lower incidence of adverse events related to the upper gastro intestinal tract.


Changes in the use of coronary artery revascularization procedures in the Department of Veterans Affairs, the National Hospital Discharge Survey, and the Nationwide Inpatient Sample, 1991-1999.
There have been dramatic increases in the number of coronary artery bypass surgeries (CABS) and percutaneous coronary interventions (PCI) performed during the last decade. Whether this finding is true for revascularization procedures performed in Department of Veterans Affairs (VA) medical centers is the subject of this paper. This study compared the number of revascularization procedures and rates of use in the VA, the National Hospital Discharge Survey, and the Nationwide Inpatient Sample. Included were men who underwent isolated CABS and/or PCI, including stenting, between 1991 and 1999, although data for the Nationwide Inpatient Sample were available only between 1993 and 1997. Age adjusted use rates were calculated with the direct method of standardization. The percent of users of VA healthcare 75 years and older increased from 10% in 1991 to 20% in 1999. In the VA, the number of isolated CABS declined from 6227 in 1991 to 6147 in 1999, whereas age adjusted rates declined from 167.6 per 100,000 in 1991 to 107.9 per 100,000 in 1999. In the 2 national surveys, both the estimated numbers of procedures and use rates increased over time. In all 3 settings, there were increases in both numbers and rate of PCI from 1993, although in the VA, use rates decreased from 191.2 per 100,000 in 1996 to 139.7 per 100,000 in 1999. VA use rates for both CABS and PCI were lower than those in the 2 national surveys. Age adjusted rates of CABS and PCI were lower in the VA than in 2 national surveys. Since 1996, there has been a decrease in the rate of use of revascularization procedures in the VA.


The pulmonary vascular response to propofol in the isolated perfused rat lung.
This study investigated the effect of propofol on the pulmonary vascular bed of the rat. Propofol (5 x 10(-6) to 5 x 10(-4) M) did not alter the basal perfusion pressure in isolated rat lungs perfused at a constant flow (0.03 mL g body wt-1 min-1) with Krebs-Henseleit solution. When perfusion pressure was elevated by raising the K+ concentration to 30 mM (depolarizing Krebs-Henseleit solution), propofol decreased it in a concentration-dependent manner. Indomethacin (3 x 10(-6) M) and NG-nitro-L-arginine methyl ester (10(-4) M) did not affect the response to propofol, which excluded the role of cyclo-oxygenase metabolites and nitric oxide, respectively. The ATP-sensitive K+ (K+ATP) channel blocker glibenclamide (3 x 10(-6) and 10(-5) M) inhibited the vasodilator effect of propofol. When lungs were perfused with Ca(2+)-free depolarizing Krebs-Henseleit solution, 0.1-2.5 mM Ca+2 produced a concentration-dependent pressor response. Propofol (5 x 10(-5) M) attenuated the vasopressor response to Ca2+ significantly. In conclusion, the activation of K+ATP channels is probably the major mechanism of the vasodilator effect of propofol, at clinically relevant concentrations, in the rat lung. The Ca2+ antagonistic property of propofol is evident only at higher concentrations.


Calcium copper-titanate thin film growth: tailoring of the operational conditions through nanocharacterization and substrate nature effects.
A novel approach based on a molten multicomponent precursor source has been applied for the MOCVD fabrication of high-quality CaCu(3)Ti(4)O(12) (CCTO) thin films on various substrates. The adopted in situ strategy involves a molten mixture consisting of Ca(hfa)(2).tetraglyme, Ti(tmhd)(2)(O-iPr)(2), and Cu(tmhd)(2) [Hhfa = 1,1,1,5,5,5-hexafluoro-2,4-pentanedione; tetraglyme = 2,5,8,11,14-pentaoxapentadecane; Htmhd = 2,2,6,6-tetramethyl-3,5-heptandione; O-iPr = isopropoxide] precursors. Film structural and morphological characterizations have been carried out by several techniques [X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM)], and in particular the energy filtered TEM mapping and X-ray energy dispersive (EDX) analysis in TEM mode provided a suitable correlation between nanostructural properties of CCTO films and deposition conditions and/or the substrate nature. Correlation between the nanostructure and optical/dielectric properties has been investigated exploiting spectroscopic ellipsometry.


Allicin inhibits the invasion of lung adenocarcinoma cells by altering tissue inhibitor of metalloproteinase/matrix metalloproteinase balance via reducing the activity of phosphoinositide 3-kinase/AKT signaling.
Allicin, the main active principle associated with Allium sativum chemistry, has various antitumor activities. However, to the best of our knowledge, there is no available information to address the anti-invasive effect and associated mechanism in lung adenocarcinoma. In the present study, cell viability assay, cell adhesion assay, western blot analysis, Transwell migration and invasion assays and reverse transcription-quantitative polymerase chain reaction were performed. Allicin was identified to inhibit the adhesion, invasion and migration of lung adenocarcinoma cells in a dose-dependent manner, accompanied by decreasing mRNA and protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. Conversely, the mRNA and protein levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were increased in a dose-dependent manner. Furthermore, it was revealed that allicin treatment significantly suppressed the phosphorylation of AKT (P<0.05), but not the total protein expression of AKT. Combined treatment with LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K)/AKT signaling, and allicin led to the synergistic reduction of MMP-2 and MMP-9 expression, followed by an increase in TIMP-1 and TIMP-2 expression. The invasive capabilities of lung adenocarcinoma cells were also suppressed. However, insulin-like growth factor-1 (an activator of PI3K/AKT signaling) reversed the effects of allicin on cell invasion and expression of MMP-2, MMP-9, TIMP-1 and TIMP-2. The present study concluded that allicin may inhibit invasion of lung adenocarcinoma cells by altering TIMP/MMP balance, via reducing the activity of the PI3K/AKT signaling pathway. This indicated that allicin may be recognized as an anti-invasive agent for lung adenocarcinoma treatment.


A randomized controlled trial of the efficacy and cost-effectiveness of a brief intensified cognitive behavioral therapy and/or pharmacotherapy for mood and anxiety disorders: design and methods.
Anxiety and mood disorders involve a high disease burden and are associated with high economic costs. A stepped-care approach intervention and abbreviated diagnostic method are assumed to increase effectiveness and efficiency of the mental healthcare and are expected to reduce economic costs. Presented are the rationale, design, and methods of a two-armed randomized controlled trial comparing 'treatment as usual' (TAU) with a brief intensified cognitive behavioral therapy (CBT) and/or pharmacotherapy. Eligible participants (N=500) of five Dutch outpatient Mental Healthcare Centers are randomly assigned to either TAU or to the experimental condition (brief CBT and/or pharmacotherapy). Data on patients' progress and clinical effectiveness of treatment are assessed at baseline, post-treatment (3 months after baseline), and at 6 and 12 months post-treatment by Routine Outcome Monitoring (ROM). Cost analysis is performed on the obtained data. Since few studies have investigated both the clinical and cost effectiveness of a stepped-care approach intervention and a shortened diagnostic ROM method in both anxiety and/or mood disorders within secondary mental health care, the results of this study might contribute to the improvement of (cost)-effective treatment options and diagnostic methods for these disorders.


Sports-related mild traumatic brain injury in female youths.
Sports-related concussion or mild-traumatic brain injury (mTBI) is common in children who participate in organised sports. We describe two case studies involving 14-year-old girls who each sustained a mTBI during ice hockey competition. Neurocognitive functioning post-injury is compared to baseline pre-injury assessment on the same measures. Results from Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT), Conners' Continuous Performance Test II (CPT-II) and the Attention Network Test (ANT) revealed decreased performance in attention, memory functioning and reaction time. Furthermore, some measures had not returned to baseline at midseason testing sessions approximately 30-40 days post-injury. The results are discussed with respect to the difference in recovery profiles and the need for thorough and ongoing evaluation following mTBI in the paediatric population, and for girls in particular.


A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2.
The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion of both autosomal dominant familial and sporadic PD cases. Our aim in the present study is to generate a mammalian model of mutant G2019S LRRK2 pathogenesis, which reproduces the robust nigral neurodegeneration characteristic of PD. We developed adenoviral vectors to drive neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in the nigrostriatal system of adult rats. Wild-type LRRK2 did not induce any significant neuronal loss. In contrast, under the same conditions and levels of expression, G2019S mutant LRRK2 causes a progressive degeneration of nigral dopaminergic neurons. Our data provide a novel rat model of PD, based on a prevalent genetic cause, that reproduces a cardinal feature of the disease within a rapid time frame suitable for testing of neuroprotective strategies.


The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism.
A loss of stromal Cav-1 in the tumor fibroblast compartment is associated with early tumor recurrence, lymph-node metastasis, and tamoxifen-resistance, resulting in poor clinical outcome in breast cancer patients. Here, we have used Cav-1 (-/-) null mice as a pre-clinical model for this "lethal tumor micro-environment." Metabolic profiling of Cav-1 (-/-) mammary fat pads revealed the upregulation of numerous metabolites (nearly 100), indicative of a major catabolic phenotype. Our results are consistent with the induction of oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy. The two most prominent metabolites that emerged from this analysis were ADMA (asymmetric dimethyl arginine) and BHB (beta-hydroxybutyrate; a ketone body), which are markers of oxidative stress and mitochondrial dysfunction, respectively. Transcriptional profiling of Cav-1 (-/-) stromal cells and human tumor stroma from breast cancer patients directly supported an association with oxidative stress, mitochondrial dysfunction, and autophagy/mitophagy, as well as ADMA and ketone production. MircoRNA profiling of Cav-1 (-/-) stromal cells revealed the upregulation of two key cancer-related miR's, namely miR-31 and miR-34c. Consistent with our metabolic findings, these miR's are associated with oxidative stress (miR-34c) or activation of the hypoxic response/HIF1a (miR-31), which is sufficient to drive authophagy/mitophagy. Thus, via an unbiased comprehensive analysis of a lethal tumor micro-environment, we have identified a number of candidate biomarkers (ADMA, ketones, and miR-31/34c) that could be used to identify high-risk cancer patients at diagnosis, for treatment stratification and/or for evaluating therapeutic efficacy during anti-cancer therapy. We propose that the levels of these key biomarkers (ADMA, ketones/BHB, miR-31, and miR-34c) could be (1) assayed using serum or plasma from cancer patients, or (2) performed directly on excised tumor tissue. Importantly, induction of oxidative stress and autophagy/mitophagy in the tumor stromal compartment provides a means by which epithelial cancer cells can directly "feed off" of stromal-derived essential nutrients, chemical building blocks (amino acids, nucleotides), and energy-rich metabolites (glutamine, pyruvate, ketones/BHB), driving tumor progression and metastasis. Essentially, aggressive cancer cells are "eating" the cancer-associated fibroblasts via autophagy/mitophagy in the tumor micro-environment. Lastly, we discuss that this "Autophagic Tumor Stroma Model of Cancer Metabolism" provides a viable solution to the "Autophagy Paradox" in cancer etiology and chemo-therapy.


The nursing staff's opinion of falls among older persons with dementia. a cross-sectional study.
The aim of this study was to describe the nursing staff's opinion of caring for older persons with dementia with the focus on causes of falls, fall-preventing interventions, routines of documentation and report and the nursing staff's experiences and reactions when fall incidents occur. A further aim was to compare these areas between registered nurses (RNs) and enrolled nurses (ENs) and staff with ≤5 and >5 years of employment in the care units in question. Falls are common among older people and persons with dementia constitute an additional risk group. The study had a cross-sectional design and included nursing staff (n = 63, response rate 66%) working in four special care units for older persons with dementia. Data collection was conducted with a questionnaire consisting of 64 questions. The respondents reported that the individuals' mental and physical impairment constitute the most frequent causes of falls. The findings also revealed a lack of, or uncertainty about, routines of documentation and reporting fall-risk and fall-preventing interventions. Respondents who had been employed in the care units more than five years reported to a higher degree that colours and material on floors caused falls. RNs considered the residents' autonomy and freedom of movement as a cause of falls to a significantly higher degree than ENs. RNs also reported a significantly longer time than ENs before fall incidents were discovered, and they used conversation and closeness as fall-preventing interventions to a significantly higher degree than ENs. Individual factors were the most common causes to falls according to the nursing staff. RNs used closeness and dialog as interventions to a significantly higher degree to prevent falls than ENs. Caring of for older people with dementia consisted of a comprehensive on-going assessment by the nursing staff to balance the residents' autonomy-versus-control to minimise fall-risk. This ethical dilemma should initiate development of feasible routines of systematic risk-assessment, report and documentation.


The HDAC inhibitor FK228 enhances adenoviral transgene expression by a transduction-independent mechanism but does not increase adenovirus replication.
The histone deacetylase inhibitor FK228 has previously been shown to enhance adenoviral transgene expression when cells are pre-incubated with the drug. Upregulation of the coxsackie adenovirus receptor (CAR), leading to increased viral transduction, has been proposed as the main mechanism. In the present study, we found that the highest increase in transgene expression was achieved when non-toxic concentrations of FK228 were added immediately after transduction, demonstrating that the main effect by which FK228 enhances transgene expression is transduction-independent. FK228 had positive effects both on Ad5 and Ad5/f35 vectors with a variety of transgenes and promoters, indicating that FK228 works mainly by increasing transgene expression at the transcriptional level. In some cases, the effects were dramatic, as demonstrated by an increase in CD40L expression by FK228 from 0.3% to 62% when the murine prostate cancer cell line TRAMP-C2 was transduced with Ad[CD40L]. One unexpected finding was that FK228 decreased the transgene expression of an adenoviral vector with the prostate cell-specific PPT promoter in the human prostate adenocarcinoma cell lines LNCaP and PC-346C. This is probably a consequence of alteration of the adenocarcinoma cell lines towards a neuroendocrine differentiation after FK228 treatment. The observations in this study indicate that FK228 enhances adenoviral therapy by a transduction-independent mechanism. Furthermore, since histone deacetylase inhibitors may affect the differentiation of cells, it is important to keep in mind that the activity and specificity of tissue- and tumor-specific promoters may also be affected.


Statins for early stage chronic kidney disease: an overview of reviews.
To assess the efficacy of statin therapy on early stage chronic kidney disease through an overview of systematic reviews. We searched for systematic reviews of randomized clinical trials (RCT) on MEDLINE, Embase, Cochrane Library, CRD, and Scopus. Independent reviewers selected the studies and extracted the relevant data. We critically appraised the included systematic reviews with the AMSTAR tool and presented the available data in the studies. From 731 retrieved records, we included three systematic reviews. Statins reduced the risk of mortality for all causes and for cardiovascular causes in patients with early stage chronic kidney disease as compared to the control (high-quality evidence). Statins also reduced the incidence of any myocardial infarction, non-fatal myocardial infarction, and stroke (moderate- to high-quality evidence). No differences were observed between statins and control upon the incidence of end-stage renal disease or on the outcomes assessed in patients with coronary artery disease and diabetes. Statins reduce the incidence of death and other relevant outcomes in patients with early stage chronic kidney disease and should be considered for such individuals who also present hyperlipidemia.